Clinical indicators of bacterial meningitis among neonates and young infants in rural Kenya

<p>Abstract</p> <p>Background</p> <p>Meningitis is notoriously difficult to diagnose in infancy because its clinical features are non-specific. World Health Organization (WHO) guidelines suggest several indicative signs, based on limited data. We aimed to identify indicators of bacterial meningitis in young infants in Kenya, and compared their performance to the WHO guidelines. We also examined the feasibility of developing a scoring system for meningitis.</p> <p>Methods</p> <p>We studied all admissions aged < 60 days to Kilifi District Hospital, 2001 through 2005. We evaluated clinical indicators against microbiological findings using likelihood ratios. We prospectively validated our findings 2006 through 2007.</p> <p>Results</p> <p>We studied 2,411 and 1,512 young infants during the derivation and validation periods respectively. During derivation, 31/1,031 (3.0%) neonates aged < 7 days and 67/1,380 (4.8%) young infants aged 7-59 days (p < 0.001) had meningitis. 90% of cases could be diagnosed macroscopically (turbidity) or by microscopic leukocyte counting. Independent indicators of meningitis were: fever, convulsions, irritability, bulging fontanel and temperature ≥ 39°C. Areas under the receiver operating characteristic curve in the validation period were 0.62 [95%CI: 0.49-0.75] age < 7 days and 0.76 [95%CI: 0.68-0.85] thereafter (P = 0.07), and using the WHO signs, 0.50 [95%CI 0.35-0.65] age < 7 days and 0.82 [95%CI: 0.75-0.89] thereafter (P = 0.0001). The number needed to LP to identify one case was 21 [95%CI: 15-35] for our signs, and 28 [95%CI: 18-61] for WHO signs. With a scoring system, a cut-off of ≥ 1 sign offered the best compromise on sensitivity and specificity.</p> <p>Conclusion</p> <p>Simple clinical signs at admission identify two thirds of meningitis cases in neonates and young infants. Lumbar puncture is essential to diagnosis and avoidance of unnecessary treatment, and is worthwhile without CSF biochemistry or bacterial culture. The signs of Meningitis suggested by the WHO perform poorly in the first week of life. A scoring system for meningitis in this age group is not helpful.</p

Use of clinical syndromes to target antibiotic prescribing in seriously ill children in malaria endemic area: observational study.

OBJECTIVES: To determine how well antibiotic treatment is targeted by simple clinical syndromes and to what extent drug resistance threatens affordable antibiotics. DESIGN: Observational study involving a priori definition of a hierarchy of syndromic indications for antibiotic therapy derived from World Health Organization integrated management of childhood illness and inpatient guidelines and application of these rules to a prospectively collected dataset. SETTING: Kilifi District Hospital, Kenya. PARTICIPANTS: 11,847 acute paediatric admissions. MAIN OUTCOME MEASURES: Presence of invasive bacterial infection (bacteraemia or meningitis) or Plasmodium falciparum parasitaemia; antimicrobial sensitivities of isolated bacteria. RESULTS: 6254 (53%) admissions met criteria for syndromes requiring antibiotics (sick young infants; meningitis/encephalopathy; severe malnutrition; very severe, severe, or mild pneumonia; skin or soft tissue infection): 672 (11%) had an invasive bacterial infection (80% of all invasive bacterial infections identified), and 753 (12%) died (93% of all inpatient deaths). Among P falciparum infected children with a syndromic indication for parenteral antibiotics, an invasive bacterial infection was detected in 4.0-8.8%. For the syndrome of meningitis/encephalopathy, 96/123 (76%) isolates were fully sensitive in vitro to penicillin or chloramphenicol. CONCLUSIONS: Simple clinical syndromes effectively target children admitted with invasive bacterial infection and those at risk of death. Malaria parasitaemia does not justify withholding empirical parenteral antibiotics. Lumbar puncture is critical to the rational use of antibiotics

Defining childhood severe falciparum malaria for intervention studies.

