BackgroundTackling severe acute malnutrition (SAM) is a global health priority. Heightened risk of non-communicable diseases (NCD) in children exposed to SAM at around 2 years of age is plausible in view of previously described consequences of other early nutritional insults. By applying developmental origins of health and disease (DOHaD) theory to this group, we aimed to explore the long-term effects of SAM.MethodsWe followed up 352 Malawian children (median age 9·3 years) who were still alive following SAM inpatient treatment between July 12, 2006, and March 7, 2007, (median age 24 months) and compared them with 217 sibling controls and 184 age-and-sex matched community controls. Our outcomes of interest were anthropometry, body composition, lung function, physical capacity (hand grip, step test, and physical activity), and blood markers of NCD risk. For comparisons of all outcomes, we used multivariable linear regression, adjusted for age, sex, HIV status, and socioeconomic status. We also adjusted for puberty in the body composition regression model.FindingsCompared with controls, children who had survived SAM had lower height-for-age Z scores (adjusted difference vs community controls 0·4, 95% CI 0·6 to 0·2, p=0·001; adjusted difference vs sibling controls 0·2, 0·0 to 0·4, p=0·04), although they showed evidence of catch-up growth. These children also had shorter leg length (adjusted difference vs community controls 2·0 cm, 1·0 to 3·0, p<0·0001; adjusted difference vs sibling controls 1·4 cm, 0·5 to 2·3, p=0·002), smaller mid-upper arm circumference (adjusted difference vs community controls 5·6 mm, 1·9 to 9·4, p=0·001; adjusted difference vs sibling controls 5·7 mm, 2·3 to 9·1, p=0·02), calf circumference (adjusted difference vs community controls 0·49 cm, 0·1 to 0·9, p=0·01; adjusted difference vs sibling controls 0·62 cm, 0·2 to 1·0, p=0·001), and hip circumference (adjusted difference vs community controls 1·56 cm, 0·5 to 2·7, p=0·01; adjusted difference vs sibling controls 1·83 cm, 0·8 to 2·8, p<0·0001), and less lean mass (adjusted difference vs community controls −24·5, −43 to −5·5, p=0·01; adjusted difference vs sibling controls −11·5, −29 to −6, p=0·19) than did either sibling or community controls. Survivors of SAM had functional deficits consisting of weaker hand grip (adjusted difference vs community controls −1·7 kg, 95% CI −2·4 to −0·9, p<0·0001; adjusted difference vs sibling controls 1·01 kg, 0·3 to 1·7, p=0·005,)) and fewer minutes completed of an exercise test (sibling odds ratio [OR] 1·59, 95% CI 1·0 to 2·5, p=0·04; community OR 1·59, 95% CI 1·0 to 2·5, p=0·05). We did not detect significant differences between cases and controls in terms of lung function, lipid profile, glucose tolerance, glycated haemoglobin A1c, salivary cortisol, sitting height, and head circumference.InterpretationOur results suggest that SAM has long-term adverse effects. Survivors show patterns of so-called thrifty growth, which is associated with future cardiovascular and metabolic disease. The evidence of catch-up growth and largely preserved cardiometabolic and pulmonary functions suggest the potential for near-full rehabilitation. Future follow-up should try to establish the effects of puberty and later dietary or social transitions on these parameters, as well as explore how best to optimise recovery and quality of life for survivors.FundingThe Wellcome Trust.

