PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (97551)

Clipboard (0)
None

Related Articles

1.  Differences in Reporting of Analyses in Internal Company Documents Versus Published Trial Reports: Comparisons in Industry-Sponsored Trials in Off-Label Uses of Gabapentin 
PLoS Medicine  2013;10(1):e1001378.
Using documents obtained through litigation, S. Swaroop Vedula and colleagues compared internal company documents regarding industry-sponsored trials of off-label uses of gabapentin with the published trial reports and find discrepancies in reporting of analyses.
Background
Details about the type of analysis (e.g., intent to treat [ITT]) and definitions (i.e., criteria for including participants in the analysis) are necessary for interpreting a clinical trial's findings. Our objective was to compare the description of types of analyses and criteria for including participants in the publication (i.e., what was reported) with descriptions in the corresponding internal company documents (i.e., what was planned and what was done). Trials were for off-label uses of gabapentin sponsored by Pfizer and Parke-Davis, and documents were obtained through litigation.
Methods and Findings
For each trial, we compared internal company documents (protocols, statistical analysis plans, and research reports, all unpublished), with publications. One author extracted data and another verified, with a third person verifying discordant items and a sample of the rest. Extracted data included the number of participants randomized and analyzed for efficacy, and types of analyses for efficacy and safety and their definitions (i.e., criteria for including participants in each type of analysis). We identified 21 trials, 11 of which were published randomized controlled trials, and that provided the documents needed for planned comparisons. For three trials, there was disagreement on the number of randomized participants between the research report and publication. Seven types of efficacy analyses were described in the protocols, statistical analysis plans, and publications, including ITT and six others. The protocol or publication described ITT using six different definitions, resulting in frequent disagreements between the two documents (i.e., different numbers of participants were included in the analyses).
Conclusions
Descriptions of analyses conducted did not agree between internal company documents and what was publicly reported. Internal company documents provide extensive documentation of methods planned and used, and trial findings, and should be publicly accessible. Reporting standards for randomized controlled trials should recommend transparent descriptions and definitions of analyses performed and which study participants are excluded.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
To be credible, published research must present an unbiased, transparent, and accurate description of the study methods and findings so that readers can assess all relevant information to make informed decisions about the impact of any conclusions. Therefore, research publications should conform to universally adopted guidelines and checklists. Studies to establish whether a treatment is effective, termed randomized controlled trials (RCTs), are checked against a comprehensive set of guidelines: The robustness of trial protocols are measured through the Standard Protocol Items for Randomized Trials (SPIRIT), and the Consolidated Standards of Reporting Trials (CONSORT) statement (which was constructed and agreed by a meeting of journal editors in 1996, and has been updated over the years) includes a 25-point checklist that covers all of the key points in reporting RCTs.
Why Was This Study Done?
Although the CONSORT statement has helped improve transparency in the reporting of the methods and findings from RCTs, the statement does not define how certain types of analyses should be conducted and which patients should be included in the analyses, for example, in an intention-to-treat analysis (in which all participants are included in the data analysis of the group to which they were assigned, whether or not they completed the intervention given to the group). So in this study, the researchers used internal company documents released in the course of litigation against the pharmaceutical company Pfizer regarding the drug gabapentin, to compare between the internal and published reports the reporting of the numbers of participants, the description of the types of analyses, and the definitions of each type of analysis. The reports involved studies of gabapentin used for medical reasons not approved for marketing by the US Food and Drug Administration, known as “off-label” uses.
What Did the Researchers Do and Find?
The researchers identified trials sponsored by Pfizer relating to four off-label uses of gabapentin and examined the internal company protocols, statistical analysis plans, research reports, and the main publications related to each trial. The researchers then compared the numbers of participants randomized and analyzed for the main (primary) outcome and the type of analysis for efficacy and safety in both the internal research report and the trial publication. The researchers identified 21 trials, 11 of which were published RCTs that had the associated documents necessary for comparison.
The researchers found that in three out of ten trials there were differences in the internal research report and the main publication regarding the number of randomized participants. Furthermore, in six out of ten trials, the researchers were unable to compare the internal research report with the main publication for the number of participants analyzed for efficacy, because the research report either did not describe the primary outcome or did not describe the type of analysis. Overall, the researchers found that seven different types of efficacy analyses were described in the protocols, statistical analysis plans, and publications, including intention-to-treat analysis. However, the protocol or publication used six different descriptions for the intention-to-treat analysis, resulting in several important differences between the internal and published documents about the number of patients included in the analysis.
What Do These Findings Mean?
These findings from a sample of industry-sponsored trials on the off-label use of gabapentin suggest that when compared to the internal research reports, the trial publications did not always accurately reflect what was actually done in the trial. Therefore, the trial publication could not be considered to be an accurate and transparent record of the numbers of participants randomized and analyzed for efficacy. These findings support the need for further revisions of the CONSORT statement, such as including explicit statements about the criteria used to define each type of analysis and the numbers of participants excluded from each type of analysis. Further guidance is also needed to ensure consistent terminology for types of analysis. Of course, these revisions will improve reporting only if authors and journals adhere to them. These findings also highlight the need for all individual patient data to be made accessible to readers of the published article.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001378.
For more information, see the CONSORT statement website
The EQUATOR Network website is a resource center for the good reporting of health research studies and has more information about the SPIRIT initiative and the CONSORT statement
doi:10.1371/journal.pmed.1001378
PMCID: PMC3558476  PMID: 23382656
2.  A Head-to-Head Comparison of Four Artemisinin-Based Combinations for Treating Uncomplicated Malaria in African Children: A Randomized Trial 
PLoS Medicine  2011;8(11):e1001119.
The Four Artemisinin-Based Combinations (4ABC) Study Group reports a randomized, non-inferiority trial comparing the efficacy and safety of four ACTs in children with mild Plasmodium falciparum malaria from seven sub-Saharan African countries.
Background
Artemisinin-based combination therapies (ACTs) are the mainstay for the management of uncomplicated malaria cases. However, up-to-date data able to assist sub-Saharan African countries formulating appropriate antimalarial drug policies are scarce.
Methods and Findings
Between 9 July 2007 and 19 June 2009, a randomized, non-inferiority (10% difference threshold in efficacy at day 28) clinical trial was carried out at 12 sites in seven sub-Saharan African countries. Each site compared three of four ACTs, namely amodiaquine-artesunate (ASAQ), dihydroartemisinin-piperaquine (DHAPQ), artemether-lumefantrine (AL), or chlorproguanil-dapsone-artesunate (CD+A). Overall, 4,116 children 6–59 mo old with uncomplicated Plasmodium falciparum malaria were treated (1,226 with AL, 1,002 with ASAQ, 413 with CD+A, and 1,475 with DHAPQ), actively followed up until day 28, and then passively followed up for the next 6 mo. At day 28, for the PCR-adjusted efficacy, non-inferiority was established for three pair-wise comparisons: DHAPQ (97.3%) versus AL (95.5%) (odds ratio [OR]: 0.59, 95% CI: 0.37–0.94); DHAPQ (97.6%) versus ASAQ (96.8%) (OR: 0.74, 95% CI: 0.41–1.34), and ASAQ (97.1%) versus AL (94.4%) (OR: 0.50, 95% CI: 0.28–0.92). For the PCR-unadjusted efficacy, AL was significantly less efficacious than DHAPQ (72.7% versus 89.5%) (OR: 0.27, 95% CI: 0.21–0.34) and ASAQ (66.2% versus 80.4%) (OR: 0.40, 95% CI: 0.30–0.53), while DHAPQ (92.2%) had higher efficacy than ASAQ (80.8%) but non-inferiority could not be excluded (OR: 0.35, 95% CI: 0.26–0.48). CD+A was significantly less efficacious than the other three treatments. Day 63 results were similar to those observed at day 28.
Conclusions
This large head-to-head comparison of most currently available ACTs in sub-Saharan Africa showed that AL, ASAQ, and DHAPQ had excellent efficacy, up to day 63 post-treatment. The risk of recurrent infections was significantly lower for DHAPQ, followed by ASAQ and then AL, supporting the recent recommendation of considering DHAPQ as a valid option for the treatment of uncomplicated P. falciparum malaria.
Trial Registration
ClinicalTrials.gov NCT00393679; Pan African Clinical Trials Registry PACTR2009010000911750
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Malaria is a global public-health problem. Half the world's population is at risk of this mosquito-borne parasitic disease, which kills a million people (mainly children living in sub-Saharan Africa) every year. Although several parasites cause malaria, Plasmodium falciparum is responsible for most of these deaths. During the second half of the 20th century, the main treatments for malaria were inexpensive “monotherapies” such as chloroquine and sulfadoxine-pyrimethamine. Unfortunately, the malaria parasite quickly developed resistance to many of these monotherapies, and in the 1990 s, there was a widespread upsurge in P. falciparum malaria. To combat this increase, the World Health Organization (WHO) now recommends artemisinin-based combination therapy (ACT) for first-line treatment of P. falciparum malaria in all regions where there is drug-resistant malaria. In ACT, artemisinin derivatives (new, fast-acting antimalarial drugs) are used in combination with another antimalarial drug (a partner drug) to reduce the chances of P. falciparum becoming resistant to either drug.
Why Was This Study Done?
WHO currently recommends five ACTs—amodiaquine-artesunate (ASAQ), dihydroartemisinin-piperaquine (DHAPQ), artemether-lumefantrine (AL), artesunate-mefloquine, and artesunate-sulfadoxine-pyrimethamine—for the treatment of malaria. Its treatment guidelines state that the choice of ACT in a country or region should be based on the local level of resistance to the non-artemisinin-based partner drug in the combination. However, data on resistance levels to these partner drugs are scarce or unavailable for many sub-Saharan African countries. To help these countries make an informed choice about their national antimalarial treatment policies, in this randomized, non-inferiority trial, the researchers compare the efficacy and safety of four ACTs in African children with uncomplicated (mild) P. falciparum malaria. In a randomized trial, groups of randomly chosen patients with a specific disease are given different treatments and then followed to compare the outcomes of these interventions. A non-inferiority trial investigates whether one treatment is not worse than another treatment.
What Did the Researchers Do and Find?
Each of twelve sites in seven sub-Saharan African countries compared three ACTs out of ASAQ, DHAPQ, AL, and chlorproguanil-dapsone-artesunate (CD+A). Overall, 4,116 young children with uncomplicated malaria were treated with ACT, actively followed up for 28 days (their parents brought them back to the site for pre-arranged check-ups), and passively followed up for six months (parents brought their children back if they developed any illnesses). At each visit, blood samples were examined for the presence of parasites, and a technique called PCR was used to determine which cases of malaria were new infections and which were recurrences of the original infection. The researchers then calculated the percentage of patients with no infection or with a new infection (the PCR-adjusted adequate clinical and parasitological response [ACPR]) and the percentage of patients with no infection (the PCR-unadjusted ACPR). For the PCR-adjusted efficacy, three pair-wise comparisons (DHAPQ versus AL, DHAPQ versus ASAQ, and ASAQ versus AL) showed non-inferiority at 28 days. That is, for example, similar percentages of patients given DHAPQ or AL (97.3% and 95.5%, respectively) had either no infection or a new infection. CD+A was less efficacious than the other three treatments. For the PCR-unadjusted efficacy, AL was significantly less efficacious than DHAPQ and ASAQ; DHAPQ had a higher efficacy than ASAQ, but non-inferiority could not be excluded. That is, the difference in efficacy of these two drugs might have happened by chance.
What Do These Findings Mean?
These findings suggest that AL, ASAQ, and DHAPQ are all efficacious for the treatment of uncomplicated malaria in children; CD+A was withdrawn partway through the trial because of side effects, but these findings also suggest that it was less efficacious than the other ACTs. Importantly, the PCR-unadjusted results indicate that the risk of children becoming re-infected with malaria parasites soon after treatment was lowest for DHAPQ, followed by ASAQ, and then AL. Because these findings are based on pooled results from seven sub-Saharan African countries, they are likely to be generalizable and thus of use in setting national antimalarial drug policies throughout the region. AL and ASAQ are already included in the antimalarial drug policies of many sub-Saharan African countries, note the researchers, but these findings support the WHO recommendation that DHAPQ should also be considered for the treatment for uncomplicated P. falciparum malaria.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001119.
Information is available from WHO on malaria (in several languages); the 2010 World Malaria Report provides details of the current global malaria situation; the WHO Guidelines for the Treatment of Malaria and the report Assessment and Monitoring of Antimalarial Drug Efficacy for the Treatment of Uncomplicated 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 ACTs and about malaria in Africa
MedlinePlus provides links to additional information on malaria (in English and Spanish)
doi:10.1371/journal.pmed.1001119
PMCID: PMC3210754  PMID: 22087077
3.  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
4.  Mediating roles of medication –taking self-efficacy and depressive symptoms on self-reported medication adherence in persons with HIV: A questionnaire survey 
Summary
What is already known about the topic?
Highly active antiretroviral therapy has dramatically decreased morbidity and mortality and improved the quality of life in persons with HIVMedication-taking self-efficacy beliefs may predict medication adherence in persons with HIV.Depressive symptoms and perceived social support consistently influence medication-taking self-efficacy beliefs
What this paper adds.
Depressive symptoms mediated the prediction of medication-taking self-efficacy by perceived social support.Medication adherence self-efficacy mediated the prediction of self-reported medication adherence by perceived social support and depressive symptoms as self-efficacy theory suggests.This study provides researchers with increased understanding of the mediating role of medication-taking self-efficacy beliefs between selected psychological variables and self-reported medication adherence in persons with HIV.
Background
To date, only a few studies have examined the mediating role of self-efficacy on the relationship between depressive symptoms or perceived social support and medication adherence in persons with HIV.
Objectives
The purpose of this study was to examine the impact of perceived social support, depressive symptoms and medication-taking self-efficacy on self-reported medication adherence in persons with HIV. A proposed comprehensive model included three mediation hypotheses in order to examine the mediating roles of medication-taking self-efficacy and depressive symptoms
Method
Baseline data from “Adherence to Protease Inhibitors” were used. The 215 persons with HIV aged 19–61 (mean= 40.7, SD= 7.58) were recruited from multiple sites in Pittsburgh, PA (USA) and through self-referral. The participants were assessed using the Beck Depression Inventory, Interpersonal Support Evaluation List, the Medication Taking Self-Efficacy Scale, and the modified Morisky Self-report Medication Taking Scale. Structural equation modeling (EQS version 6.1) was used. The Satorra-Bentler Scaled χ2 test statistics (S-B χ2), comparative fit index (CFI), and the Standardized Root Mean Squared Residual (SRMR) were used to assess the fit of a comprehensive model including three mediation hypotheses.