Background Clinical trials of interventions designed to prevent severe falciparum malaria in children require a clear endpoint. The internationally accepted definition of severe malaria is sensitive, and appropriate for clinical purposes. However, this definition includes individuals with severe nonmalarial disease and coincident parasitaemia, so may lack specificity in vaccine trials. Although there is no “gold standard” individual test for severe malaria, malaria-attributable fractions (MAFs) can be estimated among groups of children using a logistic model, which we use to test the suitability of various case definitions as trial endpoints. Methods and Findings A total of 4,583 blood samples were taken from well children in cross-sectional surveys and from 1,361 children admitted to a Kenyan District hospital with severe disease. Among children under 2 y old with severe disease and over 2,500 parasites per microliter of blood, the MAFs were above 85% in moderate- and low-transmission areas, but only 61% in a high-transmission area. HIV and malnutrition were not associated with reduced MAFs, but gastroenteritis with severe dehydration (defined by reduced skin turgor), lower respiratory tract infection (clinician's final diagnosis), meningitis (on cerebrospinal fluid [CSF] examination), and bacteraemia were associated with reduced MAFs. The overall MAF was 85% (95% confidence interval [CI] 83.8%–86.1%) without excluding these conditions, 89% (95% CI 88.4%–90.2%) after exclusions, and 95% (95% CI 94.0%–95.5%) when a threshold of 2,500 parasites/μl was also applied. Applying a threshold and exclusion criteria reduced sensitivity to 80% (95% CI 77%–83%). Conclusions The specificity of a case definition for severe malaria is improved by applying a parasite density threshold and by excluding children with meningitis, lower respiratory tract infection (clinician's diagnosis), bacteraemia, and gastroenteritis with severe dehydration, but not by excluding children with HIV or malnutrition

Bacteremia among children admitted to a rural hospital in Kenya.

BACKGROUND: There are few epidemiologic data on invasive bacterial infections among children in sub-Saharan Africa. We studied every acute pediatric admission to a rural district hospital in Kenya to examine the prevalence, incidence, types, and outcome of community-acquired bacteremia. METHODS: Between August 1998 and July 2002, we cultured blood on admission from 19,339 inpatients and calculated the incidence of bacteremia on the basis of the population served by the hospital. RESULTS: Of a total of 1783 infants who were under 60 days old, 228 had bacteremia (12.8 percent), as did 866 of 14,787 children who were 60 or more days of age (5.9 percent). Among infants who were under 60 days old, Escherichia coli and group B streptococci predominated among a broad range of isolates (14 percent and 11 percent, respectively). Among infants who were 60 or more days of age, Streptococcus pneumoniae, nontyphoidal salmonella species, Haemophilus influenzae, and E. coli accounted for more than 70 percent of isolates. The minimal annual incidence of community-acquired bacteremia was estimated at 1457 cases per 100,000 children among infants under a year old, 1080 among children under 2 years, and 505 among children under 5 years. Of all in-hospital deaths, 26 percent were in children with community-acquired bacteremia. Of 308 deaths in children with bacteremia, 103 (33.4 percent) occurred on the day of admission and 217 (70.5 percent) within two days. CONCLUSIONS: Community-acquired bacteremia is a major cause of death among children at a rural sub-Saharan district hospital, a finding that highlights the need for prevention and for overcoming the political and financial barriers to widespread use of existing vaccines for bacterial diseases

HIV Prevention and Care Among Black Cisgender Sexual Minority Men and Transgender Women: Protocol for an HIV Status–Neutral Cohort Study Using an Observational-Implementation Hybrid Approach

Background: Black cisgender gay, bisexual, and other sexual minority men (SMM) and transgender women (TW) continue to be heavily affected by HIV. Further research is needed to better understand HIV prevention and care outcomes in this population. In particular, there is a need for research examining the impact of substance use and sleep health on HIV prevention and treatment outcomes among Black SMM and TW. Objective: This paper outlines the study methods being used in the recently launched follow-up study to the Neighborhoods and Networks (N2) study, which we refer to as N2 Part 2 (N2P2). N2P2 aims to address this gap in the literature, build off the findings of the original N2 study, and identify socioenvironmental determinants of health, including whether neighborhood and network factors mediate and moderate these relationships. Methods: Building on the N2 cohort study in Chicago from 2018 to 2022, N2P2 used a prospective longitudinal cohort design and an observational-implementation hybrid approach. With sustained high levels of community engagement, we aim to recruit a new sample of 600 Black SMM and TW participants residing in the Chicago metropolitan statistical area. Participants are asked to participate in 3 study visits across an 18-month study period (1 visit every 9 months). Four different forms of data are collected per wave: (1) an in-person survey, (2) biological specimen collection, (3) a daily remote ecological momentary assessment for 14 days after each study visit, and (4) data from electronic health records. These forms of data collection continue to assess neighborhood and network factors and specifically explore substance use, sleep, immune function, obesity, and the implementation of potential interventions that address relevant constructs (eg, alcohol use and pre-exposure prophylaxis adherence). Results: The N2P2 study was funded in August 2021 by the National Institute of Drug Abuse (R01DA054553 and R21DA053156) and National Heart, Lung, and Blood Institute (R01HL160325). This study was launched in November 2022. Recruitment and enrollment for the first wave of data collection are currently ongoing. Conclusions: The N2P2 study is applying innovative methods to comprehensively explore the impacts of substance use and sleep health on HIV-related outcomes among an HIV status-neutral cohort of Black SMM and TW in Chicago. This study is applying an observational-implementation hybrid design to help us achieve findings that support rapid translation, a critical priority among populations such as Black SMM and TW that experience long-standing inequities with regard to HIV and other health-related outcomes. N2P2 will directly build off the findings that have resulted from the original N2 study among Black SMM and TW in Chicago. These findings provide a better understanding of multilevel (eg, individual, network, and neighborhood) factors that contribute to HIV-related outcomes and viral suppression among Black SMM and TW. International registered report identifier (irrid): DERR1-10.2196/48548.</p

