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BackgroundTens of millions of children are exposed to Mycobacterium tuberculosis globally every year; however, there are no contemporary estimates of the risk of developing tuberculosis in exposed children. The effectiveness of contact investigations and preventive therapy remains poorly understood.MethodsIn this systematic review and meta-analysis, we investigated the development of tuberculosis in children closely exposed to a tuberculosis case and followed for incident disease. We restricted our search to cohort studies published between Jan 1, 1998, and April 6, 2018, in MEDLINE, Web of Science, BIOSIS, and Embase electronic databases. Individual-participant data and a pre-specified list of variables were requested from authors of all eligible studies. These included characteristics of the exposed child, the index case, and environmental characteristics. To be eligible for inclusion in the final analysis, a dataset needed to include: (1) individuals below 19 years of age; (2) follow-up for tuberculosis for a minimum of 6 months; (3) individuals with household or close exposure to an individual with tuberculosis; (4) information on the age and sex of the child; and (5) start and end follow-up dates. Studies assessing incident tuberculosis but without dates or time of follow-up were excluded. Our analysis had two primary aims: (1) estimating the risk of developing tuberculosis by time-period of follow-up, demographics (age, region), and clinical attributes (HIV, tuberculosis infection status, previous tuberculosis); and (2) estimating the effectiveness of preventive therapy and BCG vaccination on the risk of developing tuberculosis. We estimated the odds of prevalent tuberculosis with mixed-effects logistic models and estimated adjusted hazard ratios (HRs) for incident tuberculosis with mixed-effects Poisson regression models. The effectiveness of preventive therapy against incident tuberculosis was estimated through propensity score matching. The study protocol is registered with PROSPERO (CRD42018087022).FindingsIn total, study groups from 46 cohort studies in 34 countries-29 (63%) prospective studies and 17 (37%) retrospective-agreed to share their data and were included in the final analysis. 137 647 tuberculosis-exposed children were evaluated at baseline and 130 512 children were followed for 429 538 person-years, during which 1299 prevalent and 999 incident tuberculosis cases were diagnosed. Children not receiving preventive therapy with a positive result for tuberculosis infection had significantly higher 2-year cumulative tuberculosis incidence than children with a negative result for tuberculosis infection, and this incidence was greatest among children below 5 years of age (19·0% [95% CI 8·4-37·4]). The effectiveness of preventive therapy was 63% (adjusted HR 0·37 [95% CI 0·30-0·47]) among all exposed children, and 91% (adjusted HR 0·09 [0·05-0·15]) among those with a positive result for tuberculosis infection. Among all children

Tuberculosis (TB) is a leading contributor to the burden of infectious disease worldwide, causing >1.2 million deaths in 2019 (1,2). Latent tuberculosis infection (LTBI), defined as infection with Mycobacterium tuberculosis [...]

Three phase 2 trials were conducted to assess the efficacy and long-term safety of weight-based memantine extended release (ER) treatment in children with autism spectrum disorder. MEM-MD-91, a 50-week open-label trial, identified memantine extended-release treatment responders for enrollment into MEM-MD-68, a 12-week randomized, double-blind, placebo-controlled withdrawal trial. MEM-MD-69 was an open-label extension trial in which participants from MEM-MD-68, MEM-MD-91, and open-label trial MEM-MD-67 were treated ⩽48 weeks with memantine extended release. In MEM-MD-91, 517 (59.6%) participants were confirmed Social Responsiveness Scale responders at week 12; mean Social Responsiveness Scale total raw scores improved two to three times a minimal clinically important difference of 10 points. In MEM-MD-68, there was no difference between memantine and placebo on the primary efficacy parameter, the proportion of patients with a loss of therapeutic response (defined as ⩾10-point increase from baseline in Social Responsiveness Scale total raw score). MEM-MD-69 exploratory analyses revealed mean standard deviation improvement in Social Responsiveness Scale total raw score of 32.4 (26.4) from baseline of the first lead-in study. No new safety concerns were evident. While the a priori-defined efficacy results of the double-blind trial were not achieved, the considerable improvements in mean Social Responsiveness Scale scores from baseline in the open-label trials were presumed to be clinically important.