Background Management of Severe Acute Malnutrition (SAM) plays a vital role in achieving global child survival targets. Effective treatment programmes are available but little is known about longer term outcomes following programme discharge. Methods From July 2006 to March 2007, 1024 children (median age 21.5 months, IQR 15–32) contributed 1187 admission episodes to an inpatient-based SAM treatment centre in Blantyre, Malawi. Long term outcomes, were determined in a longitudinal cohort study, a year or more after initial programme discharge. We found information on 88%(899/1024). Results In total, 42%(427/1024) children died during or after treatment. 25%(105/427) of deaths occurred after normal programme discharge, >90 days after admission. Mortality was greatest among HIV seropositive children: 62%(274/445). Other risk factors included age <12 months; severity of malnutrition at admission; and disability. In survivors, weight-for-height and weight-for-age improved but height-for-age remained low, mean −2.97 z-scores (SD 1.3). Conclusions Although SAM mortality in this setting was unacceptably high, our findings offer important lessons for future programming, policy and research. First is the need for improved programme evaluation: most routine reporting systems would have missed late deaths and underestimated total mortality due to SAM. Second, a more holistic view of SAM is needed: while treatment will always focus on nutritional interventions, it is vital to also identify and manage underlying clinical conditions such as HIV and disability. Finally early identification and treatment of SAM should be emphasised: our results suggest that this could improve longer term as well as short term outcomes. As international policy and programming becomes increasingly focused on stunting and post-malnutrition chronic disease outcomes, SAM should not be forgotten. Proactive prevention and treatment services are essential, not only to reduce mortality in the short term but also because they have potential to impact on longer term morbidity, growth and development of survivors.

It has become clear in recent years that the human intestinal microbiota plays an important role in maintaining health and thus is an attractive target for clinical interventions. Scientists and clinicians have become increasingly interested in assessing the ability of probiotics and prebiotics to enhance the nutritional status of malnourished children, pregnant women, the elderly, and individuals with non-communicable disease-associated malnutrition. A workshop was held by the International Scientific Association for Probiotics and Prebiotics (ISAPP), drawing on the knowledge of experts from industry, medicine, and academia, with the objective to assess the status of our understanding of the link between the microbiome and under-nutrition, specifically in relation to probiotic and prebiotic treatments for under-nourished individuals. These discussions led to four recommendations: (1) The categories of malnourished individuals need to be differentiated To improve treatment outcomes, subjects should first be categorized based on the cause of malnutrition, additional health-concerns, differences in the gut microbiota, and sociological considerations. (2) Define a baseline “healthy” gut microbiota for each category Altered nutrient requirement (for example, in pregnancy and old age) and individual variation may change what constitutes a healthy gut microbiota for the individual. (3) Perform studies using model systems to test the effectiveness of potential probiotics and prebiotics against these specific categories These should illustrate how certain microbiota profiles can be altered, as members of different categories may respond differently to the same treatment. (4) Perform robust well-designed human studies with probiotics and/or prebiotics, with appropriate, defined primary outcomes and sample size These are critical to show efficacy and understand responder and non-responder outcomes. It is hoped that these recommendations will lead to new approaches that combat malnutrition. This report is the result of discussion during an expert workshop titled “How do the microbiota and probiotics and/or prebiotics influence poor nutritional status?” held during the 10th Meeting of the International Scientific Association for Probiotics and Prebiotics (ISAPP) in Cork, Ireland from October 1–3, 2012. The complete list of workshop attendees is shown in Table 1.

Aims Severe acute malnutrition (SAM) causes over 1 million under-5 child deaths in developing countries each year. Among those at risk are children with disabilities. Because their growth often differs from that of non-disabled peers, they are often excluded from SAM-related studies. Little data is therefore available on their outcomes from SAM. We aimed to address this gap by describing: ▶ Prevalence of disability among a cohort of children with SAM ▶ Short and long term outcomes among disabled children with SAM. Methods Secondary data analysis. All children admitted to an urban nutrition rehabilitation unit in Malawi between July 2006 and March 2007 were monitored and followed-up at 1 year post discharge. Results Of 1024 children, 60 (5.9%) had an obvious disability: most commonly developmental delay or cerebral palsy (46/60, 77%). Multivariable logistic regression incorporating age, sex, admission anthropometry, oedema and HIV status showed that disabled children were significantly less likely to be HIV positive (p<0.001) and more likely to have a weight-for-height Z score of <−3 (p=0.047). Disabled children were significantly more likely to die in the first 90 days of treatment (hazard ratio 2.29, 95% CI 1.36-3.85, p=0.002 and also more likely to die in the longer term (HR 2.29, 95% CI 1.51-3.45, p<0.001). Conclusions Our data suggest that children with disability are a particularly vulnerable SAM subgroup, with high risk of mortality both short and long term. It is important to recognise that there may be many modifiable factors underlying this observation: it is unlikely explained by greater physiological vulnerability alone. Social factors might include suboptimal care practices at home and in communities which increase the risk of a disabled child developing SAM; delayed presentation to care when problems do arise; suboptimal post-SAM care. Treatment services also need to be more proactive about their approach to disability. Protocols should recognise and offer guidance to help identify and care for children with disability. This might include closer referral linkages with disability support services. Finally, more research focusing on this group is needed to determine how treatments might be improved and better tailored to those with underlying disability.

