Effectiveness of kangaroo mother care before clinical stabilisation versus standard care among neonates at five hospitals in Uganda (OMWaNA): a parallel-group, individually randomised controlled trial and economic evaluation.

BACKGROUND: Preterm birth is the leading cause of death in children younger than 5 years worldwide. WHO recommends kangaroo mother care (KMC); however, its effects on mortality in sub-Saharan Africa and its relative costs remain unclear. We aimed to compare the effectiveness, safety, costs, and cost-effectiveness of KMC initiated before clinical stabilisation versus standard care in neonates weighing up to 2000 g. METHODS: We conducted a parallel-group, individually randomised controlled trial in five hospitals across Uganda. Singleton or twin neonates aged younger than 48 h weighing 700-2000 g without life-threatening clinical instability were eligible for inclusion. We randomly assigned (1:1) neonates to either KMC initiated before stabilisation (intervention group) or standard care (control group) via a computer-generated random allocation sequence with permuted blocks of varying sizes, stratified by birthweight and recruitment site. Parents, caregivers, and health-care workers were unmasked to treatment allocation; however, the independent statistician who conducted the analyses was masked. After randomisation, neonates in the intervention group were placed prone and skin-to-skin on the caregiver's chest, secured with a KMC wrap. Neonates in the control group were cared for in an incubator or radiant heater, as per hospital practice; KMC was not initiated until stability criteria were met. The primary outcome was all-cause neonatal mortality at 7 days, analysed by intention to treat. The economic evaluation assessed incremental costs and cost-effectiveness from a disaggregated societal perspective. This trial is registered with ClinicalTrials.gov, NCT02811432. FINDINGS: Between Oct 9, 2019, and July 31, 2022, 2221 neonates were randomly assigned: 1110 (50·0%) neonates to the intervention group and 1111 (50·0%) neonates to the control group. From randomisation to age 7 days, 81 (7·5%) of 1083 neonates in the intervention group and 83 (7·5%) of 1102 neonates in the control group died (adjusted relative risk [RR] 0·97 [95% CI 0·74-1·28]; p=0·85). From randomisation to 28 days, 119 (11·3%) of 1051 neonates in the intervention group and 134 (12·8%) of 1049 neonates in the control group died (RR 0·88 [0·71-1·09]; p=0·23). Even if policy makers place no value on averting neonatal deaths, the intervention would have 97% probability from the provider perspective and 84% probability from the societal perspective of being more cost-effective than standard care. INTERPRETATION: KMC initiated before stabilisation did not reduce early neonatal mortality; however, it was cost-effective from the societal and provider perspectives compared with standard care. Additional investment in neonatal care is needed for increased impact, particularly in sub-Saharan Africa. FUNDING: Joint Global Health Trials scheme of the Department of Health and Social Care, Foreign, Commonwealth and Development Office, UKRI Medical Research Council, and Wellcome Trust; Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Elevated Plasma Matrix Metalloproteinases Are Associated With Mycobacterium tuberculosis Bloodstream Infection and Mortality in Human Immunodeficiency Virus-Associated Tuberculosis.

Mortality from human immunodeficiency virus (HIV)-associated tuberculosis (TB) is high, particularly among hospitalized patients. In 433 people with HIV hospitalized with symptoms of TB, we investigated plasma matrix metalloproteinases (MMP) and matrix-derived biomarkers in relation to TB diagnosis, mortality, and Mycobacterium tuberculosis (Mtb) bloodstream infection (BSI). Compared to other diagnoses, MMP-8 was elevated in confirmed TB and in Mtb-BSI, positively correlating with extracellular matrix breakdown products. Baseline MMP-3, -7, -8, -10, and PIIINP were associated with Mtb-BSI and 12-week mortality. These findings implicate MMP dysregulation in pathophysiology of advanced HIV-TB and support MMP inhibition as a host-directed therapeutic strategy for HIV-TB.

Impact of a school-based water and hygiene intervention on child health and school attendance in Addis Ababa, Ethiopia: a cluster-randomised controlled trial.