ObjectiveAbnormal glutamatergic neurotransmission is implicated in the pathophysiology of autism spectrum disorder (ASD). In this study, the safety, tolerability, and efficacy of the glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist memantine (once-daily extended-release [ER]) were investigated in children with autism in a randomized, placebo-controlled, 12 week trial and a 48 week open-label extension.MethodsA total of 121 children 6-12 years of age with Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR)-defined autistic disorder were randomized (1:1) to placebo or memantine ER for 12 weeks; 104 children entered the subsequent extension trial. Maximum memantine doses were determined by body weight and ranged from 3 to 15 mg/day.ResultsThere was one serious adverse event (SAE) (affective disorder, with memantine) in the 12 week study and one SAE (lobar pneumonia) in the 48 week extension; both were deemed unrelated to treatment. Other AEs were considered mild or moderate and most were deemed not related to treatment. No clinically significant changes occurred in clinical laboratory values, vital signs, or electrocardiogram (ECG). There was no significant between-group difference on the primary efficacy outcome of caregiver/parent ratings on the Social Responsiveness Scale (SRS), although an improvement over baseline at Week 12 was observed in both groups. A trend for improvement at the end of the 48 week extension was observed. No improvements in the active group were observed on any of the secondary end-points, with one communication measure showing significant worsening with memantine compared with placebo (p = 0.02) after 12 weeks.ConclusionsThis trial did not demonstrate clinical efficacy of memantine ER in autism; however, the tolerability and safety data were reassuring. Our results could inform future trial design in this population and may facilitate the investigation of memantine ER for other clinical applications.

Advances in pediatric TB care are promising, the result of decades of advocacy, operational and clinical trials research, and political will by national and local TB programs in high-burden countries. However, implementation challenges remain in linking policy to practice and scaling up innovations for prevention, diagnosis, and treatment of TB in children, especially in resource-limited settings. There is both need and opportunity to strengthen clinician confidence in making a TB diagnosis and managing the various manifestations of TB in children, which can facilitate the translation of evidence to action and expand access to new tools and strategies to address TB in this population. This review aims to summarize existing guidance and best practices for clinicians and health care providers in low-resource, TB-endemic settings and identify resources with more detailed and actionable information for decision-making along the clinical cascade to prevent, find, and cure TB in children. [ABSTRACT FROM AUTHOR]

Effective case management is an important strategy to reduce pneumonia-related morbidity and mortality in children. Guidelines based on sound evidence are avallable but are used variably. This review outlines current guidelines for childhood pneumonia management in the setting where most child pneumonia deaths occur and identifies challenges for improved management in a variety of settings and different "at-risk" groups. These include appropriate choice of antibiotic, clinical overlap with other conditions, prompt and appropriate referral for inpatient care, and management of treatment failure. Management of neonates, and of HIV-infected or severely malnourished children is more complicated. The influence of co-morbidities on pneumonia outcome means that pneumonia case management must be integrated within strategies to improve overall paediatric care. The greatest potential for reducing pneumonia-related deaths in health facilities is wider implementation of the current guidelines built around a few core activities: training, antibiotics and oxygen. This requires investment in human resources and in equipment for the optimal management of hypoxaemia. It is important to provide data from a variety of epidemiological settings for formal cost-effectiveness analyses. Improvements in the quality of case management of pneumonia can be a vehicle for overall improvements in child healthcare practices. La prise en charge efficace des cas joue un role important dans la reduction de la morbidite et de la mortalite dues a la pneumonie. Des recommandations reposant sur des elements factuels solides sont disponibles, mais sont appliquees diversement. Le present article expose dans leurs grandes lignes les recommandations actuelles pour la prise en charge de la pneumonie chez l&apos;enfant dans les pays ou interviennent la plupart des deces d&apos;enfants par pneumonie et identifie les difficultes pour ameliorer cette prise en charge dans divers pays et chez differents groupes << a risque >>. Ces recommandations concernent notamment le choix d&apos;un antibiotique adapte, le recouvrement clinique avec d&apos;autres pathologies, l&apos;orientation rapide et appropriee vers des soins hospitaliers et la prise en charge des echecs therapeutiques. La prise en charge des nouveau-nes et des enfants infectes par le VIH ou gravement denutris est plus complexe. L&apos;influence des comorbidites sur l&apos;issue de la pneumonie implique que la prise en charge de cette maladie doit s&apos;integrer dans des strategies d&apos;amelioration des soins pediatriques en general. Le plus fort potentiel de reduction de la mortalite par pneumonie dans les etablissements de soins reside dans l&apos;elargissement de l&apos;application des recommandations actuelles, elaborees autour de quelques interventions centrales : formation, antibiotiques et oxygene. Cet elargissement necessite des investissements en ressources humaines et en equipements pour une prise en charge optimale de l&apos;hypoxemie. Il est important de fournir des donnees provenant de divers contextes epidemiologiques pour etablir des analyses cout/efficacite formelles. L&apos;amelioration en termes de qualite de la prise en charge de la pneumonie pourrait servir de moteur a des ameliorations globales des pratiques de soins pediatriques. Un manejo de casos eficaz constituye una estrategia importante para reducir la morbilidad y la mortalidad por neumonia en la ninez. Las directrices basadas en la evidencia de que se dispone se utilizan en diversa medida. En el presente analisis se describen las directrices actuales para el tratamiento de la neumonia en la ninez en las circunstancias que rodean la mayoria de las muertes por neumonia en la infancia y se senalan les retos que deben superarse para mejorar el tratamiento en diversos contextos y diferentes grupos en riesgo. Entre ellos cabe citar la eleccion apropiada del antibiotico, el solapamiento clinico con otras dolencias, la derivacion rapida y apropiada para dispensar atencion hospitalaria, y el manejo de les casos de fracaso terapeutico. El tratamiento de les recien nacidos y de les ninos infectados por el VIH o malnutridos es mis complicado. Dada la influencia de posibles comorbilidades en la evolucion de la neumonia, el tratamiento de les casos de esa enfermedad debe integrarse en estrategias orientadas a mejorar la atencion pediatrica en general. Las mayores posibilidades de reducir las defunciones relacionadas con la neumonia en les centros de salud son las que se derivan de una mis amplia aplicacion de las directrices actuales centradas en unas cuantas actividades basicas: capacitacion, antibioticos y oxigeno. Eso exige invertir en recursos humanos y en equipo para manejar optimamente la hipoxemia. Es importante aportar datos procedentes de diverses entornos epidemiologicos para poder realizar analisis formales de costo-eficacia. Las mejoras de la calidad del tratamiento de casos de neumonia pueden brindar la ocasion para introducir otras mejoras mas generales en las practicas de salud infantil. [TEXT NOT REPRODUCIBLE IN ASCII], Introduction Pneumonia is the leading cause of death in children worldwide and the great majority of these deaths occur in resource-limited settings. (1) WHO developed a case-management strategy in the [...]