Results
A comprehensive model with the three hypotheses showed a good model fit (S-B χ2 (24, N=215) = 69.06, p<.001; CFI=0.95; SRMR=0.057). Medication adherence self-efficacy fully mediated the prediction of self-reported medication adherence by perceived social support and depressive symptoms. Depressive symptoms partially mediated the prediction of medication-taking self-efficacy by perceived social support
Conclusions
The findings of this study provide researchers with increased understanding of the mediating role of medication-taking self-efficacy beliefs between selected psychological variables and self-reported medication adherence in persons with HIV. Future studies need to test the moderating effect of gender, ethnicity and risk factors for HIV on this model and the intervention effect of self-efficacy beliefs using longitudinal data.
doi:10.1016/j.ijnurstu.2007.08.003
PMCID: PMC2518216  PMID: 17949723
Mediation; medication-taking self-efficacy; highly active antiretroviral therapy regimen adherence
5.  A Randomised Controlled Trial of Artemether-Lumefantrine Versus Artesunate for Uncomplicated Plasmodium falciparum Treatment in Pregnancy 
PLoS Medicine  2008;5(12):e253.
Background
To date no comparative trials have been done, to our knowledge, of fixed-dose artemisinin combination therapies (ACTs) for the treatment of Plasmodium falciparum malaria in pregnancy. Evidence on the safety and efficacy of ACTs in pregnancy is needed as these drugs are being used increasingly throughout the malaria-affected world. The objective of this study was to compare the efficacy, tolerability, and safety of artemether-lumefantrine, the most widely used fixed ACT, with 7 d artesunate monotherapy in the second and third trimesters of pregnancy.
Methods and Findings
An open-label randomised controlled trial comparing directly observed treatment with artemether-lumefantrine 3 d (AL) or artesunate monotherapy 7 d (AS7) was conducted in Karen women in the border area of northwestern Thailand who had uncomplicated P. falciparum malaria in the second and third trimesters of pregnancy. The primary endpoint was efficacy defined as the P. falciparum PCR-adjusted cure rates assessed at delivery or by day 42 if this occurred later than delivery, as estimated by Kaplan-Meier survival analysis. Infants were assessed at birth and followed until 1 y of life. Blood sampling was performed to characterise the pharmacokinetics of lumefantrine in pregnancy. Both regimens were very well tolerated. The cure rates (95% confidence interval) for the intention to treat (ITT) population were: AS7 89.2% (82.3%–96.1%) and AL 82.0% (74.8%–89.3%), p = 0.054 (ITT); and AS7 89.7% (82.6%–96.8%) and AL 81.2% (73.6%–88.8%), p = 0.031 (per-protocol population). One-third of the PCR-confirmed recrudescent cases occurred after 42 d of follow-up. Birth outcomes and infant (up to age 1 y) outcomes did not differ significantly between the two groups. The pharmacokinetic study indicated that low concentrations of artemether and lumefantrine were the main contributors to the poor efficacy of AL.
Conclusion
The current standard six-dose artemether-lumefantrine regimen was well tolerated and safe in pregnant Karen women with uncomplicated falciparum malaria, but efficacy was inferior to 7 d artesunate monotherapy and was unsatisfactory for general deployment in this geographic area. Reduced efficacy probably results from low drug concentrations in later pregnancy. A longer or more frequent AL dose regimen may be needed to treat pregnant women effectively and should now be evaluated. Parasitological endpoints in clinical trials of any antimalarial drug treatment in pregnancy should be extended to delivery or day 42 if it comes later.
Trial Registration: Current Controlled Trials ISRCTN86353884
Rose McGready and colleagues show that an artemether-lumefantrine regimen is well tolerated and safe in pregnant Karen women with uncomplicated falciparum malaria, but efficacy is inferior to artesunate, probably because of low drug concentrations in later pregnancy.
Editors' Summary
Background.
Plasmodium falciparum, a mosquito-borne parasite that causes malaria, kills nearly one million people every year. Although most deaths occur among young children, malaria during pregnancy is also an important public-health problem. In areas where malaria transmission is high (stable transmission), women acquire a degree of immunity. Although less symptomatic than women who lack natural protection, their babies are often small and sickly because malaria-related anemia (lack of red blood cells) and parasites in the placenta limit the nutrients supplied to the baby before birth. By contrast, in areas where malaria transmission is low (unstable transmission or sporadic outbreaks), women have little immunity to P. falciparum. If these women become infected during pregnancy, “uncomplicated” malaria (fever, chills, and anemia) can rapidly progress to “severe” malaria (in which vital organs are damaged), which can be fatal to the mother and/or her unborn child unless prompt and effective treatment is given.
Why Was This Study Done?
Malaria parasites are now resistant to many of the older antimalarial drugs (for example, quinine). So, since 2006, the World Health Organization (WHO) has recommended that uncomplicated malaria during the second and third trimester of pregnancy is treated with short course (3 d) fixed-dose artemisinin combination therapy (ACT; quinine is still used in early pregnancy because it is not known whether ACT damages fetal development, which mainly occurs during the first 3 mo of pregnancy). Artemisinin derivatives are fast-acting antimalarial agents that are used in combination with another antimalarial drug to reduce the chances of P. falciparum becoming resistant to either drug. The most widely used fixed-dose ACT is artemether–lumefantrine (AL) but, although several trials have examined the safety and efficacy of this treatment in non-pregnant women, little is known about how well it works in pregnant women. In this study, the researchers compare the efficacy, tolerability, and safety of AL with a 7-d course of artesunate monotherapy (AS7; another artemisinin derivative) in the treatment of uncomplicated malaria in pregnancy in northwest Thailand, an area with unstable but highly drug resistant malaria transmission.
What Did the Researchers Do and Find?
The researchers enrolled 253 women with uncomplicated malaria during the second and third trimesters of pregnancy into their open-label trial (a trial in which the patients and their health-care workers know who is receiving which drug regimen). Half the women received each type of treatment. The trial's main outcome was the “PCR-adjusted cure rate” at delivery or 42 d after treatment if this occurred after delivery. This cure rate was assessed by examining blood smears for parasites and then using a technique called PCR to determine which cases of malaria were new infections (classified as treatment successes along with negative blood smears) and which were recurrences of an old infection (classified as treatment failures). The PCR-adjusted cure rates were 89.7% and 81.2% for AS7 and AL, respectively. Both treatments were well tolerated, few side effects were seen with either treatment, and infant health and development at birth and up to 1 y old were similar with both regimens. Finally, an analysis of blood samples taken 7 d after treatment with AL showed that blood levels of lumefantrine were below those previously associated with treatment failure in about a third of the women tested.
What Do These Findings Mean?
Although these findings indicate that the AL regimen is a well tolerated and safe treatment for uncomplicated malaria in pregnant women living in northwest Thailand, the efficacy of this treatment was lower than that of artesunate monotherapy. In fact, neither treatment reached the 90% cure rate recommended by WHO for ACTs and it is likely that cure rates in a more realistic situation (that is, not in a trial where efforts are made to make sure everyone completes their treatment) would be even lower. The findings also suggest that the reduced efficacy of the AL regimen in pregnant women compared to the efficacy previously seen in non-pregnant women may be caused by lower drug blood levels during pregnancy. Thus, a higher-dose AL regimen (or an alternative ACT) may be needed to successfully treat uncomplicated malaria during pregnancy.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050253.
The MedlinePlus encyclopedia contains a page on malaria (in English and Spanish)
Information is available from the World Health Organization on malaria (in several languages), and their 2006 Guidelines for the Treatment of Malaria includes specific recommendations for the treatment of pregnant women
The US Centers for Disease Control and Prevention provide information on malaria and on malaria during pregnancy (in English and Spanish)
Information is available from the Roll Back Malaria Partnership on malaria during pregnancy, on artemisinin-based combination therapies, and on malaria in Thailand
doi:10.1371/journal.pmed.0050253
PMCID: PMC2605900  PMID: 19265453
6.  Premenstrual syndrome 
Clinical Evidence  2009;2009:0806.
Introduction
Premenstrual symptoms occur in 95% of women of reproductive age. Severe, debilitating symptoms (PMS) occur in about 5% of those women. There is no consensus on how symptom severity should be assessed, which has led to a wide variety of symptoms scales, making it difficult to synthesise data on treatment efficacy. The cyclical nature of the condition also makes it difficult to conduct RCTs.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of drug treatments in women with premenstrual syndrome? What are the effects of hormonal treatments in women with premenstrual syndrome? What are the effects of psychological interventions in women with premenstrual syndrome? What are the effects of physical therapy in women with premenstrual syndrome? What are the effects of dietary supplements in women with premenstrual syndrome? What are the effects of surgical treatments in women with premenstrual syndrome? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 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 56 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: acupuncture; alprazolam; bright light therapy; buspirone; chiropractic manipulation; clomipramine; cognitive behavioural therapy (CBT); danazol; endometrial ablation; evening primrose oil; exercise; gonadorelin analogues; hysterectomy; laparoscopic bilateral oophorectomy; magnesium supplements; metolazone; non-steroidal anti-inflammatory drugs (NSAIDs); oestrogens; oral contraceptives; progesterone; progestogens; pyridoxine; reflexology; relaxation; selective serotonin reuptake inhibitors (SSRIs); spironolactone; and tibolone.
Key Points
A woman has premenstrual syndrome (PMS) if she complains of recurrent psychological and/or physical symptoms occurring during the luteal phase of the menstrual cycle, and often resolving by the end of menstruation. Symptom severity can vary between women. Premenstrual symptoms occur in 95% of all women of reproductive age. Severe, debilitating symptoms (PMS) occur in about 5% of those women.There is no consensus on how symptom severity should be assessed, which has led to a wide variety of symptoms scales, making it difficult to synthesise data on treatment efficacy. The cyclical nature of the condition also makes it difficult to conduct RCTs.There is little good evidence for any of the wide range of treatments available, and the selection of treatment is mainly governed by personal choice. The clinician plays a key role in facilitating this choice, and in reassuring women with PMS without coexisting gynaecological problems that there is nothing seriously wrong.
Drug treatments can be effective at reducing premenstrual symptoms, but some are associated with significant adverse effects. There is good evidence that spironolactone improves mood and somatic symptoms in women with PMS. Alprazolam (during the luteal phase), metolazone, and NSAIDs (such as mefenamic acid and naproxen sodium) may also be effective in treating the main physical and psychological symptoms of PMS. Buspirone (luteal or continuous) and gonadorelin analogues seem to improve overall self-rated symptoms. Gonadorelin is effective in improving symptoms, but is associated with serious risks of osteoporosis when used for more than 6 months.Other drug treatments such as clomipramine, danazol, and SSRIs may improve psychological symptoms, but are associated with serious adverse effects.
We don't know whetherprogesterone is effective in reducing symptoms of PMS. There is some evidence thatprogesterone-like drugs reduce premenstrual symptoms, but both progesterone and progesterone-like drugs are associated with several adverse effects. We don't know whether other hormonal treatments such as oestrogen and tibolone are effective in reducing symptoms of PMS. Oral contraceptives containing drospirenone (24/4 schedule [24 out of 28 days]) are likely to be effective in reducing symptoms of PMS.
There is not enough evidence for us to assess the efficacy of CBT in treating the psychological symptoms of PMS.
We also don't know how effective physical therapy techniques (bright light therapy, chiropractic manipulation, exercise, reflexology, relaxation, and acupuncture) are in relieving symptoms of PMS.
We found evidence that pyridoxine (vitamin B6) reduces the overall symptoms of PMS. Calcium supplements may also be effective. We don't know whether other supplements, such as evening primrose oil or magnesium, are a useful treatment for PMS.
Surgery is indicated only if there are coexisting gynaecological problems. There is a consensus that hysterectomy with bilateral oophorectomy or laparoscopic bilateral oophorectomy almost completely eradicate the symptoms of PMS, although we found no RCTs examining this.We don't know whether endometrial ablation has the same effect.
PMCID: PMC2907788
7.  Relationship Between Self-Efficacy and Symptoms of Anxiety, Depression, Worry and Social Avoidance in a Normal Sample of Students 
Objective: Self-efficacy beliefs determine how people feel, think, motivate themselves and behave. Regarding to similar findings it is supposed that concept of self efficacy has a general role on mental health. The present study focused on examining the relationships between self-efficacy and symptoms of depression, anxiety, worry and social avoidance in a large sample of normal students (n=549).
Methods: The sample included of 266 female and 283 male high school students from schools of distinct areas 6, 8 and 9 (Tehran, Iran). The schools were chosen randomly. Participants completed the Self-Efficacy Questionnaire for Children and Social Avoidance & Distress Scale and also the scales measuring trait anxiety, depression, worry and social avoidance. Stepwise regression analyses were used as methods of analysis.
Results: Main results distinguished that there is a significant and negative relationship between total self-efficacy, physical self-efficacy and academic self-efficacy and depression. Also significant and negative relationships were found between total self-efficacy, physical self-efficacy and emotional self-efficacy and anxiety. Emotional self-efficacy and physical self-efficacy had significantly a negative relationship to worry. On the other hand, social self-efficacy and physical self-efficacy were significantly and negatively related to social avoidance
Conclusion: According to what is discussed the various aspects of mental health is influenced by the sense of self efficacy appraisal. So low self efficacy usually increases some problems such as emotional and social problems which involves in mental health.
PMCID: PMC3939966  PMID: 24644452
Anxiety; Depression; Self-Efficacy; Social Avoidance; Worry
8.  Efficacy of Pneumococcal Nontypable Haemophilus influenzae Protein D Conjugate Vaccine (PHiD-CV) in Young Latin American Children: A Double-Blind Randomized Controlled Trial 
PLoS Medicine  2014;11(6):e1001657.
In a double-blind randomized controlled trial, Xavier Saez-Llorens and colleagues examine the vaccine efficacy of PHiD-CV against community-acquired pneumonia in young children in Panama, Argentina, and Columbia.