BACKGROUND: School-based water, sanitation and hygiene (WASH) may improve the health and attendance of schoolchildren, particularly post-menarcheal girls, but existing evidence is mixed. We examined the impact of an urban school-based WASH programme (Project WISE) on child health and attendance. METHODS: The WISE cluster-randomised trial, conducted in 60 public primary schools in Addis Ababa, Ethiopia over one academic year, enrolled 2-4 randomly selected classes per school (~ 100 pupils) from grades 2 to 8 (aged 7-16) in an 'open cohort'. Schools were assigned 1:1 by stratified randomisation to receive the intervention during the 2021/2022 or the 2022/2023 academic year (waitlist control). The intervention included improvements to drinking water storage, filtration and access, handwashing stations and behaviour change promotion. Planned sanitation improvements were not realised. At four unannounced classroom visits post-intervention (March-June 2022), enumerators recorded primary outcomes of roll-call absence, and pupil-reported respiratory illness and diarrhoea in the past 7 days among pupils present. Analysis was by intention-to-treat. RESULTS: Of 83 eligible schools, 60 were randomly selected and assigned. In total, 6229 eligible pupils were enrolled (median per school 101.5; IQR 94-112), 5987 enrolled at study initiation (23rd November-22nd December 2021) and the remaining 242 during follow-up. Data were available on roll-call absence for 6166 pupils (99.0%), and pupil-reported illness for 6145 pupils (98.6%). We observed a 16% relative reduction in odds of pupil-reported respiratory illness in the past 7 days during follow-up in intervention vs. control schools (aOR 0.84; 95% CI 0.71-1.00; p = 0.046). There was no evidence of effect on pupil-reported diarrhoea in the past 7 days (aOR 1.15; 95% CI 0.84-1.59; p = 0.39) nor roll-call absence (aOR 1.07; 95% 0.83-1.38; p = 0.59). There was a small increase in menstrual care self-efficacy (aMD 3.32 on 0-100 scale; 95% CI 0.05-6.59), and no evidence of effects on other secondary outcomes. CONCLUSIONS: This large-scale intervention to improve school WASH conditions city-wide had a borderline impact on pupil-reported respiratory illness but no effect on diarrhoeal disease nor pupil absence. Future research should establish relationships between WASH-related illness, absence and other educational outcomes. TRIAL REGISTRATION: ClinicalTrials.gov, number NCT05024890.

Postpartum haemorrhage and risk of cardiovascular disease in later life: A population-based record linkage cohort study.

OBJECTIVE: To investigate the association between postpartum haemorrhage (PPH) and subsequent cardiovascular disease. DESIGN: Population-based retrospective cohort study, using record linkage between Aberdeen Maternity and Neonatal Databank (AMND) and Scottish healthcare data sets. SETTING: Grampian region, Scotland. POPULATION: A cohort of 70 904 women who gave birth after 24 weeks of gestation in the period 1986-2016. METHODS: We used extended Cox regression models to investigate the association between having had one or more occurrences of PPH in any (first or subsequent) births (exposure) and subsequent cardiovascular disease, adjusted for sociodemographic, medical, and pregnancy and birth-related factors. MAIN OUTCOME MEASURES: Cardiovascular disease identified from the prescription of selected cardiovascular medications, hospital discharge records or death from cardiovascular disease. RESULTS: In our cohort of 70 904 women (with 124 795 birth records), 25 177 women (36%) had at least one PPH. Compared with not having a PPH, having at least one PPH was associated with an increased risk of developing cardiovascular disease, as defined above, in the first year after birth (adjusted hazard ratio, aHR 1.96; 95% confidence interval, 95% CI 1.51-2.53; p < 0.001). The association was attenuated over time, but strong evidence of increased risk remained at 2-5 years (aHR 1.19, 95% CI 1.11-1.30, P < 0.001) and at 6-15 years after giving birth (aHR 1.17, 95% CI 1.05-1.30, p = 0.005). CONCLUSIONS: Compared with women who have never had a PPH, women who have had at least one episode of PPH are twice as likely to develop cardiovascular disease in the first year after birth, and some increased risk persists for up to 15 years.

Factors associated with posttraumatic stress and anxiety among the parents of babies admitted to neonatal care: a systematic review.

BACKGROUND: Posttraumatic stress (PTS) and anxiety are common mental health problems among parents of babies admitted to a neonatal unit (NNU). This review aimed to identify sociodemographic, pregnancy and birth, and psychological factors associated with PTS and anxiety in this population. METHOD: Studies published up to December 2022 were retrieved by searching Medline, Embase, PsychoINFO, Cumulative Index to Nursing and Allied Health electronic databases. The modified Newcastle-Ottawa Scale for cohort and cross-sectional studies was used to assess the methodological quality of included studies. This review was pre-registered in PROSPERO (CRD42021270526). RESULTS: Forty-nine studies involving 8,447 parents were included; 18 studies examined factors for PTS, 24 for anxiety and 7 for both. Only one study of anxiety factors was deemed to be of good quality. Studies generally included a small sample size and were methodologically heterogeneous. Pooling of data was not feasible. Previous history of mental health problems (four studies) and parental perception of more severe infant illness (five studies) were associated with increased risk of PTS, and had the strongest evidence. Shorter gestational age (≤ 33 weeks) was associated with an increased risk of anxiety (three studies) and very low birth weight (< 1000g) was associated with an increased risk of both PTS and anxiety (one study). Stress related to the NNU environment was associated with both PTS (one study) and anxiety (two studies), and limited data suggested that early engagement in infant's care (one study), efficient parent-staff communication (one study), adequate social support (two studies) and positive coping mechanisms (one study) may be protective factors for both PTS and anxiety. Perinatal anxiety, depression and PTS were all highly comorbid conditions (as with the general population) and the existence of one mental health condition was a risk factor for others. CONCLUSION: Heterogeneity limits the interpretation of findings. Until clearer evidence is available on which parents are most at risk, good communication with parents and universal screening of PTS and anxiety for all parents whose babies are admitted to NNU is needed to identify those parents who may benefit most from mental health interventions.

