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1.  Dispersible formulation of artemether/lumefantrine: specifically developed for infants and young children 
Malaria Journal  2009;8(Suppl 1):S7.
Infants and children under five years of age are the most vulnerable to malaria with over 1,700 deaths per day from malaria in this group. However, until recently, there were no WHO-endorsed paediatric anti-malarial formulations available.
Artemisinin-based combination therapy is the current standard of care for patients with uncomplicated falciparum malaria in Africa. Artemether/lumefantrine (AL) meets WHO pre-qualification criteria for efficacy, safety and quality. Coartem®, a fixed dose combination of artemether and lumefantrine, has consistently achieved cure rates of >95% in clinical trials. However, AL tablets are inconvenient for caregivers to administer as they need to be crushed and mixed with water or food for infants and young children. Further, in common with other anti-malarials, they have a bitter taste, which may result in children spitting the medicine out and not receiving the full therapeutic dose. There was a clear unmet medical need for a formulation of AL specifically designed for children.
Ahead of a call from WHO for child-friendly medicines, Novartis, working in partnership with Medicines for Malaria Venture (MMV), started the development of a new formulation of AL for infants and young children: Coartem® Dispersible. The excellent efficacy, safety and tolerability already demonstrated by AL tablets were confirmed with dispersible AL in a large trial comparing the crushed tablets with dispersible tablets in 899 African children with falciparum malaria. In the evaluable population, 28-day PCR-corrected cure rates of >96% were achieved. Further, its sweet taste means that it is palatable for children, and the dispersible formulation makes it easier for caregivers to administer than bitter crushed tablets. Easing administration may foster compliance, hence improving therapeutic outcomes in infants and young children and helping to preserve the efficacy of ACT.
doi:10.1186/1475-2875-8-S1-S7
PMCID: PMC2760242  PMID: 19818174
2.  Number of Patients Studied Prior to Approval of New Medicines: A Database Analysis 
PLoS Medicine  2013;10(3):e1001407.
In an evaluation of medicines approved by the European Medicines Agency 2000 to 2010, Ruben Duijnhoven and colleagues find that the number of patients evaluated for medicines approved for chronic use are inadequate for evaluation of safety or long-term efficacy.
Background
At the time of approval of a new medicine, there are few long-term data on the medicine's benefit–risk balance. Clinical trials are designed to demonstrate efficacy, but have major limitations with regard to safety in terms of patient exposure and length of follow-up. This study of the number of patients who had been administered medicines at the time of medicine approval by the European Medicines Agency aimed to determine the total number of patients studied, as well as the number of patients studied long term for chronic medication use, compared with the International Conference on Harmonisation's E1 guideline recommendations.
Methods and Findings
All medicines containing new molecular entities approved between 2000 and 2010 were included in the study, including orphan medicines as a separate category. The total number of patients studied before approval was extracted (main outcome). In addition, the number of patients with long-term use (6 or 12 mo) was determined for chronic medication. 200 unique new medicines were identified: 161 standard and 39 orphan medicines. The median total number of patients studied before approval was 1,708 (interquartile range [IQR] 968–3,195) for standard medicines and 438 (IQR 132–915) for orphan medicines. On average, chronic medication was studied in a larger number of patients (median 2,338, IQR 1,462–4,135) than medication for intermediate (878, IQR 513–1,559) or short-term use (1,315, IQR 609–2,420). Safety and efficacy of chronic use was studied in fewer than 1,000 patients for at least 6 and 12 mo in 46.4% and 58.3% of new medicines, respectively. Among the 84 medicines intended for chronic use, 68 (82.1%) met the guideline recommendations for 6-mo use (at least 300 participants studied for 6 mo and at least 1,000 participants studied for any length of time), whereas 67 (79.8%) of the medicines met the criteria for 12-mo patient exposure (at least 100 participants studied for 12 mo).
Conclusions
For medicines intended for chronic use, the number of patients studied before marketing is insufficient to evaluate safety and long-term efficacy. Both safety and efficacy require continued study after approval. New epidemiologic tools and legislative actions necessitate a review of the requirements for the number of patients studied prior to approval, particularly for chronic use, and adequate use of post-marketing studies.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Before any new medicine is marketed for the treatment of a human disease, it has to go through extensive laboratory and clinical research. In the laboratory, scientists investigate the causes of diseases, identify potential new treatments, and test these interventions in disease models, some of which involve animals. The safety and efficacy of potential new interventions is then investigated in a series of clinical trials—studies in which the new treatment is tested in selected groups of patients under strictly controlled conditions, first to determine whether the drug is tolerated by humans and then to assess its efficacy. Finally, the results of these trials are reviewed by the government body responsible for drug approval; in the US, this body is the Food and Drug Administration, and in the European Union, the European Medicines Agency (EMA) is responsible for the scientific evaluation and approval of new medicines.
Why Was This Study Done?
Clinical trials are primarily designed to test the efficacy—the ability to produce the desired therapeutic effect—of new medicines. The number of patients needed to establish efficacy determines the size of a clinical trial, and the indications for which efficacy must be shown determine the trial's duration. However, identifying adverse effects of drugs generally requires the drug to be taken by more patients than are required to show efficacy, so the information about adverse effects is often relatively limited at the end of clinical testing. Consequently, when new medicines are approved, their benefit–risk ratios are often poorly defined, even though physicians need this information to decide which treatment to recommend to their patients. For the evaluation of risk or adverse effects of medicines being developed for chronic (long-term) treatment of non-life-threatening diseases, current guidelines recommend that at least 1,000–1,500 patients are exposed to the new drug and that 300 and 100 patients use the drug for six and twelve months, respectively, before approval. But are these guidelines being followed? In this database analysis, the researchers use data collected by the EMA to determine how many patients are exposed to new medicines before approval in the European Union and how many are exposed for extended periods of time to medicines intended for chronic use.
What Did the Researchers Do and Find?
Using the European Commission's Community Register of Medicinal Products, the researchers identified 161 standard medicines and 39 orphan medicines (medicines to treat or prevent rare life-threatening diseases) that contained new active substances and that were approved in the European Union between 2000 and 2010. They extracted information on the total number of patients studied and on the number exposed to the medicines for six months and twelve months before approval of each medicine from EMA's European public assessment reports. The average number of patients studied before approval was 1,708 for standard medicines and 438 for orphan medicines (marketing approval is easier to obtain for orphan medicines than for standard medicines to encourage drug companies to develop medicines that might otherwise be unprofitable). On average, medicines for chronic use (for example, asthma medications) were studied in more patients (2,338) than those for intermediate use such as anticancer drugs (878), or short-term use such as antibiotics (1,315). The safety and efficacy of chronic use was studied in fewer than 1,000 patients for at least six and twelve months in 46.4% and 58.4% of new medicines, respectively. Finally, among the 84 medicines intended for chronic use, 72 were studied in at least 300 patients for six months, and 70 were studied in at least 100 patients for twelve months.
What Do These Findings Mean?
These findings suggest that although the number of patients studied before approval is sufficient to determine the short-term efficacy of new medicines, it is insufficient to determine safety or long-term efficacy. Any move by drug approval bodies to require pharmaceutical companies to increase the total number of patients exposed to a drug, or the number exposed for extended periods of time to drugs intended for chronic use, would inevitably delay the entry of new products into the market, which likely would be unacceptable to patients and healthcare providers. Nevertheless, the researchers suggest that a reevaluation of the study size and long-term data requirements that need to be met for the approval of new medicines, particularly those designed for long-term use, is merited. They also stress the need for continued study of both the safety and efficacy of new medicines after approval and the importance of post-marketing studies that actively examine safety issues.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001407.
The European Medicines Agency (EMA) provides information about all aspects of the scientific evaluation and approval of new medicines in the European Union; its European public assessment reports are publicly available
The European Commission's Community Register of Medicinal Products is a publicly searchable database of medicinal products approved for human use in the European Union
The US Food and Drug Administration provides information about drug approval in the US for consumers and for health professionals
The US National Institutes of Health provides information (including personal stories) about clinical trials
doi:10.1371/journal.pmed.1001407
PMCID: PMC3601954  PMID: 23526887
3.  Treatment guided by rapid diagnostic tests for malaria in Tanzanian children: safety and alternative bacterial diagnoses 
Malaria Journal  2011;10:290.
Background
WHO guidelines for the treatment of young children with suspected malaria have recently changed from presumptive treatment to anti-malarial treatment guided by a blood slide or malaria rapid diagnostic test (RDT). However, there is limited evidence of the safety of this policy in routine outpatient settings in Africa.
Methods
Children 3-59 months of age with a non-severe febrile illness and no obvious cause were enrolled over a period of one year in a malaria endemic area of Tanzania. Treatment was determined by the results of a clinical examination and RDT result, and blood culture and serum lactate were also collected. RDT-negative children were followed up over 14 days.
Results
Over the course of one year, 965 children were enrolled; 158 (16.4%) were RDT-positive and treated with artemether-lumefantrine and 807 (83.4%) were RDT-negative and treated with non-anti-malarial medicines. Compared with RDT-positives, RDT-negative children were on average younger with a lower axillary temperature and more likely to have a history of cough or difficulty in breathing. Six (0.6%) children became RDT-positive after enrolment, all of whom were PCR-negative for Plasmodium falciparum DNA at enrolment. In addition, 12 (1.2%) children were admitted to hospital, one with possible malaria, none of whom died. A bacterial pathogen was identified in 9/965 (0.9%) children, eight of whom were RDT-negative and one was RDT-positive, but slide-negative. Excluding three children with Salmonella typhi, all of the children with bacteraemia were ≤12 months of age. Compared to double-read research slide results RDTs had a sensitivity of 97.8% (95%CI 96.9-98.7) and specificity of 96.3% (95%CI 96.3-98.4).
Conclusions
Use of RDTs to direct the use of anti-malarial drugs in young children did not result in any missed diagnoses of malaria although new infections soon after a consultation with a negative RDT result may undermine confidence in results. Invasive bacterial disease is uncommon in children with non-severe illness and most cases occurred in infants with a current fever.
doi:10.1186/1475-2875-10-290
PMCID: PMC3210100  PMID: 21978238
4.  Lead Encephalopathy Due to Traditional Medicines 
Current drug safety  2008;3(1):54-59.
Traditional medicine use is common in developing countries and increasingly popular in the western world. Despite the popularity of traditional medicines, scientific research on safety and efficacy is limited. However documented fatalities and severe illness due to lead poisoning are increasingly recognized to be associated with traditional medicine use. As society becomes more globalized, it is imperative for pharmacists and health care providers to learn about the safety of traditional medical practices. The information presented educates and alerts pharmacists and health care providers about the potential of traditional medicines to cause lead encephalopathy. Case reports were located through systematic literature searches using MEDLINE, CINAHL, AMED, CISCOM, EMBASE and The Cochrane library from 1966 to the February 2007. Reference lists of identified articles and the authors' own files were also searched. Inclusion criteria were cases of human lead encephalopathy associated with traditional medical practices. There were no restrictions regarding the language of publication. Data were subsequently extracted and summarized in narrative and tabular form. We found 76 cases of lead encephalopathy potentially associated with traditional medicine. Ayurvedic medicines were associated with 5 cases (7%), Middle eastern traditional medicines with 66 cases (87%) and 5 cases (7%) with other traditional medicines. Of the 76 cases, 5% were in adults and 95% were in infants and young children. Of the 4 adult cases, at least one was left with residual neurological impairment. In infants and young children, among 72 cases 8 (11%) were fatal, and at least 15 (21%) had residual neurological deficits. Traditional medicine users should be screened for lead exposure and strongly encouraged to discontinue metal–containing remedies. Therefore, the United States Food and Drug Administration and corresponding agencies in other countries should require and enforce heavy metal testing for all imported traditional medicines and “dietary supplements”.
PMCID: PMC2538609  PMID: 18690981
Lead encephalopathy; traditional medicines; CAM; herbal medicines; folk medicine; herbal medicines
5.  Artemisinin-Naphthoquine versus Artemether-Lumefantrine for Uncomplicated Malaria in Papua New Guinean Children: An Open-Label Randomized Trial 
PLoS Medicine  2014;11(12):e1001773.
In a randomized controlled trial Tim Davis and colleagues investigate Artemisinin-naphthoquine versus artemether-lumefantrine for the treatment of P. falciparum and P. vivax malaria.
Please see later in the article for the Editors' Summary
Background
Artemisinin combination therapies (ACTs) with broad efficacy are needed where multiple Plasmodium species are transmitted, especially in children, who bear the brunt of infection in endemic areas. In Papua New Guinea (PNG), artemether-lumefantrine is the first-line treatment for uncomplicated malaria, but it has limited efficacy against P. vivax. Artemisinin-naphthoquine should have greater activity in vivax malaria because the elimination of naphthoquine is slower than that of lumefantrine. In this study, the efficacy, tolerability, and safety of these ACTs were assessed in PNG children aged 0.5–5 y.
Methods and Findings
An open-label, randomized, parallel-group trial of artemether-lumefantrine (six doses over 3 d) and artemisinin-naphthoquine (three daily doses) was conducted between 28 March 2011 and 22 April 2013. Parasitologic outcomes were assessed without knowledge of treatment allocation. Primary endpoints were the 42-d P. falciparum PCR-corrected adequate clinical and parasitologic response (ACPR) and the P. vivax PCR-uncorrected 42-d ACPR. Non-inferiority and superiority designs were used for falciparum and vivax malaria, respectively. Because the artemisinin-naphthoquine regimen involved three doses rather than the manufacturer-specified single dose, the first 188 children underwent detailed safety monitoring. Of 2,542 febrile children screened, 267 were randomized, and 186 with falciparum and 47 with vivax malaria completed the 42-d follow-up. Both ACTs were safe and well tolerated. P. falciparum ACPRs were 97.8% and 100.0% in artemether-lumefantrine and artemisinin-naphthoquine-treated patients, respectively (difference 2.2% [95% CI −3.0% to 8.4%] versus −5.0% non-inferiority margin, p = 0.24), and P. vivax ACPRs were 30.0% and 100.0%, respectively (difference 70.0% [95% CI 40.9%–87.2%], p<0.001). Limitations included the exclusion of 11% of randomized patients with sub-threshold parasitemias on confirmatory microscopy and direct observation of only morning artemether-lumefantrine dosing.
Conclusions
Artemisinin-naphthoquine is non-inferior to artemether-lumefantrine in PNG children with falciparum malaria but has greater efficacy against vivax malaria, findings with implications in similar geo-epidemiologic settings within and beyond Oceania.
Trial registration
Australian New Zealand Clinical Trials Registry ACTRN12610000913077
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Malaria is a mosquito-borne parasitic disease that kills more than 600,000 people (mainly young children in sub-Saharan Africa) every year. Plasmodium falciparum causes most of these deaths, but P. vivax is the most common and most widely distributed cause of malaria outside sub-Saharan Africa. Infection with malaria parasites causes recurring flu-like symptoms and must be treated promptly with antimalarial drugs to prevent the development of anemia and potentially fatal damage to the brain and other organs. In the past, malaria was treated with “monotherapies” such as chloroquine, but the parasites quickly developed resistance to many of these inexpensive drugs. The World Health Organization now recommends artemisinin combination therapy (ACT) for first-line treatment of malaria in all regions where there is drug-resistant malaria. In ACT, artemisinin derivatives (fast-acting antimalarial drugs that are rapidly cleared from the body) are used in combination with a slower acting, more slowly eliminated partner drug to prevent reemergence of the original infection and to reduce the chances of the malaria parasites becoming resistant to either drug.
Why Was This Study Done?
Because falciparum and vivax malaria respond differently to antimalarial drugs, wherever there is transmission of both types of malaria but limited facilities for species-specific malaria diagnosis—as in Papua New Guinea—compromises have to be made about which ACT should be used for the treatment of malaria. Thus, Papua New Guinea's national guidelines recommend artemether-lumefantrine, which is effective against the more deadly P. falciparum, for first-line treatment of uncomplicated (mild) malaria even though this ACT is ineffective against the more common P. vivax. In this open-label randomized trial (a study in which participants are randomly assigned to receive different drugs but know which drug they are being given), the researchers ask whether an alternative ACT might be preferable for the treatment of uncomplicated malaria in young children in Papua New Guinea by comparing outcomes after treatment with artemether-lumefantrine versus artemisinin-naphthoquine (an ACT that should be more effective against vivax malaria than artemether-lumefantrine because naphthoquine stays in the body longer than lumefantrine). Specifically, the researchers test the non-inferiority of artemisinin-naphthoquine compared to artemether-lumefantrine for the treatment of falciparum malaria (whether artemisinin-naphthoquine is not worse than artemether-lumefantrine) and the superiority of artemisinin-naphthoquine compared to artemether-lumefantrine for the treatment of vivax malaria (whether artemisinin-naphthoquine is better than artemether-lumefantrine).
