Prevalence and Sequelae of Cryptococcal Antigenemia in Antiretroviral Therapy-Experienced Populations: An Evaluation of Reflex Cryptococcal Antigen Screening in Botswana.

BACKGROUND: Evidence to inform cryptococcal antigen (CrAg)-screening guidelines among ART-experienced populations is lacking. We performed a study evaluating the utility of reflex CrAg screening in Gaborone, Botswana. METHODS: CD4 count data were collected from the HIV reference laboratory from 2014-2016. CrAg screening was performed on samples with CD4 ≤100 cells/µL beginning January 2015. The proportion of CD4 counts ≤100 cells/µL was determined and the frequency of repeat CrAg testing described. Analyses ascertained the impact of ART status on CrAg prevalence and outcomes, and whether CrAg titers could be used for risk stratification. RESULTS: Overall, 5.6% (3335/59 300) of individuals tested had CD4 ≤100 cells/µL; 2108 samples with CD4 ≤100 cells/µL from 1645 unique patients were CrAg tested. Over half of samples were from ART-experienced individuals: 40.9% (863) on ART and 12.1% (255) defaulters; 22% (463) of CrAg tests were on repeat samples. CrAg prevalence was 4.8% (72/1494; 95% CI, 3.8-6.0%) among outpatients and 21.9% (32/151; 95% CI, 15.3-28.5%) among inpatients. CrAg prevalence rates did not differ by ART status, but 6-month mortality was significantly lower in CrAg-positive individuals on ART at screening. Ten CrAg positives were identified through repeat testing. A CrAg titer cutoff ≥1:80 provided the best discrimination for 6-month survival. CONCLUSIONS: CrAg-positivity rates in an ART-experienced population were comparable to those seen in ART-naive populations. Repeat screening identified individuals who seroconverted to CrAg positivity and were at risk of cryptococcal disease. CrAg titers ≥1:80 can help identify the individuals at highest risk of death for more intensive management.

Undergraduate teaching in geriatric medicine: mapping the British Geriatrics Society undergraduate curriculum to Tomorrow's Doctors 2009.

INTRODUCTION: in 2008, the British Geriatrics Society (BGS) developed the Recommended Undergraduate Curriculum in Geriatric Medicine. This was subsequently mapped to the second edition of Tomorrows' Doctors (TD2, 2003). Following the publication of the third edition of Tomorrow's Doctors in 2009 (TD3), the mapping exercise was repeated to verify the extent to which the updated General Medical Council recommendations supported teaching in ageing and geriatric medicine. METHOD: we analysed TD3 and identified 48 aspects of its general guidance that were relevant to the teaching of medicine for older people. We then mapped these to the 2009 BGS curriculum. RESULTS: the BGS curriculum was supported in full by TD3. However, learning outcomes relating to the interpretation and conduct of research in TD3 had no corresponding outcomes in the BGS curriculum. CONCLUSION: the BGS curriculum for medical undergraduates continues to provide a specific and complete list of learning objectives, all of which could help to operationalise the general statements made in TD3 with relation to ageing and geriatric medicine. Learning outcomes in research in frail older patients have been added following this mapping exercise.

UK medical teaching about ageing is improving but there is still work to be done: the Second National Survey of Undergraduate Teaching in Ageing and Geriatric Medicine.

INTRODUCTION: in 2008, a UK national survey of undergraduate teaching about ageing and geriatric medicine identified deficiencies, including failure to adequately teach about elder abuse, pressure ulcers and bio- and social gerontology. We repeated the survey in 2013 to consider whether the situation had improved. METHOD: the deans of all 31 UK medical schools were invited to nominate a respondent with an overview of their undergraduate curriculum. Nominees were invited by email and letter to complete an online questionnaire quantifying topics taught, type of teaching and assessment undertaken, and the amount of time spent on teaching. RESULTS: one school only taught pre-clinical medicine and declined to participate. Of the 30 remaining schools, 20 responded and 19 provided analysable data. The majority of the schools (95-100%) provided teaching in delirium, dementia, stroke, falls, osteoporosis, extra-pyramidal disorders, polypharmacy, incontinence, ethics and mental capacity. Only 68% of the schools taught about elder abuse. Thirty-seven per cent taught a recognised classification of the domains of health used in Comprehensive Geriatric Assessment (CGA). The median (range) total time spent on teaching in ageing and geriatric medicine was 55.5 (26-192) h. There was less reliance on informal teaching and improved assessment:teaching ratios compared with the 2008 survey. CONCLUSIONS: there was an improvement in teaching and assessment of learning outcomes in ageing and geriatric medicine for UK undergraduates between 2008 and 2013. However, further work is needed to increase the amount of teaching time devoted to ageing and to improve teaching around elder abuse and the domains of health used in CGA.