Potassium Supplementation and Prevention of Atrial Fibrillation After Cardiac Surgery: The TIGHT K Randomized Clinical Trial.

IMPORTANCE: Supplementing potassium in an effort to maintain high-normal serum concentrations is a widespread strategy used to prevent atrial fibrillation after cardiac surgery (AFACS), but is not evidence-based, carries risks, and is costly. OBJECTIVE: To determine whether a lower serum potassium concentration trigger for supplementation is noninferior to a high-normal trigger. DESIGN, SETTING, AND PARTICIPANTS: This open-label, noninferiority, randomized clinical trial was conducted at 23 cardiac surgical centers in the United Kingdom and Germany. Between October 20, 2020, and November 16, 2023, patients with no history of atrial dysrhythmias scheduled for isolated coronary artery bypass grafting (CABG) surgery were enrolled. The last study patient was discharged from the hospital on December 11, 2023. INTERVENTIONS: Patients were randomly assigned to a strategy of tight or relaxed potassium control (only supplementing if serum potassium concentration fell below 4.5 mEq/L or 3.6 mEq/L, respectively). Patients wore an ambulatory heart rhythm monitor, which was analyzed by a core laboratory masked to treatment assignment. MAIN OUTCOMES AND MEASURES: The prespecified primary end point was clinically detected and electrocardiographically confirmed new-onset AFACS in the first 120 hours after CABG surgery or until hospital discharge, whichever occurred first. All primary outcome events were validated by an event validation committee, which was masked to treatment assignment. Noninferiority of relaxed potassium control was defined as a risk difference for new-onset AFACS with associated upper bound of a 1-sided 97.5% CI of less than 10%. Secondary outcomes included other heart rhythm-related events, clinical outcomes, and cost related to the intervention. RESULTS: A total of 1690 patients (mean age, 65 years; 256 [15%] females) were randomized. The primary end point occurred in 26.2% of patients (n = 219) in the tight group and 27.8% of patients (n = 231) in the relaxed group, which is a risk difference of 1.7% (95% CI, -2.6% to 5.9%). There was no difference between the groups in the incidence of at least 1 AFACS episode detected by any means or by ambulatory heart rhythm monitor alone, non-AFACS dysrhythmias, in-patient mortality, or length of stay. Per-patient cost for purchasing and administering potassium was significantly lower in the relaxed group (mean difference, $111.89 [95% CI, $103.60-$120.19]; P <.001). CONCLUSIONS AND RELEVANCE: For AFACS prophylaxis, supplementation only when serum potassium concentration fell below 3.6 mEq/L was noninferior to the current widespread practice of supplementing potassium to maintain a serum potassium concentration greater than or equal to 4.5 mEq/L. The lower threshold of supplementation was not associated with any increase in dysrhythmias or adverse clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04053816.

Before and after study of a national complementary and supplementary feeding programme in Rwanda, 2017-2021.

To address high rates of malnutrition among children from vulnerable households in Rwanda, the government initiated a national food supplementation programme. A before and after evaluation, using repeat cross-sectional surveys in randomly selected villages was conducted; aimed at assessing the effectiveness of providing fortified blended food (FBF) to children 18-23 months of age, pregnant and lactating women in the lowest tier of Rwanda's social support system. Data were collected in 2017, 2018 and 2021 through interviews with caregivers; anthropometric measurements and a capillary blood sample were obtained from children. The primary statistical analysis compared the nutritional status of children before and after the introduction of FBF. We enroled 724 children during each survey. The prevalence of stunting declined from 47% to 35% between 2017 and 2021; in 2018, the prevalence of stunting was 43%. Children had a 42% reduction in the odds of being stunted (adjusted odds ratio [AOR]: 0.58, 95% confidence interval [CI]: 0.47-0.74, p < 0.001) from 2017 to 2021 even after adjusting for inherent, distal, proximal, and intermediate covariates. The reduction in stunting observed within the first year of the programme was not statistically significant (AOR: 0.83, 95% CI: 0.67-1.03, p < 0.091). We observed meaningful reductions in the prevalence of stunting among children which coincided with the introduction of Government-led initiative to reduce malnutrition. The Rwandan Government has committed to improving the living conditions of vulnerable households and has made strong investments in reducing malnutrition. The impact of these investments can be seen in the overall trend towards improved nutritional status highlighted in this evaluation.

Children with disabilities lack access to nutrition, health and WASH services: A secondary data analysis.

