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1.  The first 1000 days of life: prenatal and postnatal risk factors for morbidity and growth in a birth cohort in southern India 
BMJ Open  2014;4(7):e005404.
Objective
To estimate the burden and assess prenatal and postnatal determinants of illnesses experienced by children residing in a semiurban slum, during the first 1000 days of life.
Design
Community-based birth cohort
Setting
Southern India
Participants
Four hundred and ninety-seven children of 561 pregnant women recruited and followed for 2 years with surveillance and anthropometry.
Main outcome measure
Incidence rates of illness; rates of clinic visits and hospitalisations; factors associated with low birth weight, various illnesses and growth.
Results
Data on 10 377.7 child-months of follow-up estimated an average rate of 14.8 illnesses/child-year. Gastrointestinal and respiratory illnesses were 20.6% and 47.8% of the total disease burden, respectively. The hospitalisation rate reduced from 46/100 child-years during infancy to 19/100 child-years in the second year. Anaemia during pregnancy (OR=2.3, 95% CI=1.08 to 5.18), less than four antenatal visits (OR=6.8, 95% CI=2.1 to 22.5) and preterm birth (OR=3.3, 95% CI=1.1 to 9.7) were independent prenatal risk factors for low birth weight. Female gender (HR=0.88, 95% CI=0.79 to 0.99) and 6 months of exclusive breast feeding (HR=0.76, 95% CI=0.66 to 0.88) offered protection against all morbidity. Average monthly height and weight gain were lower in female child and children exclusively breast fed for 6 months.
Conclusions
The high morbidity in Indian slum children in the first 1000 days of life was mainly due to prenatal factors and gastrointestinal and respiratory illness. Policymakers need disease prevalence and pathways to target high-risk groups with appropriate interventions in the community.
doi:10.1136/bmjopen-2014-005404
PMCID: PMC4120427  PMID: 25056979
2.  Burden of childhood diseases and malnutrition in a semi-urban slum in southern India 
BMC Public Health  2013;13:87.
Background
India has seen rapid unorganized urbanization in the past few decades. However, the burden of childhood diseases and malnutrition in such populations is difficult to quantify. The morbidity experience of children living in semi-urban slums of a southern Indian city is described.
Methods
A total of 176 children were recruited pre-weaning from four geographically adjacent, semi-urban slums located in the western outskirts of Vellore, Tamil Nadu for a study on water safety and enteric infections and received either bottled or municipal drinking water based on their area of residence. Children were visited weekly at home and had anthropometry measured monthly until their second birthday.
Results
A total of 3932 episodes of illness were recorded during the follow-up period, resulting in an incidence of 12.5 illnesses/child-year, with more illness during infancy than in the second year of life. Respiratory, mostly upper respiratory infections, and gastrointestinal illnesses were most common. Approximately one-third of children were stunted at two years of age, and two-thirds had at least one episode of growth failure during the two years of follow up. No differences in morbidity were seen between children who received bottled and municipal water.
Conclusions
Our study found a high burden of childhood diseases and malnutrition among urban slum dwellers in southern India. Frequent illnesses may adversely impact children’s health and development, besides placing an additional burden on families who need to seek healthcare and find resources to manage illness.
doi:10.1186/1471-2458-13-87
PMCID: PMC3577473  PMID: 23360429
Children; Morbidity; Incidence; Slum; Longitudinal study; India
3.  Hand Sanitiser Provision for Reducing Illness Absences in Primary School Children: A Cluster Randomised Trial 
PLoS Medicine  2014;11(8):e1001700.
In a cluster randomized trial, Patricia Priest and colleagues find that providing hand sanitizer along with hand hygiene education in primary school classrooms, compared with hand hygiene alone, does not reduce school absences.
Please see later in the article for the Editors' Summary
Background
The potential for transmission of infectious diseases offered by the school environment are likely to be an important contributor to the rates of infectious disease experienced by children. This study aimed to test whether the addition of hand sanitiser in primary school classrooms compared with usual hand hygiene would reduce illness absences in primary school children in New Zealand.
Methods and Findings
This parallel-group cluster randomised trial took place in 68 primary schools, where schools were allocated using restricted randomisation (1∶1 ratio) to the intervention or control group. All children (aged 5 to 11 y) in attendance at participating schools received an in-class hand hygiene education session. Schools in the intervention group were provided with alcohol-based hand sanitiser dispensers in classrooms for the winter school terms (27 April to 25 September 2009). Control schools received only the hand hygiene education session. The primary outcome was the number of absence episodes due to any illness among 2,443 follow-up children whose caregivers were telephoned after each absence from school. Secondary outcomes measured among follow-up children were the number of absence episodes due to specific illness (respiratory or gastrointestinal), length of illness and illness absence episodes, and number of episodes where at least one other member of the household became ill subsequently (child or adult). We also examined whether provision of sanitiser was associated with experience of a skin reaction. The number of absences for any reason and the length of the absence episode were measured in all primary school children enrolled at the schools. Children, school administrative staff, and the school liaison research assistants were not blind to group allocation. Outcome assessors of follow-up children were blind to group allocation. Of the 1,301 and 1,142 follow-up children in the hand sanitiser and control groups, respectively, the rate of absence episodes due to illness per 100 child-days was similar (1.21 and 1.16, respectively, incidence rate ratio 1.06, 95% CI 0.94 to 1.18). The provision of an alcohol-based hand sanitiser dispenser in classrooms was not effective in reducing rates of absence episodes due to respiratory or gastrointestinal illness, the length of illness or illness absence episodes, or the rate of subsequent infection for other members of the household in these children. The percentage of children experiencing a skin reaction was similar (10.4% hand sanitiser versus 10.3% control, risk ratio 1.01, 95% CI 0.78 to 1.30). The rate or length of absence episodes for any reason measured for all children also did not differ between groups. Limitations of the study include that the study was conducted during an influenza pandemic, with associated public health messaging about hand hygiene, which may have increased hand hygiene among all children and thereby reduced any additional effectiveness of sanitiser provision. We did not quite achieve the planned sample size of 1,350 follow-up children per group, although we still obtained precise estimates of the intervention effects. Also, it is possible that follow-up children were healthier than non-participating eligible children, with therefore less to gain from improved hand hygiene. However, lack of effectiveness of hand sanitiser provision on the rate of absences among all children suggests that this may not be the explanation.
Conclusions
The provision of hand sanitiser in addition to usual hand hygiene in primary schools in New Zealand did not prevent disease of severity sufficient to cause school absence.
Trial registration
Australian New Zealand Clinical Trials Registry ACTRN12609000478213
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Throughout human history, infectious diseases have been major killers. In the 1300 s, for example, the black death killed a third of the European population. Other diseases such as smallpox and cholera have also devastated human populations. Now, though, a better understanding of the bacteria, viruses, and other microbes that cause infectious diseases and the availability of effective vaccines and antibiotics mean that, for the first time in human history, non-communicable (chronic) diseases such as heart attacks and strokes are killing and disabling more people around the world than infectious diseases. But this does not mean that we can be complacent about infectious diseases. The control of infectious diseases remains important, even in high-income countries, because of the contribution of infectious diseases to ill-health and because we need to manage the risk of epidemics and pandemics (disease outbreaks that affect a large proportion of the population of a country or the world, respectively) of influenza and other diseases.
Why Was This Study Done?
The control of infectious disease transmission in children is a particularly important component of disease control because children tend to have high rates of infectious disease and to have more physical contact with peers and with adults than other age groups, particularly in the school environment. It might be possible, therefore, to reduce the occurrence of many infectious respiratory and gastrointestinal diseases in communities by interrupting the transmission of infectious diseases between children at school, but how can this be achieved? In health care settings, good hand hygiene is a key component of infectious disease control, so, here, the researchers undertake a cluster randomized trial among primary school children in New Zealand to investigate whether the promotion of extra hand cleaning through the provision of alcohol-based hand sanitizer in classrooms can reduce illness absences among school children compared with normal hand hygiene (washing with soap and water, mainly in school bathrooms). A cluster randomized trial compares the outcomes of groups of participants (in this case, schools) chosen randomly to receive different interventions.
What Did the Researchers Do and Find?
The researchers randomly assigned 68 city primary schools to the intervention or control group. All the children (aged 5–11 years) attending the participating schools received a thirty-minute in-class hand hygiene education session. Alcohol-based hand sanitizer dispensers were installed in the classrooms of the intervention schools during the winter term, and the children were asked to use the dispensers after coughing or sneezing and on the way out of the classroom for morning break and lunch. The researchers report that the trial's primary outcome—the rate of absence episodes per 100 child-days due to any illness among “follow-up” children, individuals whose caregivers agreed to be asked about the reason for any absence—was similar in the intervention and control groups. Moreover, among the follow-up children, the provision of hand sanitizer did not reduce the number of absences due to a specific illness (respiratory or gastrointestinal), the length of illness and length of absence from school, or the number of episodes in which at least one other family member became ill. Finally, the number of absences for any reason, and length of absence episodes, in all the children enrolled at the participating schools did not differ between the intervention and control groups.
What Do These Findings Mean?
These findings suggest that the provision of hand sanitizer in addition to usual hand hygiene in primary schools in New Zealand did not prevent any infectious diseases severe enough to warrant school absence. Because the trial was undertaken during an influenza epidemic, influenza-related public health messages about good hand hygiene may have increased hand hygiene among all the children in the study and lessened the intervention's effectiveness. Other study limitations—including that only a third of caregivers agreed to be contacted about their child's absences, and these may have been caregivers who had already taught their children good hand hygiene—may also affect the accuracy of these findings and their generalizability to other high-income countries. However, these findings suggest that, in high-income countries where clean water for hand washing is readily available, putting resources into extra hand hygiene by providing hand sanitizer in classrooms may not be an effective way to break the child-to-child transmission of infectious diseases.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001700.