Day-Level Associations Between Substance Use and HIV Risk Behavior Among a Diverse Sample of Transgender Women

Purpose: Transgender women in the United States face elevated rates of HIV and of substance use. Studies measuring overall or aggregate levels of substance use have linked use to increased HIV transmission risk behavior (TRB). Although intensive longitudinal studies in other populations have found day-level links between substance use and TRB, no study has yet explored such links among transgender women. This study aimed to fill this gap in the literature. Methods: Utilizing survey and 60-day timeline follow-back interview data from a sample of 214 transgender women in New York City, we tested whether day-level heavy drinking, marijuana use, and/or nonprescription stimulant use were associated with odds of engaging in any sex (vs. no sexual activity) or engaging in TRB (vs. sex without TRB), adjusting for overall levels of use. Results: Multilevel models showed that each of the three substance types was associated with greater odds of engaging in sex on a given day—and more strongly so for heavy drinking among those with higher rates of heavy drinking, and for stimulant use among those with lower rates of stimulant use. Only marijuana use was associated with greater odds of TRB on a given day, but only among those with higher rates of use. Conclusion: These findings substantiate day-level links between substance use and engaging in sexual activity among transgender women, and importantly, between marijuana use and greater likelihood of TRB on a day when sexual activity occurs. This highlights the importance of addressing substance use for sexual health among transgender women especially focusing on marijuana use

Prevalence and Associations between Food Insecurity and Overweight/Obesity among Native Hawaiian and Pacific Islander Adolescents

Abstract Objective: This study estimates the prevalence of, and associations between, family food insecurity and overweight/obesity among Native Hawaiian and Pacific Islander (NHPI) adolescents and explores sociodemographic factors which might have a moderation effect on the association. Design: Cross-sectional study using 2014 NHPI-National Health Interview Survey (NHIS) data reported by a parent or guardian. Family-level food security was assessed by the United States (US) Department of Agriculture 10-item questionnaire. BMI for age and sex >=85th and 95th percentiles defined overweight and obesity, respectively, according to US Centers for Disease Control and Prevention criteria. Setting: The US, including all 50 states and the District of Columbia. Participants: 383 NHPI adolescents aged 12-17 in the US. Results: A third (33.5%) of NHPI adolescents aged 12-17 were overweight (19.1%) or obese (14.4%); 8.1% had low food security; and 8.5% had very low food security. Mean family food security score was 1.06, which corresponds to marginal food security. We found no association between family food insecurity and adolescent overweight/obesity or between any other covariates and overweight/obesity, except for family Supplemental Nutrition Assistance Program (SNAP) participation. Odds of being overweight/obese were 77% lower for adolescents in families participating in SNAP (OR: 0.23, 95% CI: 0.08-0.64, p=0.007). The association between SNAP participation and lower odds of overweight/obesity was particularly pronounced for adolescent girls in food insecure families. Conclusions: The association between SNAP participation and lower odds of overweight/obesity suggests potential benefit of research to determine whether interventions to increase SNAP enrollment would improve NHPI adolescents’ health outcomes