Introduction In Europe alone, over 70 million people experience tinnitus. Despite its considerable socioeconomic relevance, progress in developing successful treatments has been limited. Clinical effectiveness is judged according to change in primary outcome measures, but because tinnitus is a subjective condition, the definition of outcomes is challenging and it remains unclear which distinct aspects of tinnitus (ie, ‘domains’) are most relevant for assessment. The development of a minimum outcome reporting standard would go a long way towards addressing these problems. In 2006, a consensus meeting recommended using 1 of 4 questionnaires for tinnitus severity as an outcome in clinical trials, in part because of availability in different language translations. Our initiative takes an approach motivated by clinimetrics, first by determining what to measure before seeking to determine how to measure it. Agreeing on the domains that contribute to tinnitus severity (ie, ‘what’) is the first step towards achieving a minimum outcome reporting standard for tinnitus that has been reached via a methodologically rigorous and transparent process. Methods and analysis Deciding what should be the core set of outcomes requires a great deal of discussion and so lends itself well to international effort. This protocol lays out the first-step methodology in defining a Core Domain Set for clinical trials of tinnitus by establishing existing knowledge and practice with respect to which outcome domains have been measured and which instruments used in recent registered and published clinical trials. Ethics and dissemination No ethical issues are foreseen. Findings will be reported at national and international ear, nose and throat (ENT) and audiology conferences and in a peer-reviewed journal, using PRISMA (Preferred Reporting Items for Systematic reviews and Meta-analysis) guidelines. Trial registration number The systematic review protocol is registered on PROSPERO (International Prospective Register of Systematic Reviews): CRD42015017525.

Common mental disorder (CMD) affecting women during the childbearing years is an important health problem in low and middle income countries. This study investigates CMD and associated factors amongst women with young infants in rural Malawi.

Aims Effectively tackling severe acute malnutrition (SAM) is a global public health priority. Most treatment programmes report short-term outcomes at discharge. There is limited evidence about subsequent mortality and morbidity. The authors aimed to address this research gap by describing longer-term outcomes following SAM treatment. Methods One year after discharge, the authors attempted to trace all survivors from a large urban, inpatient-based SAM treatment programme. 796/1024 (78%) had been enrolled in a probiotic randomised controlled trial which had no overall effect. Detailed baseline and follow-up data were available. Results From July 2006 to March 2007, 1024 patients contributed to 1187 admission episodes for SAM treatment. 697/1024 (68.1%) had oedematous malnutrition. 459/1024 (45%) were known HIV seronegative, 445/1024 (43%) known seropositive. Long-term outcomes were determined for 899/1024 (88%). Mortality risk was greatest early in the programme: 238/1024 (23%) children died during initial inpatient treatment, 84/1024 (8%) in the subsequent 90 days and a further 105/1024 (10%) over the subsequent year. Preliminary Cox regression showed that HIV was strongly associated with mortality. Of the total 427 deaths, 274/427 (64%) were known seropositive but only 77/427 (18%) were known seronegative. Low admission weight-for-age, low admission weight-for-height were and age <12 months were also associated with mortality after adjusting for age, sex, height-for-age, mid-upper arm circumference, and admission oedema. Initial treatment cure (reaching weight-for-height >80% of NCHS median) was associated with long-term survival. Of 471 initial cures, 372/471 (79%) were still alive at 1 year. Total known long-term programme survivors were 472/1024 (46%). At 1 year, mean weight-for-height z-score (WHZ) of those measured was −0.03 (SD 1.2, n=396) compared to baseline WHZ of −2.25 (SD1.3, n=976). Height-for-age (HAZ) remained low: HAZ −3.05 (SD 1.4) at 1 year compared to −3.23 (SD 1.4) at baseline. Putting these in context, mean WHZ of the oldest sibling in the family was −0.23 (SD 0.9, n=59) and HAZ −1.75 (SD 1.7, n=59). Conclusions In this study, most children who were successfully cured in a SAM treatment programme remained alive 1 year after discharge. Overall mortality was however high. Community-based strategies could play an important role in earlier identification and treatment of high-risk children as well as longer-term support of children discharged from nutrition programmes.