What Did the Researchers Do and Find?
The researchers assigned nearly 250 children (aged 0.5 to 5 years) with falciparum malaria, vivax malaria, or both types of malaria to receive six doses of artemether-lumefantrine over three days or three daily doses of artemisinin-naphthoquine. They then followed the children to see how many children in each treatment group and with each type of malaria were free of malaria 42 days after treatment (an “adequate clinical and parasitological response”). Among the patients originally infected with P. falciparum, 97.8% of those treated with artemether-lumefantrine and 100% of those treated with artemisinin-naphthoquine were clear of their original P. falciparum infection (though some had acquired a new P. falciparum infection) 42 days after treatment. By contrast, among the patients infected with P. vivax, 30% of those treated with artemether-lumefantrine and 100% of those treated with artemisinin-naphthoquine were clear of P. vivax infection 42 days after treatment. Both ACTs were safe and well tolerated.
What Do These Findings Mean?
These findings indicate that artemisinin-naphthoquine was non-inferior to artemether-lumefantrine for the treatment of uncomplicated falciparum malaria among young children in Papua New Guinea and had greater efficacy than artemether-lumefantrine against vivax malaria. The accuracy of these findings may be limited by several aspects of the study design. For example, not all the artemether-lumefantrine doses were directly observed, so some children may not have received the full treatment course. Moreover, because all the study participants lived in coastal communities in Papua New Guinea where malaria is highly endemic, treatment responses among children living in areas with lower levels of malaria transmission might be different. Nevertheless, these findings suggest that artemisinin-naphthoquine should be considered alongside other ACTs for the treatment of uncomplicated malaria in regions where there is transmission of multiple Plasmodium species and that artemisinin-naphthoquine may be better than artemether-lumefantrine for the treatment of uncomplicated malaria in young children in regions where P. vivax predominates.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001773.
Information is available from the World Health Organization on malaria (in several languages); the World Malaria Report 2013 provides details on the current global malaria situation, including information on malaria in Papua New Guinea; the World Health Organization's Guidelines for the Treatment of Malaria is available
The US Centers for Disease Control and Prevention provides information on malaria (in English and Spanish), including personal stories about malaria
Information is available from the Roll Back Malaria Partnership on the global control of malaria, including information about malaria in Papua New Guinea, malaria in children, and ACTs
The Malaria Vaccine Initiative has a fact sheet on Plasmodium vivax malaria
MedlinePlus provides links to additional information on malaria (in English and Spanish)
More information about this trial is available
doi:10.1371/journal.pmed.1001773
PMCID: PMC4280121  PMID: 25549086
6.  Efficacy and Safety of the RTS,S/AS01 Malaria Vaccine during 18 Months after Vaccination: A Phase 3 Randomized, Controlled Trial in Children and Young Infants at 11 African Sites 
PLoS Medicine  2014;11(7):e1001685.
Mary Hamel and colleagues in the RTS,S Clinical Trials Partnership report updated safety and efficacy results from an ongoing Phase 3 trial, including calculations of vaccine impact (malaria cases prevented).
Please see later in the article for the Editors' Summary
Background
A malaria vaccine could be an important addition to current control strategies. We report the safety and vaccine efficacy (VE) of the RTS,S/AS01 vaccine during 18 mo following vaccination at 11 African sites with varying malaria transmission.
Methods and Findings
6,537 infants aged 6–12 wk and 8,923 children aged 5–17 mo were randomized to receive three doses of RTS,S/AS01 or comparator vaccine.
VE against clinical malaria in children during the 18 mo after vaccine dose 3 (per protocol) was 46% (95% CI 42% to 50%) (range 40% to 77%; VE, p<0.01 across all sites). VE during the 20 mo after vaccine dose 1 (intention to treat [ITT]) was 45% (95% CI 41% to 49%). VE against severe malaria, malaria hospitalization, and all-cause hospitalization was 34% (95% CI 15% to 48%), 41% (95% CI 30% to 50%), and 19% (95% CI 11% to 27%), respectively (ITT).
VE against clinical malaria in infants was 27% (95% CI 20% to 32%, per protocol; 27% [95% CI 21% to 33%], ITT), with no significant protection against severe malaria, malaria hospitalization, or all-cause hospitalization.
Post-vaccination anti-circumsporozoite antibody geometric mean titer varied from 348 to 787 EU/ml across sites in children and from 117 to 335 EU/ml in infants (per protocol).
VE waned over time in both age categories (Schoenfeld residuals p<0.001). The number of clinical and severe malaria cases averted per 1,000 children vaccinated ranged across sites from 37 to 2,365 and from −1 to 49, respectively; corresponding ranges among infants were −10 to 1,402 and −13 to 37, respectively (ITT). Meningitis was reported as a serious adverse event in 16/5,949 and 1/2,974 children and in 9/4,358 and 3/2,179 infants in the RTS,S/AS01 and control groups, respectively.
Conclusions
RTS,S/AS01 prevented many cases of clinical and severe malaria over the 18 mo after vaccine dose 3, with the highest impact in areas with the greatest malaria incidence. VE was higher in children than in infants, but even at modest levels of VE, the number of malaria cases averted was substantial. RTS,S/AS01 could be an important addition to current malaria control in Africa.
Trial registration
www.ClinicalTrials.gov NCT00866619
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, more than 200 million cases of malaria occur worldwide, and more than 600,000 people, mainly children living in sub-Saharan Africa, die from this parasitic disease. Malaria parasites are transmitted to people through the bites of infected night-flying mosquitoes and cause fever that needs to be treated promptly with anti-malarial drugs to prevent anemia (a reduction in red blood cell numbers) and life-threatening organ damage. Malaria transmission can be prevented by using long-lasting insecticides sprayed on the indoor walls of homes to kill the mosquitoes that spread the malaria parasite or by sleeping under insecticide-treated nets to avoid mosquito bites and further reduce mosquito numbers. Widespread use of these preventative measures, together with the introduction of artemisinin combination therapy (an effective anti-malarial treatment), has reduced the global burden of malaria by 45% in all age groups, and by 51% among young children, since 2000.
Why Was This Study Done?
Unfortunately, the emergence of insecticide and drug resistance is threatening this advance in malaria control. Moreover, additional interventions—specifically, effective malaria vaccines—will be needed to eliminate malaria in the large areas of Africa where malaria transmission remains high. Currently, there is no licensed malaria vaccine, but RTS,S/AS01, the most advanced malaria vaccine candidate, is undergoing phase 3 clinical trials (the last stage of testing before licensing) in infants and children in seven African countries. The RTS,S Clinical Trials Partnership reported encouraging results on the efficacy and safety of RTS,S/AS01 during 12 months of follow-up in 2011 and 2012. Here, researchers report on the 18-month efficacy and safety of RTS,S/AS01. Vaccine efficacy (VE) is the reduction in the incidence of a disease (the number of new cases that occur in a population in a given period) among trial participants who receive the vaccine compared to the incidence among participants who do not receive the vaccine.
What Did the Researchers Do and Find?
The researchers randomly assigned 6,537 infants aged 6–12 weeks and 8,923 children aged 5–17 months to receive three doses of RTS,S/AS01 or a control vaccine. During 18 months of follow-up, there were 0.69 episodes of clinical malaria (a high temperature and parasites in the blood) per person-year among the children who received all the planned doses of RTS,S/AS01 (the “per protocol” population) and 1.17 episodes per person-year among the control children—a VE against clinical malaria in the per-protocol population of 46%. A similar VE was seen in an intention-to-treat analysis that included all the enrolled children, regardless of whether they received all of the planned vaccine doses; intention-to-treat analyses reflect the real-life situation—in which children sometimes miss vaccine doses—better than per-protocol analyses. In intention-to-treat analyses, the VE among children against severe malaria (fever, parasites in the blood, and symptoms such as anemia) and hospitalization for malaria was 34% and 41%, respectively. Among infants, the VE against clinical malaria was 27% in both per-protocol and intention-to-treat analyses; the vaccine showed no protection against severe malaria or hospitalization. In both infants and children, VE waned with time since vaccination. Across all the study sites, RTS,S/AS01 averted an average of 829 and 449 cases of clinical malaria per 1,000 children and infants vaccinated, respectively. Finally, the serious adverse event meningitis (inflammation of the tissues lining the brain and spinal cord) occurred more frequently in trial participants given RTS,S/AS01 than in those given the control vaccine, but the incidence of other serious adverse events was similar in both groups of participants.
What Do These Findings Mean?
These and other findings show that, during 18 months of follow-up, vaccination of children and young infants with RTS,S/AS01 prevented many cases of clinical and severe malaria and that the impact of vaccination was highest in regions with the highest incidence of malaria. They indicate, as in the earlier analysis, that the VE against clinical and severe malaria is higher in children than in young infants and suggest that protection wanes over time. Whether or not the vaccine played a causal role in the observed cases of meningitis cannot be determined from these results, and the occurrence of meningitis will be followed closely during the remainder of the trial. Other study limitations (for example, variations in the clinical characteristics of participants from one center to another) may also affect the accuracy of these findings and their interpretation. However, by showing that even a modest VE can avert a substantial number of malaria cases, these findings suggest that vaccination with RTS,S/AS01 could have a major public health impact in sub-Saharan Africa.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001685.
Information is available from the World Health Organization on all aspects of malaria (in several languages), including malaria immunization; the World Malaria Report 2013 provides details of the current global malaria situation; the World Health Organization also provides information on its Global Immunization Vision and Strategy (in English and French)
The US Centers for Disease Control and Prevention provides information on malaria, including a selection of personal stories about malaria
Information is available from the Roll Back Malaria Partnership on the global control of malaria and on the Global Malaria Action Plan (in English and French); its website includes a fact sheet about malaria in Africa
The latest results from the phase 3 trial of RTS,S are available on the website of the PATH Malaria Vaccine Initiative, a global program of the international nonprofit organization PATH that aims to accelerate the development of malaria vaccines and ensure their availability and accessibility in the developing world
MedlinePlus provides links to additional information on malaria and on immunization (in English and Spanish)
doi:10.1371/journal.pmed.1001685
PMCID: PMC4114488  PMID: 25072396
7.  Sleep disorders in children 
Clinical Evidence  2010;2010:2304.
Introduction
Sleep disorders may affect between 20% and 30% of young children, and include problems getting to sleep (dyssomnias), or undesirable phenomena during sleep (parasomnias), such as sleep terrors and sleepwalking. Children with physical or learning disabilities are at increased risk of sleep disorders.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for dyssomnias in children? What are the effects of treatments for parasomnias in children? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 28 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: antihistamines; behavioural therapy plus antihistamines, plus benzodiazepines, or plus chloral and derivatives; benzodiazepines alone; exercise; extinction and graduated extinction; 5-hydroxytryptophan; light therapy; melatonin; safety/protective interventions for parasomnias; scheduled waking (for parasomnias); sleep hygiene; and sleep restriction.
Key Points
Sleep disorders may affect between 20% and 30% of young children, and include problems getting to sleep (dyssomnias) or undesirable phenomena during sleep (parasomnias), such as sleep terrors and sleepwalking. Children with physical or learning disabilities are at increased risk of sleep disorders. Other risk factors include the child being the first born, having a difficult temperament or having had colic, and increased maternal responsiveness.
There is a paucity of evidence about effective treatments for sleep disorders in children, especially parasomnias, but behavioural interventions may be the best first-line approach.
Extinction and graduated extinction in otherwise healthy children with dyssomnia may improve sleep quality and settling, and reduce the number of tantrums and wakenings compared with no treatment. Extinction and graduated extinction in children with physical disabilities, learning disabilities, epilepsy, or attention-deficit disorder with dyssomnia may be more effective at improving settling, reducing the frequency and duration of night wakings, and improving parental sleep compared with no treatment; however, we don't know whether it is more effective in improving sleep duration.Graduated extinction may be less distressing for parents, and therefore may have better compliance.
Sleep hygiene for dyssomnia in otherwise healthy children may be more effective in reducing the number and duration of bedtime tantrums compared with placebo, but we don’t know if it is more effective at reducing night wakenings, improving sleep latency, improving total sleep duration, or improving maternal mood. Sleep hygiene and graduated extinction seem to be equally effective at reducing bedtime tantrums in otherwise healthy children with dyssomnia.We don't know whether sleep hygiene for dyssomnia in children with physical disabilities, learning disabilities, epilepsy, or attention-deficit disorder is effective.
Melatonin for dyssomnia in otherwise healthy children may be more effective at improving sleep-onset time, total sleep time, and general health compared with placebo. Evidence of improvements in dyssomnia with melatonin is slightly stronger in children with physical disabilities, learning disabilities, epilepsy, or attention-deficit disorder.
Little is known about the long-term effects of melatonin, and the quality of the product purchased could be variable as melatonin is classified as a food supplement.
Antihistamines for dyssomnia may be more effective than placebo at reducing night wakenings and decreasing sleep latency, but we don’t know if they are more effective at increasing sleep duration. The evidence for antihistamines in dyssomnia comes from only one small, short-term study.
We don’t know whether behavioural therapy plus antihistamines, plus benzodiazepines, or plus chloral and derivatives, exercise, light therapy, or sleep restriction are effective in children with dyssomnia.
We don’t know whether antihistamines, behavioural therapy plus benzodiazepines or plus chloral and derivatives, benzodiazepines, 5-hydroxytryptophan, melatonin, safety/protective interventions, scheduled waking, sleep hygiene, or sleep restriction are effective in children with parasomnia.
PMCID: PMC3217667  PMID: 21418676
8.  Sleep disorders in children 
Clinical Evidence  2007;2007:2304.
Introduction
Sleep disorders may affect 20-30% of young children, and include excessive daytime sleepiness, problems getting to sleep (dysomnias), or undesirable phenomena during sleep (parasomnias), such as sleep terrors, and sleepwalking. Children with physical or learning disabilities are at increased risk of sleep disorders.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for dysomnias in children? What are the effects of treatments for parasomnias in children? We searched: Medline, Embase, The Cochrane Library and other important databases up to September 2006 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 14 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: antihistamines, behavioural therapy plus benzodiazepines, or plus chloral and derivates, exercise, extinction and graduated extinction, light therapy, melatonin, safety/protective interventions for parasomnias, scheduled waking (for parasomnias), sleep hygiene, and sleep restriction.
Key Points
Sleep disorders may affect 20-30% of young children, and include excessive daytime sleepiness, problems getting to sleep (dysomnias), or undesirable phenomena during sleep (parasomnias), such as sleep terrors, and sleepwalking. Children with physical or learning disabilities are at increased risk of sleep disorders. Other risk factors include the child being the first born, having a difficult temperament or having had colic, and increased maternal responsiveness.
There is a paucity of evidence about effective treatments for sleep disorders in children, especially parasomnias, but behavioural interventions may be the best first-line approach.
Extinction and graduated extinction interventions improve settling and reduce night wakes compared with placebo in healthy children, and in children with learning disabilities. Graduated extinction may be less distressing for parents, and therefore may have better compliance.Sleep hygiene interventions may reduce bedtime tantrums in healthy children compared with placebo, with similar effectiveness to graduated extinction.Sleep hygiene plus graduated extinction may reduce bedtime tantrums in children with physical or learning disabilities.We don't know whether combining behavioural therapy with benzodiazepines or with chloral improves sleep or parasomnias.
Melatonin may improve sleep onset and sleep time compared with placebo in healthy children, but we don't know if it is beneficial in children with disabilities, if it improves parasomnias, or what its long-term effects might be. We don't know whether antihistamines, exercise, light therapy, or sleep restriction improve dysomnias or parasomnias in children.We don't know whether safety or protective interventions, scheduled waking, extinction, or sleep hygiene are effective in children with parasomnias.
PMCID: PMC2943792  PMID: 19450298
9.  The Effect of Dosing Regimens on the Antimalarial Efficacy of Dihydroartemisinin-Piperaquine: A Pooled Analysis of Individual Patient Data 
PLoS Medicine  2013;10(12):e1001564.