Prevalence of gender dysphoria and suicidality and self-harm in a national database of paediatric inpatients in the USA: a population-based, serial cross-sectional study.

BACKGROUND: Transgender and non-binary young people experience discrimination that has been linked to suicidal ideation and self-harm, but few studies have examined this association systematically. We aimed to study the association between gender dysphoria-related diagnostic coding and hospital admission for suicidality or self-harm in a large representative pediatric inpatient database from the USA. METHODS: Using the 2016 and 2019 Kids' Inpatient Database (KID), we identified transgender and non-binary young people (aged 6-20 years) with International Classification of Diseases (ICD)-10 codes related to gender dysphoria. We identified suicidal ideation using explicit suicidality ICD-10 codes, and self-harm using 355 self-harm ICD-10 codes. Prevalence of suicidality (primary outcome), self-harm, and the combination of suicidality and self-harm (secondary outcomes) was compared between young people with and without gender dysphoria-related codes. Univariable and multivariable regression was used to test for an association between gender dysphoria and suicidality, self-harm, or suicidality and self-harm combined. FINDINGS: 1 090 544 individuals were included from KID 2016 and 1 026 752 from KID 2019. Gender dysphoria-related diagnoses were prevalent in 161 per 100 000 hospital admissions in KID 2016 and 475 per 100 000 hospital admissions in KID 2019. In KID 2016 and KID 2019, among individuals who were White, privately insured, or from higher median income ZIP code areas, proportionately more had gender dysphoria-related codes. Prevalence of suicidality was greater in individuals with gender dysphoria-related codes than in individuals without gender dysphoria-related codes in KID 2016 (635 [36%] of 1755 individuals with gender dysphoria-related codes vs 55 351 [5%] of 1 088 789 individuals without gender dysphoria-related codes; unadjusted prevalence ratio [PR] 7·19 [95% CI 6·75-7·66]) and KID 2019 (2680 [55%] of 4872 individuals with gender dysphoria-related codes vs 38 831 [4%] of 1 021 880 individuals without gender dysphoria-related codes; unadjusted PR 5·45 [5·30-5·60]). This association persisted in multivariable modelling adjusting for confounders in KID 2016 (adjusted PR 5·02 [95% CI 4·67-5·41]) and KID 2019 (4·14 [4·02-4·28]). Increased unadjusted and adjusted PRs for individuals with gender dysphoria-related codes, relative to those without, were also evident for self-harm and when combining suicidality and self-harm in both the 2016 and 2019 datasets. INTERPRETATION: In a large representative national sample, transgender and non-binary young people with gender dysphoria-related diagnoses were frequently admitted to hospital for suicidality or self-harm. The lower rates of gender-dysphoria-related codes among young people who were non-White, publicly insured, and from low-income households suggest that underlying inequities might shape the identification and management of gender dysphoria. Structural and health-care provider-level interventions are needed to reduce discrimination and expand gender-affirming competencies to prevent adverse outcomes for hospitalised transgender and non-binary young people with gender dysphoria. FUNDING: National Institutes of Health.

Hospital outcomes for children with severe sepsis in the USA by race or ethnicity and insurance status: a population-based, retrospective cohort study.

BACKGROUND: Disparities in outcomes of adult sepsis are well described by insurance status and race and ethnicity. There is a paucity of data looking at disparities in sepsis outcomes in children. We aimed to determine whether hospital outcomes in childhood severe sepsis were influenced by race or ethnicity and insurance status, a proxy for socioeconomic position. METHODS: This population-based, retrospective cohort study used data from the 2016 database release from the Healthcare Cost and Utilization Project Kids' Inpatient Database (KID). The 2016 KID included 3 117 413 discharges, accounting for 80% of national paediatric discharges from 4200 US hospitals across 47 states. Using multilevel logistic regression, clustered by hospital, we tested the association between race or ethnicity and insurance status and hospital mortality, adjusting for individual-level and hospital-level characteristics, in children with severe sepsis. The secondary outcome of length of hospital stay was examined through multilevel time to event (hospital discharge) regression, with death as a competing risk. FINDINGS: 12 297 children (aged 0-21 years) with severe sepsis with or without shock were admitted to 1253 hospitals in the 2016 KID dataset. 1265 (10·3%) of 12 297 patients did not have race or ethnicity data recorded, 15 (0·1%) were missing data on insurance, and 1324 (10·8%) were transferred out of hospital, resulting in a final cohort of 9816 children. Black children had higher odds of death than did White children (adjusted odds ratio [OR] 1·19, 95 % CI 1·02-1·38; p=0·028), driven by higher Black mortality in the south (1·30, 1·04-1·62; p=0·019) and west (1·58, 1·05-2·38; p=0·027) of the USA. We found evidence of longer hospital stays for Hispanic children (adjusted hazard ratio 0·94, 95% CI 0·88-1·00; p=0·049) and Black children (0·88, 0·82-0·94; p=0·0002), particularly Black neonates (0·53, 95% CI 0·36-0·77; p=0·0011). We observed no difference in survival between publicly and privately insured children; however, other insurance status (self-pay, no charge, and other) was associated with increased mortality (adjusted OR 1·30, 95% CI 1·04-1·61; p=0·021). INTERPRETATION: In this large, representative analysis of paediatric severe sepsis in the USA, we found evidence of outcome disparities by race or ethnicity and insurance status. Our findings suggest that there might be differential sepsis recognition, approaches to treatment, access to health-care services, and provider bias that contribute to poorer sepsis outcomes for racial and ethnic minority patients and those of lower socioeconomic position. Studies are warranted to investigate the mechanisms of poorer sepsis outcomes in Black and Hispanic children. FUNDING: None.