Correctly identifying malnourished or at-risk children is the critical first step towards appropriate nutritional interventions. To improve weight-for-height assessment and classification of nutritional status, we present a novel, low-cost, weight-for-height slide chart. We also describe a target weight system for monitoring children's progress towards nutritional recovery.

In many settings, HIV infected children are looked after with limited access to CD4 cell count or viral load. The decision to initiate antiretroviral therapy (ART) is made clinically, based on the WHO paediatric staging criteria, which were revised in 2006. Results of using new and old criteria were compared. Of 694 children, 626 (90.2%) fulfilled criteria to start ART when applying the new WHO staging guidelines, whereas 330 (47.6%) children were eligible for ART when using the old WHO criteria. This signifies a marked rise in the number of paediatric patients qualifying for ART on clinical grounds.

IntroductionUp to half of all children presenting to Nutrition Rehabilitation Units (NRUs) in Malawi with severe acute malnutrition (SAM) are infected with HIV. There are many similarities in the clinical presentation of SAM and HIV.It is important to identify HIV infected children, in order to improve case management. This study aims to identify features suggestive of HIV in children with SAM.MethodsAll 1024 children admitted to the Blantyre NRU between July 2006 and March 2007 had demographic, anthropometric and clinical characteristics documented on admission. HIV status was known for 904 children, with 445 (43%) seropositive and 459 (45%) seronegative. Features associated with HIV were determined.ResultsAssociations were found for the following signs: chronic ear discharge (OR 14.6, 95%CI 5.8-36.7), lymphadenopathy (6.4, 3.5-11.7), clubbing (4.9, 2.6-9.4), marasmus (4.9, 3.5- 6.8), hepato-splenomegally (3.2, 1.8-5.6), and oral candida (2.4, 1.8-3.27). Any one of these signs was present in 74% of the HIV seropositive, and 38% of HIV uninfected children. A history of recurrent respiratory infection (OR 9.6, 4.8-18.6), persistent fever, recent outpatient attendance, or hospital admission were also associated with HIV. Persistent diarrhoea was no more frequent in HIV (OR 1.1).Orphaning (OR 2.1, 1.4-3.3) or a household contact with TB (OR 1.7, 1.1-2.6), were more common in HIV. Each of these features were present in >10% of seropositive children. HIV infected children were more stunted, wasted, and anaemic than uninfected children.ConclusionsFeatures commonly associated with HIV were often present in uninfected children with SAM, and HIV could neither be diagnosed, nor excluded using these. We recommend HIV testing be offered to all children with SAM where HIV is prevalent.

During Plasmodium falciparum malaria infections, von Willebrand factor (VWF) levels are elevated, postmortem studies show platelets colocalized with sequestered infected erythrocytes (IEs) at brain microvascular sites, whereas in vitro studies have demonstrated platelet-mediated IE adhesion to tumor necrosis factor-activated brain endothelium via a bridging mechanism. This current study demonstrates how all these observations could be linked through a completely novel mechanism whereby IEs adhere via platelet decorated ultra-large VWF strings on activated endothelium. Using an in vitro laminar flow model, we have demonstrated tethering and firm adhesion of IEs to the endothelium specifically at sites of platelet accumulation. We also show that an IE pro-adhesive state, capable of supporting high levels of binding within minutes of induction, can be removed through the action of the VWF protease ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13). We propose that this new mechanism contributes to sequestration both independently of and in concert with current adhesion mechanisms.