Malnutrition and disability are major global public health problems. Poor diets, inadequate access to nutrition/health services (NaHS), and poor water, sanitation and hygiene (WASH) all increase the risk of malnutrition and infection. This leads to poor health outcomes, including disability. To better understand the relationship between these factors, we explored access to NaHS and household WASH and dietary adequacy among households with and without children with disabilities in Uganda. We used cross-sectional secondary data from 2021. Adjusted logistic regression was used to explore associations between disabilities, access to NaHS, WASH and dietary adequacy. Of the 6924 households, 4019 (57.9%) reported having access to necessary NaHS, with deworming and vaccination reported as both the most important and most difficult to access services. Access to services was lower for households with children with disabilities compared to those without, after adjusting for likely confounding factors (Odds ratio = 0.70; 95% CI 0.55-0.89, p = 0.003). There is evidence of an interaction between disability and WASH adequacy, with improved WASH adequacy associated with improved access to services, including for children with disabilities (interaction odds ratio = 1.12, 95% CI: 1.02-1.22, p = 0.012). The proportion of malnourished children was higher among households with children with disabilities than households without it (6.3% vs. 2.4% p < 0.001). There are concerning gaps in access to NaHS services in Uganda, with households with children with disabilities reporting worse access, particularly for those with low WASH adequacy. Improved and inclusive access to NaHS and WASH needs to be urgently prioritized, especially for children with disabilities.

The complex relationship between iron status and anemia in pregnant and postpartum women in India: Analysis of two Indian study cohorts of uncomplicated pregnancies.

Low hemoglobin is widely used as an indicator of iron deficiency anemia in India and other low-and-middle income counties, but anemia need not accurately reflect iron deficiency. We examined the relationship between hemoglobin and biomarkers of iron status in antenatal and postnatal period. Secondary analysis of uncomplicated singleton pregnancies in two Indian study cohorts: 1132 antenatal women in third trimester and 837 postnatal women 12-72 h after childbirth. Associations of hemoglobin with ferritin in both data sets, and with sTfR, TSAT, and hepcidin in the postnatal cohort were examined using multivariable linear regression. Multinomial logistic regression was used to examine the association between severity of anemia and iron status. Regression models were adjusted for potential confounders. Over 55% of the women were anemic; 34% of antenatal and 40% of postnatal women had low ferritin, but 4% antenatal and 6% postnatal women had high ferritin. No evidence of association between hemoglobin and ferritin was observed (antenatal: adjusted coefficient [aCoef] -0.0004, 95% confidence interval [CI] -0.001, 0.001; postnatal: aCoef -0.0001, 95% CI -0.001, 0.001). We found a significant linear association of hemoglobin with sTfR (aCoef -0.04, 95% CI -0.07, -0.01), TSAT (aCoef -0.005, 95% CI -0.008, -0.002), and hepcidin (aCoef 0.02, 95% CI 0.02, 0.03) in postnatal women. Likelihood of low ferritin was more common in anemic than non-anemic women, but high ferritin was also more common in women with severe anemia in both cohorts. Causes of anemia in pregnant and postpartum women in India are multifactorial; low hemoglobin alone is not be a useful marker of iron deficiency.

The relationship between perineal trauma and postpartum psychological outcomes: a secondary analysis of a population-based survey.

BACKGROUND: Perineal trauma, involving either naturally occurring tears or episiotomy, is common during childbirth but little is known about its psychological impact. This study aimed to determine the associations between childbirth related perineal trauma and psychological outcomes reported by women three months after giving birth and to explore factors that could mediate relationships between perineal trauma and maternal psychological outcomes. METHODS: This study was a secondary analysis of data from a cross-sectional population-based survey of maternal and infant health. A total of 4,578 women responded to the survey, of which 3,307 had a vaginal birth and were eligible for inclusion into the analysis. Symptoms of depression, anxiety, and post-traumatic stress (PTS) symptoms were assessed using validated self- report measures. Physical symptoms were derived from a checklist and combined to produce a composite physical symptoms score. Regression models were fitted to explore the associations. RESULTS: Nearly three quarters of women experienced some degree of perineal trauma. Women who experienced perineal trauma reported having more postnatal physical symptoms (adjusted proportional odds ratio 1.47, 95%CI 1.38 to 1.57, p-value < 0.001), were more likely to report PTS symptoms (adjusted OR 1.19, 95%CI 1.04 to 1.36, p-value 0.010), and there was strong evidence that each unit increase in the physical symptoms score was associated with between 38 and 90% increased adjusted odds of adverse psychological symptoms. There was no evidence of association between perineal trauma and satisfaction with postnatal care, although there was strong evidence that satisfaction with labour and birth was associated with 16% reduced adjusted odds of depression and 30% reduced adjusted odds of PTS symptoms. CONCLUSIONS: Women who experienced perineal trauma were more likely to experience physical symptoms, and the more physical symptoms a woman experienced the more likely she was to report having postnatal depression, anxiety and PTS symptoms. There was some evidence of a direct association between perineal trauma and PTS symptoms but no evidence of a direct association between perineal trauma and depression or anxiety. Assessment and management of physical symptoms in the postnatal period may play an important role in reducing both physical and psychological postnatal morbidity.

