Post hospital admission blood lactate measurements are associated with mortality but not neurologic morbidity in children with cerebral malaria.

BACKGROUND: In children with cerebral malaria (CM) admission blood lactate has previously guided intravenous fluid therapy and been validated as a prognostic biomarker associated with death. The usefulness of post-admission measurements of blood lactate in children with CM is less clear. The strength of association between blood lactate and neurological sequelae in CM survivors, as well as the optimal duration of post-admission measurements of blood lactate to identify children at higher risk of adverse outcomes is unknown. METHODS: A retrospective cohort study of 1674 Malawian children with CM hospitalized from 2000 to 2018 who had blood lactate measurements every 6 h for the first 24 h after admission was performed. The strength of association between admission lactate or values measured at any time point in the first 24 h post-admission and outcomes (mortality and neurological morbidity in survivors) was estimated. The duration of time after admission that lactate remained a valid prognostic biomarker was assessed. RESULTS: When lactate is analysed as a continuous variable, children with CM who have higher values at admission have a 1.05-fold higher odds (95% CI 0.99-1.11) of death compared to those with lower lactate values. Children with higher blood lactate at 6 h have 1.16-fold higher odds (95% CI 1.09-1.23) of death, compared to those with lower values. If lactate levels are dichotomized into hyperlactataemic (lactate > 5.0 mmol/L) or not, the strength of association between admission lactate and mortality increases (OR = 2.49, 95% CI 1.47-4.22). Blood lactate levels obtained after 18 h post-admission are not associated with outcomes. Similarly, the change in lactate concentrations through time during the first 24 h of hospital admission is not associated with outcomes. Blood lactate during hospitalization is not associated with adverse neurologic outcomes in CM survivors. CONCLUSIONS: In children with CM, blood lactate is associated with death but not neurologic morbidity in survivors. To comprehensively estimate prognosis, blood lactate in children with CM should be assessed at admission and for 18 h afterwards.

Temporal Trends of Blood Glucose in Children with Cerebral Malaria.

Hypoglycemia, defined as a blood glucose < 2.2 mmol/L, is associated with death in pediatric cerebral malaria (CM). The optimal duration of glucose monitoring in CM is unknown. We collected data from 1,674 hospitalized Malawian children with CM to evaluate the association between hypoglycemia and death or neurologic disability in survivors. We assessed the optimal duration of routine periodic measurements of blood glucose. Children with hypoglycemia at admission had a 2.87-fold higher odds (95% CI: 1.35-6.09) of death and, if they survived, a 3.21-fold greater odds (95% CI: 1.51-6.86) of sequelae at hospital discharge. If hypoglycemia was detected at 6 hours but not at admission, there was a 7.27-fold higher odds of death (95% CI: 1.85-8.56). The presence of newly developed hypoglycemia after admission was not independently associated with neurological sequelae in CM survivors. Among all new episodes of blood sugar below a treatment threshold of 3.0 mmol/L, 94.7% occurred within 24 hours of admission. In those with blood sugar below 3.0 mmol/L in the first 24 hours, low blood sugar persisted or recurred for up to 42 hours. Hypoglycemia at admission or 6 hours afterward is strongly associated with mortality in CM. Children with CM should have 24 hours of post-admission blood glucose measurements. If a blood glucose less than the treatment threshold of 3.0 mmol/L is not detected, routine assessments may cease. Children who have blood sugar values below the treatment threshold detected within the first 24 hours should continue to have periodic glucose measurements for 48 hours post-admission.

Verbal Autopsies for Out-of-Hospital Infant Deaths in Zambia.

OBJECTIVES: In Zambia, a significant number of infants die in the community. It is hypothesized that delays in care contribute to many of these so-called "brought in dead" infants. METHODS: We analyzed free-text narratives from verbal autopsies, in which families narrate the final series of events leading to each infant's death. Using the 3-delays model framework and working iteratively to achieve consensus, we coded each narrative using NVivo software to identify, characterize, and quantify the contribution of delays and other factors to the fatal outcome. RESULTS: Verbal autopsies were collected from 230 families of brought in dead infants younger than 6 months of age. As many as 82.8% of infants had 1 or more delays in care. The most-common delay was in the family's decision to seek care (54.8%), even as severe symptoms were frequently described. Similarly, 27.8% of infants died en route to a health care facility. Delays in receiving adequate care, including infants dying while waiting in line at a clinic or during referral from a clinic to a hospital, occurred in 24.7% of infants. A third of infants had been previously evaluated by a clinician in the days before their death. CONCLUSIONS: Delays in care were the rule rather than the exception in this population of Zambian infants. Accessing care requires families to navigate significant logistic barriers, and balance complex forces in deciding to seek care. Strategies to avoid such delays could save many infants lives.

Menstrual experience of adolescents in the USA: protocol for a scoping review.