Background Severe acute malnutrition affects 13 million children worldwide and causes 1-2 million deaths every year. Our aim was to assess the clinical and nutritional efficacy of a probiotic and prebiotic functional food for the treatment of severe acute malnutrition in a HIV-prevalent setting.Methods We recruited 795 Malawian children (age range 5 to 168 months [median 22, IQR 15 to 32]) from July 12, 2006, to March 7, 2007, into a double-blind, randomised, placebo-controlled efficacy trial. For generalisability, all admissions for severe acute malnutrition treatment were eligible for recruitment. After stabilisation with milk feeds, children were randomly assigned to ready-to-use therapeutic food either with (n=399) or without (n=396) Synbiotic2000 Forte. Average prescribed Synbiotic dose was 1010 colony-forming units or more of lactic acid bacteria per day for the duration of treatment (median 3.3 days). Primary outcome was nutritional cure (weight-for-height >80% of National Center for Health Statistics median on two consecutive outpatient visits). Secondary outcomes included death, weight gain, time to cure, and prevalence of clinical symptoms (diarrhoea, fever, and respiratory problems). Analysis was on an intention-to-treat basis. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN19364765.Findings Nutritional cure was similar in both Synbiotic and control groups (53.9% [215 of 399] and 51.3% [203 of 396]; p=0.40). Secondary outcomes were also similar between groups. HIV seropositivity was associated with worse outcomes overall, but did not modify or confound the negative results. Subgroup analyses showed possible trends towards reduced outpatient mortality in the Synbiotic group (p=0.06).Interpretation In Malawi, Synbiotic2000 Forte did not improve severe acute malnutrition outcomes. The observation of reduced outpatient mortality might be caused by bias, confounding, or chance, but is biologically plausible, has potential for public health impact, and should be explored in future studies.

Plasmodium falciparum infection results in adhesion of infected erythrocytes to blood vessel endothelium, and acute endothelial cell activation, together with sequestration of platelets and leucocytes. We have previously shown that patients with severe infection or fulminant cerebral malaria have significantly increased circulatory levels of the adhesive glycoprotein von Willebrand factor (VWF) and its propeptide, both of which are indices of endothelial cell activation. In this prospective study of patients from Ghana with severe (n = 20) and cerebral (n = 13) P. falciparum malaria, we demonstrate that increased plasma VWF antigen (VWF:Ag) level is associated with disproportionately increased VWF function. VWF collagen binding (VWF:CB) was significantly increased in patients with cerebral malaria and severe malaria (medians 7.6 and 7.0 IU/ml versus 1.9 IU/ml; p<0.005). This increased VWF:CB correlated with the presence of abnormal ultra-large VWF multimers in patient rather than control plasmas. Concomitant with the increase in VWF:Ag and VWF:CB was a significant persistent reduction in the activity of the VWF-specific cleaving protease ADAMTS13 (approximately 55% of normal; p<0.005). Mixing studies were performed using P. falciparum patient plasma and normal pooled plasma, in the presence or absence of exogenous recombinant ADAMTS13. These studies demonstrated that in malarial plasma, ADAMTS13 function was persistently inhibited in a time-dependent manner. Furthermore, this inhibitory effect was not associated with the presence of known inhibitors of ADAMTS13 enzymatic function (interleukin-6, free haemoglobin, factor VIII or thrombospondin-1). These novel findings suggest that severe P. falciparum infection is associated with acute endothelial cell activation, abnormal circulating ULVWF multimers, and a significant reduction in plasma ADAMTS13 function which is mediated at least in part by an unidentified inhibitor.