Post-malnutrition growth and its associations with child survival and non-communicable disease risk: a secondary analysis of the Malawi 'ChroSAM' cohort.

OBJECTIVE: To explore patterns of post-malnutrition growth (PMGr) during and after treatment for severe malnutrition and describe associations with survival and non-communicable disease (NCD) risk 7 years post-treatment. DESIGN: Six indicators of PMGr were derived based on a variety of timepoints, weight, weight-for-age z-score and height-for-age z-score (HAZ). Three categorisation methods included no categorisation, quintiles and latent class analysis (LCA). Associations with mortality risk and seven NCD indicators were analysed. SETTING: Secondary data from Blantyre, Malawi between 2006 and 2014. PARTICIPANTS: A cohort of 1024 children treated for severe malnutrition (weight-for-length z-score < 70 % median and/or MUAC (mid-upper arm circumference) < 110 mm and/or bilateral oedema) at ages 5-168 months. RESULTS: Faster weight gain during treatment (g/d) and after treatment (g/kg/day) was associated with lower risk of death (adjusted OR 0·99, 95 % CI 0·99, 1·00; and adjusted OR 0·91, 95 % CI 0·87, 0·94, respectively). In survivors (mean age 9 years), it was associated with greater hand grip strength (0·02, 95 % CI 0·00, 0·03) and larger HAZ (6·62, 95 % CI 1·31, 11·9), both indicators of better health. However, faster weight gain was also associated with increased waist:hip ratio (0·02, 95 % CI 0·01, 0·03), an indicator of later-life NCD risk. The clearest patterns of association were seen when defining PMGr based on weight gain in g/d during treatment and using the LCA method to describe growth patterns. Weight deficit at admission was a major confounder. CONCLUSIONS: A complex pattern of benefits and risks is associated with faster PMGr. Both initial weight deficit and rate of weight gain have important implications for future health.

How age and sex affect treatment outcomes for children with severe malnutrition: A multi-country secondary data analysis.

Age and sex influence the risk of childhood wasting. We aimed to determine if wasting treatment outcomes differ by age and sex in children under 5 years, enroled in therapeutic and supplementary feeding programmes. Utilising data from stage 1 of the ComPAS trial, we used logistic regression to assess the association between age, sex and wasting treatment outcomes (recovery, death, default, non-response, and transfer), modelling the likelihood of recovery versus all other outcomes. We used linear regression to calculate differences in mean length of stay (LOS) and mean daily weight gain by age and sex. Data from 6929 children from Kenya, Chad, Yemen and South Sudan was analysed. Girls in therapeutic feeding programmes were less likely to recover than boys (pooled odds ratio [OR]: 0.84, 95% confidence interval [CI]: 0.72-0.97, p = 0.018). This association was statistically significant in Chad (OR: 0.61, 95% CI: 0.39-0.95, p = 0.030) and Yemen (OR: 0.47, 95% CI: 0.27-0.81, p = 0.006), but not in Kenya and South Sudan. Multinomial analysis, however, showed no difference in recovery between sexes. There was no difference between sexes for LOS, but older children (24-59 months) had a shorter mean LOS than younger children (6-23 months). Mean daily weight gain was consistently lower in boys compared with girls. We found few differences in wasting treatment outcomes by sex and age. The results do not indicate a need to change current programme inclusion requirements or treatment protocols on the basis of sex or age, but future research in other settings should continue to investigate the aetiology of differences in recovery and implications for treatment protocols.

Measuring and valuing broader impacts in public health: Development of a sanitation-related quality of life instrument in Maputo, Mozambique.

Two billion people globally lack access to a basic toilet. While improving sanitation reduces infectious disease, toilet users often identify privacy, safety and dignity as more important. However, these outcomes have not been incorporated in sanitation-related economic evaluations. This illustrates the general challenge of outcome measurement and valuation in the economic evaluation of public health interventions, and risks misallocating the US$ 20 billion invested in sanitation in low- and middle-income countries every year. In this study in urban Mozambique, we develop an instrument to measure sanitation-related quality of life (SanQoL). Applying methods from health economics and the capability approach, we develop a descriptive system to measure five attributes identified in prior qualitative research: disgust, health, shame, safety and privacy. Sampling individuals from the intervention and control groups of a sanitation intervention trial, we elicit attribute ranks to value a SanQoL index and assess its validity and reliability. In combination with a measure of time using a sanitation service, SanQoL can quantify incremental benefits in a sanitation-focused cost-effectiveness analysis. After monetary valuation based on willingness to pay, QoL benefits could be summed with health gains in cost-benefit analysis, the most common method in sanitation economic evaluations.