The US Centers for Disease Control and Prevention has information about hand-washing, when and how to wash your hands and use sanitizer, and hand-washing as a family activity; it also provides information about the importance of hand hygiene in health care settings
Public Health England provides information about hand-washing; its webpage about hand-washing in primary schools contains links to lesson plans about hand-washing for children aged 5–7 years and to e-Bug, a web-based student resource about infectious diseases and their prevention for children aged 7–14 years
Kidshealth, a US-based not-for-profit organization, also provides information about the importance of hand-washing for parents, kids, and teens (in English and Spanish)
doi:10.1371/journal.pmed.1001700
PMCID: PMC4130492  PMID: 25117155
4.  Chronic growth faltering amongst a birth cohort of Indian children begins prior to weaning and is highly prevalent at three years of age 
Nutrition Journal  2009;8:44.
Background
Poor growth of children in developing countries is a major public health problem associated with mortality, morbidity and developmental delay. We describe growth up to three years of age and investigate factors related to stunting (low height-for-age) at three years of age in a birth cohort from an urban slum.
Methods
452 children born between March 2002 and August 2003 were followed until their third birthday in three neighbouring slums in Vellore, South India. Field workers visited homes to collect details of morbidity twice a week. Height and weight were measured monthly from one month of age in a study-run clinic. For analysis, standardised z-scores were generated using the 2006 WHO child growth standards. Risk factors for stunting at three years of age were analysed in logistic regression models. A sensitivity analysis was conducted to examine the effect of missing values.
Results
At age three years, of 186 boys and 187 girls still under follow-up, 109 (66%, 95% Confidence interval 58-73%) boys and 93 (56%, 95% CI 49-64%) girls were stunted, 14 (8%, 95% CI 4-13%) boys and 12 (7%, 95% CI 3-11%) girls were wasted (low weight-for-height) and 72 (43%, 95% CI 36-51) boys and 66 (39%, 95% CI 31-47%) girls were underweight (low weight-for-age). In total 224/331 (68%) children at three years had at least one growth deficiency (were stunted and/or underweight and/or wasted); even as early as one month of age 186/377 (49%) children had at least one growth deficiency. Factors associated with stunting at three years were birth weight less than 2.5 kg (OR 3.63, 95% CI 1.36-9.70) 'beedi-making' (manual production of cigarettes for a daily wage) in the household (OR 1.74, 95% CI 1.05-2.86), maternal height less than 150 cm (OR 2.02, 95% CI 1.12-3.62), being stunted, wasted or underweight at six months of age (OR 1.75, 95% CI 1.05-2.93) and having at least one older sibling (OR 2.00, 95% CI 1.14-3.51).
Conclusion
A high proportion of urban slum dwelling children had poor growth throughout the first three years of life. Interventions are needed urgently during pregnancy, early breastfeeding and weaning in this population.
doi:10.1186/1475-2891-8-44
PMCID: PMC2761939  PMID: 19788734
5.  Community Mobilization in Mumbai Slums to Improve Perinatal Care and Outcomes: A Cluster Randomized Controlled Trial 
PLoS Medicine  2012;9(7):e1001257.
David Osrin and colleagues report findings from a cluster-randomized trial conducted in Mumbai slums; the trial aimed to evaluate whether facilitator-supported women's groups could improve perinatal outcomes.
Introduction
Improving maternal and newborn health in low-income settings requires both health service and community action. Previous community initiatives have been predominantly rural, but India is urbanizing. While working to improve health service quality, we tested an intervention in which urban slum-dweller women's groups worked to improve local perinatal health.
Methods and Findings
A cluster randomized controlled trial in 24 intervention and 24 control settlements covered a population of 283,000. In each intervention cluster, a facilitator supported women's groups through an action learning cycle in which they discussed perinatal experiences, improved their knowledge, and took local action. We monitored births, stillbirths, and neonatal deaths, and interviewed mothers at 6 weeks postpartum. The primary outcomes described perinatal care, maternal morbidity, and extended perinatal mortality. The analysis included 18,197 births over 3 years from 2006 to 2009. We found no differences between trial arms in uptake of antenatal care, reported work, rest, and diet in later pregnancy, institutional delivery, early and exclusive breastfeeding, or care-seeking. The stillbirth rate was non-significantly lower in the intervention arm (odds ratio 0.86, 95% CI 0.60–1.22), and the neonatal mortality rate higher (1.48, 1.06–2.08). The extended perinatal mortality rate did not differ between arms (1.19, 0.90–1.57). We have no evidence that these differences could be explained by the intervention.
Conclusions
Facilitating urban community groups was feasible, and there was evidence of behaviour change, but we did not see population-level effects on health care or mortality. In cities with multiple sources of health care, but inequitable access to services, community mobilization should be integrated with attempts to deliver services for the poorest and most vulnerable, and with initiatives to improve quality of care in both public and private sectors.
Trial registration
Current Controlled Trials ISRCTN96256793
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Substantial progress is being made to reduce global child mortality (deaths of children before the age of 5 years) and maternal mortality (deaths among women because of complications of pregnancy and childbirth)—two of the Millennium Development Goals agreed by world leaders in 2000 to end extreme poverty. Even so, worldwide, in 2010, 7.6 million children died before their fifth birthday and there were nearly 360,000 maternal deaths. Almost all child and maternal deaths occur in developing countries—a fifth of under-five deaths and more than a quarter of neonatal deaths (deaths during the first month of life, which account for two-fifths of all child deaths) occur in India alone. Moreover, most child and maternal deaths are caused by avoidable conditions. Specifically, the major causes of neonatal death—complications of preterm delivery, breathing problems during or after delivery, and infections of the blood (sepsis) and lungs (pneumonia)—and of maternal deaths—hemorrhage (abnormal bleeding), sepsis, unsafe abortion, obstructed labor, and hypertensive diseases of pregnancy—could all be largely prevented by improved access to reproductive health services and skilled health care workers.
Why Was This Study Done?
Experts believe that improvements to maternal and newborn health in low-income settings require both health service strengthening and community action. That is, the demand for better services, driven by improved knowledge about maternal and newborn health (perinatal issues), has to be increased in parallel with the supply of those services. To date, community mobilization around perinatal issues has largely been undertaken in rural settings but populations in developing countries are becoming increasingly urban. In India, for example, 30% of the population now lives in cities. In this cluster randomized controlled trial (a study in which groups of people are randomly assigned to receive alternative interventions and the outcomes in the differently treated “clusters” are compared), City Initiative for Newborn Health (CINH) researchers investigate the effect of an intervention designed to help women's groups in the slums of Mumbai work towards improving local perinatal health. The CINH aims to improve maternal and newborn health in slum communities by improving public health care provision and by working with community members to improve maternal and newborn care practices and care-seeking behaviors.
What Did the Researchers Do and Find?
The researchers enrolled 48 Mumbai slum communities of at least 1,000 households into their trial. In each of the 24 intervention clusters, a facilitator supported local women's groups through a 36-meeting learning cycle during which group members discussed their perinatal experiences, improved their knowledge, and took action. To measure the effect of the intervention, the researchers monitored births, stillbirths, and neonatal deaths in all the clusters and interviewed mothers 6 weeks after delivery. During the 3-year trial, there were 18,197 births in the participating settlements. The women in the intervention clusters were enthusiastic about acquiring new knowledge and made substantial efforts to reach out to other women but were less successful in undertaking collective action such as negotiations with civic authorities for more amenities. There were no differences between the intervention and control communities in the uptake of antenatal care, reported work, rest, and diet in late pregnancy, institutional delivery, or in breast feeding and care-seeking behavior. Finally, the combined rate of stillbirths and neonatal deaths (the extended perinatal mortality rate) was the same in both arms of the trial, as was maternal mortality.
What Do These Findings Mean?
These findings indicate that it is possible to facilitate the discussion of perinatal health care by urban women's groups in the challenging conditions that exist in the slums of Mumbai. However, they fail to show any measureable effect of community mobilization through the facilitation of women's groups on perinatal health at the population level. The researchers acknowledge that more intensive community activities that target the poorest, most vulnerable slum dwellers might produce measurable effects on perinatal mortality, and they conclude that, in cities with multiple sources of health care and inequitable access to services, it remains important to integrate community mobilization with attempts to deliver services to the poorest and most vulnerable, and with initiatives to improve the quality of health care in both the public and private sector.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001257.
The United Nations Childrens Fund (UNICEF) works for children's rights, survival, development, and protection around the world; it provides information on the reduction of child mortality (Millennium Development Goal 4); its Childinfo website provides information about all the Millennium Development Goals and detailed statistics about on child survival and health, newborn care, and maternal health (some information in several languages)
The World Health Organization also has information about Millennium Development Goal 4 and Millennium Development Goal 5, the reduction of maternal mortality, provides information on newborn infants, and provides estimates of child mortality rates (some information in several languages)
Further information about the Millennium Development Goals is available
Information on the City Initiative for Newborn Health and its partners and a detailed description of its trial of community mobilization in Mumbai slums to improve care during pregnancy, delivery, postnatally and for the newborn are available
Further information about the Society for Nutrition, Education and Health Action (SNEHA) is available
doi:10.1371/journal.pmed.1001257
PMCID: PMC3389036  PMID: 22802737
6.  Infant Mortality in an Urban Slum 
Indian journal of pediatrics  2007;74(5):449-453.
Objective
Infant and child mortality are important indicators of the level of development of a society, but are usually collected by governmental agencies on a region wide scale, with little local stratification. In order to formulate appropriate local policies for intervention, it is important to know the patterns of morbidity and mortality in children in the local setting.