Association of Neighborhood Gun Violence With Mental Health-Related Pediatric Emergency Department Utilization.

Importance: Many children and adolescents in the United States are exposed to neighborhood gun violence. Associations between violence exposure and children's short-term mental health are not well understood. Objective: To examine the association between neighborhood gun violence and subsequent mental health-related pediatric emergency department (ED) utilization. Design, Setting, and Participants: This location-based cross-sectional study included 128 683 ED encounters for children aged 0 to 19 years living in 12 zip codes in Philadelphia, Pennsylvania, who presented to an urban academic pediatric ED from January 1, 2014, to December 31, 2018. Children were included if they (1) had 1 or more ED visits in the 60 days before or after a neighborhood shooting and (2) lived within a quarter-mile radius of the location where this shooting occurred. Analysis began August 2020 and ended May 2021. Exposure: Neighborhood violence exposure, as measured by whether a patient resided near 1 or more episodes of police-reported gun violence. Main Outcomes and Measures: ED encounters for a mental health-related chief complaint or primary diagnosis. Results: A total of 2629 people were shot in the study area between 2014 and 2018, and 54 341 children living nearby had 1 or more ED visits within 60 days of a shooting. The majority of these children were Black (45 946 [84.5%]) and were insured by Medicaid (42 480 [78.1%]). After adjusting for age, sex, race and ethnicity, median household income by zip code, and insurance, children residing within one-eighth of a mile (2-3 blocks) of a shooting had greater odds of mental health-related ED presentations in the subsequent 14 days (adjusted odds ratio, 1.86 [95% CI, 1.20-2.88]), 30 days (adjusted odds ratio, 1.49 [95% CI, 1.11-2.03]), and 60 days (adjusted odds ratio, 1.35 [95% CI, 1.06-1.72]). Conclusions and Relevance: Exposure to neighborhood gun violence is associated with an increase in children's acute mental health symptoms. City health departments and pediatric health care systems should work together to provide community-based support for children and families exposed to violence and trauma-informed care for the subset of these children who subsequently present to the ED. Policies aimed at reducing children's exposure to neighborhood gun violence and mitigating the mental symptoms associated with gun violence exposure must be a public health priority.

Racial, ethnic, and socioeconomic disparities in paediatric critical care in the USA.

In an era of tremendous medical advancements, it is important to characterise and address inequities in the provision of health care and in outcomes. There is a large body of evidence describing such disparities by race or ethnicity and socioeconomic position in critically ill adults; however, this important issue has received less attention in children and adolescents (aged ≤21 years). This Review presents a summary of the available evidence on disparities in outcomes in paediatric critical illness in the USA as a result of racism and socioeconomic privilege. The majority of evidence of racial and socioeconomic disparities in paediatric critical care originates from the USA and is retrospective, with only one prospective intervention-based study. Although there is mixed evidence of disparities by race or ethnicity and socioeconomic position in general paediatric intensive care unit admissions and outcomes in the USA, there are striking trends within some disease processes. Notably, there is evidence of disparities in management and outcomes for out-of-hospital cardiac arrest, asthma, severe trauma, sepsis, and oncology, and in families' perceptions of care. Furthermore, there is clear evidence that critical care research is limited by under-enrolment of participants from minority race or ethnicity groups. We advocate for rigorous research standards and increases in the recruitment and enrolment of a diverse range of participants in paediatric critical care research to better understand the disparities observed, including the effects of racism and poverty. A clearer understanding of when, where, and how such disparities affect patients will better enable the development of effective strategies to inform practice, interventions, and policy.