Ric Price and colleagues pool individual patient data from efficacy trials of dihydroartemisinin-piperaquine shared with WWARN (Worldwide Antimalarial Resistance Network) to examine the potential for underdosing in young children.
Please see later in the article for the Editors' Summary
Background
Dihydroartemisinin-piperaquine (DP) is increasingly recommended for antimalarial treatment in many endemic countries; however, concerns have been raised over its potential under dosing in young children. We investigated the influence of different dosing schedules on DP's clinical efficacy.
Methods and Findings
A systematic search of the literature was conducted to identify all studies published between 1960 and February 2013, in which patients were enrolled and treated with DP. Principal investigators were approached and invited to share individual patient data with the WorldWide Antimalarial Resistance Network (WWARN). Data were pooled using a standardised methodology. Univariable and multivariable risk factors for parasite recrudescence were identified using a Cox's regression model with shared frailty across the study sites. Twenty-four published and two unpublished studies (n = 7,072 patients) were included in the analysis. After correcting for reinfection by parasite genotyping, Kaplan–Meier survival estimates were 97.7% (95% CI 97.3%–98.1%) at day 42 and 97.2% (95% CI 96.7%–97.7%) at day 63. Overall 28.6% (979/3,429) of children aged 1 to 5 years received a total dose of piperaquine below 48 mg/kg (the lower limit recommended by WHO); this risk was 2.3–2.9-fold greater compared to that in the other age groups and was associated with reduced efficacy at day 63 (94.4% [95% CI 92.6%–96.2%], p<0.001). After adjusting for confounding factors, the mg/kg dose of piperaquine was found to be a significant predictor for recrudescence, the risk increasing by 13% (95% CI 5.0%–21%) for every 5 mg/kg decrease in dose; p = 0.002. In a multivariable model increasing the target minimum total dose of piperaquine in children aged 1 to 5 years old from 48 mg/kg to 59 mg/kg would halve the risk of treatment failure and cure at least 95% of patients; such an increment was not associated with gastrointestinal toxicity in the ten studies in which this could be assessed.
Conclusions
DP demonstrates excellent efficacy in a wide range of transmission settings; however, treatment failure is associated with a lower dose of piperaquine, particularly in young children, suggesting potential for further dose optimisation.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Half of the world's population is at risk of malaria, a mosquito-borne parasitic disease that kills a million people (mainly young children in sub-Saharan Africa) every year. During the second half of the 20th century, the main treatments for malaria were “monotherapies” such as chloroquine and sulfadoxine-pyrimethamine. Unfortunately, parasitic resistance to these drugs rapidly spread and, in the 1990s, there was an upsurge in the illness and death caused by Plasmodium falciparum, the parasite responsible for most malarial deaths. To combat this increase, the World Health Organization (WHO) now recommends artemisinin-based combination therapy (ACT) for first-line treatment of P. falciparum malaria wherever malaria is endemic (always present). In ACT, artemisinin derivatives (antimalarial drugs that rapidly reduce the parasitic load in the patient and that are rapidly cleared from the body) are used in combination with a slower acting, more slowly eliminated partner drug that prevents recrudescent infections (re-emergences of the original infection).
Why Was This Study Done?
ACT reduces the chances of P. falciparum becoming resistant to either the artemisinin derivative or the partner drug, but sub-optimal dosing can result in incomplete elimination of the initial parasitic infection and/or recrudescence. Both these situations drive the selection of parasites with reduced drug susceptibility. Unfortunately, current dosing strategies are usually based on weight or age bands that were determined during early drug development. Inevitably, some patients at the margins of these bands receive inappropriate doses—either too high or too low. Moreover, the doses recommended for children are extrapolated from adult doses and may not be optimal because children are not merely small adults—their drug responses often differ from those of adults. Here, researchers from the WorldWide Antimalarial Resistance Network (WWARN) investigate the influence of different dosing schedules on the clinical efficacy of dihydroartemisinin-piperaquine (DP, an ACT first recommended by WHO for the treatment of uncomplicated P. falciparum malaria in 2010) by undertaking a pooled analysis of individual patient data collected during ACT clinical studies.
What Did the Researchers Do and Find?
The researchers identified all the studies published between 1960 and February 2013 in which patients were treated with DP and obtained individual patient data for almost 70% of study participants (more than 7,000 patients living in Asia, Africa, and South America) from the principal investigators. These data were pooled and statistical models were used to identify risk factors for parasite recrudescence (parasite genotyping was used to correct for re-infection with a new parasite). Overall, DP treatment was successful (judged by parasitological clearance) in 97.7% and 97.2% of patients at day 42 and 63, respectively, after treatment. However, 28.6% of children aged 1–5 years received a total dose of piperaquine over the 3-day DP dosing schedule of below 48 mg/kg body weight (the lower limit of dosing recommended by WHO). Children aged 1–5 years had a 2.9-fold higher risk of receiving a dose of piperaquine below 48 mg/kg than children aged 5–12 years. Moreover, the piperaquine dose was a significant predictor of recrudescence. For every 5 mg/kg decrease in dose, the risk of recrudescence increased by 13%. Finally, the researchers estimated that increasing the target dose of piperaquine in children aged 1–5 years to 59 mg/kg would halve the risk of treatment failure and cure at least 95% of young children.
What Do These Findings Mean?
These findings suggest that DP treatment of malaria has a good efficacy in a wide range of settings but indicate that young children are at a higher risk of treatment failure than the overall population and that treatment failure, particularly in young children, is associated with a lower dose of piperaquine. Although the accuracy of these findings may be limited by some aspects of this study (for example, drug doses could only be calculated from the actual tablets taken in a quarter of the patients; in the remainder, they were extrapolated from the relevant study protocol), they nevertheless suggest that further detailed dose optimization studies in young children are essential to prolong the useful therapeutic life of DP. Moreover, if global elimination of malaria is to be achieved, similar pooled analyses to assess the efficacy of other drug combinations should be undertaken to ensure that ACT remains therapeutically useful for as long as possible.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001564.
This study is further discussed in a PLoS Medicine Perspective by Paul Garner
Information is available from the World Health Organization on malaria (in several languages); the 2012 World Malaria Report provides details of the current global malaria situation; the 2010 WHO Guidelines for the Treatment of Malaria are available
The US Centers for Disease Control and Prevention provide information on malaria (in English and Spanish), including a selection of personal stories about malaria
Information is available from the Roll Back Malaria Partnership on the global control of malaria including fact sheets about ACT
MedlinePlus provides links to additional information on malaria (in English and Spanish)
Information on the WorldWide Antimalarial Resistance Network is available
doi:10.1371/journal.pmed.1001564
PMCID: PMC3848996  PMID: 24311989
10.  Decline in Diarrhea Mortality and Admissions after Routine Childhood Rotavirus Immunization in Brazil: A Time-Series Analysis 
PLoS Medicine  2011;8(4):e1001024.
A time series analysis by Manish Patel and colleagues shows that the introduction of rotavirus vaccination in Brazil is associated with reduced diarrhea-related deaths and hospital admissions in children under 5 years of age.
Background
In 2006, Brazil began routine immunization of infants <15 wk of age with a single-strain rotavirus vaccine. We evaluated whether the rotavirus vaccination program was associated with declines in childhood diarrhea deaths and hospital admissions by monitoring disease trends before and after vaccine introduction in all five regions of Brazil with varying disease burden and distinct socioeconomic and health indicators.
Methods and Findings
National data were analyzed with an interrupted time-series analysis that used diarrhea-related mortality or hospitalization rates as the main outcomes. Monthly mortality and admission rates estimated for the years after rotavirus vaccination (2007–2009) were compared with expected rates calculated from pre-vaccine years (2002–2005), adjusting for secular and seasonal trends. During the three years following rotavirus vaccination in Brazil, rates for diarrhea-related mortality and admissions among children <5 y of age were 22% (95% confidence interval 6%–44%) and 17% (95% confidence interval 5%–27%) lower than expected, respectively. A cumulative total of ∼1,500 fewer diarrhea deaths and 130,000 fewer admissions were observed among children <5 y during the three years after rotavirus vaccination. The largest reductions in deaths (22%–28%) and admissions (21%–25%) were among children younger than 2 y, who had the highest rates of vaccination. In contrast, lower reductions in deaths (4%) and admissions (7%) were noted among children two years of age and older, who were not age-eligible for vaccination during the study period.
Conclusions
After the introduction of rotavirus vaccination for infants, significant declines for three full years were observed in under-5-y diarrhea-related mortality and hospital admissions for diarrhea in Brazil. The largest reductions in diarrhea-related mortality and hospital admissions for diarrhea were among children younger than 2 y, who were eligible for vaccination as infants, which suggests that the reduced diarrhea burden in this age group was associated with introduction of the rotavirus vaccine. These real-world data are consistent with evidence obtained from clinical trials and strengthen the evidence base for the introduction of rotavirus vaccination as an effective measure for controlling severe and fatal childhood diarrhea.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Diarrheal disease, usually caused by infectious agents, is the second major cause of death in children aged under five years. As highlighted in a recent PLoS Medicine series, access to clean water and improved sanitation is the key to the primary prevention of diarrheal illnesses. Yet despite the targets of Millennium Development Goal 7 to half the number of people without access to clean water or improved sanitation by 2015, over one billion people worldwide do not currently have access to clean water and over two billion do not currently have access to improved sanitation.
Since enteric viruses are primarily transmitted directly from one person to another, they cannot be controlled completely by improvements in sanitation. Therefore, although not replacing the urgent need to provide access to clean water and improved sanitation for all, vaccination programs that protect young children against some infections that cause diarrhea, such as rotavirus, which accounts for one-third of all child deaths caused by diarrhea, are a pragmatic way forward. As large clinical trials have shown the safety and efficacy of rotavirus vaccines in population settings, in July 2009, the World Health Organization recommended including rotavirus vaccines into every country's national immunization programs.
Why Was This Study Done?
Although the protective effect of rotavirus vaccines has been assessed in various high-, middle-, and low-income settings, for reasons that remain unclear, the efficacy of live, oral rotavirus vaccines appears to be dependent on geographical location and correlated to the socioeconomic status of the population. Because of these concerns, evaluating the health impact of large-scale rotavirus vaccine programs and ensuring their equity in a real-world setting (rather than in clinical trial conditions) is important.
Therefore, the researchers addressed this issue by conducting this study to evaluate the effect of rotavirus vaccination on mortality and hospital admissions for diarrhea due to all causes among young children in the five regions of Brazil. The researchers chose to do this study in Brazil because of the high incidence of diarrhea-related deaths and hospital admissions and because five years ago, in July 2006, the Brazilian Ministry of Health introduced the single-strain rotavirus vaccine simultaneously in all 27 states through its national immunization program—allowing for “before” and “after” intervention analysis.
What Did the Researchers Do and Find?
The researchers obtained data on diarrheal deaths and hospital admissions in children aged under five years for the period 2002–2005 and 2007–2009 and data on rotavirus vaccination rates. The researchers got the data on diarrhea deaths from the Brazilian Mortality Information System—the national database of information collected from death certificates that covers 90% of all deaths in Brazil. The data on hospital admissions came from the electronic Hospital Information System of Brazil's Unified Health System (Sistema Unico de Saúde, SUS)—the publicly funded health-care system that covers roughly 70% of the hospitalizations and includes information on all admissions (from public hospitals and some private hospitals) authorized for payment by the Unified Health System. The researchers got regional rotavirus vaccination coverage estimates for 2007–2009 from the information department of the Ministry of Health, and estimated coverage of the two doses of oral rotavirus vaccine by taking the annual number of second doses administered divided by the number of infants in the region.
In 2007, an estimated 80% of infants received two doses of rotavirus vaccine, and by 2009, this proportion rose to 84% of children younger than one year of age. The researchers found that in the three years following the introduction of rotavirus vaccination, diarrhea-related mortality rates and admissions among children aged under five years were respectively 22% and 17% lower than expected, with a cumulative total of 1,500 fewer diarrhea deaths and 130,000 fewer admissions. Furthermore, the largest reductions in deaths and admissions were among children who had the highest rates of vaccination (less than two years of age), and the lowest reductions were among children who were not eligible for vaccination during the study period (aged 2–4 years).
What Do These Findings Mean?
These findings suggest that the introduction of rotavirus vaccination in all areas of Brazil is associated with reduced diarrhea-related deaths and hospital admissions in children aged under five years. These real-world impact data are consistent with the clinical trials and strengthen the evidence base for rotavirus vaccination as an effective measure for controlling severe and fatal childhood diarrhea.
These findings have important global policy implications. In middle-income countries, such as Brazil, that are not eligible for financial support from donors, the potential reductions in admissions and other health-care costs will be important for cost-effectiveness considerations to justify the purchase of these still relatively expensive vaccines.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001024
PLoS Medicine has published a series on water and sanitation
More information is available from the World Health Organization on diarrheal illness in children
More information is available about rotavirus vaccines from the World Health Organization, the US Centers for Disease Control and Prevention, and the Rotavirus Vaccine Program
doi:10.1371/journal.pmed.1001024
PMCID: PMC3079643  PMID: 21526228
11.  Regulation (EC) No 1901/2006 on medicinal products for paediatric use & clinical research in vulnerable populations 
Before any medicinal product is authorised for use in adults, it must undergo extensive pharmaceutical consistency and stability tests, toxicological tests and clinical trials to ensure that it is of high quality, safe and effective.
The same approach may not always be applied to medicinal products used to treat children.
Studies showed that over 50% of the medicinal products used in children may not have been tested for use in this age group. The absence of suitable authorised medicinal products to treat conditions in children results from the fact that pharmaceutical companies do not adapt medicinal products to the needs of the paediatric population. This leaves health care professionals with no alternative other than to use medicinal products "off-label" and to use unauthorised products with the associated risks of inefficacy and/or adverse reactions.
The Regulation (EC) No 1901/2006 sets up a system of requirements, rewards and incentives, together with horizontal measures, to ensure that medicinal products are researched, developed and authorised to meet the therapeutic needs of children.
The Regulation is addressed to:
1. The pharmaceutical industry by setting out the legal framework for receiving rewards and incentives by conducting clinical trials in the paediatric population.
2. The Member States to set out to support research into, and the development and availability of, medicinal products for paediatric use.
3. The Community as funds for research into medicinal products for the paediatric population shall be provided for in the Community budget in order to support studies relating to medicinal products or active substances not covered by a patent or a supplementary protection certificate.
The legal framework for conducting clinical trials, including children/minors, is set up in Directive 2001/20/EC, the Clinical Trials Directive (CTD), for the European Union (EU). The CTD establishes specific provisions regarding conduct of clinical trials, including multi-centre trials, on human subjects involving medicinal products and in particular relating to the implementation of good clinical practice. Compliance with this good practice provides assurance that the rights, safety and well-being of trial subjects are protected, and that the results of the clinical trials are credible. The CTD is addressed to all investigators conducting clinical trials including clinical trials in the paediatric population and had to be applied accordingly.
In the framework of the authorisation of medicinal products regulated by the Regulation (EC) No 726/2004 and Directive 2001/83/EC as amended and the CTD, and additional implementing Directives and guidelines, the new Regulation (EC) No 1901/2006 is an important new piece of legislation focusing on the requirements to improve the situation for the paediatric population.
All Regulations/Directives to be found:
doi:10.1186/1753-2000-2-37
PMCID: PMC2633263  PMID: 19063722
12.  Loperamide Therapy for Acute Diarrhea in Children: Systematic Review and Meta-Analysis 
PLoS Medicine  2007;4(3):e98.
Background
Loperamide is widely used in adults for acute diarrhea. However, its use in children has been discouraged by the World Health Organization and the American Academy of Pediatrics owing to concerns over safety and efficacy in young children.
Methods and Findings
To assess the efficacy and adverse effects of loperamide compared with placebo for acute diarrhea in children, we reviewed Medline, EMBase, the Cochrane Central Register of Controlled Trials, and bibliographies of known clinical trials and of review articles, and we also interviewed key investigators in the field. We undertook a systematic review and meta-analysis of randomized controlled trials of children younger than 12 y of age with acute diarrhea, comparing loperamide with placebo. Included trials reported data on diarrhea duration or severity, or provided data on adverse effects. Compared with patients who received placebo, patients allocated to loperamide were less likely to continue to have diarrhea at 24 h (prevalence ratio 0.66, 95% confidence interval [CI]: 0.57 to 0.78), had a shorter duration of diarrhea by 0.8 d (95% CI: 0.7 to 0.9 d), and had a lower count of stools at 24 h (0.84, 95% CI: 0.77 to 0.92). Results were similar when random-effects summaries were estimated. Serious adverse events, defined as ileus, lethargy, or death, were reported in eight out of 927 children allocated to loperamide (0.9%, 95% CI: 0.4% to 1.7%). Serious adverse events were not reported in any of the 764 children allocated to placebo (0%, 95% CI: 0% to 0.5%). Among the children allocated to loperamide, serious adverse events were reported only among children younger than 3 y.