Methods
This retrospective study collected and analyzed data on infant mortality for the period 1995 to 2003 in an urban slum area in Vellore, southern India from government health records maintained at the urban health clinic.
Results
The infant mortality rate over this period was 37.9 per 1000 live births. Over half (54.3%) of the deaths occurred in the neonatal period. Neonatal deaths were mainly due to perinatal asphyxia (31.9%), pre-maturity (16.8%) and aspiration pneumonia or acute respiratory distress (16.8%), while infant deaths occurring after the first mth of life were mainly due to diarrheal disease (43%) and respiratory infections (21%).
Conclusion
These results emphasize the need to improved antenatal and perinatal care to improve survival in the neonatal period. The strikingly high death rate due to diarrheal illness highlights the requirements for better sanitation and water quality.
PMCID: PMC2483298  PMID: 17526955
Infant mortality; Gastroenteritis; India
7.  Randomized placebo-controlled trial on azithromycin to reduce the morbidity of bronchiolitis in Indigenous Australian infants: rationale and protocol 
Trials  2011;12:94.
Background
Acute lower respiratory infections are the commonest cause of morbidity and potentially preventable mortality in Indigenous infants. Infancy is also a critical time for post-natal lung growth and development. Severe or repeated lower airway injury in very young children likely increases the likelihood of chronic pulmonary disorders later in life. Globally, bronchiolitis is the most common form of acute lower respiratory infections during infancy. Compared with non-Indigenous Australian infants, Indigenous infants have greater bacterial density in their upper airways and more severe bronchiolitis episodes. Our study tests the hypothesis that the anti-microbial and anti-inflammatory properties of azithromycin, improve the clinical outcomes of Indigenous Australian infants hospitalised with bronchiolitis.
Methods
We are conducting a dual centre, randomised, double-blind, placebo-controlled, parallel group trial in northern Australia. Indigenous infants (aged ≤ 24-months, expected number = 200) admitted to one of two regional hospitals (Darwin, Northern Territory and Townsville, Queensland) with a clinical diagnosis of bronchiolitis and fulfilling inclusion criteria are randomised (allocation concealed) to either azithromycin (30 mg/kg/dose) or placebo administered once weekly for three doses. Clinical data are recorded twice daily and nasopharyngeal swab are collected at enrolment and at the time of discharge from hospital. Primary outcomes are 'length of oxygen requirement' and 'duration of stay,' the latter based upon being judged as 'ready for respiratory discharge'. The main secondary outcome is readmission for a respiratory illness within 6-months of leaving hospital. Descriptive virological and bacteriological (including development of antibiotic resistance) data from nasopharyngeal samples will also be reported.
Discussion
Two published studies, both involving different patient populations and settings, as well as different macrolide antibiotics and treatment duration, have produced conflicting results. Our randomised, placebo-controlled trial of azithromycin in Indigenous infants hospitalised with bronchiolitis is designed to determine whether it can reduce short-term (and potentially long-term) morbidity from respiratory illness in Australian Indigenous infants who are at high risk of developing chronic respiratory illness. If azithromycin is efficacious in reducing the morbidly of Indigenous infants hospitalised with bronchiolitis, the intervention would lead to improved short term (and possibly long term) health benefits.
Trial registration
Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12610000326099
doi:10.1186/1745-6215-12-94
PMCID: PMC3094234  PMID: 21492416
8.  The Effect of Adding Ready-to-Use Supplementary Food to a General Food Distribution on Child Nutritional Status and Morbidity: A Cluster-Randomized Controlled Trial 
PLoS Medicine  2012;9(9):e1001313.
Lieven Huybregts and colleagues investigate how supplementing a general food distribution with a fortified lipid-based spread during a seasonal hunger gap in Chad affects anthropometric and morbidity outcomes for children aged 6 to 36 months.
Background
Recently, operational organizations active in child nutrition in developing countries have suggested that blanket feeding strategies be adopted to enable the prevention of child wasting. A new range of nutritional supplements is now available, with claims that they can prevent wasting in populations at risk of periodic food shortages. Evidence is lacking as to the effectiveness of such preventive interventions. This study examined the effect of a ready-to-use supplementary food (RUSF) on the prevention of wasting in 6- to 36-mo-old children within the framework of a general food distribution program.
Methods and Findings
We conducted a two-arm cluster-randomized controlled pragmatic intervention study in a sample of 1,038 children aged 6 to 36 mo in the city of Abeche, Chad. Both arms were included in a general food distribution program providing staple foods. The intervention group was given a daily 46 g of RUSF for 4 mo. Anthropometric measurements and morbidity were recorded monthly. Adding RUSF to a package of monthly household food rations for households containing a child assigned to the intervention group did not result in a reduction in cumulative incidence of wasting (incidence risk ratio: 0.86; 95% CI: 0.67, 1.11; p = 0.25). However, the intervention group had a modestly higher gain in height-for-age (+0.03 Z-score/mo; 95% CI: 0.01, 0.04; p<0.001). In addition, children in the intervention group had a significantly higher hemoglobin concentration at the end of the study than children in the control group (+3.8 g/l; 95% CI: 0.6, 7.0; p = 0.02), thereby reducing the odds of anemia (odds ratio: 0.52; 95% CI: 0.34, 0.82; p = 0.004). Adding RUSF also resulted in a significantly lower risk of self-reported diarrhea (−29.3%; 95% CI: 20.5, 37.2; p<0.001) and fever episodes (−22.5%; 95% CI: 14.0, 30.2; p<0.001). Limitations of this study include that the projected sample size was not fully attained and that significantly fewer children from the control group were present at follow-up sessions.
Conclusions
Providing RUSF as part of a general food distribution resulted in improvements in hemoglobin status and small improvements in linear growth, accompanied by an apparent reduction in morbidity.
Trial registration
ClinicalTrials.gov NCT01154595
Please see later in the article for the Editors' Summary.
Editors' Summary
Background
Good nutrition during childhood is essential for health and survival. Undernourished children are more susceptible to infections and are more likely to die from common ailments such as diarrhea than well-nourished children. Globally, undernutrition contributes to about a third of deaths among children under five years old. Experts use three physical measurements to determine whether a child is undernourished. An “underweight” child has a low weight for his or her age and gender when compared to the World Health Organization Child Growth Standards, which chart the growth of a reference population. A “stunted” child has a low height for his or her age; stunting indicates chronic undernutrition. A “wasted” child has a low weight for his or her height; wasting indicates acute undernutrition and can be caused by disasters or seasonal food shortages. Recent estimates indicate that about a fifth of young children in developing countries are underweight, and one third are stunted; in south Asia and west/central Africa, more than one tenth of children are wasted, a condition that markedly increases the risk of death.
Why Was This Study Done?
In emergency situations, international organizations support affected populations by providing “general food distributions.” Recently, there have been claims that the provision of targeted nutritional supplements within a general food distribution framework effectively prevents child wasting, but there is little evidence to support these claims. In this cluster-randomized controlled trial, the researchers investigate the effect of a targeted daily dose of a “ready-to-use supplementary food” (RUSF; a lipid-based nutrient supplement) on indicators of undernutrition in 6- to 36-month-old, non-wasted children in Chad, a country beset by a severe food crisis. Political instability in this central African country has severely reduced the nutritional status of children, and annual droughts, which affect crop production, cause a “hunger gap” between June and October. In a recent survey, one fifth of children in Chad were wasted at the beginning of this hunger gap. A cluster-randomized trial randomly assigns groups of people to receive alternative interventions and compares the outcomes in the differently treated “clusters.”
What Did the Researchers Do and Find?
The researchers randomly assigned fourteen household clusters in the city of Abeche, Chad, to the trial's intervention or control arm. All the households received a general food distribution that included staple foods; eligible children in the intervention households were also given a daily RUSF ration between June and September 2010. The researchers regularly measured the children's weights and heights, recorded illnesses reported by caregivers, and measured each child's blood hemoglobin level before and after the intervention to assess their risk of anemia, an indicator of poor nutrition. The addition of RUSF to the household food rations did not significantly reduce the cumulative incidence of wasting. That is, although fewer children in the intervention group became wasted during the trial than in the control group, this difference was not statistically significant—it could have happened by chance. However, compared to the children in the control group, those in the intervention group had a significantly greater gain in height-for-age (equivalent to a difference in height gain of 0.09 cm/month), slightly higher hemoglobin levels at the end of the study, which significantly reduced their anemia risk, and a significantly lower risk of self-reported diarrhea and fever.
What Do These Findings Mean?
Although targeted RUSF provided as part of a general food distribution had no significant effect on wasting in young children in Abeche, Chad, the intervention improved their hemoglobin status and linear growth, and reduced illness among them. Why didn't targeted RUSF prevent wasting effectively in this trial? Maybe the effect of RUSF was diluted out by the effect of the general food distribution or maybe the trial was too short to see a clear effect. Most importantly, though, the trial may have been too small to see a clear effect—the researchers were unable to enroll as many children into their trial as they had planned because of political instability in Chad, and this probably limited the trial's ability to detect small differences between the control and intervention groups. Nevertheless, because these findings provide no clear evidence that adding RUSF to a household food ration effectively prevents wasting, alternative ways to prevent acute malnutrition in Chad and other vulnerable regions of the world should be investigated.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001313.