Background: Depressive disorder affecting women during the perinatal period is common in low-income countries. The detection and study of maternal depression in a resource-poor setting requires a brief screening tool that is both accurate and practical to administer.Method: A Chichewa version of the Self Reporting Questionnaire (SRQ) was developed through a rigorous process of forward and back translation, focus-group discussion and piloting. Criterion validation was conducted as part of a larger study in a sample of women who had brought their infants to a child health clinic in rural Malawi, using DSM-IV major and minor depressive episode as the gold standard diagnoses.Results: The criterion validation was conducted on 114 subjects who did not differ on health and sociodemographic characteristics from the total study sample (n=501). Test characteristics for each possible SRQ cut-off were calculated and Receiver Operator Characteristic (ROC) curves derived. Area under the ROC curve (AUROC) for detection of current major depressive disorder was 0.856 (95% CI 0.8 13 to 0.900), and for current major or minor depressive disorder was 0.826 (95% CI 0.783 to 0.869). Internal consistency of the SRQ was high (Cronbach's alpha 0.85).Limitation: Inter-rater reliability testing was not conducted.Conclusion: This Chichewa version of the SRQ shows utility as a brief screening measure for detection of probable maternal depression in rural Malawi. (c) 2008 Elsevier B.V. All rights reserved.

The objective of the study was to investigate the association between maternal common mental disorder (CMD) and infant growth in rural Malawi. A cross-sectional study was conducted at a district hospital child health clinic. Participants were consecutive infants due for measles vaccination, and their mothers. Mean infant weight-for-age and length-for-age z-scores were compared between infants of mothers with and without CMD as measured using the self-reporting questionnaire (SRQ). Of 519 eligible infants/mothers, 501 were included in the analysis. Median infant age was 9.9 months. 29.9% of mothers scored 8 or above on the SRQ indicating CMD. Mean length-for-age z-score for infants of mothers with CMD (-1.50 SD 1.24) was significantly lower than for infants of mothers without CMD (-1.11 SD 1.12) Student's t-test: P = 0.001. This association was confirmed in multivariate analysis. Mean weight-for-age z-score for infants of mothers with CMD (-1.77 SD 1.16) was lower than for infants of mothers without CMD (-1.59 SD 1.09) but this difference was not significant on univariate (Student's t-test: P = 0.097) or multivariate analysis. The study demonstrates an association between maternal CMD and infant growth impairment in rural sub-Saharan Africa.

In the ideal situation, use of WHO therapeutic guidelines for management of severe malnutrition 5 and a continuum of care for malnourished children 6 through community therapeutic care pro grammes would successfully improve survival in children without HIV infection. An alarming consequence of the HIV epidemic is an increase in the need by severely malnourished, seriously ill children for facility-based treatment. Ready-to-use therapeutic foods that facilitate eff ective home-based therapy have resulted in recovery rates for uncomplicated severe malnutrition of more than 90%, with reported case-fatality rates of less than 5%; 7

Host susceptibility to Plasmodium falciparum infection is central for improved understanding of malaria in human populations. Red blood cell (RBC) polymorphisms have been proposed as factors associated with malaria infection or its severity, although no systematic appraisal of ABO phenotypes and malaria risk has been undertaken. This analysis summarises epidemiological, clinical and immunological evidence on the nature of ABO histo-blood antigens and their interaction with malaria in terms of population genetics, infection risk, severe malaria and placental malaria. In non-pregnant subjects, a meta-analysis showed no conclusive evidence associating ABO phenotypes with risk of uncomplicated malaria. There was stronger evidence that ABO phenotype modulates severity of P. falciparum malaria, with group A associated with severe disease and blood group O with milder disease. Among pregnant subjects, group O was associated with increased risk of placental malaria in primigravidae and reduced risk in multigravidae. The biological basis for ABO-related susceptibility to malaria is reviewed. Several mechanisms relate to these associations including affinity for Anopheles gambiae; shared ABO antigens with P. falciparum; impairment of merozoite penetration of RBCs; and cytoadherence, endothelial activation and rosetting. ABO phenotypic associations with malaria are related to its pathogenesis and improved understanding of these interactions is required for understanding the glycobiology of malaria infection.