Please see later in the article for the Editors' Summary
Background
The relationship between pneumococcal conjugate vaccine–induced antibody responses and protection against community-acquired pneumonia (CAP) and acute otitis media (AOM) is unclear. This study assessed the impact of the ten-valent pneumococcal nontypable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) on these end points. The primary objective was to demonstrate vaccine efficacy (VE) in a per-protocol analysis against likely bacterial CAP (B-CAP: radiologically confirmed CAP with alveolar consolidation/pleural effusion on chest X-ray, or non-alveolar infiltrates and C-reactive protein ≥ 40 µg/ml); other protocol-specified outcomes were also assessed.
Methods and Findings
This phase III double-blind randomized controlled study was conducted between 28 June 2007 and 28 July 2011 in Argentine, Panamanian, and Colombian populations with good access to health care. Approximately 24,000 infants received PHiD-CV or hepatitis control vaccine (hepatitis B for primary vaccination, hepatitis A at booster) at 2, 4, 6, and 15–18 mo of age. Interim analysis of the primary end point was planned when 535 first B-CAP episodes, occurring ≥2 wk after dose 3, were identified in the per-protocol cohort. After a mean follow-up of 23 mo (PHiD-CV, n = 10,295; control, n = 10,201), per-protocol VE was 22.0% (95% CI: 7.7, 34.2; one-sided p = 0.002) against B-CAP (conclusive for primary objective) and 25.7% (95% CI: 8.4%, 39.6%) against World Health Organization–defined consolidated CAP. Intent-to-treat VE was 18.2% (95% CI: 5.5%, 29.1%) against B-CAP and 23.4% (95% CI: 8.8%, 35.7%) against consolidated CAP. End-of-study per-protocol analyses were performed after a mean follow-up of 28–30 mo for CAP and invasive pneumococcal disease (IPD) (PHiD-CV, n = 10,211; control, n = 10,140) and AOM (n = 3,010 and 2,979, respectively). Per-protocol VE was 16.1% (95% CI: −1.1%, 30.4%; one-sided p = 0.032) against clinically confirmed AOM, 67.1% (95% CI: 17.0%, 86.9%) against vaccine serotype clinically confirmed AOM, 100% (95% CI: 74.3%, 100%) against vaccine serotype IPD, and 65.0% (95% CI: 11.1%, 86.2%) against any IPD. Results were consistent between intent-to-treat and per-protocol analyses. Serious adverse events were reported for 21.5% (95% CI: 20.7%, 22.2%) and 22.6% (95% CI: 21.9%, 23.4%) of PHiD-CV and control recipients, respectively. There were 19 deaths (n = 11,798; 0.16%) in the PHiD-CV group and 26 deaths (n = 11,799; 0.22%) in the control group. A significant study limitation was the lower than expected number of captured AOM cases.
Conclusions
Efficacy was demonstrated against a broad range of pneumococcal diseases commonly encountered in young children in clinical practice.
Trial registration
www.ClinicalTrials.gov NCT00466947
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Pneumococcal diseases are illnesses caused by Streptococcus pneumoniae bacteria, pathogens (disease-causing organisms) that are transmitted through contact with infected respiratory secretions. S. pneumoniae causes mucosal diseases–infections of the lining of the body cavities that are connected to the outside world–such as community-acquired pneumonia (CAP; lung infection) and acute otitis media (AOM; middle-ear infection). It also causes invasive pneumococcal diseases (IPDs) such as septicemia and meningitis (infections of the bloodstream and the covering of the brain, respectively). Although pneumococcal diseases can sometimes be treated with antibiotics, CAP and IPDs are leading global causes of childhood deaths, particularly in developing countries. It is best therefore to avoid S. pneumoniae infections through vaccination. Vaccination primes the immune system to recognize and attack pathogens rapidly and effectively by exposing it to weakened or dead pathogens or to pathogen molecules that it recognizes as foreign (antigens). Because there are more than 90 S. pneumoniae variants (“serotypes”), each characterized by a different antigenic polysaccharide (complex sugar) coat, S. pneumoniae vaccines have to include antigens from multiple serotypes. For example, the PHiD-CV vaccine contains polysaccharides from ten S. pneumoniae serotypes.
Why Was This Study Done?
Although in most countries PHiD-CV has been licensed for protection against IPD and pneumococcal AOM, at the time of study, it was not known how well it protected against CAP and overall AOM, which are important public health problems. In this double-blind randomized controlled trial (the Clinical Otitis Media and Pneumonia Study; COMPAS), the researchers investigate the efficacy of PHiD-CV against CAP and AOM and assess other clinical end points, such as IPD, in Latin American infants. Double-blind randomized controlled trials compare the effects of interventions by assigning study participants to different interventions randomly and measuring predefined outcomes without the study participants or researchers knowing who has received which intervention until the trial is completed. Vaccine efficacy is the reduction in the incidence of a disease (the number of new cases that occur in a population in a given time) 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 enrolled around 24,000 infants living in urban areas of Argentina, Panama, and Colombia. Half the infants were given PHiD-CV at 2, 4, and 6 months of age and a booster dose at age 15–18 months. The remaining infants were given a hepatitis control vaccine at the same intervals. The trial's primary end point was likely bacterial CAP (B-CAP) –radiologically confirmed CAP, with the airspaces (alveoli) in the lungs filled with liquid instead of gas (alveolar consolidation) or with non-alveolar infiltrates and raised blood levels of C-reactive protein (a marker of inflammation). In a planned interim analysis, which was undertaken after an average follow-up of 23 months, the vaccine efficacy in the per-protocol cohort (the group of participants who actually received their assigned intervention) was 22% against B-CAP. Intent-to-treat vaccine efficacy in the interim analysis (which considered all the trial participants regardless of whether they received their assigned intervention) was 18.2%. At the end of the study (average follow up 30 months), the vaccine efficacy against B-CAP was 18.2% and 16.7% in the per-protocol and intent-to-treat cohorts, respectively. Per-protocol vaccine efficacies against clinically confirmed AOM and vaccine serotype AOM were 16.1% and 67.1%, respectively. Against any IPD and against vaccine serotype IPD, the respective vaccine efficacies were 65% and 100%. Finally, about one-fifth of children who received PHiD-CV and a similar proportion who received the control vaccine experienced a serious adverse event (for example, gastroenteritis); 19 children who received PHiD-CV died compared to 26 children who received the control vaccine.
What Do These Findings Mean?
These findings indicate that in Latin America, a region with an intermediate burden of pneumococcal disease, PHiD-CV is efficacious against a broad range of pneumococcal diseases that often affect young children. The accuracy of these findings may be limited by the withdrawal of 14% of participants from the trial because of adverse media coverage and by the low number of reported cases of AOM. Moreover, because most study participants lived in urban areas, these findings may not be generalizable to rural settings. Despite these and other study limitations, these findings provide new information about the magnitude of the effect of PHiD-CV vaccination against CAP and AOM, two mucosal pneumococcal diseases of global public health importance.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001657.
The US Centers for Disease Control and Prevention provides information for patients and health professionals on all aspects of pneumococcal disease and pneumococcal vaccination, including personal stories
Public Health England provides information on pneumococcal disease and on pneumococcal vaccines
The not-for-profit Immunization Action Coalition has information on pneumococcal disease, including personal stories
The GAVI Alliance provides information about pneumococcal disease and the importance of vaccination
MedlinePlus has links to further information about pneumococcal infections, including pneumonia and otitis media (in English and Spanish)
More information about COMPAS is available
The European Medicines Agency provides information about PHiD-CV (Synflorix)
doi:10.1371/journal.pmed.1001657
PMCID: PMC4043495  PMID: 24892763
9.  Local treatments for cutaneous warts: systematic review 
BMJ : British Medical Journal  2002;325(7362):461.
Objective
To assess the evidence for the efficacy of local treatments for cutaneous warts.
Methods
Systematic review of randomised controlled trials.
Main outcomes measures
Total clearance of warts and adverse effects such as irritation, pain, and blistering.
Study selection
Randomised controlled trials of any local treatment for uncomplicated cutaneous warts. All published and unpublished material was considered, with no restriction on date or language.
Results
50 included trials provided generally weak evidence because of poor methods and reporting. The best evidence was for topical treatments containing salicylic acid. Data pooled from six placebo controlled trials showed a cure rate of 75% (144 of 191) in cases compared with 48% (89 of 185) in controls (odds ratio 3.91, 95% confidence interval 2.40 to 6.36). Some evidence for the efficacy of contact immunotherapy was provided by two small trials comparing dinitrochlorobenzene with placebo. Evidence for the efficacy of cryotherapy was limited. No consistent evidence was found for the efficacy of intralesional bleomycin, and only limited evidence was found for the efficacy of topical fluorouracil, intralesional interferons, photodynamic therapy, and pulsed dye laser.
Conclusions
Reviewed trials of local treatments for cutaneous warts were highly variable in methods and quality, and there was a paucity of evidence from randomised, placebo controlled trials on which to base the rational use of the treatments. There is good evidence that topical treatments containing salicylic acid have a therapeutic effect and some evidence for the efficacy of dinitrochlorobenzene. Less evidence was found for the efficacy of all the other treatments reviewed, including cryotherapy.
What is already known on this topicA wide range of local treatments is available for treating wartsNo one treatment is strikingly effective and little is known about the absolute and relative efficacy of these treatmentsWhat this study addsHigh quality research on the efficacy of various local treatments for warts is lackingEvidence, which is generally of a poor quality, shows a beneficial effect of topical salicylic acid and contact immunotherapy with dinitrochlorobenzeneLittle evidence exists for the efficacy of cryotherapy and no consistent evidence for the efficacy of all the other treatments reviewed
PMCID: PMC119440  PMID: 12202325
10.  Reporting Bias in Drug Trials Submitted to the Food and Drug Administration: Review of Publication and Presentation 
PLoS Medicine  2008;5(11):e217.
Background
Previous studies of drug trials submitted to regulatory authorities have documented selective reporting of both entire trials and favorable results. The objective of this study is to determine the publication rate of efficacy trials submitted to the Food and Drug Administration (FDA) in approved New Drug Applications (NDAs) and to compare the trial characteristics as reported by the FDA with those reported in publications.
Methods and Findings
This is an observational study of all efficacy trials found in approved NDAs for New Molecular Entities (NMEs) from 2001 to 2002 inclusive and all published clinical trials corresponding to the trials within the NDAs. For each trial included in the NDA, we assessed its publication status, primary outcome(s) reported and their statistical significance, and conclusions. Seventy-eight percent (128/164) of efficacy trials contained in FDA reviews of NDAs were published. In a multivariate model, trials with favorable primary outcomes (OR = 4.7, 95% confidence interval [CI] 1.33–17.1, p = 0.018) and active controls (OR = 3.4, 95% CI 1.02–11.2, p = 0.047) were more likely to be published. Forty-one primary outcomes from the NDAs were omitted from the papers. Papers included 155 outcomes that were in the NDAs, 15 additional outcomes that favored the test drug, and two other neutral or unknown additional outcomes. Excluding outcomes with unknown significance, there were 43 outcomes in the NDAs that did not favor the NDA drug. Of these, 20 (47%) were not included in the papers. The statistical significance of five of the remaining 23 outcomes (22%) changed between the NDA and the paper, with four changing to favor the test drug in the paper (p = 0.38). Excluding unknowns, 99 conclusions were provided in both NDAs and papers, nine conclusions (9%) changed from the FDA review of the NDA to the paper, and all nine did so to favor the test drug (100%, 95% CI 72%–100%, p = 0.0039).
Conclusions
Many trials were still not published 5 y after FDA approval. Discrepancies between the trial information reviewed by the FDA and information found in published trials tended to lead to more favorable presentations of the NDA drugs in the publications. Thus, the information that is readily available in the scientific literature to health care professionals is incomplete and potentially biased.
Lisa Bero and colleagues review the publication status of all efficacy trials carried out in support of new drug approvals from 2001 and 2002, and find that a quarter of trials remain unpublished.
Editors' Summary
Background.
All health-care professionals want their patients to have the best available clinical care—but how can they identify the optimum drug or intervention? In the past, clinicians used their own experience or advice from colleagues to make treatment decisions. Nowadays, they rely on evidence-based medicine—the systematic review and appraisal of clinical research findings. So, for example, before a new drug is approved for the treatment of a specific disease in the United States and becomes available for doctors to prescribe, the drug's sponsors (usually a pharmaceutical company) must submit a “New Drug Application” (NDA) to the US Food and Drug Administration (FDA). The NDA tells the story of the drug's development from laboratory and animal studies through to clinical trials, including “efficacy” trials in which the efficacy and safety of the new drug and of a standard drug for the disease are compared by giving groups of patients the different drugs and measuring several key (primary) “outcomes.” FDA reviewers use this evidence to decide whether to approve a drug.
Why Was This Study Done?
Although the information in NDAs is publicly available, clinicians and patients usually learn about new drugs from articles published in medical journals after drug approval. Unfortunately, drug sponsors sometimes publish the results only of the trials in which their drug performed well and in which statistical analyses indicate that the drug's improved performance was a real effect rather than a lucky coincidence. Trials in which a drug did not show a “statistically significant benefit” or where the drug was found to have unwanted side effects often remain unpublished. This “publication bias” means that the scientific literature can contain an inaccurate picture of a drug's efficacy and safety relative to other therapies. This may lead to clinicians preferentially prescribing newer, more expensive drugs that are not necessarily better than older drugs. In this study, the researchers test the hypothesis that not all the trial results in NDAs are published in medical journals. They also investigate whether there are any discrepancies between the trial data included in NDAs and in published articles.
What Did the Researchers Do and Find?
The researchers identified all the efficacy trials included in NDAs for totally new drugs that were approved by the FDA in 2001 and 2002 and searched the scientific literature for publications between July 2006 and June 2007 relating to these trials. Only three-quarters of the efficacy trials in the NDAs were published; trials with favorable outcomes were nearly five times as likely to be published as those without favorable outcomes. Although 155 primary outcomes were in both the papers and the NDAs, 41 outcomes were only in the NDAs. Conversely, 17 outcomes were only in the papers; 15 of these favored the test drug. Of the 43 primary outcomes reported in the NDAs that showed no statistically significant benefit for the test drug, only half were included in the papers; for five of the reported primary outcomes, the statistical significance differed between the NDA and the paper and generally favored the test drug in the papers. Finally, nine out of 99 conclusions differed between the NDAs and the papers; each time, the published conclusion favored the test drug.