This study is further discussed in a PLOS Medicine Perspective by Kathryn Dewey and Mary Arimond
Action Contra la Faim–France has a web page that describes the situation in Chad
The United Nations Childrens Fund, which protects the rights of children and young people around the world, provides detailed statistics on child undernutrition; it has detailed information, including videos, about the current food crisis in Chad and the Sahel
The WHO Child Growth Standards are available (in several languages)
The United Nations provides information on ongoing world efforts to reduce hunger and child mortality
The World Food Programme is the world's largest humanitarian agency fighting hunger worldwide; its website provides detailed information about malnutrition in Chad, including a video of the current food crisis in the country
Starved for Attention is an international multimedia campaign launched in 2010 by Médecins Sans Frontiéres (MSF) and the VII Photo agency to rewrite the story of childhood malnutrition; information about MSFs work in Chad to tackle malnutrition is available
doi:10.1371/journal.pmed.1001313
PMCID: PMC3445445  PMID: 23028263
9.  Acute bronchiolitis in infancy as risk factor for wheezing and reduced pulmonary function by seven years in Akershus County, Norway 
BMC Pediatrics  2005;5:31.
Background
Acute viral bronchiolitis is one of the most common causes of hospitalisation during infancy in our region with respiratory syncytial virus (RSV) historically being the major causative agent. Many infants with early-life RSV bronchiolitis have sustained bronchial hyperreactivity for many years after hospitalisation and the reasons for this are probably multifactorial. The principal aim of the present study was to investigate if children hospitalised for any acute viral bronchiolitis during infancy in our region, and not only those due to RSV, had more episodes of subsequent wheezing up to age seven years and reduced lung function at that age compared to children not hospitalised for acute bronchiolitis during infancy. A secondary aim was to compare the hospitalised infants with proven RSV bronchiolitis (RS+) to the hospitalised infants with non-RSV bronchiolitis (RS-) according to the same endpoints.
Methods
57 infants hospitalised at least once with acute viral bronchiolitis during two consecutive winter seasons in 1993–1994 were examined at age seven years. An age-matched control group of 64 children, who had not been hospitalised for acute viral bronchiolitis during infancy, were recruited from a local primary school. Epidemiological and clinical data were collected retrospectively from hospital discharge records and through structured clinical interviews and physical examinations at the follow-up visit.
Results
The children hospitalised for bronchiolitis during infancy had decreased lung function, more often wheezing episodes, current medication and follow-up for asthma at age seven years than did the age matched controls. They also had lower average birth weight and more often first order family members with asthma. We did not find significant differences between the RSV+ and RSV- groups.
Conclusion
Children hospitalised for early-life bronchiolitis are susceptible to recurrent wheezing and reduced pulmonary function by seven years compared to age-matched children not hospitalised for early-life bronchiolitis. We propose that prolonged bronchial hyperreactivity could follow early-life RSV negative as well as RSV positive bronchiolitis.
doi:10.1186/1471-2431-5-31
PMCID: PMC1199604  PMID: 16109158
10.  Morbidity in Canadian Indian and non-Indian children in the first year of life. 
A cohort study of health status was undertaken to determine the patterns of morbidity in the first year of life for Indian and non-Indian infants living in southern Ontario. The annual incidence of office-reported health problems was 8.0 episodes for the 99 Indians and 4.5 for the 316 non-Indians studied. The risk of illness of most diagnostic categories was more than 1.5 times greater and the rate of hospital admission 4 times greater for the Indian infants. There was no difference between the two cohorts in the rates of visits to hospital emergency departments. The main cause of illness in both cohorts was respiratory tract infection; lower respiratory tract infections, particularly pneumonia, were a major health problem among the Indian infants. Only 36% of the Indian infants compared with 68% of the non-Indian infants attended five or more well-baby examinations. Part of the difference in morbidity between the Indian and non-Indian infants may be attributed to environmental factors, health care behaviour and geographic constraints.
PMCID: PMC1862859  PMID: 7059900
11.  Diarrhea as a risk factor for acute lower respiratory tract infections among young children in low income settings 
Journal of Global Health  2013;3(1):010402.
Background
Diarrhea and acute lower respiratory tract infections (ALRI) are leading causes of morbidity and mortality among children under 5 years of age. We sought to quantify the correlation of diarrhea and respiratory infections within an individual child and to determine if infection with one illness increases the risk of infection with the other during the same time period.
Methods
We quantified the likelihood of an ALRI and a diarrhea episode occurring during the same week compared to the likelihood of each occurring independently in two cohorts of children under 3 years of age using a bivariate probit regression model. We also quantified the likelihood of an ALRI episode conditioned on a child’s diarrhea history and the likelihood of a diarrhea episode conditioned on a child’s ALRI history using Cox Proportional Hazard models.
Results
In Indian and Nepali children, diarrhea and ALRI occurred simultaneously more than chance alone. Incidence of ALRI increased in both cohorts as the number of days with diarrhea in the prior 28 days increased; the greatest incident rate ratio was reported among children with 20 or more days of diarrhea (1.02, 95% confidence interval (CI) 1.01 – 1.03 in Nepal and 1.07, 95% CI 1.05 – 1.09 in South India). Incidence of diarrhea was affected differently by ALRI prevalence depending on season.
Conclusions
Diarrhea may be a direct risk factor for ALRI among children under 3 years of age. The risk of comorbidity increases as disease severity increases, providing additional rationale for prompt community case–management of both diarrhea and pneumonia.
doi:10.7189/jogh.03.010402
PMCID: PMC3700029  PMID: 23826506
12.  Influenza 
Clinical Evidence  2009;2009:0911.
Introduction
During the autumn-winter months (influenza seasons), influenza circulates more frequently, causing a greater proportion of influenza-like illness, and sometimes serious seasonal epidemics. The incidence of infection depends on the underlying immunity of the population.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of vaccines to prevent influenza? What are the effects of antiviral chemoprophylaxis of influenza? What are the effects of antiviral medications to treat influenza? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 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 21 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: vaccines, amantadine, oseltamivir, zanamivir, rimantadine.
Key Points
Influenza viruses are constantly altering their antigenic structure, and every year the WHO recommends which strains of influenza should be included in vaccines. During the autumn-winter months, influenza circulates more frequently (influenza seasons), causing a greater proportion of influenza-like illness, and sometimes serious seasonal epidemics.The incidence of infection depends on the underlying immunity of the population.
When a significantly different form of influenza occurs by mutation, it can greatly increase infection rates, as well as morbidity and mortality (a pandemic).
Influenza and influenza-like illness (caused by a range of other viruses) are clinically indistinguishable. Trials of vaccines assess how to prevent the symptoms and consequences of both, as well as infection rates.
Vaccines are effective in reducing infection and school absence in children over 2 years old, but there is no evidence that they reduce transmission, hospitalisation, pneumonia, or death.
Live or inactivated vaccines are effective in reducing infection and in slightly reducing absence from work in adults, but there is no evidence that they reduce transmission, hospitalisation, pneumonia, or death.
There is poor-quality evidence from cohort studies that vaccines are effective in elderly people living in institutions, but there is little good-quality evidence for the elderly population in general.
Zanamivir and oseltamivir provide symptomatic relief, or prevent symptoms if administered early in the disease, but do not prevent infection. Zanamivir and oseltamivir interrupt household transmission of seasonal influenza, prevent hospitalisations, and reduce, but do not suppress, viral excretion from the nose.These agents cause fewer adverse effects than amantadine and rimantadine, and there is less evidence of resistance.
Although amantadine and rimantadine provide symptomatic relief or prevent symptoms if administered early in influenza A, they engender viral resistance. Amantadine and rimantadine do not prevent infection and transmission, and cause harms, especially in a prophylactic role.
Amantadine was ineffective in the 1968-1969 pandemic, and zanamivir, oseltamivir, and newer vaccines are untested in a pandemic.
Symptomatic relief with echinacea, vitamin C, and decongestants in influenza-like illness is covered in the review on the common cold.
Single studies reporting data for one or two seasons are difficult to interpret, and not easy to generalise from, because of the marked variability of viral circulation.
PMCID: PMC2907815  PMID: 19445759
13.  Burden of Illness in the First 3 Years of Life in an Indian Slum 
Journal of Tropical Pediatrics  2009;56(4):221-226.
The morbidity and mortality in a cohort of 452 children followed up from birth up to 3 years of age, in an urban slum in India, is described. These children were recruited and followed from March 2002 to September 2006. A prospective morbidity survey was established. There were 1162 child-years of follow-up. The average morbidity rate was 11.26 episodes/child-year. Respiratory infections caused 58.3 and diarrheal disease 18.4% of the illnesses. Respiratory illnesses resulted in 48, 67.5 and 50 days of illnesses, and there were 3.6, 1.64 and 1.16 diarrheal episodes per child in the 3 years, respectively. There were five deaths in the cohort in the 3 years of follow-up. Of the 77 drop-outs 44 were contacted for mortality data. The morbidity in the area is high, comparable to other studies. The mortality is low, and is attributed to the facilitated access to care.
doi:10.1093/tropej/fmp116
PMCID: PMC3693507  PMID: 20028725
childhood morbidity; acute respiratory infections; India
14.  Gastrointestinal and Respiratory Illness in Children That Do and Do Not Attend Child Day Care Centers: A Cost-of-Illness Study 
PLoS ONE  2014;9(8):e104940.
Background
Gastrointestinal and respiratory diseases are major causes of morbidity for young children, particularly for those children attending child day care centers (DCCs). Although both diseases are presumed to cause considerable societal costs for care and treatment of illness, the extent of these costs, and the difference of these costs between children that do and do not attend such centers, is largely unknown.
Objective
Estimate the societal costs for care and treatment of episodes of gastroenteritis (GE) and influenza-like illness (ILI) experienced by Dutch children that attend a DCC, compared to children that do not attend a DCC.