Management of Gastroschisis: Results From the NETS2G Study, a Joint British, Irish, and Canadian Prospective Cohort Study of 1268 Infants.

OBJECTIVE: In infants with gastroschisis, outcomes were compared between those where operative reduction and fascial closure were attempted ≤24 hours of age (PC), and those who underwent planned closure of their defect >24 hours of age following reduction with a pre-formed silo (SR). SUMMARY OF BACKGROUND DATA: Inadequate evidence exists to determine how best to treat infants with gastroschisis. METHODS: A secondary analysis was conducted of data collected 2006-2008 using the British Association of Pediatric Surgeons Congenital Anomalies Surveillance System, and 2005-2016 using the Canadian Pediatric Surgery Network.28-day outcomes were compared between infants undergoing PC and SR. Primary outcome was number of gastrointestinal complications. Interactions were investigated between infant characteristics and treatment to determine whether intervention effect varied in sub-groups of infants. RESULTS: Data from 341 British and Irish infants (27%) and 927 Canadian infants (73%) were used. 671 infants (42%) underwent PC and 597 (37%) underwent SR. The effect of SR on outcome varied according to the presence/absence of intestinal perforation, intestinal matting and intestinal necrosis. In infants without these features, SR was associated with fewer gastrointestinal complications [aIRR 0.25 (95% CI 0.09-0.67, P = 0.006)], more operations [aIRR 1.40 (95% CI 1.22-1.60, P < 0.001)], more days PN [aIRR 1.08 (95% CI 1.03-1.13, P < 0.001)], and a higher infection risk [aOR 2.06 (95% CI 1.10-3.87, P = 0.025)]. In infants with these features, SR was associated with a greater number of operations [aIRR 1.30 (95% CI 1.17-1.45, P < 0.001)], and more days PN [aIRR 1.06 (95% CI 1.02-1.10, P = 0.003)]. CONCLUSIONS: In infants without intestinal perforation, matting, or necrosis, the benefits of SR outweigh its drawbacks. In infants with these features, the opposite is true. Treatment choice should be based upon these features.

Cost-Utility Analysis of a Complex Intervention to Reduce School-Based Bullying and Aggression: An Analysis of the Inclusive RCT.

OBJECTIVES: Bullying and aggression among children and young people are key public mental health priorities. In this study, we evaluated the cost-effectiveness of a complex school-based intervention to address these outcomes within a large-cluster randomized trial (Inclusive). METHODS: Forty state secondary schools were randomly allocated (1:1) to receive the intervention or continue with current practice as controls. Data were collected using paper questionnaires completed in classrooms including measures of their health-related quality of life using the Childhood Utility Index and police and National Health Service resource use. Further detailed data were collected on the cost of delivering the intervention. We calculated incremental cost-effectiveness ratios following the intention-to-treat principle using multilevel linear regression models that allowed for clustering of pupils at the school level. RESULTS: Overall, we found that the intervention was highly cost-effective, with cost-per quality-adjusted life year thresholds of £13 284 and £1875 at 2 years and 3 years, respectively. Analysis of uncertainty in the result at 2 years revealed a 65% chance of being cost-effective, but after 3 years there was a 90% chance that it was cost-effective. CONCLUSION: This study provides strong evidence collected prospectively from a randomized study that this school-based intervention is highly cost-effective. Education- and health-sector policy makers should consider investment in scaling up this intervention.

Validated screening tools to identify common mental disorders in perinatal and postpartum women in India: a systematic review and meta-analysis.

BACKGROUND: Perinatal common mental disorders are associated with significant adverse outcomes for women and their families, particularly in low- and middle-income settings. Early detection through screening with locally-validated tools can improve outcomes. METHODS: We searched MEDLINE, Embase, PsycINFO, Global Health, Cochrane Library, Web of Science and Google Scholar for articles on the validation of screening tools for common mental disorders in perinatal women in India, with no language or date restrictions. Quality was assessed using the QUADAS-2 tool. We used bivariate and hierarchical summary receiver operating characteristic models to calculate pooled summary estimates of sensitivity and specificity. Heterogeneity was assessed by visualising the distance of individual studies from the summary curve. RESULTS: Seven studies involving 1003 women were analysed. All studies assessed the validity of the Edinburgh Postnatal Depression Scale (EPDS) in identifying perinatal depression. No validation studies of any other screening tools were identified. Using a common threshold of ≥13 the EPDS had a pooled sensitivity and specificity of 88·9% (95%CI 77·4-94·9) and 93·4 (95%CI 81·5-97·8), respectively. Using optimal thresholds (range ≥ 9 to ≥13) the EPDS had a pooled sensitivity and specificity of 94·4% (95%CI 81·7-98·4) and 90·8 (95%CI 83·7-95·0), respectively. CONCLUSION: The EPDS is psychometrically valid in diverse Indian settings and its use in routine maternity care could improve detection of perinatal depression. Further research is required to validate screening tools for other perinatal common mental disorders in India.