What Do These Findings Mean?
These findings indicate that the results of many trials of new drugs are not published 5 years after FDA approval of the drug. Furthermore, unexplained discrepancies between the data and conclusions in NDAs and in medical journals are common and tend to paint a more favorable picture of the new drug in the scientific literature than in the NDAs. Overall, these findings suggest that the information on the efficacy of new drugs that is readily available to clinicians and patients through the published scientific literature is incomplete and potentially biased. The recent introduction in the US and elsewhere of mandatory registration of all clinical trials before they start and of mandatory publication in trial registers of the full results of all the predefined primary outcomes should reduce publication bias over the next few years and should allow clinicians and patients to make fully informed treatment decisions.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050217.
This study is further discussed in a PLoS Medicine Perspective by An-Wen Chan
PLoS Medicine recently published a related article by Ida Sim and colleagues: Lee K, Bacchetti P, Sim I (2008) Publication of clinical trials supporting successful new drug applications: A literature analysis. PLoS Med 5: e191. doi:10.1371/journal.pmed.0050191
The Food and Drug Administration provides information about drug approval in the US for consumers and for health-care professionals; detailed information about the process by which drugs are approved is on the Web site of the FDA Center for Drug Evaluation and Research (in English and Spanish)
NDAs for approved drugs can also be found on this Web site
The ClinicalTrials.gov Web site provides information about the US National Institutes of Health clinical trial registry, background information about clinical trials, and a fact sheet detailing the requirements of the FDA Amendments Act 2007 for trial registration
The World Health Organization's International Clinical Trials Registry Platform is working toward setting international norms and standards for the reporting of clinical trials (in several languages)
doi:10.1371/journal.pmed.0050217
PMCID: PMC2586350  PMID: 19067477
11.  Candidiasis (vulvovaginal) 
Clinical Evidence  2010;2010:0815.
Introduction
Vulvovaginal candidiasis is estimated to be the second most common cause of vaginitis after bacterial vaginosis. Candida albicans accounts for 85% to 90% of cases.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of drug treatments for acute vulvovaginal candidiasis in non-pregnant symptomatic women? What are the effects of alternative or complementary treatments for acute vulvovaginal candidiasis in non-pregnant symptomatic women? What are the effects of treating a male sexual partner to resolve symptoms and prevent recurrence in non-pregnant women with symptomatic acute vulvovaginal candidiasis? What are the effects of alternative or complementary treatments for symptomatic recurrent vulvovaginal candidiasis in non-pregnant women? What are the effects of treating a male sexual partner in non-pregnant women with symptomatic recurrent vulvovaginal candidiasis? What are the effects of treating asymptomatic non-pregnant women with a positive swab for candidiasis? We searched: Medline, Embase, The Cochrane Library, and other important databases up to March 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 61 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: alternative or complementary treatments; douching; drug treatments; garlic; intravaginal preparations (boric acid, nystatin, imidazoles, tea tree oil); oral fluconazole; oral itraconazole; treating a male sexual partner; and yoghurt containing Lactobacillus acidophilus (oral or vaginal).
Key Points
Vulvovaginal candidiasis is characterised by vulval itching and abnormal "cheese-like" or watery vaginal discharge. Vulvovaginal candidiasis is estimated to be the second most common cause of vaginitis after bacterial vaginosis. Candida albicans accounts for 85% to 90% of cases.Risk factors include pregnancy, diabetes mellitus, and systemic antibiotics. Incidence increases with the onset of sexual activity, but associations with different types of contraceptives are unclear.Recurrent symptoms are common, but are caused by candidiasis in only one third of cases.
Intravaginal imidazoles reduce symptoms of acute vulvovaginal candidiasis in non-pregnant women. Intravaginal imidazoles (butoconazole, clotrimazole, miconazole) reduce symptoms compared with placebo and all seem to have similar efficacy compared with each other. RCTs suggest that single-dose regimens may be as effective as multiple-dose regimens.Intravaginal imidazoles and oral fluconazole or itraconazole seem equally effective in treating acute attacks.
Intravaginal nystatin reduces symptoms compared with placebo, but we don't know how it compares with intravaginal imidazoles or oral fluconazole or itraconazole.
The benefits of other intravaginal treatments, to treat acute attacks or prevent recurrence, remain unclear, and some may be associated with serious adverse effects. We found no RCT evidence assessing intravaginal boric acid or tea tree oil.We found no RCT evidence assessing garlic or yoghurt, used intravaginally or orally.We found no RCT evidence on efficacy of douching, but it is associated with serious adverse effects such as PID and infections, endometritis, and ectopic pregnancy. Oral fluconazole and itraconazole are likely to be beneficial in preventing recurrence of infection. Treating the woman's male sexual partner does not reduce symptoms or prevent recurrence in the woman.
PMCID: PMC2907618  PMID: 21718579
12.  Protective Efficacy and Safety of Three Antimalarial Regimens for the Prevention of Malaria in Young Ugandan Children: A Randomized Controlled Trial 
PLoS Medicine  2014;11(8):e1001689.
Grant Dorsey and colleagues investigate the efficacy of three antimalarial drugs for preventing malaria in children living in Uganda, an area of high transmission intensity.
Please see later in the article for the Editors' Summary
Background
Chemoprevention offers a promising strategy for prevention of malaria in African children. However, the optimal chemoprevention drug and dosing strategy is unclear in areas of year-round transmission and resistance to many antimalarial drugs. To compare three available regimens, we conducted an open-label randomized controlled trial of chemoprevention in Ugandan children.
Methods and Findings
This study was conducted between June 28, 2010, and September 25, 2013. 400 infants were enrolled and 393 randomized at 6 mo of age to no chemoprevention, monthly sulfadoxine-pyrimethamine (SP), daily trimethoprim-sulfamethoxazole (TS), or monthly dihydroartemisinin-piperaquine (DP). Study drugs were administered at home without supervision. Piperaquine (PQ) levels were used as a measure of compliance in the DP arm. Participants were given insecticide-treated bednets, and caregivers were encouraged to bring their child to a study clinic whenever they were ill. Chemoprevention was stopped at 24 mo of age, and participants followed-up an additional year. Primary outcome was the incidence of malaria during the intervention period. During the intervention, the incidence of malaria in the no chemoprevention arm was 6.95 episodes per person-year at risk. Protective efficacy was 58% (95% CI, 45%–67%, p<0.001) for DP, 28% (95% CI, 7%–44%, p = 0.01) for TS, and 7% for SP (95% CI, −19% to 28%, p = 0.57). PQ levels were below the detection limit 52% of the time when malaria was diagnosed in the DP arm, suggesting non-adherence. There were no differences between the study arms in the incidence of serious adverse events during the intervention and the incidence of malaria during the 1-y period after the intervention was stopped.
Conclusions
For preventing malaria in children living in an area of high transmission intensity, monthly DP was the most efficacious and safe, although adherence may pose a problem. Monthly SP and daily TS may not be appropriate in areas with high transmission intensity and frequent resistance to antifolates.
Trial registration
www.ClinicalTrials.gov NCT00948896
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Malaria is a parasitic disease that kills more than 600,000 people (mainly young children living in sub-Saharan Africa) every year. Malaria parasites, which are transmitted to people through the bites of night-flying mosquitoes, cause a characteristic fever that needs to be treated promptly with antimalarial drugs to prevent anemia and organ damage. Prompt treatment also helps to reduce malaria transmission and is a component of the Global Malaria Action Plan, which aims to control and eventually eliminate malaria. Other components of this plan include the provision of insecticide-treated bednets for people to sleep under to avoid mosquito bites and indoor residual spraying with insecticides. Widespread deployment of these preventative tools and the increased availability of effective antimalarial drugs have greatly reduced malaria-related deaths worldwide over the past decade, but new strategies are still urgently needed to reduce the burden of malaria among those most at risk—young children living in Africa.
Why Was This Study Done?
One promising strategy for the prevention of malaria in African children is the use of antimalarial drugs to prevent rather than treat malaria. In trials, giving infants sulfadoxine-pyrimethamine (SP) alongside routine vaccinations, for example, reduced the incidence of malaria (the number of new cases in the population in a year) by about 30% during the first year of life (a protective efficacy of 30%). However, the optimal chemoprevention drug and dosing strategy for children living in African regions where there is year-round transmission of malaria and where resistance to antimalarial drugs is common remains unclear. Here, the researchers undertake an open-label randomized controlled trial (RCT) of chemoprevention in infants in the Tororo District of eastern Uganda, an area with intense year-round malaria transmission. RCTs compare outcomes in groups of people chosen to receive different interventions through the play of chance; in open-label RCTs, both the researchers and the participants know which treatment is being administered.
What Did the Researchers Do and Find?
The researchers assigned 393 six-month-old infants to receive no chemoprevention, monthly SP, daily trimethoprim-sulfamethoxazole (TS), or monthly dihydroartemisinin-piperaquine (DP) until they were 24 months old. SP and TS block the production of folic acid, which malaria needs for survival, whereas DP is a newer artemisinin-based combination therapy (ACT). All the drugs were given at home without supervision, and caregivers were asked to bring their children to a study clinic whenever they were ill. During the intervention, the incidence of malaria was 6.95 episodes per person-year at risk in the no chemoprevention arm but only three episodes per person-year at risk in the DP arm. That is, the protective efficacy of DP was 58%. By contrast, the protective efficacies of TS and SP were 28% and 7%, respectively. However, for SP the protective efficacy was not statistically different compared to the no chemoprevention arm. Notably, piperaquine levels on the day that malaria was diagnosed were below the detection limit in half of the malaria episodes in the DP arm, which suggests that a complete dose of DP had not been given to the infant in the previous month, despite caregivers reporting that they had administered virtually all the assigned doses. Finally, the incidence of serious adverse events was similar in all the study arms during the intervention, as was the incidence of malaria during the year after the intervention, which suggests that the chemoprevention strategies did not affect the development of naturally acquired immunity.
What Do These Findings Mean?
These findings show that, for children living in an area of intense malaria transmission, monthly DP was the most efficacious strategy for malaria chemoprevention but that adherence to the strategy may have been a problem. These findings also suggest that monthly SP and daily TS may not be appropriate chemoprevention strategies in areas of high transmission intensity, particularly those where resistance to antifolate drugs is common. The accuracy of these findings may be affected by drug administration being self-reported and by the number of comparisons included in the trial, which may have increased the risk of false-positive results. Moreover, the results of this trial may not be generalizable to other regions of sub-Saharan Africa. Overall, however, these results suggest that monthly DP is a strategy worth considering in regions in need of improved malaria control measures, with the important caveat that widespread ACT use for chemoprevention could compromise the efficacy of ACT when used for treatment.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001689.
Information is available from the World Health Organization on malaria (in several languages), including information on malaria chemoprevention; the World Malaria Report 2013 provides details of the current global malaria situation, including information on malaria in Uganda
The US Centers for Disease Control and Prevention provide information on malaria, including information on ways to reduce malaria cases and deaths; it also provides a selection of personal stories about malaria, including a story about malaria in a child in Africa
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 fact sheets about malaria in Africa and about children and 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.1001689
PMCID: PMC4122345  PMID: 25093754
13.  Statins in the Treatment of Chronic Heart Failure: A Systematic Review 
PLoS Medicine  2006;3(8):e333.
Background
The efficacy of statin therapy in patients with established chronic heart failure (CHF) is a subject of much debate.
Methods and Findings
We conducted three systematic literature searches to assess the evidence supporting the prescription of statins in CHF. First, we investigated the participation of CHF patients in randomized placebo-controlled clinical trials designed to evaluate the efficacy of statins in reducing major cardiovascular events and mortality. Second, we assessed the association between serum cholesterol and outcome in CHF. Finally, we evaluated the ability of statin treatment to modify surrogate endpoint parameters in CHF.
Using validated search strategies, we systematically searched PubMed for our three queries. In addition, we searched the reference lists from eligible studies, used the “see related articles” feature for key publications in PubMed, consulted the Cochrane Library, and searched the ISI Web of Knowledge for papers citing key publications.
Search 1 resulted in the retrieval of 47 placebo-controlled clinical statin trials involving more than 100,000 patients. CHF patients had, however, been systematically excluded from these trials. Search 2 resulted in the retrieval of eight studies assessing the relationship between cholesterol levels and outcome in CHF patients. Lower serum cholesterol was consistently associated with increased mortality. Search 3 resulted in the retrieval of 18 studies on the efficacy of statin treatment in CHF. On the whole, these studies reported favorable outcomes for almost all surrogate endpoints.
Conclusions
Since CHF patients have been systematically excluded from randomized, controlled clinical cholesterol-lowering trials, the effect of statin therapy in these patients remains to be established. Currently, two large, randomized, placebo-controlled statin trials are under way to evaluate the efficacy of statin treatment in terms of reducing clinical endpoints in CHF patients in particular.
A systematic review found that patients with heart failure have been excluded from randomised controlled trials on the use of statins. Evidence from other studies on the effectiveness of statins for patients with heart failure is weak and conflicting.
Editors' Summary
Background.
When medical researchers test a drug—or some other treatment—for a particular medical condition, they often decide not to include in their study anyone who has, in addition to the disease they are interested in, certain other health problems. This is because including patients with two or more conditions can complicate the analysis of the results and make it hard to reach firm conclusions. However, excluding patients in this way can result in uncertainty as to whether treatments are effective for anyone who suffers from the disease in question, or just for people like those who took part in the research.
A great deal of research has been conducted with drugs known as statins, which lower cholesterol levels in the blood. (A raised level of cholesterol is known to be a major risk factor for cardiovascular disease, which causes heart attacks and strokes.) As a result of this research, statins have been accepted as effective and safe. They are now, in consequence, among the most commonly prescribed medicines. Heart failure, however, is not the same thing as a heart attack. It is the name given to the condition where the muscles of the heart have become weakened, most often as a result of aging, and the heart becomes gradually less efficient at pumping blood around the body. (Some people with heart failure live for many years, but 70% of those with the condition die within ten years.) It is common for people with cardiovascular disease also to have heart failure. Nevertheless, some researchers who have studied the effects of statins have made the decision not to include in their studies any patients with cardiovascular disease who, in addition, have heart failure.
Why Was This Study Done?