Conclusions
In children who are younger than 3 y, malnourished, moderately or severely dehydrated, systemically ill, or have bloody diarrhea, adverse events outweigh benefits even at doses ≤0.25 mg/kg/d. In children who are older than 3 y with no/minimal dehydration, loperamide may be a useful adjunct to oral rehydration and early refeeding.
In seriously ill children under 3 years of age with diarrhea the adverse effects of loperamide outweighed the benefits, but the drug could be useful as part of treatment for other children.
Editors' Summary
Background.
While diarrhea is often thought of as a mild, inconvenient condition, it is estimated that, worldwide, 1.6–2.5 million children under 5 y old die each year from diarrhea, most of them in developing countries. Dehydration is the key factor in the deaths of these children. In richer countries, diarrhea is rarely deadly, but it has been calculated that, in the United States, the annual national health-care cost associated with the condition amounts to around US$1.5 billion. Some of the cost results from the purchase of anti-diarrheal drugs. Loperamide is one of the most widely used of these drugs. In most countries, it can be obtained without a prescription. The use of loperamide is intended to reduce the frequency of bowel movements, but taking it will not lead to rehydration, nor will it kill the infectious organisms responsible for the condition.
Why Was This Study Done?
The World Health Organization and other health authorities have concerns that loperamide may not be effective in young children and that it may not be safe. In the United States, the Food and Drug Administration approves its use for children older than 2 y of age. The researchers wanted to know whether loperamide could play a useful part in treating diarrhea in children.
What Did the Researchers Do and Find?
They did not do any new work with children suffering from diarrhea. Instead, they searched the medical literature for previously conducted trials involving the use of loperamide. They used these previously conducted trials to estimate whether use of loperamide influenced the duration of diarrhea or the number of diarrheal stools in children under 12 y of age. They also used these trials to examine adverse effects of loperamide. In total they found 13 studies that met the criteria they had set for inclusion in their study. More than 900 children in these studies had been given loperamide for their diarrhea; each trial also had a control group of children whose treatment did not include loperamide. Most of the children in the studies had only mild diarrhea. The researchers found that, compared with children in the control groups, those treated with loperamide were less likely to continue to have diarrhea 24 h later, had a shorter duration of diarrhea, and had a lower count of diarrheal stools. However, eight of the children given loperamide and none of the control group did have serious adverse effects. All those who had serious adverse effects were less than 3 y of age.
What Do These Findings Mean?
The researchers concluded that if a child is less than 3 y of age, malnourished, moderately or severely dehydrated, or has bloody diarrhea, the risk of adverse events from loperamide treatment outweighs the benefits, even at low doses. In other children, loperamide may be a useful part of treatment. However, they advise that rehydrating the child (by giving fluids orally) and progressively returning him or her to a normal diet should still be the main focus in the treatment of childhood diarrhea.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040098.
For advice on the treatment of diarrhea, visit the Web sites of BestTreatments (produced by BMJ Publications) and of FamilyDoctor (produced by the American Academy of Family Physicians)
The World Health Organization has a Web page about diarrhea that gives a global perspective on this major cause of childhood death
UNICEF (the children's organization of the United Nations) includes diarrhea in its Facts for Life series, which aims to provide parents and other caregivers with the information they need to save and improve children's lives; the messages contained in Facts for Life are based on the latest scientific findings, but are presented in nontechnical language
doi:10.1371/journal.pmed.0040098
PMCID: PMC1831735  PMID: 17388664
13.  Natural products as starting points for future anti-malarial therapies: going back to our roots? 
Malaria Journal  2011;10(Suppl 1):S3.
Background
The discovery and development of new anti-malarials are at a crossroads. Fixed dose artemisinin combination therapy is now being used to treat a hundred million children each year, with a cost as low as 30 cents per child, with cure rates of over 95%. However, as with all anti-infective strategies, this triumph brings with it the seeds of its own downfall, the emergence of resistance. It takes ten years to develop a new medicine. New classes of medicines to combat malaria, as a result of infection by Plasmodium falciparum and Plasmodium vivax are urgently needed.
Results
Natural product scaffolds have been the basis of the majority of current anti-malarial medicines. Molecules such as quinine, lapachol and artemisinin were originally isolated from herbal medicinal products. After improvement with medicinal chemistry and formulation technologies, and combination with other active ingredients, they now make up the current armamentarium of medicines. In recent years advances in screening technologies have allowed testing of millions of compounds from pharmaceutical diversity for anti-malarial activity in cellular assays. These initiatives have resulted in thousands of new sub-micromolar active compounds – starting points for new drug discovery programmes. Against this backdrop, the paucity of potent natural products identified has been disappointing. Now is a good time to reflect on the current approach to screening herbal medicinal products and suggest revisions. Nearly sixty years ago, the Chinese doctor Chen Guofu, suggested natural products should be approached by dao-xing-ni-shi or ‘acting in the reversed order’, starting with observational clinical studies. Natural products based on herbal remedies are in use in the community, and have the potential unique advantage that clinical observational data exist, or can be generated. The first step should be the confirmation and definition of the clinical activity of herbal medicinal products already used by the community. This first step forms a solid basis of observations, before moving to in vivo pharmacological characterization and ultimately identifying the active ingredient. A large part of the population uses herbal medicinal products despite limited numbers of well-controlled clinical studies. Increased awareness by the regulators and public health bodies of the need for safety information on herbal medicinal products also lends support to obtaining more clinical data on such products.
Conclusions
The relative paucity of new herbal medicinal product scaffolds active against malaria results discovered in recent years suggest it is time to re-evaluate the ‘smash and grab’ approach of randomly testing purified natural products and replace it with a patient-data led approach. This will require a change of perspective form many in the field. It will require an investment in standardisation in several areas, including: the ethnopharmacology and design and reporting of clinical observation studies, systems for characterizing anti-malarial activity of patient plasma samples ex vivo followed by chemical and pharmacological characterisation of extracts from promising sources. Such work falls outside of the core mandate of the product development partnerships, such as MMV, and so will require additional support. This call is timely, given the strong interest from researchers in disease endemic countries to support the research arm of a malaria eradication agenda. Para-national institutions such as the African Network for Drugs and Diagnostics Innovation (ANDi) will play a major role in facilitating the development of their natural products patrimony and possibly clinical best practice to bring forward new therapeutics. As in the past, with quinine, lapinone and artemisinin, once the activity of herbal medicinal products in humans is characterised, it can be used to identify new molecular scaffolds which will form the basis of the next generation of anti-malarial therapies.
doi:10.1186/1475-2875-10-S1-S3
PMCID: PMC3059461  PMID: 21411014
14.  The Effect of Adding Ready-to-Use Supplementary Food to a General Food Distribution on Child Nutritional Status and Morbidity: A Cluster-Randomized Controlled Trial 
PLoS Medicine  2012;9(9):e1001313.
Lieven Huybregts and colleagues investigate how supplementing a general food distribution with a fortified lipid-based spread during a seasonal hunger gap in Chad affects anthropometric and morbidity outcomes for children aged 6 to 36 months.
Background
Recently, operational organizations active in child nutrition in developing countries have suggested that blanket feeding strategies be adopted to enable the prevention of child wasting. A new range of nutritional supplements is now available, with claims that they can prevent wasting in populations at risk of periodic food shortages. Evidence is lacking as to the effectiveness of such preventive interventions. This study examined the effect of a ready-to-use supplementary food (RUSF) on the prevention of wasting in 6- to 36-mo-old children within the framework of a general food distribution program.
Methods and Findings
We conducted a two-arm cluster-randomized controlled pragmatic intervention study in a sample of 1,038 children aged 6 to 36 mo in the city of Abeche, Chad. Both arms were included in a general food distribution program providing staple foods. The intervention group was given a daily 46 g of RUSF for 4 mo. Anthropometric measurements and morbidity were recorded monthly. Adding RUSF to a package of monthly household food rations for households containing a child assigned to the intervention group did not result in a reduction in cumulative incidence of wasting (incidence risk ratio: 0.86; 95% CI: 0.67, 1.11; p = 0.25). However, the intervention group had a modestly higher gain in height-for-age (+0.03 Z-score/mo; 95% CI: 0.01, 0.04; p<0.001). In addition, children in the intervention group had a significantly higher hemoglobin concentration at the end of the study than children in the control group (+3.8 g/l; 95% CI: 0.6, 7.0; p = 0.02), thereby reducing the odds of anemia (odds ratio: 0.52; 95% CI: 0.34, 0.82; p = 0.004). Adding RUSF also resulted in a significantly lower risk of self-reported diarrhea (−29.3%; 95% CI: 20.5, 37.2; p<0.001) and fever episodes (−22.5%; 95% CI: 14.0, 30.2; p<0.001). Limitations of this study include that the projected sample size was not fully attained and that significantly fewer children from the control group were present at follow-up sessions.
Conclusions
Providing RUSF as part of a general food distribution resulted in improvements in hemoglobin status and small improvements in linear growth, accompanied by an apparent reduction in morbidity.
Trial registration
ClinicalTrials.gov NCT01154595
Please see later in the article for the Editors' Summary.
Editors' Summary
Background
Good nutrition during childhood is essential for health and survival. Undernourished children are more susceptible to infections and are more likely to die from common ailments such as diarrhea than well-nourished children. Globally, undernutrition contributes to about a third of deaths among children under five years old. Experts use three physical measurements to determine whether a child is undernourished. An “underweight” child has a low weight for his or her age and gender when compared to the World Health Organization Child Growth Standards, which chart the growth of a reference population. A “stunted” child has a low height for his or her age; stunting indicates chronic undernutrition. A “wasted” child has a low weight for his or her height; wasting indicates acute undernutrition and can be caused by disasters or seasonal food shortages. Recent estimates indicate that about a fifth of young children in developing countries are underweight, and one third are stunted; in south Asia and west/central Africa, more than one tenth of children are wasted, a condition that markedly increases the risk of death.
Why Was This Study Done?
In emergency situations, international organizations support affected populations by providing “general food distributions.” Recently, there have been claims that the provision of targeted nutritional supplements within a general food distribution framework effectively prevents child wasting, but there is little evidence to support these claims. In this cluster-randomized controlled trial, the researchers investigate the effect of a targeted daily dose of a “ready-to-use supplementary food” (RUSF; a lipid-based nutrient supplement) on indicators of undernutrition in 6- to 36-month-old, non-wasted children in Chad, a country beset by a severe food crisis. Political instability in this central African country has severely reduced the nutritional status of children, and annual droughts, which affect crop production, cause a “hunger gap” between June and October. In a recent survey, one fifth of children in Chad were wasted at the beginning of this hunger gap. A cluster-randomized trial randomly assigns groups of people to receive alternative interventions and compares the outcomes in the differently treated “clusters.”
What Did the Researchers Do and Find?
The researchers randomly assigned fourteen household clusters in the city of Abeche, Chad, to the trial's intervention or control arm. All the households received a general food distribution that included staple foods; eligible children in the intervention households were also given a daily RUSF ration between June and September 2010. The researchers regularly measured the children's weights and heights, recorded illnesses reported by caregivers, and measured each child's blood hemoglobin level before and after the intervention to assess their risk of anemia, an indicator of poor nutrition. The addition of RUSF to the household food rations did not significantly reduce the cumulative incidence of wasting. That is, although fewer children in the intervention group became wasted during the trial than in the control group, this difference was not statistically significant—it could have happened by chance. However, compared to the children in the control group, those in the intervention group had a significantly greater gain in height-for-age (equivalent to a difference in height gain of 0.09 cm/month), slightly higher hemoglobin levels at the end of the study, which significantly reduced their anemia risk, and a significantly lower risk of self-reported diarrhea and fever.
What Do These Findings Mean?
Although targeted RUSF provided as part of a general food distribution had no significant effect on wasting in young children in Abeche, Chad, the intervention improved their hemoglobin status and linear growth, and reduced illness among them. Why didn't targeted RUSF prevent wasting effectively in this trial? Maybe the effect of RUSF was diluted out by the effect of the general food distribution or maybe the trial was too short to see a clear effect. Most importantly, though, the trial may have been too small to see a clear effect—the researchers were unable to enroll as many children into their trial as they had planned because of political instability in Chad, and this probably limited the trial's ability to detect small differences between the control and intervention groups. Nevertheless, because these findings provide no clear evidence that adding RUSF to a household food ration effectively prevents wasting, alternative ways to prevent acute malnutrition in Chad and other vulnerable regions of the world should be investigated.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001313.
This study is further discussed in a PLOS Medicine Perspective by Kathryn Dewey and Mary Arimond
Action Contra la Faim–France has a web page that describes the situation in Chad
The United Nations Childrens Fund, which protects the rights of children and young people around the world, provides detailed statistics on child undernutrition; it has detailed information, including videos, about the current food crisis in Chad and the Sahel
The WHO Child Growth Standards are available (in several languages)
The United Nations provides information on ongoing world efforts to reduce hunger and child mortality
The World Food Programme is the world's largest humanitarian agency fighting hunger worldwide; its website provides detailed information about malnutrition in Chad, including a video of the current food crisis in the country
Starved for Attention is an international multimedia campaign launched in 2010 by Médecins Sans Frontiéres (MSF) and the VII Photo agency to rewrite the story of childhood malnutrition; information about MSFs work in Chad to tackle malnutrition is available
doi:10.1371/journal.pmed.1001313
PMCID: PMC3445445  PMID: 23028263
15.  Asthma and other recurrent wheezing disorders in children (chronic) 
Clinical Evidence  2012;2012:0302.
Introduction
Childhood asthma is the most common chronic paediatric illness. There is no cure for asthma but good treatment to palliate symptoms is available. Asthma is more common in children with a personal or family history of atopy, increased severity and frequency of wheezing episodes, and presence of variable airway obstruction or bronchial hyperresponsiveness. Precipitating factors for symptoms and acute episodes include infection, house dust mites, allergens from pet animals, exposure to tobacco smoke, and exercise.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of single-agent prophylaxis in children taking as-needed inhaled beta2 agonists for asthma? What are the effects of additional prophylactic treatments in childhood asthma inadequately controlled by standard-dose inhaled corticosteroids? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2010 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 48 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: beta2 agonists (long-acting), corticosteroids (inhaled standard or higher doses), leukotriene receptor antagonists (oral), omalizumab, and theophylline (oral).
Key Points
Childhood asthma can be difficult to distinguish from viral wheeze and can affect up to 20% of children.
Regular monotherapy with inhaled corticosteroids improves symptoms, reduces exacerbations, and improves physiological outcomes in children with asthma symptoms requiring regular short-acting beta2 agonist treatment. Their effect on final adult height is minimal and when prescribed within recommended doses have an excellent safety record. Regular monotherapy with other treatments is not superior to low-dose inhaled corticosteroids.
Leukotriene receptor antagonists may have a role as first-line prophylaxis in very young children.
There is consensus that long-acting beta2 agonists should not be used for first-line prophylaxis. CAUTION: Monotherapy with long-acting beta2 agonists does not reduce asthma exacerbations but may increase the chance of severe asthma episodes.
Theophylline was used as first-line prevention before the introduction of inhaled corticosteroids. Although there is weak evidence that theophylline is superior to placebo, theophylline should no longer be used as first-line prophylaxis in childhood asthma because of clear evidence of the efficacy and safety of inhaled corticosteroids. Theophylline has serious adverse effects (cardiac arrhythmia, convulsions) if therapeutic blood concentrations are exceeded.