INTRODUCTION: In recent years, there has been a growing desire to address issues related to menstruation, particularly for adolescent girls. In low-income and middle-income countries, prior literature review of the adolescent menstrual experience suggests the need for further research into the impact and efficacy of interventions with this population. There is evidence to suggest the need for initiatives and research in higher-income countries like the USA. To date, the body of research on adolescent menstrual experience in the USA remains uncharacterised. Therefore, we propose a scoping review of the literature on this subject to better inform on areas for future primary study. METHODS AND ANALYSES: Using the framework proposed by Arksey and O'Malley and expounded on by Levac et al and the Joanna Briggs Institute, we will search electronic databases (MEDLINE, CINAHL, PsycINFO, Web of Science, ProQuest Public Health Database, Social Science Citation Index, Social Services Abstracts and SocINDEX) and grey literature for relevant studies in consultation with experienced librarians. The abstracts and full-text from each reference will be screened by two independent reviewers for inclusion. Bibliographic data, study characteristics and themes will be extracted from studies selected for inclusion using a rubric created by the research team. Findings will be summarised and a list of subject areas for future primary research will be generated in consultation with stakeholders. The review will be conducted using the Preferred Reporting Items from Systematic Reviews and Meta-Analyses extension for Scoping Reviews guidelines. ETHICS AND DISSEMINATION: Formal ethics training for this study is not required, as the research team will review publicly available studies. Stakeholders working in adolescent and menstrual health were consulted in designing this review. We will share key findings with stakeholders and in scholarly journals at the conclusion of the review.

The V2 loop of HIV gp120 delivers costimulatory signals to CD4+ T cells through Integrin α4ß7 and promotes cellular activation and infection.

Acute HIV infection is characterized by rapid viral seeding of immunologic inductive sites in the gut followed by the severe depletion of gut CD4+ T cells. Trafficking of α4ß7-expressing lymphocytes to the gut is mediated by MAdCAM, the natural ligand of α4ß7 that is expressed on gut endothelial cells. MAdCAM signaling through α4ß7 costimulates CD4+ T cells and promotes HIV replication. Similar to MAdCAM, the V2 domain of the gp120 HIV envelope protein binds to α4ß7 In this study, we report that gp120 V2 shares with MAdCAM the capacity to signal through α4ß7 resulting in CD4+ T cell activation and proliferation. As with MAdCAM-mediated costimulation, cellular activation induced by gp120 V2 is inhibited by anti-α4ß7 monoclonal antibodies (mAbs). It is also inhibited by anti-V2 domain antibodies including nonneutralizing mAbs that recognize an epitope in V2 that has been linked to reduced risk of acquisition in the RV144 vaccine trial. The capacity of the V2 domain of gp120 to mediate signaling through α4ß7 likely impacts early events in HIV infection. The capacity of nonneutralizing V2 antibodies to block this activity reveals a previously unrecognized mechanism whereby such antibodies might impact HIV transmission and pathogenesis.

Scoping review protocol on maternal, newborn and child health research in Ethiopia.

INTRODUCTION: There has been a tremendous reduction in maternal and child mortality in the last decade. However, a significant number of deaths still occur disproportionately in low-income country settings. Ethiopia is the second-most populous nation in sub-Saharan Africa with a high maternal mortality rate of 412 deaths per 100 000 live births and an under-five mortality rate of 55 per 1000 live births. This study presents a scoping review protocol to describe the current knowledge of maternal and child health in Ethiopia to identify gaps for prioritisation of future maternal, newborn and child health research. METHODS AND ANALYSES: A search strategy will be conducted in PubMed/MEDLINE, EMBASE and the WHO African Index Medicus. Researchers will independently screen title and abstracts followed by full texts for inclusion. Study characteristics, research topics, exposures and outcomes will be abstracted from articles meeting inclusion criteria using standardised forms. Descriptive analysis of abstracted data will be conducted. ETHICS AND DISSEMINATION: Data will be abstracted from published manuscripts and no additional ethical approval is required. The results of the review will be shared with maternal and child health experts in Ethiopia through stakeholder meetings to prioritise research questions. Findings will be submitted to a peer-reviewed journal for publication, in addition to national-level and global-level disseminations.

MAdCAM costimulation through Integrin-α4ß7 promotes HIV replication.

Human gut-associated lymphoid tissues (GALT) play a key role in the acute phase of HIV infection. The propensity of HIV to replicate in these tissues, however, is not fully understood. Access and migration of naive and memory CD4+ T cells to these sites is mediated by interactions between integrin α4ß7, expressed on CD4+ T cells, and MAdCAM, expressed on high endothelial venules. We report here that MAdCAM delivers a potent costimulatory signal to naive and memory CD4+ T cells following ligation with α4ß7. Such costimulation promotes high levels of HIV replication. An anti-α4ß7 mAb that prevents mucosal transmission of SIV blocks MAdCAM signaling through α4ß7 and MAdCAM-dependent viral replication. MAdCAM costimulation of memory CD4+ T cells is sufficient to drive cellular proliferation and the upregulation of CCR5, while naive CD4+ T cells require both MAdCAM and retinoic acid to achieve the same response. The pairing of MAdCAM and retinoic acid is unique to the GALT, leading us to propose that HIV replication in these sites is facilitated by MAdCAM-α4ß7 interactions. Moreover, complete inhibition of MAdCAM signaling by an anti-α4ß7 mAb, an analog of the clinically approved therapeutic vedolizumab, highlights the potential of such agents to control acute HIV infection.