The researchers in this study were aware that patients with heart failure have often been excluded from statin trials. They felt it was important to assess the available evidence supporting the prescription of statins for such patients. Specifically, they wanted to find out the following: how often have patients with heart failure been included in statin trials, what evidence is available as to whether it is beneficial for patients with heart failure to have low cholesterol, and what evidence is there that prescribing statins helps these patients?
What Did the Researchers Do and Find?
They did not do any new work involving patients. Instead, they did a very thorough search for all relevant studies of good quality that had already been published and they reviewed the results. “Randomized clinical trials” (RCTs) are the most reliable type of medical research. The researchers found there had been 47 such trials (involving over 100,000 patients) on the use of statins for treating cardiovascular disease, but all these trials had excluded heart failure patients. They found eight studies (which were not RCTs) looking at cholesterol levels and heart failure. These studies found, perhaps surprisingly, that death rates were higher in those patients with heart failure who had low cholesterol. However, they also found 18 studies (again not RCTs) on the use of statins in patients with heart failure. These 18 studies seemed to suggest that statins were of benefit to the patients who received them.
What Do These Findings Mean?
The evidence for or against prescribing statins for people with heart failure is limited, conflicting, and unclear. Further research involving RTCs is necessary. (Two such trials are known to be in progress.)
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030333.
General information about statins is available from the Web site of Patient UK
The American Heart Association Web site is a good source of information about all types of heart disease, including heart attacks and heart failure
For a definition of randomized controlled trials see Wikipedia, a free online encyclopedia that anyone can edit
More detailed information about the quality of evidence from medical research may be found in the James Lind Library
doi:10.1371/journal.pmed.0030333
PMCID: PMC1551909  PMID: 16933967
14.  Intermittent Preventive Treatment for Malaria in Papua New Guinean Infants Exposed to Plasmodium falciparum and P. vivax: A Randomized Controlled Trial 
PLoS Medicine  2012;9(3):e1001195.
A three-arm randomized trial conducted among infants in Papua New Guinea estimates the preventive effect against malaria episodes of intermittent preventive treatment, in an area where children are exposed to both falciparum and vivax malaria.
Background
Intermittent preventive treatment in infants (IPTi) has been shown in randomized trials to reduce malaria-related morbidity in African infants living in areas of high Plasmodium falciparum (Pf) transmission. It remains unclear whether IPTi is an appropriate prevention strategy in non-African settings or those co-endemic for P. vivax (Pv).
Methods and Findings
In this study, 1,121 Papua New Guinean infants were enrolled into a three-arm placebo-controlled randomized trial and assigned to sulfadoxine-pyrimethamine (SP) (25 mg/kg and 1.25 mg/kg) plus amodiaquine (AQ) (10 mg/kg, 3 d, n = 374), SP plus artesunate (AS) (4 mg/kg, 3 d, n = 374), or placebo (n = 373), given at 3, 6, 9 and 12 mo. Both participants and study teams were blinded to treatment allocation. The primary end point was protective efficacy (PE) against all episodes of clinical malaria from 3 to 15 mo of age. Analysis was by modified intention to treat. The PE (compared to placebo) against clinical malaria episodes (caused by all species) was 29% (95% CI, 10–43, p≤0.001) in children receiving SP-AQ and 12% (95% CI, −11 to 30, p = 0.12) in those receiving SP-AS. Efficacy was higher against Pf than Pv. In the SP-AQ group, Pf incidence was 35% (95% CI, 9–54, p = 0.012) and Pv incidence was 23% (95% CI, 0–41, p = 0.048) lower than in the placebo group. IPTi with SP-AS protected only against Pf episodes (PE = 31%, 95% CI, 4–51, p = 0.027), not against Pv episodes (PE = 6%, 95% CI, −24 to 26, p = 0.759). Number of observed adverse events/serious adverse events did not differ between treatment arms (p>0.55). None of the serious adverse events were thought to be treatment-related, and the vomiting rate was low in both treatment groups (1.4%–2.0%). No rebound in malaria morbidity was observed for 6 mo following the intervention.
Conclusions
IPTi using a long half-life drug combination is efficacious for the prevention of malaria and anemia in infants living in a region highly endemic for both Pf and Pv.
Trial registration
ClinicalTrials.gov NCT00285662
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Malaria is a major global public health problem. Half the world's population is at risk of this parasitic disease, which kills about one million people (mainly young children in sub-Saharan Africa) every year. Most of these deaths are caused by Plasmodium falciparum but P. vivax, the commonest and most widely distributed malaria parasite, is a major cause of malaria-related morbidity (illness and death) in many of the tropical and subtropical regions of the world where malaria is endemic (always present). Malaria is transmitted to people through the bites of night-flying mosquitoes. It can be prevented by controlling the mosquitoes that spread the parasite and by sleeping under insecticide-treated nets to avoid mosquito bites. Prompt treatment of malaria with antimalarial drugs can also reduce malaria transmission. In addition, intermittent preventative treatment (IPT)—the treatment of symptom-free individuals with full therapeutic courses of antimalarial drugs at fixed intervals regardless of their infection status—has been shown to reduce malaria-related morbidity among pregnant women in malaria-endemic areas and among African infants living in areas of high P. falciparum transmission.
Why Was This Study Done?
The World Health Organization recently recommended that, in Africa, IPT should be given during infancy (called IPTi) at the same time as routine immunizations. Because the studies on which this recommendation is based were all carried out in sub-Saharan Africa, in populations where P. falciparum is the predominant parasite and P. vivax is uncommon, it is not known whether IPTi would be an appropriate prevention strategy in non-African settings or in regions where both P. falciparum and P. vivax are endemic. In this randomized placebo-controlled trial, the researchers investigate the efficacy of IPTi in infants living in an area of Papua New Guinea where P. falciparum and P. vivax are both highly endemic. In a randomized placebo-controlled trial, the effects of an intervention and of a placebo (dummy) intervention are compared in groups of individuals chosen through the play of chance.
What Did the Researchers Do and Find?
The researchers assigned more than 1,000 infants to receive sulfadoxine/pyrimethamine (SP) plus amodiaquine (AQ) (SP and AQ are long-lasting antimalarial drugs), SP plus artesunate (AS) (AS is a short-lasting antimalarial), or placebo at 3, 6, 9, and 12 months old. They recorded the number of malaria episodes that occurred among the children between the ages of 3 and 15 months. Then, by comparing the number of episodes occurring among the children receiving SP-AS or SP-AQ with the number occurring among the children receiving placebo, the researchers calculated the protective efficacy of the two drug combinations over the study period. The protective efficacy of IPTi against all clinical malaria episodes (P. falciparum and P. vivax combined) was 29% for SP-AQ, but SP-AS was not associated with a statistically significant reduction in all malaria episodes as compared to placebo. For the two species of malaria separately, the incidence of P. falciparum malaria was 35% lower among the children receiving SP-AQ than among the children receiving placebo, whereas the incidence of P. vivax was reduced by 23%; IPTi with SP-AS provided protection only against P. falciparum malaria (protective efficacy 31%). Importantly, the number of adverse events (possible drug side effects) was similar in all the treatment arms, none of the severe adverse events were treatment-related, and there was no rebound in malaria-related morbidity for six months following the end of the intervention.
What Do These Findings Mean?
These findings show that IPTi using a combination of long-lasting antimalarial drugs (SP-AQ) can effectively and safely prevent malaria in a non-African population living in a region where P. falciparum and P. vivax are both highly endemic. Importantly, they also show that IPTi with SP-AQ can prevent both P. falciparum and P. vivax malaria. For Papua New Guinea, these findings suggest that SP-AQ is an appropriate drug choice for IPTi, particularly since the replacement of SP-AQ by artemether-lumefantrine as the national first line treatment for malaria will reduce the selection pressure for resistance against SP and AQ. However, although these finding provide proof-of-principle evidence for the efficacy and safety of IPTi, further studies are needed to identify the most effective combinations of long-lasting antimalarial drugs for use in IPTi in other malaria-endemic regions.
Additional Information
Please access these web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001195.
Information is available from the World Health Organization on malaria (in several languages); the 2011 World Malaria Report provides details of the current global malaria situation; and the WHO policy recommendation on IPTi for P. falciparum malaria control in Africa is 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 a fact sheet about malaria in children and information on malaria in Papua New Guinea
The IPTi Consortium was established to evaluate IPTi and inform public health policy making
The Malaria Vaccine Initiative has a fact sheet on P. vivax malaria
Vivaxmalaria.com provides information about P. vivax
MedlinePlus provides links to additional information on malaria (in English and Spanish)
doi:10.1371/journal.pmed.1001195
PMCID: PMC3313928  PMID: 22479155
15.  Knowledge, Self-Efficacy, and Perceived Barriers on the Low-Iodine Diet among Thyroid Cancer Patients Preparing for Radioactive Iodine Therapy 
Clinical Nutrition Research  2012;1(1):13-22.
The purposes of the study were to assess knowledge, self-efficacy, and perceived barriers on a low-iodine diet among thyroid cancer patients and to identify strategies for nutrition education. A self-administered questionnaire was developed based on a review of literature and pilot-tested. A total of 121 female thyroid cancer patients participated in a survey and 117 responses were used for data analysis. An average knowledge score of the thyroid cancer patients was 4.5 point (available score: 0-10 point). Majority of the respondents knew that seaweeds such as lavers, brown seaweeds, and sea tangles contain large amount of iodine. However they mistook the low iodine diet as a low salt diet and were not aware of foods and seasonings that are allowed on the low iodine diet. While self-efficacy related to consuming various fruits and vegetables, to choosing potatoes and sweet potatoes for snacks, and restricting consumption of eggs, milk and milk products, and processed foods was rated highly, self-efficacy for preparing foods without using sea salts was rated low. The self-efficacy score increased as their interest on the dietary life and perceived cooking skills were greater. Most perceived barriers toward practicing the low iodine diet were related to preparation of the low iodine menus. As their interest in the dietary life and cooking and perceived cooking skills were greater, the patients perceived barriers on practicing the low iodine diet less. While the patients showed higher self-efficacy and lower barrier perception on selecting foods low in iodine and restricting food high in iodine, they showed lower self-efficacy and higher barrier perceptions on preparing low iodine meals. Clinical dietitians should recognize the gap between what the patients should know and what they really know and identify strategies on how to improve self-efficacy and reduce perceived barriers on the low iodine diet. Recent literature and the findings of the study reveal that incorporating cooking classes into nutrition education for thyroid patients is effective to enhance self-efficacy and to reduce perceived barriers on the low iodine diet.
doi:10.7762/cnr.2012.1.1.13
PMCID: PMC3572801  PMID: 23430156
Self-efficacy; Knowledge; Perceived barriers; Low iodine diet; Radioactive iodine therapy
16.  Malaria Burden and Artemisinin Resistance in the Mobile and Migrant Population on the Thai–Myanmar Border, 1999–2011: An Observational Study 
PLoS Medicine  2013;10(3):e1001398.
Francois Nosten and colleagues evaluate malaria prevalence and incidence in the mobile population on the Myanmar side of the border with Thailand between 1999 and 2011, and also assess resistance to artemisinin.
Background
The Shoklo Malaria Research Unit has been working on the Thai–Myanmar border for 25 y providing early diagnosis and treatment (EDT) of malaria. Transmission of Plasmodium falciparum has declined, but resistance to artesunate has emerged. We expanded malaria activities through EDT and evaluated the impact over a 12-y period.
Methods and Findings
Between 1 October 1999 and 30 September 2011, the Shoklo Malaria Research Unit increased the number of cross-border (Myanmar side) health facilities from two to 11 and recorded the number of malaria consultations. Changes in malaria incidence were estimated from a cohort of pregnant women, and prevalence from cross-sectional surveys. In vivo and in vitro antimalarial drug efficacy were monitored. Over this period, the number of malaria cases detected increased initially, but then declined rapidly. In children under 5 y, the percentage of consultations due to malaria declined from 78% (95% CI 76–80) (1,048/1,344 consultations) to 7% (95% CI 6.2–7.1) (767/11,542 consultations), p<0.001. The ratio of P. falciparum/P. vivax declined from 1.4 (95% CI 1.3–1.4) to 0.7 (95% CI 0.7–0.8). The case fatality rate was low (39/75,126; 0.05% [95% CI 0.04–0.07]). The incidence of malaria declined from 1.1 to 0.1 episodes per pregnant women-year. The cumulative proportion of P. falciparum decreased significantly from 24.3% (95% CI 21.0–28.0) (143/588 pregnant women) to 3.4% (95% CI 2.8–4.3) (76/2,207 pregnant women), p<0.001. The in vivo efficacy of mefloquine-artesunate declined steadily, with a sharp drop in 2011 (day-42 PCR-adjusted cure rate 42% [95% CI 20–62]). The proportion of patients still slide positive for malaria at day 3 rose from 0% in 2000 to reach 28% (95% CI 13–45) (8/29 patients) in 2011.
Conclusions
Despite the emergence of resistance to artesunate in P. falciparum, the strategy of EDT with artemisinin-based combination treatments has been associated with a reduction in malaria in the migrant population living on the Thai–Myanmar border. Although limited by its observational nature, this study provides useful data on malaria burden in a strategically crucial geographical area. Alternative fixed combination treatments are needed urgently to replace the failing first-line regimen of mefloquine and artesunate.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
According to latest figures, the World Health Organization estimates that there are over 200 million cases of malaria each year, with over three-quarters of a million deaths. Several Plasmodium parasites cause malaria (the most serious being Plasmodium falciparum) and are transmitted to people through the bites of infected night-flying mosquitoes. Malaria transmission can be prevented by using insecticides to control the mosquitoes and by sleeping under insecticide-treated bed nets. However, in Southeast Asia the effectiveness of these measures is limited. Treating infected people with antimalarial drugs, particularly with artemisinin-based combination treatments (ACTs), is a key strategy in reducing the deaths and disability caused by malaria. However, progress is now threatened by the emergence in Southeast Asia of P. falciparum isolates that are resistant to artesunate (a common component of ACT). This development is concerning, as resistance to the artemisinin family of drugs, of which artesunate is a member, could trigger a resurgence in malaria in many parts of the world and compromise the progress made in the treatment of severe malaria.
Why Was This Study Done?