When low-dose inhaled corticosteroids fail to control asthma, most older children will respond to one of the add-on options available, which include addition of long-acting beta2 agonists, addition of leukotriene receptor antagonists, addition of theophylline, or increased dose of inhaled corticosteroid. However, we don't know for certain how effective these additional treatments are because we found no/limited RCT evidence of benefit compared with adding placebo/no additional treatments. Addition of long-acting beta2 agonists may reduce symptoms and improve physiological measures compared with increased dose of corticosteroids in older children. Long-acting beta2 agonists are not currently licensed for use in children under 5 years of age.Consensus suggests that younger children are likely to benefit from addition of leukotriene receptor antagonists. Although there is weak evidence that addition of theophylline to inhaled corticosteroids does improve symptom control and reduce exacerbations, theophylline should only be added to inhaled corticosteroids in children aged over 5 years when the addition of long-acting beta2 agonists and leukotriene receptor antagonists have both been unsuccessful.
Omalizumab may be indicated in the secondary care setting for older children (aged over 5 years) with poorly controlled allergic asthma despite use of intermediate- and high-dose inhaled corticosteroids once the diagnosis is confirmed and compliance and psychological issues are addressed. However, we need more data to draw firm conclusions.
PMCID: PMC3285219  PMID: 22305975
16.  Barriers to Provider-Initiated Testing and Counselling for Children in a High HIV Prevalence Setting: A Mixed Methods Study 
PLoS Medicine  2014;11(5):e1001649.
Rashida Ferrand and colleagues combine quantitative and qualitative methods to investigate HIV prevalence among older children receiving primary care in Harare, Zimbabwe, and reasons why providers did not pursue testing.
Please see later in the article for the Editors' Summary
Background
There is a substantial burden of HIV infection among older children in sub-Saharan Africa, the majority of whom are diagnosed after presentation with advanced disease. We investigated the provision and uptake of provider-initiated HIV testing and counselling (PITC) among children in primary health care facilities, and explored health care worker (HCW) perspectives on providing HIV testing to children.
Methods and Findings
Children aged 6 to 15 y attending six primary care clinics in Harare, Zimbabwe, were offered PITC, with guardian consent and child assent. The reasons why testing did not occur in eligible children were recorded, and factors associated with HCWs offering and children/guardians refusing HIV testing were investigated using multivariable logistic regression. Semi-structured interviews were conducted with clinic nurses and counsellors to explore these factors. Among 2,831 eligible children, 2,151 (76%) were offered PITC, of whom 1,534 (54.2%) consented to HIV testing. The main reasons HCWs gave for not offering PITC were the perceived unsuitability of the accompanying guardian to provide consent for HIV testing on behalf of the child and lack of availability of staff or HIV testing kits. Children who were asymptomatic, older, or attending with a male or a younger guardian had significantly lower odds of being offered HIV testing. Male guardians were less likely to consent to their child being tested. 82 (5.3%) children tested HIV-positive, with 95% linking to care. Of the 940 guardians who tested with the child, 186 (19.8%) were HIV-positive.
Conclusions
The HIV prevalence among children tested was high, highlighting the need for PITC. For PITC to be successfully implemented, clear legislation about consent and guardianship needs to be developed, and structural issues addressed. HCWs require training on counselling children and guardians, particularly male guardians, who are less likely to engage with health care services. Increased awareness of the risk of HIV infection in asymptomatic older children is needed.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Over 3 million children globally are estimated to be living with HIV (the virus that causes AIDS). While HIV infection is most commonly spread through unprotected sex with an infected person, most HIV infections among children are the result of mother-to-child HIV transmission during pregnancy, delivery, or breastfeeding. Mother-to-child transmission can be prevented by administering antiretroviral therapy to mothers with HIV during pregnancy, delivery, and breast feeding, and to their newborn babies. According to a report by the Joint United Nations Programme on HIV/AIDS published in 2012, 92% of pregnant women with HIV were living in sub-Saharan Africa and just under 60% were receiving antiretroviral therapy. Consequently, sub-Saharan Africa is the region where most children infected with HIV live.
Why Was This Study Done?
If an opportunity to prevent mother-to-child transmission around the time of birth is missed, diagnosis of HIV infection in a child or adolescent is likely to depend on HIV testing in health care facilities. Health care provider–initiated HIV testing and counselling (PITC) for children is important in areas where HIV infection is common because earlier diagnosis allows children to benefit from care that can prevent the development of advanced HIV disease. Even if a child or adolescent appears to be in good health, access to care and antiretroviral therapy provides a health benefit to the individual over the long term. The administration of HIV testing (and counselling) to children relies not only on health care workers (HCWs) offering HIV testing but also on parents or guardians consenting for a child to be tested. However, more than 30% of children in countries with severe HIV epidemics are AIDS orphans, and economic conditions in these countries cause many adults to migrate for work, leaving children under the care of extended families. This study aimed to investigate the reasons for acceptance and rejection of PITC in primary health care settings in Harare, Zimbabwe. By exploring HCW perspectives on providing HIV testing to children and adolescents, the study also sought to gain insight into factors that could be hindering implementation of testing procedures.
What Did the Researchers Do and Find?
The researchers identified all children aged 6 to 15 years old at six primary care clinics in Harare, who were offered HIV testing as part of routine care between 22 January and 31 May 2013. Study fieldworkers collected data on numbers of child attendances, numbers offered testing, numbers who underwent HIV testing, and reasons why HIV testing did not occur. During the study 2,831 children attending the health clinics were eligible for PITC, and just over half (1,534, 54.2%) underwent HIV testing. Eighty-two children tested HIV-positive, and nearly all of them received counselling, medication, and follow-up care. HCWs offered the test to around 75% of those eligible. The most frequent explanation given by HCWs for a diagnostic test not being offered was that the child was accompanied by a guardian not appropriate for providing consent (401 occasions, 59%); Other reasons given were a lack of available counsellors or test kits and counsellors refusing to conduct the test. The likelihood of being offered the test was lower for children not exhibiting symptoms (such as persistent skin problems), older children, or those attending with a male or a younger guardian. In addition, over 100 guardians or parents provided consent but left before the child could be tested.
The researchers also conducted semi-structured interviews with 12 clinic nurses and counsellors (two from each clinic) to explore challenges to implementation of PITC. The researchers recorded the factors associated with testing not taking place, either when offered to eligible children or when HCWs declined to offer the test. The interviewees identified the frequent absence or unavailability of parents or legal guardians as an obstacle, and showed uncertainty or misconceptions around whether testing of the guardian was mandatory (versus recommended) and whether specifically a parent (if one was living) must provide consent. The interviews also revealed HCW concerns about the availability of adequate counselling and child services, and fears that a child might experience maltreatment if he or she tested positive. HCWs also noted long waiting times and test kits being out of stock as practical hindrances to testing.
What Do These Findings Mean?
Prevalence of HIV was high among the children tested, validating the need for PITC in sub-Saharan health care settings. Although 76% of eligible attendees were offered testing, the authors note that this is likely higher than in routine settings because the researchers were actively recording reasons for not offering testing and counselling, which may have encouraged heath care staff to offer PITC more often than usual. The researchers outline strategies that may improve PITC rates and testing acceptance for Zimbabwe and other sub-Saharan settings. These strategies include developing clear laws and guidance concerning guardianship and proxy consent when testing older children for HIV, training HCWs around these policies, strengthening legislation to address discrimination, and increasing public awareness about HIV infection in older children.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001649.
This study is further discussed in a PLOS Medicine Perspective by Davies and Kalk
The Joint United Nations Programme on HIV/AIDS publishes an annual report on the global AIDS epidemic, which provides information on progress towards eliminating new HIV infections
The World Health Organization has more information on mother-to-child transmission of HIV
The World Health Organization's website also has information about treatment for children living with HIV
Personal stories about living with HIV/AIDS, including stories from young people infected with HIV, are available through Avert, through NAM/aidsmap, and through the charity website Healthtalkonline
doi:10.1371/journal.pmed.1001649
PMCID: PMC4035250  PMID: 24866209
17.  Removing the Age Restrictions for Rotavirus Vaccination: A Benefit-Risk Modeling Analysis 
PLoS Medicine  2012;9(10):e1001330.
A modeling analysis conducted by Manish Patel and colleagues predicts the possible number of rotavirus deaths prevented, and number of intussusception deaths caused, by use of an unrestricted rotavirus schedule in low- and middle-income countries.
Background
To minimize potential risk of intussusception, the World Health Organization (WHO) recommended in 2009 that rotavirus immunization should be initiated by age 15 weeks and completed before 32 weeks. These restrictions could adversely impact vaccination coverage and thereby its health impact, particularly in developing countries where delays in vaccination often occur.
Methods and Findings
We conducted a modeling study to estimate the number of rotavirus deaths prevented and the number of intussusception deaths caused by vaccination when administered on the restricted schedule versus an unrestricted schedule whereby rotavirus vaccine would be administered with DTP vaccine up to age 3 years. Countries were grouped on the basis of child mortality rates, using WHO data. Inputs were estimates of WHO rotavirus mortality by week of age from a recent study, intussusception mortality based on a literature review, predicted vaccination rates by week of age from USAID Demographic and Health Surveys, the United Nations Children's Fund (UNICEF) Multiple Indicator Cluster Surveys (MICS), and WHO-UNICEF 2010 country-specific coverage estimates, and published estimates of vaccine efficacy and vaccine-associated intussusception risk. On the basis of the error estimates and distributions for model inputs, we conducted 2,000 simulations to obtain median estimates of deaths averted and caused as well as the uncertainty ranges, defined as the 5th–95th percentile, to provide an indication of the uncertainty in the estimates.
We estimated that in low and low-middle income countries a restricted schedule would prevent 155,800 rotavirus deaths (5th–95th centiles, 83,300–217,700) while causing potentially 253 intussusception deaths (76–689). In contrast, vaccination without age restrictions would prevent 203,000 rotavirus deaths (102,000–281,500) while potentially causing 547 intussusception deaths (237–1,160). Thus, removing the age restrictions would avert an additional 47,200 rotavirus deaths (18,700–63,700) and cause an additional 294 (161–471) intussusception deaths, for an incremental benefit-risk ratio of 154 deaths averted for every death caused by vaccine. These extra deaths prevented under an unrestricted schedule reflect vaccination of an additional 21%–25% children, beyond the 63%–73% of the children who would be vaccinated under the restricted schedule. Importantly, these estimates err on the side of safety in that they assume high vaccine-associated risk of intussusception and do not account for potential herd immunity or non-fatal outcomes.
Conclusions
Our analysis suggests that in low- and middle-income countries the additional lives saved by removing age restrictions for rotavirus vaccination would far outnumber the potential excess vaccine-associated intussusception deaths.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Rotavirus causes severe diarrhea and vomiting. It is responsible for a large number of hospitalizations among young children in developed countries (an estimated 60,000 hospitalizations per year in the US in 2005, for example). In poor countries, rotavirus is a major cause of death in children under five. In 1998, the first rotavirus vaccine, called RotaShield, was approved in the US by the Food and Drug Administration. Shortly after the vaccine became widely used, doctors noticed a small increase in a problem called intussusception among the vaccinated infants. Intussusception is a rare type of bowel obstruction that occurs when the bowel telescopes in on itself. Prompt treatment of intussusception normally leads to full recovery, but some children with the condition need surgery, and when the disease is left untreated it can be fatal. Because intussusception is a serious condition and because very few children die from rotavirus infection in the United States, the US authorities stopped recommending vaccination with RotaShield in 1999. The manufacturer withdrew the vaccine from the market shortly thereafter.
Since then, two new vaccines (named Rotarix and RotaTeq) have been developed. Before they were approved in the US and elsewhere, they were extensively tested for any adverse side effects, especially intussusception. No increase in the risk for intussusception was found in these studies, and both are now approved and recommended for vaccination of infants around the world.
Why Was This Study Done?
Since 2006, hundreds of thousands of infants have been vaccinated with Rotarix or RotaTeq, with safety being closely monitored. Some countries have reported a small increase in intussusception (one to four additional cases per 100,000 vaccinated infants, compared with one per 2,000 of cases that occur in unvaccinated children). This increase is much lower than the one seen previously with RotaShield. In response to these findings, authorities in the US and other developed countries as well as the World Health Organization declared that the benefits of the vaccine outweigh the risks of the small number of additional intussusception cases in both developed and poor countries. However, because older infants have a higher risk of naturally occurring intussusception, they decided that the course of vaccination (three oral doses for Rotarix and two for RotaTeq) should be initiated before 15 weeks of age and completed before the age of 32 weeks. This is usually not a problem in countries with easy access to health facilities. However, in many poor countries where delays in infant vaccination are common, giving the vaccine only to very young children means that many others who could benefit from its protection will be excluded. In this study, the researchers examined the risks and benefits of rotavirus vaccination in poor countries where most of the rotavirus deaths occur. Specifically, they looked at the benefits and risks if the age restrictions were removed, with a particular emphasis on allowing infants to initiate rotavirus immunization even if they arrive after 15 weeks of age.
What Did the Researchers Do and Find?
The researchers used the most recent estimates for how well the vaccines protect children in Africa and Asia from becoming infected with rotavirus, how many deaths from rotavirus infection can be avoided by vaccination, how many additional cases of intussusception will likely occur in vaccinated children, and what proportion of children would be excluded from rotavirus vaccination because they are too old when they come to a health facility for their infant vaccination. They then estimated the number of rotavirus deaths prevented and the number of intussusception deaths caused by vaccination in two scenarios. The first one (the restricted scenario) corresponds to previous guidelines from WHO and others, in which rotavirus vaccination needs to be initiated before 15 weeks and the full series completed before 32 weeks. The second one (called the unrestricted scenario) allows rotavirus vaccination of children alongside current routinely administered vaccines up to three years of age, recognizing that most children receive their vaccination by 1 year of life.
The researchers estimated that removing the age restriction would prevent an additional 154 rotavirus deaths for each intussusception death caused by the vaccine. Under the unrestricted scenario, roughly a third more children would get vaccinated, which would prevent an additional approximately 47,000 death from rotavirus while causing approximately 300 additional intussusception deaths.
They also calculated some best- and worst-case scenarios. The worst-case scenario assumed a much higher risk of intussusception for children receiving their first dose after 15 weeks of life than what has been seen anywhere, and also that an additional 20% of children with intussusception would die from it than what was already assumed in their routine scenario (again, a higher number than seen in reality). In addition, it assumes a lower protection from rotavirus death for the vaccine than has been observed in children vaccinated so far. In this pessimistic case, the number of rotavirus deaths prevented was 24 for each intussusception death caused by the vaccine.
What Do These Findings Mean?
If one accepts that deaths caused by a vaccine are not fundamentally different from deaths caused by a failure to vaccinate, then these results show that the benefits of lifting the age restriction for rotavirus vaccine clearly outweigh the risks, at least when only examining mortality outcomes. The calculations are valid only for low-income countries in Africa and Asia where both vaccination delays and deaths from rotavirus are common. The risk-benefit ratio will be different elsewhere. There are also additional risks and benefits that are not included in the study's estimates. For example, early vaccination might be seen as less of an urgent priority when this vaccine can be had at a later date, leaving very young children more vulnerable. On the other hand, when many children in the community are vaccinated, even the unvaccinated children are less likely to get infected (what is known as “herd immunity”), something that has not been taken into account in the benefits here. The results of this study (and its limitations) were reviewed in April 2012 by WHO's Strategic Advisory Group of Experts. The group then recommended that, while early vaccination is still strongly encouraged, the age restriction on rotavirus vaccination should be removed in countries where delays in vaccination and rotavirus mortality are common so that more vulnerable children can be vaccinated and deaths from rotavirus averted.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001330.
The World Health Organization provides information on rotavirus
Wikipedia has information on rotavirus vaccine and intussusception (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The US Centers for Disease Control and Prevention rotavirus vaccination page includes a link to frequently asked questions
PATH Rotavirus Vaccine Access and Delivery has timely, useful updates on status of rotavirus vaccines globally
doi:10.1371/journal.pmed.1001330
PMCID: PMC3479108  PMID: 23109915
18.  Description of 3,180 Courses of Chelation with Dimercaptosuccinic Acid in Children ≤5 y with Severe Lead Poisoning in Zamfara, Northern Nigeria: A Retrospective Analysis of Programme Data 
PLoS Medicine  2014;11(10):e1001739.
Jane Greig and colleagues from the medical humanitarian organization Médecins Sans Frontières describe the use of the oral chelating agent dimercaptosuccinic acid (DMSA) in several thousand young children with severe lead poisoning as a result of an environmental disaster in Zamfara, northern Nigeria.