Invariant Natural Killer T-cell Dynamics in Human Immunodeficiency Virus-associated Tuberculosis.

BACKGROUND: Tuberculosis (TB) is the leading cause of mortality and morbidity in people living with human immunodeficiency virus (HIV) infection (PLWH). PLWH with TB disease are at risk of the paradoxical TB-associated immune reconstitution inflammatory syndrome (TB-IRIS) when they commence antiretroviral therapy. However, the pathophysiology is incompletely understood and specific therapy is lacking. We investigated the hypothesis that invariant natural killer T (iNKT) cells contribute to innate immune dysfunction associated with TB-IRIS. METHODS: In a cross-sectional study of 101 PLWH and HIV-uninfected South African patients with active TB and controls, iNKT cells were enumerated using α-galactosylceramide-loaded CD1d tetramers and subsequently functionally characterized by flow cytometry. In a second study of 49 people with HIV type 1 (HIV-1) and active TB commencing antiretroviral therapy, iNKT cells in TB-IRIS patients and non-IRIS controls were compared longitudinally. RESULTS: Circulating iNKT cells were reduced in HIV-1 infection, most significantly the CD4+ subset, which was inversely associated with HIV-1 viral load. iNKT cells in HIV-associated TB had increased surface CD107a expression, indicating cytotoxic degranulation. Relatively increased iNKT cell frequency in patients with HIV-1 infection and active TB was associated with development of TB-IRIS following antiretroviral therapy initiation. iNKT cells in TB-IRIS were CD4+CD8- subset depleted and degranulated around the time of TB-IRIS onset. CONCLUSIONS: Reduced iNKT cell CD4+ subsets as a result of HIV-1 infection may skew iNKT cell functionality toward cytotoxicity. Increased CD4- cytotoxic iNKT cells may contribute to immunopathology in TB-IRIS.

A simplified, combined protocol versus standard treatment for acute malnutrition in children 6-59 months (ComPAS trial): A cluster-randomized controlled non-inferiority trial in Kenya and South Sudan.

BACKGROUND: Malnutrition underlies 3 million child deaths worldwide. Current treatments differentiate severe acute malnutrition (SAM) from moderate acute malnutrition (MAM) with different products and programs. This differentiation is complex and costly. The Combined Protocol for Acute Malnutrition Study (ComPAS) assessed the effectiveness of a simplified, unified SAM/MAM protocol for children aged 6-59 months. Eliminating the need for separate products and protocols could improve the impact of programs by treating children more easily and cost-effectively, reaching more children globally. METHODS AND FINDINGS: A cluster-randomized non-inferiority trial compared a combined protocol against standard care in Kenya and South Sudan. Randomization was stratified by country. Combined protocol clinics treated children using 2 sachets of ready-to-use therapeutic food (RUTF) per day for those with mid-upper arm circumference (MUAC) < 11.5 cm and/or edema, and 1 sachet of RUTF per day for those with MUAC 11.5 to <12.5 cm. Standard care clinics treated SAM with weight-based RUTF rations, and MAM with ready-to-use supplementary food (RUSF). The primary outcome was nutritional recovery. Secondary outcomes included cost-effectiveness, coverage, defaulting, death, length of stay, and average daily weight and MUAC gains. Main analyses were per-protocol, with intention-to-treat analyses also conducted. The non-inferiority margin was 10%. From 8 May 2017 to 31 March 2018, 2,071 children were enrolled in 12 combined protocol clinics (mean age 17.4 months, 41% male), and 2,039 in 12 standard care clinics (mean age 16.7 months, 41% male). In total, 1,286 (62.1%) and 1,202 (59.0%), respectively, completed treatment; 981 (76.3%) on the combined protocol and 884 (73.5%) on the standard protocol recovered, yielding a risk difference of 0.03 (95% CI -0.05 to 0.10, p = 0.52; per-protocol analysis, adjusted for country, age, and sex). The amount of ready-to-use food (RUTF or RUSF) required for a child with SAM to reach full recovery was less in the combined protocol (122 versus 193 sachets), and the combined protocol cost US$123 less per child recovered (US$918 versus US$1,041). There were 23 (1.8%) deaths in the combined protocol arm and 21 (1.8%) deaths in the standard protocol arm (adjusted risk difference 95% CI -0.01 to 0.01, p = 0.87). There was no evidence of a difference between the protocols for any of the other secondary outcomes. Study limitations included contextual factors leading to defaulting, a combined multi-country power estimate, and operational constraints. CONCLUSIONS: Combined treatment for SAM and MAM is non-inferior to standard care. Further research should focus on operational implications, cost-effectiveness, and context (Asia versus Africa; emergency versus food-secure settings). This trial is complete and registered at ISRCTN (ISRCTN30393230). TRIAL REGISTRATION: The trial is registered at ISRCTN, trial number ISRCTN30393230.