P. falciparum resistance to artemisinin has been confirmed in the area around the border between Thailand and Myanmar. Malaria control in this border area is particularly challenging, as there is a reservoir of malaria in Myanmar (where the disease burden is higher than in Thailand), frequent population movement, and differences in adequate control measures on the two sides of the border. In this study the authors evaluated malaria prevalence and incidence in the mobile population on the Myanmar side of the border between 1 October 1999 and 30 September 2011 to assess whether increasing access to early diagnosis and treatment with ACT was associated with a decline in the malaria burden.
What Did the Researchers Do and Find?
The Shoklo Malaria Research Unit (SMRU) has been working on the Thai–Myanmar border for 25 years providing early diagnosis and treatment of malaria and has extended its services from two to 11 health care facilities (health posts) on the Myanmar side of the border over the past few years. In order to evaluate any changes in the malaria burden since the expansion of services, the researchers recorded the number of consultations in all SMRU clinics and health posts with confirmed malaria diagnosis and tracked changes in the prevalence of malaria in the population on the Myanmar side of the border (via cross-sectional surveys in villages). The researchers also assessed the incidence of malaria in a cohort of pregnant women living on both sides of the border and monitored antimalarial drug efficacy over this time period.
The researchers found that although the mobile population on the Thai side of the border remained constant, the population in villages covered by the clinics and health posts in the border area increased four-fold. Over the time period, the researchers found that the number of confirmed malaria cases (P. falciparum) increased initially, rising from just over 5,000 in 2000 to a peak of 13,764 in 2006, and then declined to just over 3,500 in 2011. A striking finding was the predominance of infections in young adult males (50,316/90,321; 55.7%). Encouragingly, the percentage of consultations due to malaria in children under five years fell from 78% to 7%, and the incidence of malaria declined from 1.1 to 0.1 episodes per pregnant woman-year. In addition, the proportion of patients admitted to hospital with severe disease was stable, and the number of deaths from malaria remained extremely low, with an overall case fatality rate of 0.05%. The researchers also found that the ratio of P. falciparum to P. vivax infections declined from 1.4 to 0.7, and the prevalence of P. falciparum decreased from 24.3% to 3.4%. However, worryingly, in the small number of patients undertaking drug efficacy tests, the drug efficacy of artesunate declined steadily, with the proportion of patients still infected with malaria at day 3 of treatment increasing from 0% in 2000 to 28% in 2011.
What Do These Findings Mean?
These findings indicate that despite the emergence of resistance to artesunate in P. falciparum, and the decline in the efficacy of ACT, the strategy of early diagnosis and treatment with ACTs has been associated with a reduction in malaria in the population living on the Thai–Myanmar border. Furthermore, these findings suggest that an aggressive strategy based on early detection and treatment of cases, combined with vector control and information, could be the way forward to eliminate malaria. Although there were only a small number of patients involved in drug efficacy tests in 2011, this study shows that alternative fixed combination treatments are needed urgently to replace the failing first-line regimen of mefloquine and artesunate.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001398.
More information about the Shoklo Malaria Research Unit is available
The World Health Organization website has more information about antimalarial drug efficacy and drug resistance
The Bill & Melinda Gates Foundation website tells the malaria resistance story
doi:10.1371/journal.pmed.1001398
PMCID: PMC3589269  PMID: 23472056
17.  Artemisinin Combination Therapies for Treatment of Uncomplicated Malaria in Uganda 
PLoS Clinical Trials  2006;1(1):e7.
Objectives:
To compare the efficacy and safety of artemisinin combination therapies for the treatment of uncomplicated falciparum malaria in Uganda.
Design:
Randomized single-blind controlled trial.
Setting:
Tororo, Uganda, an area of high-level malaria transmission.
Participants:
Children aged one to ten years with confirmed uncomplicated P. falciparum malaria.
Interventions:
Amodiaquine + artesunate or artemether–lumefantrine.
Outcome Measures:
Risks of recurrent symptomatic malaria and recurrent parasitemia at 28 days, unadjusted and adjusted by genotyping to distinguish recrudescences and new infections.
Results:
Of 408 participants enrolled, 403 with unadjusted efficacy outcomes were included in the per-protocol analysis. Both treatment regimens were highly efficacious; no recrudescences occurred in patients treated with amodiaquine + artesunate, and only two occurred in those treated with artemether–lumefantrine. However, recurrent malaria due to new infections was common. The unadjusted risk of recurrent symptomatic malaria was significantly lower for participants treated with artemether–lumefantrine than for those treated with amodiaquine + artesunate (27% versus 42%, risk difference 15%, 95% CI 5.9%–24.2%). Similar results were seen for the risk of recurrent parasitemia (51% artemether–lumefantrine versus 66% amodiaquine + artesunate, risk difference 16%, 95% CI 6.2%–25.2%). Amodiaquine + artesunate and artemether–lumefantrine were both well-tolerated. Serious adverse events were uncommon with both regimens.
Conclusions:
Amodiaquine + artesunate and artemether–lumefantrine were both highly efficacious for treatment of uncomplicated malaria. However, in this holoendemic area, despite the excellent performance of both regimens in terms of efficacy, many patients experienced recurrent parasitemia due to new infections. Artemether–lumefantrine was superior to amodiaquine + artesunate for prevention of new infections. To maximize the benefit of artemisinin combination therapy in Africa, treatment should be integrated with strategies to prevent malaria transmission. The impact of frequent repeated therapy on the efficacy, safety, and cost-effectiveness of new artemisinin regimens should be further investigated.
Editorial Commentary
Background: Malaria parasites have become resistant in much of Africa to many commonly used treatments, such as chloroquine and sulfadoxine–pyrimethamine. Newer drugs, such as artemisinin-based combination therapies (ACTs), have been used extensively in Southeast Asia. Artemether–lumefantrine (an ACT) has now been adopted as first-line malaria treatment in Uganda, with the combination of amodiaquine and artesunate as a backup treatment. There are two ways that successful treatment is measured; first by whether the treatment works in curing the infection; and second by whether it prevents the disease recurring—either the same infection (known as recrudescence), or a new infection. The researchers wanted to look at how artemether–lumefantrine compared with amodiaquine and artesunate for treating symptomatic malaria, and also at whether there were any differences in recurrence, either of clinical malaria, or of parasite infection without symptoms, for 28 days after treatment.
What this trial shows: This randomized trial in young children with confirmed malaria in Uganda showed that both treatments resulted in a similar initial response to therapy, as measured by the risk of early treatment failure (within three days). The researchers found that artemether–lumefantrine was more effective at reducing the risk and delayed the time to recurrence of malaria, compared with amodiaquine and artesunate. Additionally, treatment with artemether–lumefantrine resulted in a reduced rate of parasite infection without malaria symptoms, as compared with amodiaquine and artesunate. Nearly all cases of recurrent malaria after either treatment combination arose from new infections, rather than from recrudescences.
Strengths and limitations: The trial was correctly designed to test the questions of interest, and enough patients were recruited to properly examine the relative effects of the two treatment combinations. However, patients were only followed up for 28 days after treatment. A longer follow-up period might have revealed a higher rate of recurrence of malaria after treatment. In the trial, artemether–lumefantrine was not administered with food, and it's known that lumefantrine is absorbed better when it is taken with a small amount of fat. It's possible that the effect of artemether–lumefantrine seen in the trial could have been an underestimate of what might be achieved in ideal conditions.
Contribution to the evidence: This trial adds information on the efficacy of artemether–lumefantrine as compared with amodiaquine and artesunate in East Africa for treatment of uncomplicated (i.e., non-severe) symptomatic malaria. The results are consistent with those of other trials on the efficacy of ACTs that have been performed in the region. The study also adds data on the risk of recurrent infections in an area where malaria occurs very frequently. Even following treatment with either ACT, the risk of recurrence was very high.
doi:10.1371/journal.pctr.0010007
PMCID: PMC1488893  PMID: 16871329
18.  Young Men’s Shame about Their Desire for other Men Predicts Risky Sex and Moderates the Knowledge – Self-Efficacy Link 
Background: Nationally, HIV incidence is rising rapidly among young (18–24 years old) men who have sex with men (YMSM). Knowledge of safer sex generally enhances self-efficacy for safer sex, an important predictor of safer-sex behaviors. Recent findings suggest that a strong negative social emotion (i.e., shame) increases YMSM’s sexual risk-taking. Unchangeable shame (e.g., desire for other men) might undermine (moderate) the link between knowledge and self-efficacy or between self-efficacy and unprotected anal intercourse (UAI): this may be less likely for changeable shame (e.g., shame about risky sexual behavior).
Aim: To test the hypotheses that shame (i.e., sexual desire shame), but not shame about behavior (i.e., sexual behavior shame), will be positively related to UAI and will moderate the relationship between knowledge and self-efficacy and/or self-efficacy and UAI among YMSM.
Method: In an online national study, 1177 young adult (18–24 years old) MSM reported one or more acts of UAI in the past 90 days with a casual partner. Eligible MSM filled out a survey in which they provided information about their knowledge of safer sex, self-efficacy for safer sex, reported levels of shame, and reported past 90-day UAI.
Results: Sexual desire shame was negatively correlated with knowledge and self-efficacy and positively correlated with UAI, the pattern reversed for sexual behavior shame. Sexual desire shame significantly lowered the knowledge to self-efficacy and the self-efficacy to UAI links. Sexual behavior shame also reduced the link from knowledge to self-efficacy, but not the self-efficacy to UAI link.
Conclusion: The present study shows that there are different types of shame that may produce different effects with different implications for health behavior. Sexual desire shame may better reflect an emotion that is activated prior to risky behavior (e.g., when men reflect upon or feel desire for another man). Sexual behavior shame, on the other hand, better reflects what has already happened, thus, those higher in knowledge, efficacy, and therefore, safer sex are least likely to experience shame behavior.
doi:10.3389/fpubh.2014.00183
PMCID: PMC4202720  PMID: 25368860
young MSM; young adult; shame; self-efficacy; safe sex; sex behaviors; safe-sex knowledge; HIV/AIDS
19.  Schizophrenia 
Clinical Evidence  2012;2012:1007.
Introduction
The lifetime prevalence of schizophrenia is approximately 0.7% and incidence rates vary between 7.7 and 43.0 per 100,000; about 75% of people have relapses and continued disability, and one third fail to respond to standard treatment. Positive symptoms include auditory hallucinations, delusions, and thought disorder. Negative symptoms (demotivation, self-neglect, and reduced emotion) have not been consistently improved by any treatment.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of drug treatments for positive, negative, or cognitive symptoms of schizophrenia? What are the effects of drug treatments in people with schizophrenia who are resistant to standard antipsychotic drugs? What are the effects of interventions to improve adherence to antipsychotic medication in people with schizophrenia? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 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 51 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: amisulpride, chlorpromazine, clozapine, depot haloperidol decanoate, haloperidol, olanzapine, pimozide, quetiapine, risperidone, sulpiride, ziprasidone, zotepine, aripiprazole, sertindole, paliperidone, flupentixol, depot flupentixol decanoate, zuclopenthixol, depot zuclopenthixol decanoate, behavioural therapy, clozapine, compliance therapy, first-generation antipsychotic drugs in treatment-resistant people, multiple-session family interventions, psychoeducational interventions, and second-generation antipsychotic drugs in treatment-resistant people.
Key Points
The lifetime prevalence of schizophrenia is approximately 0.7% and incidence rates vary between 7.7 and 43.0 per 100,000; about 75% of people have relapses and continued disability, and one third fail to respond to standard treatment. Positive symptoms include auditory hallucinations, delusions, and thought disorder. Negative symptoms (anhedonia, asociality, flattening of affect, and demotivation) and cognitive dysfunction have not been consistently improved by any treatment.
Standard treatment of schizophrenia has been antipsychotic drugs, the first of which included chlorpromazine and haloperidol, but these so-called first-generation antipsychotics can all cause adverse effects such as extrapyramidal adverse effects, hyperprolactinaemia, and sedation. Attempts to address these adverse effects led to the development of second-generation antipsychotics.
The second-generation antipsychotics amisulpride, clozapine, olanzapine, and risperidone may be more effective at reducing positive symptoms compared with first-generation antipsychotic drugs, but may cause similar adverse effects, plus additional metabolic effects such as weight gain.
CAUTION: Clozapine has been associated with potentially fatal blood dyscrasias. Blood monitoring is essential, and it is recommended that its use be limited to people with treatment-resistant schizophrenia.
Pimozide, quetiapine, aripiprazole, sulpiride, ziprasidone, and zotepine seem to be as effective as standard antipsychotic drugs at improving positive symptoms. Again, these drugs cause similar adverse effects to first-generation antipsychotics and other second-generation antipsychotics.
CAUTION: Pimozide has been associated with sudden cardiac death at doses above 20 mg daily.
We found very little evidence regarding depot injections of haloperidol decanoate, flupentixol decanoate, or zuclopenthixol decanoate; thus, we don’t know if they are more effective than oral treatments at improving symptoms.
In people who are resistant to standard antipsychotic drugs, clozapine may improve symptoms compared with first-generation antipsychotic agents, but this benefit must be balanced against the likelihood of adverse effects. We found limited evidence on other individual first- or second-generation antipsychotic drugs other than clozapine in people with treatment-resistant schizophrenia.In people with treatment-resistant schizophrenia, we don't know how second-generation agents other than clozapine compare with each other or first-generation antipsychotic agents, or how clozapine compares with other second-generation antipsychotic agents, because of a lack of evidence.
We don't know whether behavioural interventions, compliance therapy, psychoeducational interventions, or family interventions improve adherence to antipsychotic medication compared with usual care because of a paucity of good-quality evidence.
It is clear that some included studies in this review have serious failings and that the evidence base for the efficacy of antipsychotic medication and other interventions is surprisingly weak. For example, although in many trials haloperidol has been used as the standard comparator, the clinical trial evidence for haloperidol is less impressive may be expected.
By their very nature, systematic reviews and RCTs provide average indices of probable efficacy in groups of selected individuals. Although some RCTs limit inclusion criteria to a single category of diagnosis, many studies include individuals with different diagnoses such as schizoaffective disorder. In all RCTs, even in those recruiting people with a single DSM or ICD-10 diagnosis, there is considerable clinical heterogeneity.
Genome-wide association studies of large samples with schizophrenia demonstrate that this clinical heterogeneity reflects, in turn, complex biological heterogeneity. For example, genome-wide association studies suggest that around 1000 genetic variants of low penetrance and other individually rare genetic variants of higher penetrance, along with epistasis and epigenetic mechanisms, are thought to be responsible, probably with the biological and psychological effects of environmental factors, for the resultant complex clinical phenotype. A more stratified approach to clinical trials would help to identify those subgroups that seem to be the best responders to a particular intervention.