Please see later in the article for the Editors' Summary
Background
In 2010, Médecins Sans Frontières (MSF) discovered extensive lead poisoning impacting several thousand children in rural northern Nigeria. An estimated 400 fatalities had occurred over 3 mo. The US Centers for Disease Control and Prevention (CDC) confirmed widespread contamination from lead-rich ore being processed for gold, and environmental management was begun. MSF commenced a medical management programme that included treatment with the oral chelating agent 2,3-dimercaptosuccinic acid (DMSA, succimer). Here we describe and evaluate the changes in venous blood lead level (VBLL) associated with DMSA treatment in the largest cohort of children ≤5 y of age with severe paediatric lead intoxication reported to date to our knowledge.
Methods and Findings
In a retrospective analysis of programme data, we describe change in VBLL after DMSA treatment courses in a cohort of 1,156 children ≤5 y of age who underwent between one and 15 courses of chelation treatment. Courses of DMSA of 19 or 28 d duration administered to children with VBLL ≥ 45 µg/dl were included. Impact of DMSA was calculated as end-course VBLL as a percentage of pre-course VBLL (ECP). Mixed model regression with nested random effects was used to evaluate the relative associations of covariates with ECP. Of 3,180 treatment courses administered, 36% and 6% of courses commenced with VBLL ≥ 80 µg/dl and ≥ 120 µg/dl, respectively. Overall mean ECP was 74.5% (95% CI 69.7%–79.7%); among 159 inpatient courses, ECP was 47.7% (95% CI 39.7%–57.3%). ECP after 19-d courses (n = 2,262) was lower in older children, first-ever courses, courses with a longer interval since a previous course, courses with more directly observed doses, and courses with higher pre-course VBLLs. Low haemoglobin was associated with higher ECP. Twenty children aged ≤5 y who commenced chelation died during the period studied, with lead poisoning a primary factor in six deaths. Monitoring of alanine transaminase (ALT), creatinine, and full blood count revealed moderate ALT elevation in <2.5% of courses. No clinically severe adverse drug effects were observed, and no laboratory findings required discontinuation of treatment. Limitations include that this was a retrospective analysis of clinical data, and unmeasured variables related to environmental exposures could not be accounted for.
Conclusions
Oral DMSA was a pharmacodynamically effective chelating agent for the treatment of severe childhood lead poisoning in a resource-limited setting. Re-exposure to lead, despite efforts to remediate the environment, and non-adherence may have influenced the impact of outpatient treatment.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Lead, a toxic metal that occurs naturally in the earth's crust, is now present throughout the environment because of human activities. For many years, lead was added to paint and gasoline and used in solder for water pipes. In addition, the mining, smelting, and refining of some metallic ores releases lead into the environment. Inhalation of contaminated air, consumption of contaminated food and water, and contact with dust that contains lead raises venous blood lead levels (VBLLs) and causes many health problems, particularly in children. Children who ingest large amounts of lead can develop anemia, muscle weakness, kidney damage, and life-threatening encephalopathy (brain swelling). Although fatal lead poisoning is now rare in resource-rich countries, it nevertheless remains a major global health problem. Over a three-month period in early 2010, for example, about 400 young children died in Zamfara State, Nigeria, from unexplained, intractable fits. By May 2010, it was clear that recently expanded gold mining had caused widespread environmental lead contamination in the region, and an environmental management program was begun to reduce lead levels in the surface soils.
Why Was This Study Done?
In response to the lead poisoning outbreak, the not-for-profit organization Médecins Sans Frontières (MSF) began a medical management program to reduce VBLLs that included treatment with the oral chelation agent dimercaptosuccinic acid (DMSA). Chelation agents bind metal ions and facilitate their removal from the body, thereby reducing the likelihood of lead moving from the blood to the brain. Lead encephalopathy has been commonly treated by injecting another chelator called CaNa2EDTA, but the discovery of more than 1,000 cases of childhood lead poisoning in rural villages in Nigeria meant that MSF needed a chelation approach that could be applied rapidly in a remote resource-limited setting. Additionally, although CaNa2EDTA has been in common use for severe lead poisoning for longer than DMSA, and is commonly recommended in guidelines, the evidence base does not support one treatment as superior. Here, in a retrospective analysis of MSF program data, the researchers evaluate the changes in VBLLs before and after courses of oral DMSA treatment in children aged five years and below living in Zamfara to gain new insights into this understudied treatment for severe childhood lead poisoning.
What Did the Researchers Do and Find?
The researchers measured VBLLs before and after treatment with DMSA in 1,156 children (inpatient and outpatient) with high amounts of lead in their blood who underwent one or more courses of chelation treatment lasting 19 or 28 days by calculating each child's end-course VBLL as a percentage of the child's pre-course VBLL (ECP). Considering all the treatment courses given between June 2010 and June 2011, the mean (average) ECP was 74.5%. That is, on average, VBLLs measured at the end of treatment courses were reduced by a quarter compared to VBLLs at the start of treatment courses. Among 159 inpatient courses of DMSA, the ECP was 47.7% (a halving of pre-course VBLLs). The ECP after 19-day courses was lower in older children, after first-ever courses, after courses with a longer interval since a previous course, after courses that included more directly observed doses (DMSA given in the presence of a health-care worker), and in children with higher pre-course VBLLs. Nine of the children included in this analysis died during the study period; lead poisoning was probably involved in three of these deaths. Importantly, no clinically severe adverse effects related to DMSA were seen during the study period, and no laboratory findings were recorded that required treatment discontinuation.
What Do These Findings Mean?
Because many changes were made to the treatment given to the affected children in Zamfara during the study period and because no information is presented here on clinical outcomes, these findings cannot be used to reach any definitive conclusions about the effectiveness or safety of oral DMSA as a treatment for lead poisoning in young children. However, these findings show that chelation was associated with a large reduction in the death rate among probable or suspected cases of childhood lead poisoning in Zamfara and provide new information about oral chelation that may help agencies such as MSF provide urgent treatment for lead poisoning in resource-limited settings where intravenous chelation is not feasible. Moreover, the finding of a lower ECP after inpatient treatment courses compared to after outpatient courses suggests that re-exposure to lead and non-adherence to treatment may have influenced the impact of outpatient treatments. Thus, it is essential that medical management of lead poisoning in resource-limited settings be accompanied by environmental remediation and that efforts are made to support adherence to treatment in the community by implementing directly observed treatment wherever possible.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001739.
A related PLOS ONE Research Article by Greig et al. provides information about the association between VBLLs and neurological features in children affected by the acute lead poisoning outbreak in Zamfara
MSF provides information about the lead poisoning crisis in Zamfara State
Human Rights Watch, an international organization that works to uphold human dignity and advance the cause of human rights for all, also provides information about lead poisoning in Zamfara State, including photographs and a video
Tox Town, an interactive site about environmental health concerns from the US National Library of Medicine, provides information on exposure to lead (in English and Spanish)
The US Environmental Protection Agency provides information on lead and lead poisoning (in English and Spanish)
The US Centers for Disease Control and Prevention provides information about lead in the environment and about its lead poisoning prevention program
MedlinePlus provides a list of links to further information about lead poisoning (in English and Spanish)
doi:10.1371/journal.pmed.1001739
PMCID: PMC4188566  PMID: 25291378
19.  Children’s Medicines in Tanzania: A National Survey of Administration Practices and Preferences 
PLoS ONE  2013;8(3):e58303.
Objective
The dearth of age-appropriate formulations of many medicines for children poses a major challenge to pediatric therapeutic practice, adherence, and health care delivery worldwide. We provide information on current administration practices of pediatric medicines and describe key stakeholder preferences for new formulation characteristics.
Patients and Methods
We surveyed children aged 6–12 years, parents/caregivers over age 18 with children under age 12, and healthcare workers in 10 regions of Tanzania to determine current pediatric medicine prescription and administration practices as well as preferences for new formulations. Analyses were stratified by setting, pediatric age group, parent/caregiver education, and healthcare worker cadre.
Results
Complete data were available for 206 children, 202 parents/caregivers, and 202 healthcare workers. Swallowing oral solid dosage forms whole or crushing/dissolving them and mixing with water were the two most frequently reported methods of administration. Children frequently reported disliking medication taste, and many had vomited doses. Healthcare workers reported medicine availability most significantly influences prescribing practices. Most parents/caregivers and children prefer sweet-tasting medicine. Parents/caregivers and healthcare workers prefer oral liquid dosage forms for young children, and had similar thresholds for the maximum number of oral solid dosage forms children at different ages can take.
Conclusions
There are many impediments to acceptable and accurate administration of medicines to children. Current practices are associated with poor tolerability and the potential for under- or over-dosing. Children, parents/caregivers, and healthcare workers in Tanzania have clear preferences for tastes and formulations, which should inform the development, manufacturing, and marketing of pediatric medications for resource-limited settings.
doi:10.1371/journal.pone.0058303
PMCID: PMC3590153  PMID: 23484012
20.  Measuring Under-Five Mortality: Validation of New Low-Cost Methods 
PLoS Medicine  2010;7(4):e1000253.
n/a
Background
There has been increasing interest in measuring under-five mortality as a health indicator and as a critical measure of human development. In countries with complete vital registration systems that capture all births and deaths, under-five mortality can be directly calculated. In the absence of a complete vital registration system, however, child mortality must be estimated using surveys that ask women to report the births and deaths of their children. Two survey methods exist for capturing this information: summary birth histories and complete birth histories. A summary birth history requires a minimum of only two questions: how many live births has each mother had and how many of them have survived. Indirect methods are then applied using the information from these two questions and the age of the mother to estimate under-five mortality going back in time prior to the survey. Estimates generated from complete birth histories are viewed as the most accurate when surveys are required to estimate under-five mortality, especially for the most recent time periods. However, it is much more costly and labor intensive to collect these detailed data, especially for the purpose of generating small area estimates. As a result, there is a demand for improvement of the methods employing summary birth history data to produce more accurate as well as subnational estimates of child mortality.
Methods and Findings
We used data from 166 Demographic and Health Surveys (DHS) to develop new empirically based methods of estimating under-five mortality using children ever born and children dead data. We then validated them using both in- and out-of-sample analyses. We developed a range of methods on the basis of three dimensions of the problem: (1) approximating the average length of exposure to mortality from a mother's set of children using either maternal age or time since first birth; (2) using cohort and period measures of the fraction of children ever born that are dead; and (3) capturing country and regional variation in the age pattern of fertility and mortality. We focused on improving estimates in the most recent time periods prior to a survey where the traditional indirect methods fail. In addition, all of our methods incorporated uncertainty. Validated against under-five estimates generated from complete birth histories, our methods outperformed the standard indirect method by an average of 43.7% (95% confidence interval [CI] 41.2–45.2). In the 5 y prior to the survey, the new methods resulted in a 53.3% (95% CI 51.3–55.2) improvement. To illustrate the value of this method for local area estimation, we applied our new methods to an analysis of summary birth histories in the 1990, 2000, and 2005 Mexican censuses, generating subnational estimates of under-five mortality for each of 233 jurisdictions.
Conclusions
The new methods significantly improve the estimation of under-five mortality using summary birth history data. In areas without vital registration data, summary birth histories can provide accurate estimates of child mortality. Because only two questions are required of a female respondent to generate these data, they can easily be included in existing survey programs as well as routine censuses of the population. With the wider application of these methods to census data, countries now have the means to generate estimates for subnational areas and population subgroups, important for measuring and addressing health inequalities and developing local policy to improve child survival.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, more than 8 million children die before their fifth birthdays. Most of these deaths occur in developing countries, and most are the result of diseases or combinations of diseases that could have been prevented or treated. Measles, for example, is a major killer in low-income countries and undernutrition contributes to one-third of childhood deaths. Faced with this largely avoidable loss of young lives, in 1990, the United Nations' World Summit for Children pledged to improve the survival of children. Later, in 2000, world leaders set a target of reducing child mortality to one-third of its 1990 level by 2015 as Millennium Development Goal 4. This goal, together with seven others, is designed to alleviate extreme poverty by 2015. In 2006, for the first time since mortality records began, annual deaths among children under five fell below 10 million as a result of public-health programs such as the Measles Initiative, which has reduced global measles mortality by more than two-thirds by vaccinating 500 million children, and the Nothing but Nets campaign, which distributed insecticide-treated antimalaria nets in Africa.
Why Was This Study Done?
Although global under-five mortality is declining, it is unlikely that Millennium Development Goal 4 will be reached by 2015. Indeed, in some countries, little or no progress is being made toward this goal. To improve progress and to monitor the effects of public-health interventions, accurate, up-to-date estimates of national and subnational child mortality rates are essential. In developed countries, vital registration systems—records of all births and deaths—mean that under-five mortality rates can be directly calculated. But many developing countries lack vital registration systems, and child mortality has to be estimated using data collected in surveys. In “complete birth history” surveys, mothers are asked numerous questions about each living child and each dead child. Such surveys can be used to estimate under-five mortality accurately for recent time periods but they are expensive and time-consuming. By contrast, in “summary birth history” surveys, each mother is simply asked how many live births she had and how many of her children have survived. Under-five mortality can be indirectly calculated from this information and the age of the mother, but the current methods for making this calculation cannot provide reliable estimates of under-five mortality more recently than 3 years before the survey. In this study, therefore, the researchers develop methods for estimating more recent under-five mortality rates from summary birth histories.
What Did the Researchers Do and Find?
The researchers used data about all children born and dead children extracted from 169 Demographic and Health Surveys (DHS; a project started in 1984 to help developing countries collect data on health and population trends) covering 70 countries to develop four new methods to estimate under-five mortality. They tested these new methods and a method that combined all four approaches by comparing the estimates of under-five mortality provided by these methods and the standard indirect method to the estimates obtained from an analysis of the complete birth data in the DHS. The new methods all outperformed the standard indirect method, particularly for the most recent 5 years. The researchers also used their new methods to generate estimates of under-five mortality for each of the 233 jurisdictions in Mexico from summary birth histories collected in the 1990, 2000, and 2005 Mexico censuses. The overall trends of these subnational estimates, they report, mirrored those obtained from vital registration data.
What Do These Findings Mean?
These findings suggest that application of the new methods developed by the researchers could significantly improve the accuracy of estimates of under-five mortality based on summary birth history data. The researchers warn that although their methods can provide accurate estimates of recent under-five mortality, they might not capture rapid fluctuations in mortality such as those that occur during wars. However, they suggest, the two questions needed to generate the data required to apply these new methods could easily be included in existing survey programs and in routine censuses. Consequently, systematic application of the methods proposed in this study should provide policy makers with the information about levels, recent trends, and inequalities in child mortality that they need to accelerate efforts to reduce the global toll of childhood deaths.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000253.
This study and two related PLoS Medicine Research Articles by Obermeyer et al and by Murray et al are further discussed in a PLoS Medicine Perspective by Mathers and Boerma
The United Nations Childrens Fund (UNICEF) works for children's rights, survival, development and protection around the world; it provides information on Millennium Development Goal 4 and its Childinfo website provides detailed statistics about child survival and health (some information in several languages)
Further information about the Millennium Development Goals is available
The World Health Organization also has information about Millennium Development Goal 4 and provides estimates of child mortality rates
Information is also available about the Demographic and Health Surveys
doi:10.1371/journal.pmed.1000253
PMCID: PMC2854123  PMID: 20405055
21.  Advanced Paternal Age Is Associated with Impaired Neurocognitive Outcomes during Infancy and Childhood 
PLoS Medicine  2009;6(3):e1000040.
Background
Advanced paternal age (APA) is associated with an increased risk of neurodevelopmental disorders such as autism and schizophrenia, as well as with dyslexia and reduced intelligence. The aim of this study was to examine the relationship between paternal age and performance on neurocognitive measures during infancy and childhood.
Methods and Findings
A sample of singleton children (n = 33,437) was drawn from the US Collaborative Perinatal Project. The outcome measures were assessed at 8 mo, 4 y, and 7 y (Bayley scales, Stanford Binet Intelligence Scale, Graham-Ernhart Block Sort Test, Wechsler Intelligence Scale for Children, Wide Range Achievement Test). The main analyses examined the relationship between neurocognitive measures and paternal or maternal age when adjusted for potential confounding factors. Advanced paternal age showed significant associations with poorer scores on all of the neurocognitive measures apart from the Bayley Motor score. The findings were broadly consistent in direction and effect size at all three ages. In contrast, advanced maternal age was generally associated with better scores on these same measures.