Methods
A web-based monthly survey was conducted among households with children aged 0–48 months from October 2012 to October 2013. Households filled-in a questionnaire on the incidence of GE and ILI episodes experienced by their child during the past 4 weeks, on the costs related to care and treatment of these episodes, and on DCC arrangements. Costs and incidence were adjusted for socioeconomic characteristics including education level, nationality and monthly income of parents, number of children in the household, gender and age of the child and month of survey conduct.
Results
Children attending a DCC experienced higher rates of GE (aIRR 1.4 [95%CI: 1.2–1.9]) and ILI (aIRR: 1.4 [95%CI: 1.2–1.6]) compared to children not attending a DCC. The societal costs for care and treatment of an episode of GE and ILI experienced by a DCC-attending child were estimated at €215.45 [€115.69–€315.02] and €196.32 [€161.58–€232.74] respectively, twice as high as for a non-DCC-attending child. The DCC-attributable economic burden of GE and ILI for the Netherlands was estimated at €25 million and €72 million per year.
Conclusions
Although children attending a DCC experience only slightly higher rates of GE and ILI compared to children not attending a DCC, the costs involved per episode are substantially higher.
doi:10.1371/journal.pone.0104940
PMCID: PMC4139325  PMID: 25141226
15.  Effect of routine zinc supplementation on pneumonia in children aged 6 months to 3 years: randomised controlled trial in an urban slum 
BMJ : British Medical Journal  2002;324(7350):1358.
Objectives
To evaluate the effect of daily zinc supplementation in children on the incidence of acute lower respiratory tract infections and pneumonia.
Design
Double masked, randomised placebo controlled trial.
Setting
A slum community in New Delhi, India.
Participants
2482 children aged 6 to 30 months.
Interventions
Daily elemental zinc, 10 mg to infants and 20 mg to older children or placebo for four months. Both groups received single massive dose of vitamin A (100 000 IU for infants and 200 000 IU for older children) at enrolment.
Main outcome measures
All households were visited weekly. Any children with cough and lower chest indrawing or respiratory rate 5 breaths per minute less than the World Health Organization criteria for fast breathing were brought to study physicians.
Results
At four months the mean plasma zinc concentration was higher in the zinc group (19.8 (SD 10.1) v 9.3 (2.1) μmol/l, P<0.001). The proportion of children who had acute lower respiratory tract infection during follow up was no different in the two groups (absolute risk reduction −0.2%, 95% confidence interval −3.9% to 3.6%). Zinc supplementation resulted in a lower incidence of pneumonia than placebo (absolute risk reduction 2.5%, 95% confidence interval 0.4% to 4.6%). After correction for multiple episodes in the same child by generalised estimating equations analysis the odds ratio was 0.74, 95% confidence interval 0.56 to 0.99.
Conclusions
Zinc supplementation substantially reduced the incidence of pneumonia in children who had received vitamin A.
What is already known on this topicMild to moderate zinc deficiency is common in children in developing countries and increases the risk of respiratory morbidityWhat this study addsA third of children from low socioeconomic classes in India have low plasma concentrations of zincRoutine zinc supplementation of such children aged 6 months to 3 years substantially reduced the incidence of pneumonia
PMCID: PMC115208  PMID: 12052800
16.  Incidence and prevalence of non-specific symptoms and behavioural changes in infants under the age of two years. 
BACKGROUND. The incidence and prevalence of non-specific symptoms in a group of normally healthy infants have not previously been investigated. The relationship of such symptoms to the risk of sudden unexplained infant death has been explored. AIM. This study set out to assess the usually unreported minor morbidity occurring in infants under the age of two years in a defined community. METHOD. Diary cards were completed by mothers for 323 infants on a daily basis for up to two years from birth. Analysis of the diary card data allowed the incidence and prevalence of behavioural changes and non-specific symptoms to be determined, together with the duration of the episodes of symptoms and the frequency and timing of consultations with health visitors and doctors. RESULTS. Non-specific symptoms and behavioural changes occurred commonly in this age group. Upper respiratory symptoms were especially prevalent. Episodes of symptoms relating to particular body systems tended to be of longer duration while behavioural changes tended to be of shorter duration. Parents managed 67% to 99% of infants' health problems without requiring a consultation. Parents often delayed four or five days before consulting their doctor for symptoms in conditions which could be judged to be 'normal' for the child such as some respiratory conditions, but behavioural changes and fever led to consultations on the second day on average. CONCLUSION. The prevalence of the symptoms reported here should provide the setting for any discussion of their use as indicators of serious illness in infancy or the risk of sudden unexplained infant death.
PMCID: PMC1239137  PMID: 7702884
17.  Hospitalisations for respiratory syncytial virus bronchiolitis in Akershus, Norway, 1993–2000: a population-based retrospective study 
BMC Pediatrics  2004;4:25.
Background
RSV is recognized as the most important cause of serious lower respiratory tract illness in infants and young children worldwide leading to hospitalisation in a great number of cases, especially in certain high-risk groups. The aims of the present study were to identify risk groups, outcome and incidences of hospitalisation for RSV bronchiolitis in Norwegian children under two years of age and to compare the results with other studies.
Methods
We performed a population-based retrospective survey for the period 1993–2000 in children under two years of age hospitalised for RSV bronchiolitis.
Results
822 admissions from 764 patients were identified, 93% had one hospitalisation, while 7% had two or more hospitalisations. Mean annual hospitalisation incidences were 21.7 per 1.000 children under one year of age, 6.8 per 1.000 children at 1–2 years of age and 14.1 per 1.000 children under two years of age. 77 children (85 admissions) belonged to one or more high-risk groups such as preterm birth, trisomy 21 and congenital heart disease. For preterm children under one year of age, at 1–2 years of age and under two years of age hospitalisation incidences per 1.000 children were 23.5, 8.7 and 16.2 respectively. The incidence for children under two years of age with trisomy 21 was 153.8 per 1.000 children.
Conclusion
While the overall hospitalisation incidences and outcome of RSV bronchiolitis were in agreement with other studies, hospitalisation incidences for preterm children were lower than in many other studies. Age on admission for preterm children, when corrected for prematurity, was comparable to low-risk children. Length of hospitalisation and morbidity was high in both preterm children, children with a congenital heart disease and in children with trisomy 21, the last group being at particular high risk for severe disease.
doi:10.1186/1471-2431-4-25
PMCID: PMC544884  PMID: 15606912
18.  Protective effect of breast feeding against infection. 
BMJ : British Medical Journal  1990;300(6716):11-16.
OBJECTIVE--To assess the relations between breast feeding and infant illness in the first two years of life with particular reference to gastrointestinal disease. DESIGN--Prospective observational study of mothers and babies followed up for 24 months after birth. SETTING--Community setting in Dundee. PATIENTS--750 pairs of mothers and infants, 76 of whom were excluded because the babies were preterm (less than 38 weeks), low birth weight (less than 2500 g), or treated in special care for more than 48 hours. Of the remaining cohort of 674, 618 were followed up for two years. INTERVENTIONS--Detailed observations of infant feeding and illness were made at two weeks, and one, two, three, four, five, six, nine, 12, 15, 18, 21, and 24 months by health visitors. MAIN OUTCOME MEASURE--The prevalence of gastrointestinal disease in infants during follow up. RESULTS--After confounding variables were corrected for babies who were breast fed for 13 weeks or more (227) had significantly less gastrointestinal illness than those who were bottle fed from birth (267) at ages 0-13 weeks (p less than 0.01; 95% confidence interval for reduction in incidence 6.6% to 16.8%), 14-26 weeks (p less than 0.01), 27-39 weeks (p less than 0.05), and 40-52 weeks (p less than 0.05). This reduction in illness was found whether or not supplements were introduced before 13 weeks, was maintained beyond the period of breast feeding itself, and was accompanied by a reduction in the rate of hospital admission. By contrast, babies who were breast fed for less than 13 weeks (180) had rates of gastrointestinal illness similar to those observed in bottle fed babies. Smaller reductions in the rates of respiratory illness were observed at ages 0-13 and 40-52 weeks (p less than 0.05) in babies who were breast fed for more than 13 weeks. There was no consistent protective effect of breast feeding against ear, eye, mouth, or skin infections, infantile colic, eczema, or nappy rash. CONCLUSION--Breast feeding during the first 13 weeks of life confers protection against gastrointestinal illness that persists beyond the period of breast feeding itself.
PMCID: PMC1661904  PMID: 2105113
19.  Child Mortality Estimation: Estimating Sex Differences in Childhood Mortality since the 1970s 
PLoS Medicine  2012;9(8):e1001287.
Cheryl Sawyer uses new methods to generate estimates of sex differences in child mortality which can be used to pinpoint areas where these differences in mortality merit closer examination.
Introduction
Producing estimates of infant (under age 1 y), child (age 1–4 y), and under-five (under age 5 y) mortality rates disaggregated by sex is complicated by problems with data quality and availability. Interpretation of sex differences requires nuanced analysis: girls have a biological advantage against many causes of death that may be eroded if they are disadvantaged in access to resources. Earlier studies found that girls in some regions were not experiencing the survival advantage expected at given levels of mortality. In this paper I generate new estimates of sex differences for the 1970s to the 2000s.
Methods and Findings
Simple fitting methods were applied to male-to-female ratios of infant and under-five mortality rates from vital registration, surveys, and censuses. The sex ratio estimates were used to disaggregate published series of both-sexes mortality rates that were based on a larger number of sources. In many developing countries, I found that sex ratios of mortality have changed in the same direction as historically occurred in developed countries, but typically had a lower degree of female advantage for a given level of mortality. Regional average sex ratios weighted by numbers of births were found to be highly influenced by China and India, the only countries where both infant mortality and overall under-five mortality were estimated to be higher for girls than for boys in the 2000s. For the less developed regions (comprising Africa, Asia excluding Japan, Latin America/Caribbean, and Oceania excluding Australia and New Zealand), on average, boys' under-five mortality in the 2000s was about 2% higher than girls'. A number of countries were found to still experience higher mortality for girls than boys in the 1–4-y age group, with concentrations in southern Asia, northern Africa/western Asia, and western Africa. In the more developed regions (comprising Europe, northern America, Japan, Australia, and New Zealand), I found that the sex ratio of infant mortality peaked in the 1970s or 1980s and declined thereafter.