Racial/ethnic and socioeconomic survival disparities for children and adolescents with central nervous system tumours in the United States, 2000-2015.

BACKGROUND AND OBJECTIVES: Central nervous system (CNS) malignancy is the commonest cause of cancer death in children and adolescents (0-19 years) in high-income settings. There is limited data on survival inequalities by race/ethnicity and socioeconomic position (SEP), for young patients, we aim to analyse their influence on survival from childhood CNS tumour. METHODS: 9577 children and adolescents diagnosed with primary malignant CNS tumours during 2000-2015, followed up until Dec 31 st, 2015, and reported to cancer registries (Surveillance, Epidemiology and End Results programme) were included in the analysis. Cox regression models estimated the hazard ratios for race/ethnicity, SEP, and individual insurance status, adjusting for sex, age, diagnostic period, and tumour type. Individual-level insurance status data were available from 2007. RESULTS: 62.5 % children and adolescents were non-Hispanic White, 10.6 % were non-Hispanic Black and 26.9 % were Hispanic. Race/ethnicity was strongly associated with survival (p < 0.001), even after adjusting for SEP, with Black (HR = 1.39 [95 %CI 1.23-1.58]) and Hispanic children (HR = 1.40 [95 %CI 1.28-1.54]) having higher hazards of death than White children. This association remained after adjusting for insurance status. There was an apparent positive association between SEP and survival that was largely attenuated after adjustment for insurance status (p = 0.20). Survival was comparable between those privately and Medicaid-insured. CONCLUSIONS: Non-Hispanic Black and Hispanic children had lower survival than their White counterparts. This association, not fully explained by differences in SEP, tumour subtype or health insurance, could be related to racially/ethnically-driven barriers to optimal healthcare, warranting further investigation.

Causes of Pediatric Meningitis in Botswana: Results From a 16-Year National Meningitis Audit.

BACKGROUND: Central nervous system infections are an important cause of childhood morbidity and mortality in high HIV-prevalence settings of Africa. We evaluated the epidemiology of pediatric meningitis in Botswana during the rollout of antiretroviral therapy, pneumococcal conjugate vaccine and Haemophilus influenzae type B (HiB) vaccine. METHODS: We performed a cross-sectional study of children (<15 years old) evaluated for meningitis by cerebrospinal fluid (CSF) examination from 2000 to 2015, with complete national records for 2013-2014. Clinical and laboratory characteristics of microbiologically confirmed and culture-negative meningitis were described and incidence of Streptococcus pneumoniae, H. influenzae and cryptococcal meningitis was estimated for 2013-2014. RESULTS: A total of 6796 unique cases were identified. Median age was 1 year [interquartile range 0-3]; 10.4% (435/4186) of children with available HIV-related records were known HIV-infected. Overall, 30.4% (2067/6796) had abnormal CSF findings (positive microbiologic testing or CSF pleocytosis). Ten percent (651/6796) had a confirmed microbiologic diagnosis; including 26.9% (175/651) Cryptococcus, 18.9% (123/651) S. pneumoniae, 20.3% (132/651) H. influenzae and 1.1% (7/651) Mycobacterium tuberculosis. During 2013-2014, national cryptococcal meningitis incidence was 1.3 cases per 100,000 person-years (95% confidence interval, 0.8-2.1) and pneumococcal meningitis incidence 0.7 per 100,000 person-years (95% confidence interval, 0.3-1.3), with no HiB meningitis diagnosed. CONCLUSIONS: Following HiB vaccination, a marked decline in microbiologically confirmed cases of H. influenzae meningitis occurred. Cryptococcal meningitis remains the most common confirmed etiology, demonstrating gaps in prevention-of-mother-to-child transmission and early HIV diagnosis. The high proportion of abnormal CSF samples with no microbiologic diagnosis highlights limitation in available diagnostics.

Mortality in adult patients with culture-positive and culture-negative meningitis in the Botswana national meningitis survey: a prevalent cohort study.