Conclusions
The offspring of older fathers show subtle impairments on tests of neurocognitive ability during infancy and childhood. In light of secular trends related to delayed fatherhood, the clinical implications and the mechanisms underlying these findings warrant closer scrutiny.
Using a sample of children from the US Collaborative Perinatal Project, John McGrath and colleagues show that the offspring of older fathers exhibit subtle impairments on tests of neurocognitive ability during infancy and childhood.
Editors' Summary
Background.
Over the last few decades, changes in society in the developed world have made it increasingly common for couples to wait until their late thirties to have children. In 1993, 25% of live births within marriage in England and Wales were to fathers aged 35–54 years, but by 2003 it was 40%. It is well known that women's fertility declines with age and that older mothers are more likely to have children with disabilities such as Down's syndrome. In contrast, many men can father children throughout their lives, and little attention has been paid to the effects of older fatherhood.
More recent evidence shows that a man's age does affect both fertility and the child's health. “Advanced paternal age” has been linked to miscarriages, birth deformities, cancer, and specific behavioral problems such as autism or schizophrenia.
Rates of autism have increased in recent decades, but the cause is unknown. Studies of twins and families have suggested there may be a complex genetic basis, and it is suspected that damage to sperm, which can accumulate over a man's lifetime, may be responsible. A woman's eggs are formed largely while she is herself in the womb, but sperm-making cells divide throughout a man's lifetime, increasing the chance of mutations in sperm.
Why Was This Study Done?
There is good evidence linking specific disorders with older fathers, but the link between a father's age and a child's more general intelligence is not as clear. A recent study suggested a link between reduced intelligence and both very young and older fathers. The authors wanted to use this large dataset to test the idea that older fathers have children who do worse on tests of intelligence. They also wanted to re-examine others' findings using this same dataset that older mothers have more intelligent children.
What Did the Researchers Do and Find?
The researchers gathered no new data but reanalyzed data on children from the US Collaborative Perinatal Project (CPP), which had used a variety of tests given to children at ages 8 months, 4 years, and 7 years, to measure cognitive ability—the ability to think and reason, including concentration, memory, learning, understanding, speaking, and reading. Some tests included assessments of “motor skills”—physical co-ordination.
The CPP dataset holds information on children of 55,908 expectant mothers who attended 12 university-affiliated hospital clinics in the United States from 1959 to 1965. The researchers excluded premature babies and multiple births and chose one pregnancy at random for each eligible woman, to keep their analysis simpler. This approach reduced the number of children in their analysis to 33,437.
The researchers analyzed the data using two models. In one, they took into account physical factors such as the parents' ages. In the other, they also took into account social factors such as the parents' level of education and income, which are linked to intelligence. In addition, the authors grouped the children by their mother's age and, within each group, looked for a link between the lowest-scoring children and the age of their father.
The researchers found that children with older fathers had lower scores on all of the measures except one measure of motor skills. In contrast, children with older mothers had higher scores. They found that the older the father, the more likely was this result found.
What Do These Findings Mean?
This study is the first to show that children of older fathers perform less well in a range of tests when young, but cannot say whether those children catch up with their peers after the age of 7 years. Results may also be biased because information was more likely to be missing for children whose father's age was not recorded.
Previous researchers had proposed that children of older mothers may perform better in tests because they experience a more nurturing home environment. If this is the case, children of older fathers do not experience the same benefit.
However, further work needs to be done to confirm these findings. Especially in newer datasets, current trends to delay parenthood mean these findings have implications for individuals, couples, and policymakers. Individuals and couples need to be aware that the ages of both partners can affect their ability to have healthy children, though the risks for individual children are small. Policymakers should consider promoting awareness of the risks of delaying parenthood or introducing policies to encourage childbearing at an optimal age.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000040.
Mothers 35+ is a UK Web site with resources and information for older mothers, mothers-to-be, and would-be mothers, including information on the health implications of fathering a child late in life
The American Society for Reproductive Medicine published a Patient Information Booklet on Age and Fertility in 2003, which is available online; it contains a small section called “Fertility in the Aging Male,” but otherwise focuses on women
The online encyclopedia Wikipedia has a short article on the “Paternal age effect” (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
In 2005, the UK Office of National Statistics published a booklet entitled “Perpetual postponers? Women's, men's and couple's fertility intentions and subsequent fertility behaviour” looking at data from the British Household Panel Survey
doi:10.1371/journal.pmed.1000040
PMCID: PMC2653549  PMID: 19278291
22.  Artemether-Lumefantrine versus Dihydroartemisinin-Piperaquine for Treatment of Malaria: A Randomized Trial 
PLoS Clinical Trials  2007;2(5):e20.
Objectives:
To compare the efficacy and safety of artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP) for treating uncomplicated falciparum malaria in Uganda.
Design:
Randomized single-blinded clinical trial.
Setting:
Apac, Uganda, an area of very high malaria transmission intensity.
Participants:
Children aged 6 mo to 10 y with uncomplicated falciparum malaria.
Intervention:
Treatment of malaria with AL or DP, each following standard 3-d dosing regimens.
Outcome measures:
Risks of recurrent parasitemia at 28 and 42 d, unadjusted and adjusted by genotyping to distinguish recrudescences and new infections.
Results:
Of 421 enrolled participants, 417 (99%) completed follow-up. The unadjusted risk of recurrent falciparum parasitemia was significantly lower for participants treated with DP than for those treated with AL after 28 d (11% versus 29%; risk difference [RD] 18%, 95% confidence interval [CI] 11%–26%) and 42 d (43% versus 53%; RD 9.6%, 95% CI 0%–19%) of follow-up. Similarly, the risk of recurrent parasitemia due to possible recrudescence (adjusted by genotyping) was significantly lower for participants treated with DP than for those treated with AL after 28 d (1.9% versus 8.9%; RD 7.0%, 95% CI 2.5%–12%) and 42 d (6.9% versus 16%; RD 9.5%, 95% CI 2.8%–16%). Patients treated with DP had a lower risk of recurrent parasitemia due to non-falciparum species, development of gametocytemia, and higher mean increase in hemoglobin compared to patients treated with AL. Both drugs were well tolerated; serious adverse events were uncommon and unrelated to study drugs.
Conclusion:
DP was superior to AL for reducing the risk of recurrent parasitemia and gametocytemia, and provided improved hemoglobin recovery. DP thus appears to be a good alternative to AL as first-line treatment of uncomplicated malaria in Uganda. To maximize the benefit of artemisinin-based combination therapy in Africa, treatment should be integrated with aggressive strategies to reduce malaria transmission intensity.
Editorial Commentary
Background: The burden of death and disease caused by malaria is very high, particularly amongst young children in sub-Saharan Africa. Many African countries have adopted combinations of drugs for first-line malaria treatment that include a compound based on the plant-derived molecule artemisinin. In Uganda, the artemisinin-based compound therapy (ACT) adopted as first-line therapy is artemether-lumefantrine (AL). However, there are limitations to the use of this drug; dosing is not convenient and it needs to be given with fatty food. There are also concerns that even though AL and other ACTs successfully treat the initial infection, there is a risk of malaria recurring soon after therapy, particularly in areas where mosquito attack rates are high. Therefore, the researchers here wanted to compare AL treatment with another ACT, dihydroartemisinin-piperaquine (DP), for treatment of uncomplicated malaria in children who live in an area of Uganda where malaria is transmitted at a very high rate.
What the trial shows: 421 children aged between six months and ten years arriving at a local health centre with uncomplicated malaria were recruited into the study. The children were randomly assigned to receive either AL tablets, given twice daily for 3 days, or DP tablets, given once daily for 3 days. The primary outcomes in the trial were the risks of clinical malaria recurring, and the risk of parasites reappearing in the blood but without any sign of clinical malaria, over 42 days of follow-up. The researchers also carried out tests to distinguish new malaria infections from a reappearance of the old infection.
Overall, children who received DP treatment were less likely to have malaria parasites reappear in their blood than children who received AL treatment. Similarly, the risk of a recurrence of clinical malaria was lower in the DP arm than in the AL arm; 39% of patients treated with AL went on to develop malaria symptoms by 42 days whilst only 25% of patients treated with DP did. These findings were similar if the researchers only looked at children in whom the same infection reappeared, as opposed to those who experienced a completely new infection. There did not seem to be any differences between the study groups in overall rates of adverse events, most of which were mild or moderate in nature. The serious adverse events that occurred in this trial were not thought to be related to the drugs being studied.
Strengths and limitations: This trial recruited enough participants to test whether there were any differences in efficacy between the two treatments studied, and randomization procedures and blinding of study physicians were appropriate. A further strength is the follow-up period of 42 days, in line with recent World Health Organization guidelines for such trials. This trial included children aged under 10 years, whereas children aged under 5 years are generally considered most at risk from malaria. However, the majority of children in this trial were in the under-5 age group, and the overall results were similar when only considering children in this age range. Finally, one possible limitation is that blinding of participants may not have been complete in this trial: children and parents were not informed of their treatment assignment, but the study drugs were different in appearance.
Contribution to the evidence: Studies from South-East Asia have indicated that DP has efficacy in treating malaria resistant to other drugs. However, little data exists regarding the efficacy and safety of DP in Africa. This trial adds important safety data for DP in African children, and also provides evidence that DP could be considered as an alternative treatment to AL, the current first-line therapy in many African countries.
doi:10.1371/journal.pctr.0020020
PMCID: PMC1876597  PMID: 17525792
23.  Effect of Supplementation with Zinc and Other Micronutrients on Malaria in Tanzanian Children: A Randomised Trial 
PLoS Medicine  2011;8(11):e1001125.
Hans Verhoef and colleagues report findings from a randomized trial conducted among Tanzanian children at high risk for malaria. Children in the trial received either daily oral supplementation with either zinc alone, multi-nutrients without zinc, multi-nutrients with zinc, or placebo. The investigators did not find evidence from this study that zinc or multi-nutrients protected against malaria episodes.
Background
It is uncertain to what extent oral supplementation with zinc can reduce episodes of malaria in endemic areas. Protection may depend on other nutrients. We measured the effect of supplementation with zinc and other nutrients on malaria rates.
Methods and Findings
In a 2×2 factorial trial, 612 rural Tanzanian children aged 6–60 months in an area with intense malaria transmission and with height-for-age z-score≤−1.5 SD were randomized to receive daily oral supplementation with either zinc alone (10 mg), multi-nutrients without zinc, multi-nutrients with zinc, or placebo. Intervention group was indicated by colour code, but neither participants, researchers, nor field staff knew who received what intervention. Those with Plasmodium infection at baseline were treated with artemether-lumefantrine. The primary outcome, an episode of malaria, was assessed among children reported sick at a primary care clinic, and pre-defined as current Plasmodium infection with an inflammatory response, shown by axillary temperature ≥37.5°C or whole blood C-reactive protein concentration ≥8 mg/L. Nutritional indicators were assessed at baseline and at 251 days (median; 95% reference range: 191–296 days). In the primary intention-to-treat analysis, we adjusted for pre-specified baseline factors, using Cox regression models that accounted for multiple episodes per child. 592 children completed the study. The primary analysis included 1,572 malaria episodes during 526 child-years of observation (median follow-up: 331 days). Malaria incidence in groups receiving zinc, multi-nutrients without zinc, multi-nutrients with zinc and placebo was 2.89/child-year, 2.95/child-year, 3.26/child-year, and 2.87/child-year, respectively. There was no evidence that multi-nutrients influenced the effect of zinc (or vice versa). Neither zinc nor multi-nutrients influenced malaria rates (marginal analysis; adjusted HR, 95% CI: 1.04, 0.93–1.18 and 1.10, 0.97–1.24 respectively). The prevalence of zinc deficiency (plasma zinc concentration <9.9 µmol/L) was high at baseline (67% overall; 60% in those without inflammation) and strongly reduced by zinc supplementation.
Conclusions
We found no evidence from this trial that zinc supplementation protected against malaria.
Trial Registration
ClinicalTrials.gov NCT00623857
Please see later in the article for the Editors' Summary.
Editors' Summary
Background
Malaria is a serious global public-health problem. Half of the world's population is at risk of this parasitic disease, which kills a million people (mainly children living in sub-Saharan Africa) every year. Malaria is transmitted to people through the bites of infected night-flying mosquitoes. Soon after entering the human body, the parasite begins to replicate in red blood cells, bursting out every 2–3 days and infecting more red blood cells. The presence of the parasite in the blood stream (parasitemia) causes malaria's characteristic recurring fever and can cause life-threatening organ damage and anemia (insufficient quantity of red blood cells). Malaria transmission can be reduced by using insecticide sprays to control the mosquitoes that spread the parasite and by avoiding mosquito bites by sleeping under insecticide-treated bed nets. Effective treatment with antimalarial drugs can also reduce malaria transmission.
Why Was This Study Done?
One reason why malaria kills so many children in Africa is poverty. Many children in Africa are malnourished, and malnutrition—in particular, insufficient micronutrients in the diet—impairs the immune system, which increases the frequency and severity of many childhood diseases. Micronutrients are vitamins and minerals that everyone needs in small quantities for good health. Zinc is one of the micronutrients that helps to maintain a healthy immune system, but zinc deficiency is very common among African children. Zinc supplementation has been shown to reduce the burden of diarrhea in developing countries, so might it also reduce the burden of malaria? Unfortunately, the existing evidence is confusing—some trials show that zinc supplementation protects against malaria but others show no evidence of protection. One possibility for these conflicting results could be that zinc supplementation alone is not sufficient—supplementation with other micronutrients might be needed for zinc to have an effect. In this randomized trial (a study that compares the effects of different interventions in groups that initially are similar in all characteristics except for intervention), the researchers investigate the effect of supplementation with zinc alone and in combination with other micronutrients on the rate of uncomplicated (mild) malaria among children living in Tanzania.
What Did the Researchers Do and Find?
The researchers enrolled 612 children aged 6–60 months who were living in a rural area of Tanzania with intense malaria transmission and randomly assigned them to receive daily oral supplements containing zinc alone, multi-nutrients (including iron) without zinc, multi-nutrients with zinc, or a placebo (no micronutrients). Nutritional indicators (including zinc concentrations in blood plasma) were assessed at baseline and 6–10 months after starting the intervention. During the study period, there were 1,572 malaria episodes. The incidence of malaria in all four intervention groups was very similar (about three episodes per child-year), and there was no evidence that multi-nutrients influenced the effect of zinc (or vice versa). Moreover, none of the supplements had any effect on malaria rates when compared to the placebo, even though the occurrence of zinc deficiency was strongly reduced by zinc supplementation. In a secondary analysis in which they analyzed their data by iron status at baseline, the researchers found that multi-nutrient supplementation increased the overall number of malaria episodes in children with iron deficiency by 41%, whereas multi-nutrient supplementation had no effect on the number of malaria episodes among children who were iron-replete at baseline.
What Do These Findings Mean?
In this study, the researchers found no evidence that zinc supplementation protected against malaria among young children living in Tanzania when given alone or in combination with other multi-nutrients. However, the researchers did find some evidence that multi-nutrient supplementation may increase the risk of malaria in children with iron deficiency. Because this finding came out of a secondary analysis of the data, it needs to be confirmed in a trial specifically designed to assess the effect of multi-nutrient supplements on malaria risk in iron-deficient children. Nevertheless, it is a potentially worrying result because, on the basis of evidence from a single study, the World Health Organization currently recommends that regular iron supplements be given to iron-deficient children in settings where there is adequate access to anti-malarial treatment. This recommendation should be reconsidered, suggest the researchers, and the safety of multi-nutrient mixes that contain iron and that are dispensed in countries affected by malaria should also be carefully evaluated.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001125.
Information is available from the World Health Organization on malaria (in several languages), on micronutrients, and on zinc deficiency; the 2010 World Malaria Report provides details of the current global malaria situation
The US Centers for Disease Control and Prevention provide information on malaria (in English and Spanish), including a selection of personal stories about malaria
Information is available from the Roll Back Malaria Partnership on the global control of malaria and on malaria in Africa
The Malaria Centre at the UK London School of Hygiene & Tropical Medicine develops tools, techniques, and knowledge about malaria, and has a strong emphasis on teaching, training, and translating research outcomes into practice
The Micronutrient Initiative, the Global Alliance for Improved Nutrition, and the Flour Fortification Initiative are not-for-profit organizations dedicated to ensuring that people in developing countries get the minerals and vitamins they need to survive and thrive
The International Zinc Nutrition Consultative Group (iZiNCG) is a non-profit organization that aims to promote and assist efforts to reduce zinc deficiency worldwide, through advocacy efforts, education, and technical assistance
MedlinePlus provides links to additional information on malaria (in English and Spanish)
doi:10.1371/journal.pmed.1001125
PMCID: PMC3222646  PMID: 22131908
24.  AOM in children 
Clinical Evidence  2011;2011:0301.