The impact of child soldiers on rebel groups’ fighting capacities

Several rebel groups actively recruit children to serve among their ranks. While this constitutes one of the most egregious violations of children’s rights, it remains unclear what impact recruited children have on the fighting capacities of these armed groups. The existing research suggests that, on the one hand, armed groups drafting children might also be militarily effective, since it is cheaper to provide for children, they are more obedient and aggressive than adults, and easily manipulable. On the other hand, children may negatively affect rebel groups’ fighting capacities as they are less proficient combatants than adults and often difficult to control. We add to this debate by systematically analyzing the quantitative evidence on the impact of child soldiers on rebel groups’ fighting capacities. Based on the analysis of newly compiled data on child recruitment by rebel groups between 1989 and 2010, our analyses show that children may actually increase rebel groups’ fighting capacities. That said, rebels’ ability to procure arms and the access to resources seem to be more important determinants of fighting capacity. The authors discuss these findings in light of policy implications and avenues for future research. </jats:p

Why do avian responses to change in Arctic green-up vary?

Global climate change has altered the timing of seasonal events (i.e., phenology) for a diverse range of biota. Within and among species, however, the degree to which alterations in phenology match climate variability differ substantially. To better understand factors driving these differences, we evaluated variation in timing of nesting of eight Arctic-breeding shorebird species at 18 sites over a 23-year period. We used the Normalized Difference Vegetation Index as a proxy to determine the start of spring (SOS) growing season and quantified relationships between SOS and nest initiation dates as a measure of phenological responsiveness. Among species, we tested four life history traits (migration distance, seasonal timing of breeding, female body mass, expected female reproductive effort) as species-level predictors of responsiveness. For one species (Semipalmated Sandpiper), we also evaluated whether responsiveness varied across sites. Although no species in our study completely tracked annual variation in SOS, phenological responses were strongest for Western Sandpipers, Pectoral Sandpipers, and Red Phalaropes. Migration distance was the strongest additional predictor of responsiveness, with longer-distance migrant species generally tracking variation in SOS more closely than species that migrate shorter distances. Semipalmated Sandpipers are a widely distributed species, but adjustments in timing of nesting relative to variability in SOS did not vary across sites, suggesting that different breeding populations of this species were equally responsive to climate cues despite differing migration strategies. Our results unexpectedly show that long-distance migrants are more sensitive to local environmental conditions, which may help them to adapt to ongoing changes in climate. climate change, migration, NDVI, nest initiation, phenology, shorebirdspublishedVersio

Impact of Isotype on the Mechanism of Action of Agonist Anti-OX40 Antibodies in Cancer: Implications for Therapeutic Combinations

BACKGROUND: OX40 has been widely studied as a target for immunotherapy with agonist antibodies taken forward into clinical trials for cancer where they are yet to show substantial efficacy. Here, we investigated potential mechanisms of action of anti-mouse (m) OX40 and anti-human (h) OX40 antibodies, including a clinically relevant monoclonal antibody (mAb) (GSK3174998) and evaluated how isotype can alter those mechanisms with the aim to develop improved antibodies for use in rational combination treatments for cancer. METHODS: Anti-mOX40 and anti-hOX40 mAbs were evaluated in a number of in vivo models, including an OT-I adoptive transfer immunization model in hOX40 knock-in (KI) mice and syngeneic tumor models. The impact of FcγR engagement was evaluated in hOX40 KI mice deficient for Fc gamma receptors (FcγR). Additionally, combination studies using anti-mouse programmed cell death protein-1 (mPD-1) were assessed. In vitro experiments using peripheral blood mononuclear cells (PBMCs) examining possible anti-hOX40 mAb mechanisms of action were also performed. RESULTS: Isotype variants of the clinically relevant mAb GSK3174998 showed immunomodulatory effects that differed in mechanism; mIgG1 mediated direct T-cell agonism while mIgG2a acted indirectly, likely through depletion of regulatory T cells (Tregs) via activating FcγRs. In both the OT-I and EG.7-OVA models, hIgG1 was the most effective human isotype, capable of acting both directly and through Treg depletion. The anti-hOX40 hIgG1 synergized with anti-mPD-1 to improve therapeutic outcomes in the EG.7-OVA model. Finally, in vitro assays with human peripheral blood mononuclear cells (hPBMCs), anti-hOX40 hIgG1 also showed the potential for T-cell stimulation and Treg depletion. CONCLUSIONS: These findings underline the importance of understanding the role of isotype in the mechanism of action of therapeutic mAbs. As an hIgG1, the anti-hOX40 mAb can elicit multiple mechanisms of action that could aid or hinder therapeutic outcomes, dependent on the microenvironment. This should be considered when designing potential combinatorial partners and their FcγR requirements to achieve maximal benefit and improvement of patient outcomes