Conclusions
The methods developed here pinpoint regions and countries where sex differences in mortality merit closer examination to ensure that both sexes are sharing equally in access to health resources. Further study of the distribution of causes of death in different settings will aid the interpretation of differences in survival for boys and girls.
Please see later in the article for the Editors' Summary.
Editors' Summary
Background
In 2000, world leaders agreed to eradicate extreme poverty by 2015. To help track progress towards this global commitment, eight Millennium Development Goals (MDGs) were set. MDG 4, which aims to reduce child mortality, calls for a reduction in under-five mortality (the number of children who die before their fifth birthday) to a third of its 1990 level of 12 million by 2015. The under-five mortality rate is also denoted in the literature as U5MR and 5q0. Progress towards MDG 4 has been substantial, but with only three years left to reach it, efforts to strengthen child survival programs are intensifying. Reliable estimates of trends in childhood mortality are pivotal to these efforts. So, since 2004, the United Nations Inter-agency Group for Child Mortality Estimation (UN IGME) has used statistical regression models to produce estimates of trends in under-five mortality and infant mortality (death before age one year) from data about childbearing and child survival collected by vital registration systems (records of all births and deaths), household surveys, and censuses.
Why Was This Study Done?
In addition to estimates of overall childhood mortality trends, information about sex-specific childhood mortality trends is desirable to monitor progress towards MDG 4, although the interpretation of trends in the relative mortality of girls and boys is not straightforward. Newborn girls survive better than newborn boys because they are less vulnerable to birth complications and infections and have fewer inherited abnormalities. Thus, the ratio of infant mortality among boys to infant mortality among girls is greater than one, provided both sexes have equal access to food and medical care. Beyond early infancy, girls and boys are similarly vulnerable to infections, so the sex ratio of deaths in the 1–4-year age group is generally lower than that of infant mortality. Notably, as living conditions improve in developing countries, infectious diseases become less important as causes of death. Thus, in the absence of sex-specific differences in the treatment of children, the sex ratio of childhood mortality is expected be greater than one and to increase as overall under-five mortality rates in developing countries decrease. In this study, the researcher evaluated national and regional changes in the sex ratios of childhood mortality since the 1970s to investigate whether girls and boys have equal access to medical care and other resources.
What Did the Researcher Do and Find?
The researcher developed new statistical fitting methods to estimate trends in the sex ratio of mortality for infants and young children for individual countries and world regions. When considering individual countries, the researcher found that for 92 countries in less developed regions, the median sex ratio of under-five mortality increased between the 1970s and the 2000s, in line with the expected changes just described. However, the average sex ratio of under-five mortality for less developed regions, weighted according to the number of births in each country, did not increase between the 1970s and 2000s, at which time the average under-five mortality rate of boys was about 2% higher than that of girls. This discrepancy resulted from India and China—the two most populous developing countries—having sex ratios for both infant and under-five mortality that remained constant or declined over the study period and were below one in the 2000s, a result that indicates excess female mortality. In China, for example, infant mortality was found to be 12% higher for boys than for girls in the 1970s, but 24% lower for boys than for girls in the 2000s. Finally, although in the less developed regions (excluding India and China) girls went from having a slight survival disadvantage at ages 1–4 years in the 1970s, on average, to having a slight advantage in the 2000s, girls remained more likely to die than boys in this age group in several Asian and African countries.
What Do These Findings Mean?
Although the quality of the available data is likely to affect the accuracy of these findings, in most developing countries the ratio of male to female under-five mortality has increased since the 1970s, in parallel with the decrease in overall childhood mortality. Notably, however, in a number of developing countries—including several each in sub-Saharan Africa, northern Africa/western Asia, and southern Asia—girls have higher mortality than boys at ages 1–4 years, and in India and China girls have higher mortality in infancy. Thus, girls are benefitting less than boys from the overall decline in childhood mortality in India, China, and some other developing countries. Further studies are needed to determine the underlying reasons for this observation. Nevertheless, the methods developed here to estimate trends in sex-specific childhood mortality pinpoint countries and regions where greater efforts should be made to ensure that both sexes have equal access to health care and other important resources during early life.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001287.
This paper is part of a collection of papers on Child Mortality Estimation Methods published in PLOS Medicine
The United Nations Childrens Fund works for children's rights, survival, development, and protection around the world; it provides information on Millennium Development Goal 4, and its Childinfo website provides detailed statistics about child survival and health, including a description of the United Nations Inter-agency Group for Child Mortality Estimation; the 2011 UN IGME report Levels & Trends in Child Mortality is available
The World Health Organization also has information about Millennium Development Goal 4 and provides estimates of child mortality rates (some information in several languages)
Further information about the Millennium Development Goals is available
A 2011 report by the United Nations Department of Economic and Social Affairs entitled Sex Differentials in Childhood Mortality is available
doi:10.1371/journal.pmed.1001287
PMCID: PMC3429399  PMID: 22952433
20.  Association between Respiratory Syncytial Virus Activity and Pneumococcal Disease in Infants: A Time Series Analysis of US Hospitalization Data 
PLoS Medicine  2015;12(1):e1001776.
Daniel Weinberger and colleagues examine a possible interaction between two serious respiratory infections in children under 2 years of age.
Please see later in the article for the Editors' Summary
Background
The importance of bacterial infections following respiratory syncytial virus (RSV) remains unclear. We evaluated whether variations in RSV epidemic timing and magnitude are associated with variations in pneumococcal disease epidemics and whether changes in pneumococcal disease following the introduction of seven-valent pneumococcal conjugate vaccine (PCV7) were associated with changes in the rate of hospitalizations coded as RSV.
Methods and Findings
We used data from the State Inpatient Databases (Agency for Healthcare Research and Quality), including >700,000 RSV hospitalizations and >16,000 pneumococcal pneumonia hospitalizations in 36 states (1992/1993–2008/2009). Harmonic regression was used to estimate the timing of the average seasonal peak of RSV, pneumococcal pneumonia, and pneumococcal septicemia. We then estimated the association between the incidence of pneumococcal disease in children and the activity of RSV and influenza (where there is a well-established association) using Poisson regression models that controlled for shared seasonal variations. Finally, we estimated changes in the rate of hospitalizations coded as RSV following the introduction of PCV7. RSV and pneumococcal pneumonia shared a distinctive spatiotemporal pattern (correlation of peak timing: ρ = 0.70, 95% CI: 0.45, 0.84). RSV was associated with a significant increase in the incidence of pneumococcal pneumonia in children aged <1 y (attributable percent [AP]: 20.3%, 95% CI: 17.4%, 25.1%) and among children aged 1–2 y (AP: 10.1%, 95% CI: 7.6%, 13.9%). Influenza was also associated with an increase in pneumococcal pneumonia among children aged 1–2 y (AP: 3.2%, 95% CI: 1.7%, 4.7%). Finally, we observed a significant decline in RSV-coded hospitalizations in children aged <1 y following PCV7 introduction (−18.0%, 95% CI: −22.6%, −13.1%, for 2004/2005–2008/2009 versus 1997/1998–1999/2000). This study used aggregated hospitalization data, and studies with individual-level, laboratory-confirmed data could help to confirm these findings.
Conclusions
These analyses provide evidence for an interaction between RSV and pneumococcal pneumonia. Future work should evaluate whether treatment for secondary bacterial infections could be considered for pneumonia cases even if a child tests positive for RSV.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Respiratory infections—bacterial and viral infections of the lungs and the airways (the tubes that take oxygen-rich air to the lungs)—are major causes of illness and death in children worldwide. Pneumonia (infection of the lungs) alone is responsible for about 15% of all child deaths. The leading cause of bacterial pneumonia in children is Streptococcus pneumoniae, which is transmitted through contact with infected respiratory secretions. S. pneumoniae usually causes noninvasive diseases such as bronchitis, but sometimes the bacteria invade the lungs, the bloodstream, or the covering of the brain, where they cause pneumonia, septicemia, or meningitis, respectively. These potentially fatal invasive pneumococcal diseases can be treated with antibiotics but can also be prevented by vaccination with pneumococcal conjugate vaccines such as PCV7. The leading cause of viral pneumonia is respiratory syncytial virus (RSV), which is also readily transmitted through contact with infected respiratory secretions. Almost all children have an RSV infection before their second birthday—RSV usually causes a mild cold-like illness. However, some children infected with RSV develop pneumonia and have to be admitted to hospital for supportive care such as the provision of supplemental oxygen; there is no specific treatment for RSV infection.
Why Was This Study Done?
Co-infections with bacteria and viruses can sometimes have a synergistic effect and lead to more severe disease than an infection with either type of pathogen (disease-causing organism) alone. For example, influenza infections increase the risk of invasive pneumococcal disease. But does pneumococcal disease also interact with RSV infection? It is important to understand the interaction between pneumococcal disease and RSV to improve the treatment of respiratory infections in young children, but the importance of bacterial infections following RSV infection is currently unclear. Here, the researchers undertake a time series analysis of US hospitalization data to investigate the association between RSV activity and pneumococcal disease in infants. Time series analysis uses statistical methods to analyze data collected at successive, evenly spaced time points.
What Did the Researchers Do and Find?