Health impacts of parental migration on left-behind children and adolescents: a systematic review and meta-analysis.

BACKGROUND: Globally, a growing number of children and adolescents are left behind when parents migrate. We investigated the effect of parental migration on the health of left behind-children and adolescents in low-income and middle-income countries (LMICs). METHODS: For this systematic review and meta-analysis we searched MEDLINE, Embase, CINAHL, the Cochrane Library, Web of Science, PsychINFO, Global Index Medicus, Scopus, and Popline from inception to April 27, 2017, without language restrictions, for observational studies investigating the effects of parental migration on nutrition, mental health, unintentional injuries, infectious disease, substance use, unprotected sex, early pregnancy, and abuse in left-behind children (aged 0-19 years) in LMICs. We excluded studies in which less than 50% of participants were aged 0-19 years, the mean or median age of participants was more than 19 years, fewer than 50% of parents had migrated for more than 6 months, or the mean or median duration of migration was less than 6 months. We screened studies using systematic review software and extracted summary estimates from published reports independently. The main outcomes were risk and prevalence of health outcomes, including nutrition (stunting, wasting, underweight, overweight and obesity, low birthweight, and anaemia), mental health (depressive disorder, anxiety disorder, conduct disorders, self-harm, and suicide), unintentional injuries, substance use, abuse, and infectious disease. We calculated pooled risk ratios (RRs) and standardised mean differences (SMDs) using random-effects models. This study is registered with PROSPERO, number CRD42017064871. FINDINGS: Our search identified 10 284 records, of which 111 studies were included for analysis, including a total of 264 967 children (n=106 167 left-behind children and adolescents; n=158 800 children and adolescents of non-migrant parents). 91 studies were done in China and focused on effects of internal labour migration. Compared with children of non-migrants, left-behind children had increased risk of depression and higher depression scores (RR 1·52 [95% CI 1·27-1·82]; SMD 0·16 [0·10-0·21]), anxiety (RR 1·85 [1·36-2·53]; SMD 0·18 [0·11-0·26]), suicidal ideation (RR 1·70 [1·28-2·26]), conduct disorder (SMD 0·16 [0·04-0·28]), substance use (RR 1·24 [1·00-1·52]), wasting (RR 1·13 [1·02-1·24]) and stunting (RR 1·12 [1·00-1·26]). No differences were identified between left-behind children and children of non-migrants for other nutrition outcomes, unintentional injury, abuse, or diarrhoea. No studies reported outcomes for other infectious diseases, self-harm, unprotected sex, or early pregnancy. Study quality varied across the included studies, with 43% of studies at high or unclear risk of bias across five or more domains. INTERPRETATION: Parental migration is detrimental to the health of left-behind children and adolescents, with no evidence of any benefit. Policy makers and health-care professionals need to take action to improve the health of these young people. FUNDING: Wellcome Trust.

Effects of the Learning Together intervention on bullying and aggression in English secondary schools (INCLUSIVE): a cluster randomised controlled trial.

BACKGROUND: Bullying, aggression, and violence among children and young people are some of the most consequential public mental health problems. We tested the Learning Together intervention, which involved students in efforts to modify their school environment using restorative practice and by developing social and emotional skills. METHODS: We did a cluster randomised trial, with economic and process evaluations, of the Learning Together intervention compared with standard practice (controls) over 3 years in secondary schools in south-east England. Learning Together consisted of staff training in restorative practice; convening and facilitating a school action group; and a student social and emotional skills curriculum. Primary outcomes were self-reported experience of bullying victimisation (Gatehouse Bullying Scale; GBS) and perpetration of aggression (Edinburgh Study of Youth Transitions and Crime (ESYTC) school misbehaviour subscale) measured at 36 months. We analysed data using intention-to-treat longitudinal mixed-effects models. This trial was registered with the ISRCTN registry (10751359). FINDINGS: We included 40 schools (20 in each group); no schools withdrew. 6667 (93·6%) of 7121 students participated at baseline and 5960 (83·3%) of 7154 at 36 months. Mean GBS bullying score at 36 months was 0·34 (SE 0·02) in the control group versus 0·29 (SE 0·02) in the intervention group, with a significant adjusted mean difference (-0·03, 95% CI -0·06 to -0·001; adjusted effect size -0·08). Mean ESYTC score at 36 months was 4·33 (SE 0·20) in the control group versus 4·04 (0·21) in the intervention group, with no evidence of a difference between groups (adjusted difference -0·13, 95% CI -0·43 to 0·18; adjusted effect size -0·03). Costs were an additional £58 per pupil in intervention schools than in control schools. INTERPRETATION: Learning Together had small but significant effects on bullying, which could be important for public health, but no effect on aggression. Interventions to promote student health by modifying the whole-school environment are likely to be one of the most feasible and efficient ways of addressing closely related risk and health outcomes in children and young people. FUNDING: National Institute for Health Research, Educational Endowment Foundation.