Nontyphoidal strains of Salmonella (NTS) are a common cause of bacteremia among African children. Cell-mediated immune responses control intracellular infection, but they do not protect against extracellular growth of NTS in the blood. We investigated whether antibody protects against NTS bacteremia in Malawian children, because we found this condition mainly occurs before 2 years of age, with relative sparing of infants younger than 4 months old. Sera from all healthy Malawian children tested aged more than 16 months contained anti-Salmonella antibody and successfully killed NTS. Killing was mediated by complement membrane attack complex and not augmented in the presence of blood leukocytes. Sera from most healthy children less than 16 months old lacked NTS-specific antibody, and sera lacking antibody did not kill NTS despite normal complement function. Addition of Salmonella-specific antibody, but not mannose-binding lectin, enabled NTS killing. All NTS strains tested had long-chain lipopolysaccharide and the rck gene, features that resist direct complement-mediated killing. Disruption of lipopolysaccharide biosynthesis enabled killing of NTS by serum lacking Salmonella-specific antibody. We conclude that Salmonella-specific antibody that overcomes the complement resistance of NTS develops by 2 years of life in Malawian children. This finding and the age-incidence of NTS bacteremia suggest that antibody protects against NTS bacteremia and support the development of vaccines against NTS that induce protective antibody., Introduction Nontyphoidal strains of Salmonella (NTS), principally Salmonella enterica serovars Typhimurium and Enteritidis, are a major but neglected cause of invasive disease in Africa and the commonest cause of bacteremia [...]

In a prospective study of 660 HIV-positive Malawian adults, we diagnosed Pneumocystis jirovecii pneumonia (PcP) using clinical features, induced sputum for immunofluorescent staining, real-time PCR, and posttreatment followup. PcP incidence [...]

Group B streptococci (GBS) are a recently identified cause of neonatal sepsis in Malawi. In Queen Elizabeth Central Hospital, Blantyre, Malawi, during May 2004-June 2005, GBS were isolated from routine [...]

A community-based cohort study is conducted to measure the incidence of potentially TS-preventable illnesses in Blantyre, Malawi. Results reveal a high incidence of malaria, invasive bacterial infections, and probable bacterial pneumonias but low rates of Pneumocystis jirovecci pneumonia, isoporiasis, and Toxoplasma encephalitis.