For their analysis, the researchers used data collected between 1992/1993 and 2008/2009 by the State Inpatient Databases on more than 700,000 hospitalizations for RSV and more than 16,000 hospitalizations for pneumococcal pneumonia or septicemia among children under two years old in 36 US states. Using a statistical technique called harmonic regression to measure seasonal variations in disease incidence (the rate of occurrence of new cases of a disease), the researchers show that RSV and pneumococcal pneumonia shared a distinctive spatiotemporal pattern over the study period. Next, using Poisson regression models (another type of statistical analysis), they show that RSV was associated with significant increases (increases unlikely to have happened by chance) in the incidence of pneumococcal disease. Among children under one year old, 20.3% of pneumococcal pneumonia cases were associated with RSV activity; among children 1–2 years old, 10.1% of pneumococcal pneumonia cases were associated with RSV activity. Finally, the researchers report that following the introduction of routine vaccination in the US against S. pneumoniae with PCV7 in 2000, there was a significant decline in hospitalizations for RSV among children under one year old.
What Do These Findings Mean?
These findings provide evidence for an interaction between RSV and pneumococcal pneumonia and indicate that RSV is associated with increases in the incidence of pneumococcal pneumonia, particularly in young infants. Notably, the finding that RSV hospitalizations declined after the introduction of routine pneumococcal vaccination suggests that some RSV hospitalizations may have a joint viral–bacterial etiology (cause), although it is possible that PCV7 vaccination reduced the diagnosis of RSV because fewer children were hospitalized with pneumococcal disease and subsequently tested for RSV. Because this is an ecological study (an observational investigation that looks at risk factors and outcomes in temporally and geographically defined populations), these findings do not provide evidence for a causal link between hospitalizations for RSV and pneumococcal pneumonia. The similar spatiotemporal patterns for the two infections might reflect another unknown factor shared by the children who were hospitalized for RSV or pneumococcal pneumonia. Moreover, because pooled hospitalization discharge data were used in this study, these results need to be confirmed through analysis of individual-level, laboratory-confirmed data. Importantly, however, these findings support the initiation of studies to determine whether treatment for bacterial infections should be considered for children with pneumonia even if they have tested positive for RSV.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001776.
The US National Heart, Lung, and Blood Institute provides information about the respiratory system and about pneumonia
The US Centers for Disease Control and Prevention provides information on all aspects of pneumococcal disease and pneumococcal vaccination, including personal stories and information about RSV infection
The UK National Health Service Choices website provides information about pneumonia (including a personal story) and about pneumococcal diseases
KidsHealth, a website provided by the US-based non-profit Nemours Foundation, includes information on pneumonia and on RSV (in English and Spanish)
MedlinePlus provides links to other resources about pneumonia, RSV infections, and pneumococcal infections (in English and Spanish)
HCUPnet provides aggregated hospitalization data from the State Inpatient Databases used in this study
doi:10.1371/journal.pmed.1001776
PMCID: PMC4285401  PMID: 25562317
21.  Everyday symptoms in childhood: occurrence and general practitioner consultation rates. 
BACKGROUND: Fewer than 20% of all illnesses that occur in the home require the attention of a general practitioner (GP). Whether specific illnesses in children are more likely to need the attention of a GP is poorly understood, as is the influence of various other factors. Health diaries are the most suitable method of collecting comprehensive information about children's health problems at home and in general practice simultaneously. AIM: To investigate the occurrence of, and consultation rates for, specific symptoms in childhood in relation to age, sex, birth order, and place of residence of the child, and season of the year. METHOD: The parents of 1805 children kept a health diary over three weeks and recorded symptoms and consultation behaviour. The symptoms were later combined into illness episodes. RESULTS: Over three weeks, colds/flu (157/1000 children) and respiratory symptoms (114/1000 children) occurred most frequently. More young children (0-4 years) suffered from illness generally. Eleven per cent of all illness episodes required the attention of a GP. Consultation rates differed greatly according to symptoms. A GP was consulted most often for ear (36%) and skin (28%) problems, and least often for headaches (2%) and tiredness (1%). Regardless of symptoms, young children (0-4 years) were taken to a GP twice as often as older children (10-14 years). CONCLUSIONS: This study emphasizes the enormous amount of illness that occurs in children and the fact that more than 80% of all illnesses are dealt with by parents without reference to the professional health care system.
PMCID: PMC1409911  PMID: 9604409
22.  Post-neonatal Mortality, Morbidity, and Developmental Outcome after Ultrasound-Dated Preterm Birth in Rural Malawi: A Community-Based Cohort Study 
PLoS Medicine  2011;8(11):e1001121.
Using data collected as a follow-up to a randomized trial, Melissa Gladstone and colleagues show that during the first two years of life, infants born preterm in southern Malawi are disadvantaged in terms of mortality, growth, and development.
Background
Preterm birth is considered to be associated with an estimated 27% of neonatal deaths, the majority in resource-poor countries where rates of prematurity are high. There is no information on medium term outcomes after accurately determined preterm birth in such settings.
Methods and Findings
This community-based stratified cohort study conducted between May–December 2006 in Southern Malawi followed up 840 post-neonatal infants born to mothers who had received antenatal antibiotic prophylaxis/placebo in an attempt to reduce rates of preterm birth (APPLe trial ISRCTN84023116). Gestational age at delivery was based on ultrasound measurement of fetal bi-parietal diameter in early-mid pregnancy. 247 infants born before 37 wk gestation and 593 term infants were assessed at 12, 18, or 24 months. We assessed survival (death), morbidity (reported by carer, admissions, out-patient attendance), growth (weight and height), and development (Ten Question Questionnaire [TQQ] and Malawi Developmental Assessment Tool [MDAT]). Preterm infants were at significantly greater risk of death (hazard ratio 1.79, 95% CI 1.09–2.95). Surviving preterm infants were more likely to be underweight (weight-for-age z score; p<0.001) or wasted (weight-for-length z score; p<0.01) with no effect of gestational age at delivery. Preterm infants more often screened positively for disability on the Ten Question Questionnaire (p = 0.002). They also had higher rates of developmental delay on the MDAT at 18 months (p = 0.009), with gestational age at delivery (p = 0.01) increasing this likelihood. Morbidity—visits to a health centre (93%) and admissions to hospital (22%)—was similar for both groups.
Conclusions
During the first 2 years of life, infants who are born preterm in resource poor countries, continue to be at a disadvantage in terms of mortality, growth, and development. In addition to interventions in the immediate neonatal period, a refocus on early childhood is needed to improve outcomes for infants born preterm in low-income settings.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Being born at term in Africa is not necessarily straightforward. In Malawi, 33 of every 1,000 infants born die in the first 28 days after birth; the lifetime risk for a mother dying during or shortly after pregnancy is one in 36. The comparable figures for the United Kingdom are three infants dying per 1,000 births and a lifetime risk of maternal death of one in 4,700. But for a baby, being born preterm is even more risky and the gap between low- and high-income countries widens still further. According to a World Health Organization report in 2010, a baby born at 32 weeks of gestation (weighing around 2,000 g) in Africa has little chance of survival, while the chances of survival for a baby born at 32 weeks in North America or Europe are similar to one born at term. There are very few data on the longer term outcomes of babies born preterm in Africa and there are multiple challenges involved in gathering such information. As prenatal ultrasound is not routinely available, gestational age is often uncertain. There may be little routine follow-up of preterm babies as is commonplace in high-income countries. Data are needed from recent years that take into account both improvements in perinatal care and adverse factors such as a rising number of infants becoming HIV positive around the time of birth.
Why Was This Study Done?
We could improve outcomes for babies born preterm in sub-Saharan Africa if we understood more about what happens to them after birth. We cannot assume that the progress of these babies will be the same as those born preterm in a high-income country, as the latter group will have received different care, both before and after birth. If we can document the problems that these preterm babies face in a low-income setting, we can consider why they happen and what treatments can be realistically tested in this setting. It is also helpful to establish baseline data so that changes over time can be recorded.
The aim of this study was to document four specific outcomes up to the age of two years, on which there were few data previously from rural sub-Saharan Africa: how many babies survived, visits to a health center and admissions to the hospital, growth, and developmental delay.
What Did the Researchers Do and Find?
The researchers examined a group of babies that had been born to mothers who had taken part in a randomized controlled trial of an antibiotic to prevent preterm birth. The trial had previously shown that the antibiotic (azithromycin) had no effect on how many babies were born preterm or on other measures of the infants' wellbeing, and so the researchers followed up babies from both arms of the trial to look at longer term outcomes. From the original group of 2,297 women who took part in the trial, they compared 247 infants born preterm against 593 term infants randomly chosen as controls, assessed at 12, 18, or 24 months. The majority of the preterm babies who survived past a month of age (all but ten) were born after 32 weeks of gestation. Compared to the babies born at term, the infants born preterm were nearly twice as likely to die subsequently in the next two years, were more likely to be underweight (a third were moderately underweight), and to have higher rates of developmental delay. The commonest causes of death were gastroenteritis, respiratory problems, and malaria. Visits to a health center and admissions to hospital were similar in both groups.
What Do these Findings Mean?
This study documents longer term outcomes of babies born preterm in sub-Saharan Africa in detail for the first time. The strengths of the study include prenatal ultrasound dating and correct adjustment of follow-up age (which takes into account being born before term). Because the researchers defined morbidity using routine health center attendances and self-report of illnesses by parents, this outcome does not seem to have been as useful as the others in differentiating between the preterm and term babies. Better means of measuring morbidity are needed in this setting.