BACKGROUND: CNS infections are a leading cause of HIV-related deaths in sub-Saharan Africa, but causes and outcomes are poorly defined. We aimed to determine mortality and predictors of mortality in adults evaluated for meningitis in Botswana, which has an estimated 23% HIV prevalence among adults. METHODS: In this prevalent cohort study, patient records from 2004-15 were sampled from the Botswana national meningitis survey, a nationwide audit of all cerebrospinal fluid (CSF) laboratory records from patients receiving a lumbar puncture for evaluation of meningitis. Data from all patients with culture-confirmed pneumococcal and tuberculous meningitis, and all patients with culture-negative meningitis with CSF white cell count (WCC) above 20 cells per µL were included in our analyses, in addition to a random selection of patients with culture-negative CSF and CSF WCC of up to 20 cells per µL. We used patient national identification numbers to link CSF laboratory records from the national meningitis survey to patient vital registry and HIV databases. Univariable and multivariable Cox proportional hazards models were used to evaluate clinical and laboratory predictors of mortality. FINDINGS: We included data from 238 patients with culture-confirmed pneumococcal meningitis, 48 with culture-confirmed tuberculous meningitis, and 2900 with culture-negative CSF (including 1691 with CSF WCC of up to 20 cells per µL and 1209 with CSF WCC above 20 cells per µL). Median age was 37 years (IQR 31-46), 1605 (50%) of 3184 patients were male, 2188 (72%) of 3023 patients with registry linkage had documentation of HIV infection, and median CD4 count was 139 cells per µL (IQR 63-271). 10-week and 1-year mortality was 47% (112 of 238) and 49% (117 of 238) for pneumococcal meningitis, 46% (22 of 48) and 56% (27 of 48) for tuberculous meningitis, and 41% (1181 of 2900) and 49% (1408 of 2900) for culture-negative patients. When the analysis of patients with culture-negative CSF was restricted to those with known HIV infection, WCC (0-20 cells per µL vs >20 cells per µL) was not predictive of mortality (average hazard ratio 0·93, 95% CI 0·80-1·09). INTERPRETATION: Mortality from pneumococcal, tuberculous, and culture-negative meningitis was high in this setting of high HIV prevalence. There is an urgent need for improved access to diagnostics, to better define aetiologies and develop novel diagnostic tools and treatment algorithms. FUNDING: National Institutes of Health, President's Emergency Plan for AIDS Relief, National Institute for Health Research.

Epidemiology of adult meningitis during antiretroviral therapy scale-up in southern Africa: Results from the Botswana national meningitis survey.

OBJECTIVES: Data on meningitis epidemiology in high HIV-prevalence African settings following antiretroviral therapy scale-up are lacking. We described epidemiology of adult meningitis in Botswana over a 16-year period. METHODS: Laboratory records for adults undergoing lumbar puncture (LP) 2000-2015 were collected, with complete national data 2013-2014. Cerebrospinal fluid (CSF) findings and linked HIV-data were described, and national incidence figures estimated for 2013-2014. Temporal trends in meningitis were evaluated. RESULTS: Of 21,560 adults evaluated, 41% (8759/21,560) had abnormal CSF findings with positive microbiological testing and/or pleocytosis; 43% (3755/8759) of these had no confirmed microbiological diagnosis. Of the 5004 microbiologically-confirmed meningitis cases, 89% (4432/5004) were cryptococcal (CM) and 8% (382/5004) pneumococcal (PM). Seventy-three percent (9525/13,033) of individuals undergoing LP with identifiers for HIV registry linkage had documented HIV-infection. Incidence of LP for meningitis evaluation in Botswana 2013-2014 was 142.6/100,000 person-years (95%CI:138.3-147.1); incidence of CM was 25.0/100,000 (95%CI:23.2-26.9), and incidence of PM was 2.7/100,000 (95%CI:2.4-3.1). In contrast to previously reported declines in CM incidence with ART roll-out, no significant temporal decline in pneumococcal or culture-negative meningitis was observed. CONCLUSIONS: CM remained the predominant identified aetiology of meningitis despite ART scale-up. A high proportion of cases had abnormal CSF with negative microbiological evaluation.

Neurological Sequelae of Adult Meningitis in Africa: A Systematic Literature Review.

The high human immunodeficiency virus (HIV) prevalence in sub-Saharan Africa has markedly changed the epidemiology and presentation of adult meningitis. We conducted a systematic review using PubMed, Embase, Ovid, CENTRAL, and African Index Medicus to identify studies in Africa with data on neurological outcomes in adults after meningitis. We found 22 articles meeting inclusion criteria. From 4 studies with predominately pneumococcal meningitis, a median of 19% of survivors experienced hearing loss up to 40 days. Two studies of cryptococcal meningitis evaluated 6- to 12-month outcomes; in one, 41% of survivors had global neurocognitive impairment and 20% severe impairment at 1 year, and in a second 30% of survivors had intermediate disability and 10% severe disability at 6 months. A single small study of patients with tuberculosis/HIV found marked disability in 20% (6 of 30) at 9 months. Despite the high burden of meningitis in sub-Saharan Africa, little is known about neurological outcomes of patients with HIV-associated meningitides.