To date, however, there is little to suggest that stratification on the basis of clinical characteristics successfully helps to predict which drugs work best for which people. There is a pressing need for the development of biomarkers with clinical utility for mental health problems. Such measures could help to stratify clinical populations or provide better markers of efficacy in clinical trials, and would complement the current use of clinical outcome scales. Clinicians are also well aware that many people treated with antipsychotic medication develop significant adverse effects such as extrapyramidal symptoms or weight gain. Again, our ability to identify which people will develop which adverse effects is poorly developed, and might be assisted by using biomarkers to stratify populations.
The results of this review tend to indicate that as far as antipsychotic medication goes, current drugs are of limited efficacy in some people, and that most drugs cause adverse effects in most people. Although this is a rather downbeat conclusion, it should not be too surprising, given clinical experience and our knowledge of the pharmacology of the available antipsychotic medication. All currently available antipsychotic medications have the same putative mechanism of action — namely, dopaminergic antagonism with varying degrees of antagonism at other receptor sites. More efficacious antipsychotic medication awaits a better understanding of the biological pathogenesis of these conditions so that rational treatments can be developed.
PMCID: PMC3385413  PMID: 23870705
20.  Computerized Cognitive Training in Cognitively Healthy Older Adults: A Systematic Review and Meta-Analysis of Effect Modifiers 
PLoS Medicine  2014;11(11):e1001756.
Michael Valenzuela and colleagues systematically review and meta-analyze the evidence that computerized cognitive training improves cognitive skills in older adults with normal cognition.
Please see later in the article for the Editors' Summary
Background
New effective interventions to attenuate age-related cognitive decline are a global priority. Computerized cognitive training (CCT) is believed to be safe and can be inexpensive, but neither its efficacy in enhancing cognitive performance in healthy older adults nor the impact of design factors on such efficacy has been systematically analyzed. Our aim therefore was to quantitatively assess whether CCT programs can enhance cognition in healthy older adults, discriminate responsive from nonresponsive cognitive domains, and identify the most salient design factors.
Methods and Findings
We systematically searched Medline, Embase, and PsycINFO for relevant studies from the databases' inception to 9 July 2014. Eligible studies were randomized controlled trials investigating the effects of ≥4 h of CCT on performance in neuropsychological tests in older adults without dementia or other cognitive impairment. Fifty-two studies encompassing 4,885 participants were eligible. Intervention designs varied considerably, but after removal of one outlier, heterogeneity across studies was small (I2 = 29.92%). There was no systematic evidence of publication bias. The overall effect size (Hedges' g, random effects model) for CCT versus control was small and statistically significant, g = 0.22 (95% CI 0.15 to 0.29). Small to moderate effect sizes were found for nonverbal memory, g = 0.24 (95% CI 0.09 to 0.38); verbal memory, g = 0.08 (95% CI 0.01 to 0.15); working memory (WM), g = 0.22 (95% CI 0.09 to 0.35); processing speed, g = 0.31 (95% CI 0.11 to 0.50); and visuospatial skills, g = 0.30 (95% CI 0.07 to 0.54). No significant effects were found for executive functions and attention. Moderator analyses revealed that home-based administration was ineffective compared to group-based training, and that more than three training sessions per week was ineffective versus three or fewer. There was no evidence for the effectiveness of WM training, and only weak evidence for sessions less than 30 min. These results are limited to healthy older adults, and do not address the durability of training effects.
Conclusions
CCT is modestly effective at improving cognitive performance in healthy older adults, but efficacy varies across cognitive domains and is largely determined by design choices. Unsupervised at-home training and training more than three times per week are specifically ineffective. Further research is required to enhance efficacy of the intervention.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
As we get older, we notice many bodily changes. Our hair goes grey, we develop new aches and pains, and getting out of bed in the morning takes longer than it did when we were young. Our brain may also show signs of aging. It may take us longer to learn new information, we may lose our keys more frequently, and we may forget people's names. Cognitive decline—developing worsened thinking, language, memory, understanding, and judgment—can be a normal part of aging, but it can also be an early sign of dementia, a group of brain disorders characterized by a severe, irreversible decline in cognitive functions. We know that age-related physical decline can be attenuated by keeping physically active; similarly, engaging in activities that stimulate the brain throughout life is thought to enhance cognition in later life and reduce the risk of age-related cognitive decline and dementia. Thus, having an active social life and doing challenging activities that stimulate both the brain and the body may help to stave off cognitive decline.
Why Was This Study Done?
“Brain training” may be another way of keeping mentally fit. The sale of computerized cognitive training (CCT) packages, which provide standardized, cognitively challenging tasks designed to “exercise” various cognitive functions, is a lucrative and expanding business. But does CCT work? Given the rising global incidence of dementia, effective interventions that attenuate age-related cognitive decline are urgently needed. However, the impact of CCT on cognitive performance in older adults is unclear, and little is known about what makes a good CCT package. In this systematic review and meta-analysis, the researchers assess whether CCT programs improve cognitive test performance in cognitively healthy older adults and identify the aspects of cognition (cognitive domains) that are responsive to CCT, and the CCT design features that are most important in improving cognitive performance. A systematic review uses pre-defined criteria to identify all the research on a given topic; meta-analysis uses statistical methods to combine the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 51 trials that investigated the effects of more than four hours of CCT on nearly 5,000 cognitively healthy older adults by measuring several cognitive functions before and after CCT. Meta-analysis of these studies indicated that the overall effect size for CCT (compared to control individuals who did not participate in CCT) was small but statistically significant. An effect size quantifies the difference between two groups; a statistically significant result is a result that is unlikely to have occurred by chance. So, the meta-analysis suggests that CCT slightly increased overall cognitive function. Notably, CCT also had small to moderate significant effects on individual cognitive functions. For example, some CCT slightly improved nonverbal memory (the ability to remember visual images) and working memory (the ability to remember recent events; short-term memory). However, CCT had no significant effect on executive functions (cognitive processes involved in planning and judgment) or attention (selective concentration on one aspect of the environment). The design of CCT used in the different studies varied considerably, and “moderator” analyses revealed that home-based CCT was not effective, whereas center-based CCT was effective, and that training sessions undertaken more than three times a week were not effective. There was also some weak evidence suggesting that CCT sessions lasting less than 30 minutes may be ineffective. Finally, there was no evidence for the effectiveness of working memory training by itself (for example, programs that ask individuals to recall series of letters).
What Do These Findings Mean?
These findings suggest that CCT produces small improvements in cognitive performance in cognitively healthy older adults but that the efficacy of CCT varies across cognitive domains and is largely determined by design aspects of CCT. The most important result was that “do-it-yourself” CCT at home did not produce improvements. Rather, the small improvements seen were in individuals supervised by a trainer in a center and undergoing sessions 1–3 times a week. Because only cognitively healthy older adults were enrolled in the studies considered in this systematic review and meta-analysis, these findings do not necessarily apply to cognitively impaired individuals. Moreover, because all the included studies measured cognitive function immediately after CCT, these findings provide no information about the durability of the effects of CCT or about how the effects of CCT on cognitive function translate into real-life outcomes for individuals such as independence and the long-term risk of dementia. The researchers call, therefore, for additional research into CCT, an intervention that might help to attenuate age-related cognitive decline and improve the quality of life for older individuals.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001756.
This study is further discussed in a PLOS Medicine Perspective by Druin Burch
The US National Institute on Aging provides information for patients and carers about age-related forgetfulness, about memory and cognitive health, and about dementia (in English and Spanish)
The UK National Health Service Choices website also provides information about dementia and about memory loss
MedlinePlus provides links to additional resources about memory, mild cognitive impairment, and dementia (in English and Spanish)
doi:10.1371/journal.pmed.1001756
PMCID: PMC4236015  PMID: 25405755
21.  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
22.  Efficacy of Neonatal HBV Vaccination on Liver Cancer and Other Liver Diseases over 30-Year Follow-up of the Qidong Hepatitis B Intervention Study: A Cluster Randomized Controlled Trial 
PLoS Medicine  2014;11(12):e1001774.
In a 30-year follow-up of the Qidong Hepatitis B Intervention Study, Yawei Zhang and colleagues examine the effects of neonatal vaccination on liver diseases.
Please see later in the article for the Editors' Summary
Background
Neonatal hepatitis B vaccination has been implemented worldwide to prevent hepatitis B virus (HBV) infections. Its long-term protective efficacy on primary liver cancer (PLC) and other liver diseases has not been fully examined.
Methods and Findings
The Qidong Hepatitis B Intervention Study, a population-based, cluster randomized, controlled trial between 1985 and 1990 in Qidong, China, included 39,292 newborns who were randomly assigned to the vaccination group in which 38,366 participants completed the HBV vaccination series and 34,441 newborns who were randomly assigned to the control group in which the participants received neither a vaccine nor a placebo. However, 23,368 (67.8%) participants in the control group received catch-up vaccination at age 10–14 years. By December 2013, a total of 3,895 (10.2%) in the vaccination group and 3,898 (11.3%) in the control group were lost to follow-up. Information on PLC incidence and liver disease mortality were collected through linkage of all remaining cohort members to a well-established population-based tumor registry until December 31, 2013. Two cross-sectional surveys on HBV surface antigen (HBsAg) seroprevalence were conducted in 1996–2000 and 2008–2012. The participation rates of the two surveys were 57.5% (21,770) and 50.7% (17,204) in the vaccination group and 36.3% (12,184) and 58.6% (17,395) in the control group, respectively. Using intention-to-treat analysis, we found that the incidence rate of PLC and the mortality rates of severe end-stage liver diseases and infant fulminant hepatitis were significantly lower in the vaccination group than the control group with efficacies of 84% (95% CI 23%–97%), 70% (95% CI 15%–89%), and 69% (95% CI 34%–85%), respectively. The estimated efficacy of catch-up vaccination on HBsAg seroprevalence in early adulthood was 21% (95% CI 10%–30%), substantially weaker than that of the neonatal vaccination (72%, 95% CI 68%–75%). Receiving a booster at age 10–14 years decreased HBsAg seroprevalence if participants were born to HBsAg-positive mothers (hazard ratio [HR] = 0.68, 95% CI 0.47–0.97). Limitations to consider in interpreting the study results include the small number of individuals with PLC, participants lost to follow-up, and the large proportion of participants who did not provide serum samples at follow-up.
Conclusions
Neonatal HBV vaccination was found to significantly decrease HBsAg seroprevalence in childhood through young adulthood and subsequently reduce the risk of PLC and other liver diseases in young adults in rural China. The findings underscore the importance of neonatal HBV vaccination. Our results also suggest that an adolescence booster should be considered in individuals born to HBsAg-positive mothers and who have completed the HBV neonatal vaccination series.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Hepatitis B is a life-threatening liver infection caused by the hepatitis B virus (HBV). HBV, which is transmitted through contact with the blood or other bodily fluids of an infected person, can cause both acute (short-term) and chronic (long-term) liver infections. Acute infections rarely cause any symptoms and more than 90% of adults who become infected with HBV (usually through sexual intercourse with an infected partner or through the use of contaminated needles) are virus-free within 6 months. However, in sub-Saharan Africa, East Asia, and other regions where HBV infection is common, HBV is usually transmitted from mother to child at birth or between individuals during early childhood and, unfortunately, most infants who are infected with HBV during the first year of life and many children who are infected before the age of 6 years develop a chronic HBV infection. Such infections can cause liver cancer, liver cirrhosis (scarring of the liver), and other fatal liver diseases. In addition, HBV infection around the time of birth can cause infant fulminant hepatitis, a rare but frequently fatal condition.
Why Was This Study Done?
HBV infections kill about 780,000 people worldwide annually but can be prevented by neonatal vaccination—immunization against HBV at birth. A vaccine against HBV became available in 1982 and many countries now include HBV vaccination at birth followed by additional vaccine doses during early childhood in their national vaccination programs. But, although HBV vaccination has greatly reduced the rate of chronic HBV infection, the protective efficacy of neonatal HBV vaccination against liver diseases has not been fully examined. Here, the researchers investigate how well neonatal HBV vaccination protects against primary liver cancer and other liver diseases by undertaking a 30-year follow-up of the Qidong Hepatitis B intervention Study (QHBIS). This cluster randomized controlled trial of neonatal HBV vaccination was conducted between 1983 and 1990 in Qidong County, a rural area in China with a high incidence of HBV-related primary liver cancer and other liver diseases. A cluster randomized controlled trial compares outcomes in groups of people (towns in this study) chosen at random to receive an intervention or a control treatment (here, vaccination or no vaccination; this study design was ethically acceptable during the 1980s when HBV vaccination was unavailable in rural China but would be unethical nowadays).
What Did the Researchers Do and Find?
The QHBIS assigned nearly 80,000 newborns to receive either a full course of HBV vaccinations (the vaccination group) or no vaccination (the control group); two-thirds of the control group participants received a catch-up vaccination at age 10–14 years. The researchers obtained data on how many trial participants developed primary liver cancer or died from a liver disease during the follow-up period from a population-based tumor registry. They also obtained information on HBsAg seroprevalence—the presence of HBsAg (an HBV surface protein) in the blood of the participants, an indicator of current HBV infection—from surveys undertaken in1996–2000 and 2008–2012. The researchers estimate that the protective efficacy of vaccination was 84% for primary liver cancer (vaccination reduced the incidence of liver cancer by 84%), 70% for death from liver diseases, and 69% for the incidence of infant fulminant hepatitis. Overall, the efficacy of catch-up vaccination on HBsAg seroprevalence in early adulthood was weak compared with neonatal vaccination (21% versus 72%). Notably, receiving a booster vaccination at age 10–14 years decreased HBsAg seroprevalence among participants who were born to HBsAg-positive mothers.
What Do These Findings Mean?
The small number of cases of primary liver cancer and other liver diseases observed during the 30-year follow-up, the length of follow-up, and the availability of incomplete data on seroprevalence all limit the accuracy of these findings. Nevertheless, these findings indicate that neonatal HBV vaccination greatly reduced HBsAg seroprevalence (an indicator of current HBV infection) in childhood and young adulthood and subsequently reduced the risk of liver cancer and other liver diseases in young adults. These findings therefore support the importance of neonatal HBV vaccination. In addition, they suggest that booster vaccination during adolescence might consolidate the efficacy of neonatal vaccination among individuals who were born to HBsAg-positive mothers, a suggestion that needs to be confirmed in randomized controlled trials before booster vaccines are introduced into vaccination programs.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001774.