In the developed world, there is considerable investment being made to improve care during pregnancy and in the neonatal period. This investment in care may help by predicting which mothers are more likely to give birth early and preventing preterm birth through drug or other treatments. It is to be hoped that some of the benefit will be transferable to low-income countries. A baby born at 26 weeks' gestation and admitted to a neonatal unit in the United Kingdom has a 67% chance of survival; preterm babies born in sub-Saharan Africa face a starkly contrasting future.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001121.
UNICEF presents useful statistics on mother and child outcomes
The World Health Organization has attempted to analyse preterm birth rates worldwide, including mapping the regional distribution and has also produced practical guides on strategies such as Kangaroo Mother Care, which can be used for the care of preterm infants in low resource settings
Healthy Newborn Network has good information on initiatives taking place to improve neonatal outcomes in low income settings
The March of Dimes, a nonprofit organization for pregnancy and baby health, provides information on research being conducted into preterm birth
Tommy's is a nonprofit organization that funds research and provides information on the risks and causes of premature birth
doi:10.1371/journal.pmed.1001121
PMCID: PMC3210771  PMID: 22087079
23.  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
24.  Incidence and Clinical Characteristics of Group A Rotavirus Infections among Children Admitted to Hospital in Kilifi, Kenya  
PLoS Medicine  2008;5(7):e153.
Background
Rotavirus, predominantly of group A, is a major cause of severe diarrhoea worldwide, with the greatest burden falling on young children living in less-developed countries. Vaccines directed against this virus have shown promise in recent trials, and are undergoing effectiveness evaluation in sub-Saharan Africa. In this region limited childhood data are available on the incidence and clinical characteristics of severe group A rotavirus disease. Advocacy for vaccine intervention and interpretation of effectiveness following implementation will benefit from accurate base-line estimates of the incidence and severity of rotavirus paediatric admissions in relevant populations. The study objective was to accurately define the incidence and severity of group A rotavirus disease in a resource-poor setting necessary to make informed decisions on the need for vaccine prevention.
Methods and Findings
Between 2002 and 2004 we conducted prospective surveillance for group A rotavirus infection at Kilifi District Hospital in coastal Kenya. Children < 13 y of age were eligible as “cases” if admitted with diarrhoea, and “controls” if admitted without diarrhoea. We calculated the incidence of hospital admission with group A rotavirus using data from a demographic surveillance study of 220,000 people in Kilifi District. Of 15,347 childhood admissions 3,296 (22%) had diarrhoea, 2,039 were tested for group A rotavirus antigen and, of these, 588 (29%) were positive. 372 (63%) rotavirus-positive cases were infants. Of 620 controls 19 (3.1%, 95% confidence interval [CI] 1.9–4.7) were rotavirus positive. The annual incidence (per 100,000 children) of rotavirus-positive admissions was 1,431 (95% CI 1,275–1,600) in infants and 478 (437–521) in under-5-y-olds, and highest proximal to the hospital. Compared to children with rotavirus-negative diarrhoea, rotavirus-positive cases were less likely to have coexisting illnesses and more likely to have acidosis (46% versus 17%) and severe electrolyte imbalance except hyponatraemia. In-hospital case fatality was 2% among rotavirus-positive and 9% among rotavirus-negative children.
Conclusions
In Kilifi > 2% of children are admitted to hospital with group A rotavirus diarrhoea in the first 5 y of life. This translates into over 28,000 vaccine-preventable hospitalisations per year across Kenya, and is likely to be a considerable underestimate. Group A rotavirus diarrhoea is associated with acute life-threatening metabolic derangement in otherwise healthy children. Although mortality is low in this clinical research setting this may not be generally true in African hospitals lacking rapid and appropriate management.
Combining prospective hospital-based surveillance with demographic data in Kilifi, Kenya, James Nokes and colleagues assess the burden of rotavirus diarrhea in young children.
Editors' Summary
Background.
Rotavirus is a leading global cause of diarrhea in babies and young children. Indeed, most children become infected at least once with this virus before their fifth birthday. Rotavirus is usually spread by children or their caregivers failing to wash their hands properly after going to the toilet and then contaminating food or drink. The symptoms of rotavirus infection—diarrhea, vomiting, and fever—are usually mild, but if the diarrhea is severe it can quickly lead to dehydration. Mild to moderate dehydration can be treated at home by providing the patient with plenty of fluids or with a special rehydration drink that replaces lost water and salts. However, for infants or toddlers who become severely dehydrated, rehydration with intravenous fluids (fluids injected directly into a vein) in hospital may be essential. Unfortunately, in developing countries in sub-Saharan Africa and elsewhere, this treatment is not widely available and every year more than half a million young children die from rotavirus infections.
Why Was This Study Done?
Two rotavirus vaccines that could reduce this burden of disease are currently undergoing clinical trials to determine their effectiveness in sub-Saharan Africa. However, very little is known about the incidence of severe rotavirus infections among children living in this region (that is, how many children develop severe disease every year) or about the clinical characteristics of the disease here. Public-health officials need this baseline information before they can make informed decisions about the mass introduction of rotavirus vaccination and to help them judge whether the intervention has been successful if it is introduced. In this study, the researchers examine the incidence and clinical characteristics of rotavirus infections (specifically, group A rotavirus [GARV] infections; there are several different rotaviruses but GARV causes most human infections) among children admitted to the district hospital in Kilifi, Kenya.
What Did the Researchers Do and Find?
During the 3-year study, more than 15,000 children under the age of 13 years were admitted to Kilifi District Hospital, a little under a quarter of whom had severe diarrhea. Nearly a third of the patients admitted with diarrhea who were tested had a GARV-specific protein in their stools (faeces); by contrast, only three in 100 children admitted without diarrhea showed any evidence of GARV infection. Two-thirds of the GARV-positive children were infants (under 1 year old). Using these figures and health surveillance data (records of births, deaths, and causes of death) collected in the area around the hospital, the researchers calculated that the annual incidence (per 100,000 children) of GARV-positive hospital admissions in the region was 1,431 for infants and 478 for children under age 5 years. Children with GARV-positive diarrhea were less likely to have other illnesses (for example, malnutrition) than those admitted with GARV-negative diarrhea, the researchers report, but were more likely to have life-threatening complications such as severe dehydration and salt imbalances in their blood. However, despite being more ill on admission, only 1 in 50 children with GARV-positive diarrhea died, compared to nearly 1 in 10 of the children with GARV-negative diarrhea; the GARV-positive children also left hospital quicker than those who were GARV-negative.
What Do These Findings Mean?
These findings indicate that severe GARV-positive diarrhea is a major cause of hospital admission among otherwise healthy young children in the Kilifi region of Kenya. By the time they are 5 years old, the researchers estimate that 1 in 50 of the children living in this region will have been admitted to hospital with severe GARV-positive diarrhea. Because rotavirus vaccines prevent virtually all severe rotavirus-associated disease (at least in developed countries where their effectiveness has been extensively tested), the researchers estimate that vaccination might prevent more than 28,000 hospitalizations annually across Kenya; however, this prediction assumes that it is valid to extrapolate from the data obtained from this one district hospital to the entire country.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050153.
The US Centers for Disease Control and Prevention provides information about rotavirus infections, surveillance, and vaccination (in English and Spanish)
The UK National Health Service Direct health encyclopedia provides information on rotavirus infections
MedlinePlus also provides links to information on rotavirus (in English and Spanish)
The African Rotavirus Surveillance Network is working to improve knowledge about rotavirus infections in Africa
The Rotavirus Vaccine Program aims to reduce child illness and death from diarrhea by increasing the availability of rotavirus vaccines in developing countries (in English and Spanish)
PATH, a nonprofit international organization that aims to create sustainable, culturally relevant solutions to global health problems, also provides detailed information on rotavirus surveillance and disease burden
doi:10.1371/journal.pmed.0050153
PMCID: PMC2488191  PMID: 18651787
25.  Community based study to compare the incidence and health services utilization pyramid for gastrointestinal, respiratory and dermal symptoms 
Background
Gastrointestinal (GI), respiratory and dermal symptoms are common and cause substantial morbidity, although the information on their exact incidence and comparative burden is limited. The aim of this study was to describe the epidemiology and rate these three major symptom complexes in order to improve our understanding of the health burden imposed by these symptoms.
Methods
We used data from a community based randomised control trial conducted from June 2007 to August 2008 among 277 South Australian families consuming rainwater. Using weekly health diaries, we prospectively collected information on GI (diarrhoea or vomiting), respiratory (sore throat, runny nose or cough) and dermal (rash, generalised itch or dermal infection) symptoms, as well as on relevant GP visits, time off work and/or hospitalisation due to these symptoms. Data were analysed using generalized estimating equations approach taking into account the variable number of weeks of follow-up of each individual and within-family clustering of responses.
Results
Over one year, at least one episode of GI symptoms was reported by 54% of participants (95% CI 50%-58%), at least one respiratory episode by 91% (95% CI 88%-93%) and at least one episode of dermal symptoms by 27% (95% CI 24%-30%). The average number of weeks per year during which respiratory symptoms occurred was four times greater than for GI or dermal symptoms (4.9, 1.2 and 1.2 weeks, respectively, p<0.001), with an average number of GP visits per person per year being twice as frequent (0.48, 0.26, 0.19 respectively, p<0.001). However, on a per episode basis, a higher proportion of people saw a GP or were hospitalised for GI symptoms.
Conclusions
This first comparative study of three different symptom complexes showed that although respiratory symptoms are most common, GI symptoms cause a greater per episode burden on healthcare resources. Measuring and comparing the community based burden of these symptom complexes will assist evidence-based allocation of resources.
doi:10.1186/1472-6963-12-211
PMCID: PMC3411466  PMID: 22824457
Respiratory symptoms; Gastrointestinal symptoms; Dermal symptoms; Burden of illness; Healthcare utilization

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