Introduction
In the UK, about 30% of children under 3 years of age visit their GP each year with acute otitis media (AOM), and 97% of these receive antibiotics. In the US, AOM is the most common reason for outpatient antibiotic treatment. Without antibiotics, AOM resolves within 24 hours in about 60% of children, and within 3 days in about 80% of children.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for AOM in children; and what are the effects of interventions to prevent recurrence? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 29 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: analgesics, antibiotics, delayed antibiotics, immediate antibiotics, long-term antibiotic prophylaxis, longer courses of antibiotics, myringotomy, pneumococcal vaccination, tympanostomy with ventilation tubes, xylitol syrup or gum, and influenza vaccination.
Key Points
AOM is characterised by sudden onset of earache with a cloudy or bulging erythematous eardrum caused by middle-ear infection. Middle-ear effusion without signs of infection lasting >3 months suggests otitis media with effusion ('glue ear'), while chronic suppurative otitis media is characterised by continuing middle-ear inflammation and discharge through a perforated eardrum. These disorders are assessed in separate reviews in Clinical Evidence.The most common pathogens in AOM in the US and UK are Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis.In the UK, about 30% of children under 3 years of age visit their GP each year with AOM, and 97% of these receive antibiotics. In the US, AOM is the most common reason for outpatient antibiotic treatment.
Without antibiotics, AOM resolves within 24 hours in about 60% of children, and within 3 days in about 80% of children. Analgesics and topical anaesthetics may reduce earache. Antibiotics seem to reduce pain at 2 to 7 days, but they increase the risks of vomiting, diarrhoea, and rashes compared with placebo.Immediate antibiotic use seems most beneficial in children aged <2 years with bilateral AOM and in children with AOM presenting with otorrhoea.We do not know whether any one antibiotic regimen should be used in preference to another, although amoxicillin may be more effective than macrolides, and it should be considered as first-line treatment. Longer courses of antibiotics reduce short-term treatment failure but have no benefit in the longer term compared with shorter regimens.Immediate use of antibiotics may provide short-term reduction in some symptoms of AOM, but it increases the risk of diarrhoea and rashes compared with delayed treatment.
Myringotomy seems less effective than antibiotics at reducing symptoms.
We found limited evidence of only a short-term benefit from tympanostomy with ventilation tubes, with possibly increased risks of tympanosclerosis.
Long-term antibiotic prophylaxis may reduce recurrence rates; however, the possibility of adverse effects and antibiotic resistance should be taken into account. We do not know whether any one regimen should be used in preference to another to prevent recurrent attacks.
Vaccination in infancy with pneumococcal conjugate vaccine (PCV) has some effect on recurrent AOM. Vaccination with PCV in children aged 1 to 7 years does not reduce AOM recurrence.
Influenza vaccine in healthy children has no effect on incidence of AOM.
Xylitol given 5 times daily as prophylaxis has a small preventive effect on recurrent AOM, but the compliance issues in giving a medicine 5 times daily to such young children render it an unrealistic treatment option.
PMCID: PMC3275313  PMID: 21554768
25.  Implementing the 2009 Institute of Medicine recommendations on resident physician work hours, supervision, and safety 
Long working hours and sleep deprivation have been a facet of physician training in the US since the advent of the modern residency system. However, the scientific evidence linking fatigue with deficits in human performance, accidents and errors in industries from aeronautics to medicine, nuclear power, and transportation has mounted over the last 40 years. This evidence has also spawned regulations to help ensure public safety across safety-sensitive industries, with the notable exception of medicine.
In late 2007, at the behest of the US Congress, the Institute of Medicine embarked on a year-long examination of the scientific evidence linking resident physician sleep deprivation with clinical performance deficits and medical errors. The Institute of Medicine’s report, entitled “Resident duty hours: Enhancing sleep, supervision and safety”, published in January 2009, recommended new limits on resident physician work hours and workload, increased supervision, a heightened focus on resident physician safety, training in structured handovers and quality improvement, more rigorous external oversight of work hours and other aspects of residency training, and the identification of expanded funding sources necessary to implement the recommended reforms successfully and protect the public and resident physicians themselves from preventable harm.
Given that resident physicians comprise almost a quarter of all physicians who work in hospitals, and that taxpayers, through Medicare and Medicaid, fund graduate medical education, the public has a deep investment in physician training. Patients expect to receive safe, high-quality care in the nation’s teaching hospitals. Because it is their safety that is at issue, their voices should be central in policy decisions affecting patient safety. It is likewise important to integrate the perspectives of resident physicians, policy makers, and other constituencies in designing new policies. However, since its release, discussion of the Institute of Medicine report has been largely confined to the medical education community, led by the Accreditation Council for Graduate Medical Education (ACGME).
To begin gathering these perspectives and developing a plan to implement safer work hours for resident physicians, a conference entitled “Enhancing sleep, supervision and safety: What will it take to implement the Institute of Medicine recommendations?” was held at Harvard Medical School on June 17–18, 2010. This White Paper is a product of a diverse group of 26 representative stakeholders bringing relevant new information and innovative practices to bear on a critical patient safety problem. Given that our conference included experts from across disciplines with diverse perspectives and interests, not every recommendation was endorsed by each invited conference participant. However, every recommendation made here was endorsed by the majority of the group, and many were endorsed unanimously. Conference members participated in the process, reviewed the final product, and provided input before publication. Participants provided their individual perspectives, which do not necessarily represent the formal views of any organization.
In September 2010 the ACGME issued new rules to go into effect on July 1, 2011. Unfortunately, they stop considerably short of the Institute of Medicine’s recommendations and those endorsed by this conference. In particular, the ACGME only applied the limitation of 16 hours to first-year resident physicans. Thus, it is clear that policymakers, hospital administrators, and residency program directors who wish to implement safer health care systems must go far beyond what the ACGME will require. We hope this White Paper will serve as a guide and provide encouragement for that effort.
Resident physician workload and supervision
By the end of training, a resident physician should be able to practice independently. Yet much of resident physicians’ time is dominated by tasks with little educational value. The caseload can be so great that inadequate reflective time is left for learning based on clinical experiences. In addition, supervision is often vaguely defined and discontinuous. Medical malpractice data indicate that resident physicians are frequently named in lawsuits, most often for lack of supervision. The recommendations are: The ACGME should adjust resident physicians workload requirements to optimize educational value. Resident physicians as well as faculty should be involved in work redesign that eliminates nonessential and noneducational activity from resident physician dutiesMechanisms should be developed for identifying in real time when a resident physician’s workload is excessive, and processes developed to activate additional providersTeamwork should be actively encouraged in delivery of patient care. Historically, much of medical training has focused on individual knowledge, skills, and responsibility. As health care delivery has become more complex, it will be essential to train resident and attending physicians in effective teamwork that emphasizes collective responsibility for patient care and recognizes the signs, both individual and systemic, of a schedule and working conditions that are too demanding to be safeHospitals should embrace the opportunities that resident physician training redesign offers. Hospitals should recognize and act on the potential benefits of work redesign, eg, increased efficiency, reduced costs, improved quality of care, and resident physician and attending job satisfactionAttending physicians should supervise all hospital admissions. Resident physicians should directly discuss all admissions with attending physicians. Attending physicians should be both cognizant of and have input into the care patients are to receive upon admission to the hospitalInhouse supervision should be required for all critical care services, including emergency rooms, intensive care units, and trauma services. Resident physicians should not be left unsupervised to care for critically ill patients. In settings in which the acuity is high, physicians who have completed residency should provide direct supervision for resident physicians. Supervising physicians should always be physically in the hospital for supervision of resident physicians who care for critically ill patientsThe ACGME should explicitly define “good” supervision by specialty and by year of training. Explicit requirements for intensity and level of training for supervision of specific clinical scenarios should be providedCenters for Medicare and Medicaid Services (CMS) should use graduate medical education funding to provide incentives to programs with proven, effective levels of supervision. Although this action would require federal legislation, reimbursement rules would help to ensure that hospitals pay attention to the importance of good supervision and require it from their training programs
Resident physician work hours
Although the IOM “Sleep, supervision and safety” report provides a comprehensive review and discussion of all aspects of graduate medical education training, the report’s focal point is its recommendations regarding the hours that resident physicians are currently required to work. A considerable body of scientific evidence, much of it cited by the Institute of Medicine report, describes deteriorating performance in fatigued humans, as well as specific studies on resident physician fatigue and preventable medical errors.
The question before this conference was what work redesign and cultural changes are needed to reform work hours as recommended by the Institute of Medicine’s evidence-based report? Extensive scientific data demonstrate that shifts exceeding 12–16 hours without sleep are unsafe. Several principles should be followed in efforts to reduce consecutive hours below this level and achieve safer work schedules. The recommendations are: Limit resident physician work hours to 12–16 hour maximum shiftsA minimum of 10 hours off duty should be scheduled between shiftsResident physician input into work redesign should be actively solicitedSchedules should be designed that adhere to principles of sleep and circadian science; this includes careful consideration of the effects of multiple consecutive night shifts, and provision of adequate time off after night work, as specified in the IOM reportResident physicians should not be scheduled up to the maximum permissible limits; emergencies frequently occur that require resident physicians to stay longer than their scheduled shifts, and this should be anticipated in scheduling resident physicians’ work shiftsHospitals should anticipate the need for iterative improvement as new schedules are initiated; be prepared to learn from the initial phase-in, and change the plan as neededAs resident physician work hours are redesigned, attending physicians should also be considered; a potential consequence of resident physician work hour reduction and increased supervisory requirements may be an increase in work for attending physicians; this should be carefully monitored, and adjustments to attending physician work schedules made as needed to prevent unsafe work hours or working conditions for this group“Home call” should be brought under the overall limits of working hours; work load and hours should be monitored in each residency program to ensure that resident physicians and fellows on home call are getting sufficient sleepMedicare funding for graduate medical education in each hospital should be linked with adherence to the Institute of Medicine limits on resident physician work hours
Moonlighting by resident physicians
The Institute of Medicine report recommended including external as well as internal moonlighting in working hour limits. The recommendation is: All moonlighting work hours should be included in the ACGME working hour limits and actively monitored. Hospitals should formalize a moonlighting policy and establish systems for actively monitoring resident physician moonlighting
Safety of resident physicians
The “Sleep, supervision and safety” report also addresses fatigue-related harm done to resident physicians themselves. The report focuses on two main sources of physical injury to resident physicians impaired by fatigue, ie, needle-stick exposure to blood-borne pathogens and motor vehicle crashes. Providing safe transportation home for resident physicians is a logistical and financial challenge for hospitals. Educating physicians at all levels on the dangers of fatigue is clearly required to change driving behavior so that safe hospital-funded transport home is used effectively. Fatigue-related injury prevention (including not driving while drowsy) should be taught in medical school and during residency, and reinforced with attending physicians; hospitals and residency programs must be informed that resident physicians’ ability to judge their own level of impairment is impaired when they are sleep deprived; hence, leaving decisions about the capacity to drive to impaired resident physicians is not recommendedHospitals should provide transportation to all resident physicians who report feeling too tired to drive safely; in addition, although consecutive work should not exceed 16 hours, hospitals should provide transportation for all resident physicians who, because of unforeseen reasons or emergencies, work for longer than consecutive 24 hours; transportation under these circumstances should be automatically provided to house staff, and should not rely on self-identification or request
Training in effective handovers and quality improvement
Handover practice for resident physicians, attendings, and other health care providers has long been identified as a weak link in patient safety throughout health care settings. Policies to improve handovers of care must be tailored to fit the appropriate clinical scenario, recognizing that information overload can also be a problem. At the heart of improving handovers is the organizational effort to improve quality, an effort in which resident physicians have typically been insufficiently engaged. The recommendations are: Hospitals should train attending and resident physicians in effective handovers of careHospitals should create uniform processes for handovers that are tailored to meet each clinical setting; all handovers should be done verbally and face-to-face, but should also utilize written toolsWhen possible, hospitals should integrate hand-over tools into their electronic medical records (EMR) systems; these systems should be standardized to the extent possible across residency programs in a hospital, but may be tailored to the needs of specific programs and services; federal government should help subsidize adoption of electronic medical records by hospitals to improve signoutWhen feasible, handovers should be a team effort including nurses, patients, and familiesHospitals should include residents in their quality improvement and patient safety efforts; the ACGME should specify in their core competency requirements that resident physicians work on quality improvement projects; likewise, the Joint Commission should require that resident physicians be included in quality improvement and patient safety programs at teaching hospitals; hospital administrators and residency program directors should create opportunities for resident physicians to become involved in ongoing quality improvement projects and root cause analysis teams; feedback on successful quality improvement interventions should be shared with resident physicians and broadly disseminatedQuality improvement/patient safety concepts should be integral to the medical school curriculum; medical school deans should elevate the topics of patient safety, quality improvement, and teamwork; these concepts should be integrated throughout the medical school curriculum and reinforced throughout residency; mastery of these concepts by medical students should be tested on the United States Medical Licensing Examination (USMLE) stepsFederal government should support involvement of resident physicians in quality improvement efforts; initiatives to improve quality by including resident physicians in quality improvement projects should be financially supported by the Department of Health and Human Services
Monitoring and oversight of the ACGME
While the ACGME is a key stakeholder in residency training, external voices are essential to ensure that public interests are heard in the development and monitoring of standards. Consequently, the Institute of Medicine report recommended external oversight and monitoring through the Joint Commission and Centers for Medicare and Medicaid Services (CMS). The recommendations are: Make comprehensive fatigue management a Joint Commission National Patient Safety Goal; fatigue is a safety concern not only for resident physicians, but also for nurses, attending physicians, and other health care workers; the Joint Commission should seek to ensure that all health care workers, not just resident physicians, are working as safely as possibleFederal government, including the Centers for Medicare and Medicaid Services and the Agency for Healthcare Research and Quality, should encourage development of comprehensive fatigue management programs which all health systems would eventually be required to implementMake ACGME compliance with working hours a “ condition of participation” for reimbursement of direct and indirect graduate medical education costs; financial incentives will greatly increase the adoption of and compliance with ACGME standards
Future financial support for implementation
The Institute of Medicine’s report estimates that $1.7 billion (in 2008 dollars) would be needed to implement its recommendations. Twenty-five percent of that amount ($376 million) will be required just to bring hospitals into compliance with the existing 2003 ACGME rules. Downstream savings to the health care system could potentially result from safer care, but these benefits typically do not accrue to hospitals and residency programs, who have been asked historically to bear the burden of residency reform costs. The recommendations are: The Institute of Medicine should convene a panel of stakeholders, including private and public funders of health care and graduate medical education, to lay down the concrete steps necessary to identify and allocate the resources needed to implement the recommendations contained in the IOM “Resident duty hours: Enhancing sleep, supervision and safety” report. Conference participants suggested several approaches to engage public and private support for this initiativeEfforts to find additional funding to implement the Institute of Medicine recommendations should focus more broadly on patient safety and health care delivery reform; policy efforts focused narrowly upon resident physician work hours are less likely to succeed than broad patient safety initiatives that include residency redesign as a key componentHospitals should view the Institute of Medicine recommendations as an opportunity to begin resident physician work redesign projects as the core of a business model that embraces safety and ultimately saves resourcesBoth the Secretary of Health and Human Services and the Director of the Centers for Medicare and Medicaid Services should take the Institute of Medicine recommendations into consideration when promulgating rules for innovation grantsThe National Health Care Workforce Commission should consider the Institute of Medicine recommendations when analyzing the nation’s physician workforce needs
Recommendations for future research
Conference participants concurred that convening the stakeholders and agreeing on a research agenda was key. Some observed that some sectors within the medical education community have been reluctant to act on the data. Several logical funders for future research were identified. But above all agencies, Centers for Medicare and Medicaid Services is the only stakeholder that funds graduate medical education upstream and will reap savings downstream if preventable medical errors are reduced as a result of reform of resident physician work hours.
doi:10.2147/NSS.S19649
PMCID: PMC3630963  PMID: 23616719
resident; hospital; working hours; safety

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