The World Health Organization provides a fact sheet about hepatitis B (available in several languages) and information about hepatitis B vaccination
The World Hepatitis Alliance (an international not-for-profit, non-governmental organization) provides information about viral hepatitis, including some personal stories about hepatitis B from Bangladesh, Pakistan, the Philippines, and Malawi
The UK National Health Service Choices website provides information about hepatitis B
The not-for-profit British Liver Trust provides information about hepatitis B, including Hepatitis B: PATH B, an interactive educational resource designed to improve the lives of people living with chronic hepatitis B
MedlinePlus provides links to other resources about hepatitis B (in English and Spanish)
Information about the Qidong Hepatitis B intervention Study is available
Chinese Center for Disease Control and Prevention provides links about hepatitis B prevention in Chinese
doi:10.1371/journal.pmed.1001774
PMCID: PMC4280122  PMID: 25549238
23.  Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration 
PLoS Medicine  2008;5(2):e45.
Background
Meta-analyses of antidepressant medications have reported only modest benefits over placebo treatment, and when unpublished trial data are included, the benefit falls below accepted criteria for clinical significance. Yet, the efficacy of the antidepressants may also depend on the severity of initial depression scores. The purpose of this analysis is to establish the relation of baseline severity and antidepressant efficacy using a relevant dataset of published and unpublished clinical trials.
Methods and Findings
We obtained data on all clinical trials submitted to the US Food and Drug Administration (FDA) for the licensing of the four new-generation antidepressants for which full datasets were available. We then used meta-analytic techniques to assess linear and quadratic effects of initial severity on improvement scores for drug and placebo groups and on drug–placebo difference scores. Drug–placebo differences increased as a function of initial severity, rising from virtually no difference at moderate levels of initial depression to a relatively small difference for patients with very severe depression, reaching conventional criteria for clinical significance only for patients at the upper end of the very severely depressed category. Meta-regression analyses indicated that the relation of baseline severity and improvement was curvilinear in drug groups and showed a strong, negative linear component in placebo groups.
Conclusions
Drug–placebo differences in antidepressant efficacy increase as a function of baseline severity, but are relatively small even for severely depressed patients. The relationship between initial severity and antidepressant efficacy is attributable to decreased responsiveness to placebo among very severely depressed patients, rather than to increased responsiveness to medication.
Kirsch and colleagues show that, in antidepressant trials, there is a greater difference in efficacy between drug and placebo amongst more severely depressed patients. However, this difference seems to result from a poorer response to placebo amongst more depressed patients.
Editors' Summary
Background.
Everyone feels miserable occasionally. But for some people—those with depression—these sad feelings last for months or years and interfere with daily life. Depression is a serious medical illness caused by imbalances in the brain chemicals that regulate mood. It affects one in six people at some time during their life, making them feel hopeless, worthless, unmotivated, even suicidal. Doctors measure the severity of depression using the “Hamilton Rating Scale of Depression” (HRSD), a 17–21 item questionnaire. The answers to each question are given a score and a total score for the questionnaire of more than 18 indicates severe depression. Mild depression is often treated with psychotherapy or talk therapy (for example, cognitive–behavioral therapy helps people to change negative ways of thinking and behaving). For more severe depression, current treatment is usually a combination of psychotherapy and an antidepressant drug, which is hypothesized to normalize the brain chemicals that affect mood. Antidepressants include “tricyclics,” “monoamine oxidases,” and “selective serotonin reuptake inhibitors” (SSRIs). SSRIs are the newest antidepressants and include fluoxetine, venlafaxine, nefazodone, and paroxetine.
Why Was This Study Done?
Although the US Food and Drug Administration (FDA), the UK National Institute for Health and Clinical Excellence (NICE), and other licensing authorities have approved SSRIs for the treatment of depression, some doubts remain about their clinical efficacy. Before an antidepressant is approved for use in patients, it must undergo clinical trials that compare its ability to improve the HRSD scores of patients with that of a placebo, a dummy tablet that contains no drug. Each individual trial provides some information about the new drug's effectiveness but additional information can be gained by combining the results of all the trials in a “meta-analysis,” a statistical method for combining the results of many studies. A previously published meta-analysis of the published and unpublished trials on SSRIs submitted to the FDA during licensing has indicated that these drugs have only a marginal clinical benefit. On average, the SSRIs improved the HRSD score of patients by 1.8 points more than the placebo, whereas NICE has defined a significant clinical benefit for antidepressants as a drug–placebo difference in the improvement of the HRSD score of 3 points. However, average improvement scores may obscure beneficial effects between different groups of patient, so in the meta-analysis in this paper, the researchers investigated whether the baseline severity of depression affects antidepressant efficacy.
What Did the Researchers Do and Find?
The researchers obtained data on all the clinical trials submitted to the FDA for the licensing of fluoxetine, venlafaxine, nefazodone, and paroxetine. They then used meta-analytic techniques to investigate whether the initial severity of depression affected the HRSD improvement scores for the drug and placebo groups in these trials. They confirmed first that the overall effect of these new generation of antidepressants was below the recommended criteria for clinical significance. Then they showed that there was virtually no difference in the improvement scores for drug and placebo in patients with moderate depression and only a small and clinically insignificant difference among patients with very severe depression. The difference in improvement between the antidepressant and placebo reached clinical significance, however, in patients with initial HRSD scores of more than 28—that is, in the most severely depressed patients. Additional analyses indicated that the apparent clinical effectiveness of the antidepressants among these most severely depressed patients reflected a decreased responsiveness to placebo rather than an increased responsiveness to antidepressants.
What Do These Findings Mean?
These findings suggest that, compared with placebo, the new-generation antidepressants do not produce clinically significant improvements in depression in patients who initially have moderate or even very severe depression, but show significant effects only in the most severely depressed patients. The findings also show that the effect for these patients seems to be due to decreased responsiveness to placebo, rather than increased responsiveness to medication. Given these results, the researchers conclude that there is little reason to prescribe new-generation antidepressant medications to any but the most severely depressed patients unless alternative treatments have been ineffective. In addition, the finding that extremely depressed patients are less responsive to placebo than less severely depressed patients but have similar responses to antidepressants is a potentially important insight into how patients with depression respond to antidepressants and placebos that should be investigated further.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050045.
The MedlinePlus encyclopedia contains a page on depression (in English and Spanish)
Detailed information for patients and caregivers is available on all aspects of depression (including symptoms and treatment) from the US National Institute of Medical Health and from the UK National Health Service Direct Health Encyclopedia
MedlinePlus provides a list of links to further information on depression
Clinical Guidance for professionals, patients, caregivers and the public is provided by the UK National Institute for Health and Clinical Excellence
doi:10.1371/journal.pmed.0050045
PMCID: PMC2253608  PMID: 18303940
24.  HIV: prevention of opportunistic infections 
Clinical Evidence  2006;2006:0908.
Introduction
Opportunistic infections can occur in up to 40% of people with HIV infection and a CD4 count less than 250/mm3, although the risks are much lower with use of highly active antiretroviral treatment.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of prophylaxis for P carinii pneumonia (PCP) and toxoplasmosis? What are the effects of antituberculosis prophylaxis in people with HIV infection? What are the effects of prophylaxis for disseminated M avium complex (MAC) disease for people with, and without, previous MAC disease? What are the effects of prophylaxis for cytomegalovirus (CMV), herpes simplex virus (HSV), and varicella zoster virus (VZV)? What are the effects of prophylaxis for invasive fungal disease in people with, and without, previous fungal disease? What are the effects of discontinuing prophylaxis against opportunistic pathogens in people on highly active antiretroviral treatment (HAART)? We searched: Medline, Embase, The Cochrane Library and other important databases up to December 2004 (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 61 systematic reviews, RCTs, or observational studies that met our inclusion criteria.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: acyclovir; antituberculosis prophylaxis; atovaquone; azithromycin (alone or plus rifabutin); clarithromycin (alone, or plus rifabutin and ethambutol, or plus clofazimine); clofazimine plus ethambutol; discontinuing prophylaxis for CMV, MAC, and PCP; ethambutol added to clarithromycin plus clofazimine; famciclovir; fluconazole; isoniazid; itraconazole; oral ganciclovir; rifabutin (alone or plus macrolides); trimethoprim-sulfamethoxazole; and valaciclovir.
Key Points
Opportunistic infections can occur in up to 40% of people with HIV infection and a CD4 count < 250/mm3, although the risks are much lower with use of highly active antiretroviral treatment.
Trimethoprim-sulfamethoxazole or azithromycin may reduce the risk of PCP, but have not been shown to reduce toxoplasmosis infection. Atovaquone may prevent PCP and toxoplasmosis in people who cannot take trimethoprim−sulfamethoxazole, although we don't know this for sure.
Tuberculosis can be prevented by standard prophylaxis in people who are tuberculin skin test positive, but not in those who are tuberculin skin test negative. Short-term combination treatment has similar efficacy to long-term isoniazid monotherapy, but has greater risk of adverse effects.
Azithromycin or clarithromycin may reduce the risk of disseminated Microbacterium avium complex (MAC) disease in people without prior MAC disease. Adding rifabutin may reduce the risk of MAC disease, while adding ethambutol decreases the risk of relapse, compared with other antibiotic regimens.Combination treatment with clarithromycin plus clofazimine may increase mortality and is usually avoided.
Aciclovir reduces the risk of herpes simplex virus (HSV) and varicella zoster virus infection and overall mortality, but has not been shown to reduce cytomegalovirus (CMV) infection. Valaciclovir and ganciclovir may reduce the risk of CMV infection, but may be associated with serious adverse effects.
Fluconazole and itraconazole may reduce the risk of invasive fungal infections or their relapse, but can cause serious adverse effects.
In people with a CD4 cell count above 100−200/mm3, discontinuation of prophylactic treatment may not increase the risk of PCP, toxoplasmosis or MAC infection.
PMCID: PMC2907634
25.  HIV: primary and secondary prophylaxis for opportunistic infections 
Clinical Evidence  2010;2010:0908.
Introduction
Opportunistic infections can occur in up to 40% of people with HIV infection and a CD4 count less than 250/mm3, although the risks are much lower with use of highly active antiretroviral treatment.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of prophylaxis for Pneumocystis jirovecii pneumonia (PCP) and toxoplasmosis? What are the effects of antituberculosis prophylaxis in people with HIV infection? What are the effects of prophylaxis for disseminated Mycobacterium avium complex (MAC) disease for people with, and without, previous MAC disease? What are the effects of prophylaxis for cytomegalovirus (CMV), herpes simplex virus (HSV), and varicella zoster virus (VZV)? What are the effects of prophylaxis for invasive fungal disease in people with, and without, previous fungal disease? What are the effects of discontinuing prophylaxis against opportunistic pathogens in people on highly active antiretroviral treatment (HAART)? We searched: Medline, Embase, The Cochrane Library, and other important databases up to March 2008 (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 43 systematic reviews, RCTs, or observational studies that met our inclusion criteria.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: aciclovir; antituberculosis prophylaxis; atovaquone; azithromycin (alone or plus rifabutin); clarithromycin (alone, or plus rifabutin and ethambutol); discontinuing prophylaxis for CMV, MAC, and PCP; ethambutol added to clarithromycin; famciclovir; fluconazole; isoniazid; itraconazole; oral ganciclovir; rifabutin (alone or plus macrolides); trimethoprim–sulfamethoxazole; and valaciclovir.
Key Points
Opportunistic infections can occur in up to 40% of people with HIV infection and a CD4 count less than 250/mm3, although the risks are much lower with use of highly active antiretroviral treatment (HAART). HAART has reduced the rate of Pneumocystis jirovecii pneumonia (PCP), toxoplasmosis, and other opportunistic infections, so the absolute benefits of prophylactic regimens for opportunistic infections are probably smaller in people with HIV who are also taking HAART, and even smaller for those whose HIV is suppressed.
Primary prophylaxis with trimethoprim–sulfamethoxazole may reduce the risk of PCP, and has been found to be more effective than pentamidine or dapsone. Atovaquone may prevent PCP in people who cannot tolerate trimethoprim−sulfamethoxazole.We don't know whether these drugs prevent toxoplasmosis as we found few RCTs, but there is consensus that standard trimethoprim–sulfamethoxazole prophylaxis or dapsone should offer adequate coverage for toxoplasmosis.
Tuberculosis can be prevented by standard primary prophylaxis in people who are tuberculin skin test positive. Short-term combination treatment has similar efficacy to long-term isoniazid monotherapy, but is associated with a greater risk of adverse effects.
Azithromycin or clarithromycin reduce the risk of disseminated Mycobacterium avium complex (MAC) disease as primary prophylaxis for people without prior MAC disease. Adding rifabutin may also be beneficial in this population, but is also associated with an increased risk of adverse effects. There is consensus that secondary prophylaxis with clarithromycin plus ethambutol decreases the risk of relapse in people with previous MAC disease. It remains unclear whether adding rifabutin to the dual drug regimen confers additional benefit as secondary prophylaxis, and the three-drug combination increases adverse effects.
Aciclovir as secondary prophylaxis reduces the risk of herpes simplex virus (HSV) and varicella zoster virus infection (VZV) and all-cause mortality. Valaciclovir may reduce the risk of recurrent HSV infection, but it may be associated with serious adverse effects.There is consensus that famciclovir is effective as secondary prophylaxis against HSV or VZV and that ganciclovir is effective as secondary prophylaxis against CMV, HSV, or VZV.
Fluconazole and itraconazole as primary prophylaxis may reduce the risk of invasive fungal infections, but azoles have been associated with potentially serious interactions with other drugs. As secondary prophylaxis, itraconazole seems effective in reducing relapse of Penicillium marneffei, but seems less effective than fluconazole at reducing recurrence of cryptococcal meningitis.
In people who have responded to HAART and have a CD4 cell count greater than 100/mm3 to 200/mm3 (depending on the condition), discontinuation of primary or secondary prophylactic treatment for PCP, toxoplasmosis, MAC, herpes virus, or invasive fungal disease infection seems safe.
PMCID: PMC3217757  PMID: 21418688

Results 1-25 (97551)