Standardized Urine-Based Tuberculosis (TB) Screening With TB-Lipoarabinomannan and Xpert MTB/RIF Ultra in Ugandan Adults With Advanced Human Immunodeficiency Virus Disease and Suspected Meningitis.

BACKGROUND: Diagnosis of extrapulmonary tuberculosis (TB) remains challenging. We sought to determine the prevalence of disseminated TB by testing urine with TB-lipoarabinomannan (TB-LAM) lateral flow assay and Xpert MTB/RIF Ultra (Ultra) in hospitalized adults. METHODS: We prospectively enrolled human immunodeficiency virus (HIV)-positive adults with suspected meningitis in Uganda during 2018-2020. Participants underwent standardized urine-based TB screening. Urine (60 mcL) was tested with TB-LAM (Alere), and remaining urine was centrifuged with the cell pellet resuspended in 2 mL of urine for Xpert Ultra testing. RESULTS: We enrolled 348 HIV-positive inpatients with median CD4 of 37 cells/mcL (interquartile range, 13-102 cells/mcL). Overall, 26% (90 of 348; 95% confidence interval [CI], 21%-30%) had evidence of disseminated TB by either urine assay. Of 243 participants with both urine TB-LAM and Ultra results, 20% (48 of 243) were TB-LAM-positive, 12% (29 of 243) were Ultra-positive, and 6% (14 of 243) were positive by both assays. In definite and probable TB meningitis, 37% (14 of 38) were TB-LAM-positive and 41% (15 of 37) were Ultra-positive. In cryptococcal meningitis, 22% (40 of 183) were TB-LAM-positive and 4.4% (6 of 135) were Ultra-positive. Mortality trended higher in those with evidence of disseminated TB by either assay (odds ratio = 1.44; 95% CI, 0.83-2.49; P = .19) and was 6-fold higher in those with definite TB meningitis who were urine Ultra-positive (odds ratio = 5.67; 95% CI, 1.13-28.5; P = .04). CONCLUSIONS: In hospitalized Ugandans with advanced HIV disease and suspected meningitis, systematic screening with urine TB-LAM and Ultra found a high prevalence of urine TB test positivity (26%). In those with TB meningitis, urine tests were positive in over one third. There was little concordance between Ultra and TB-LAM, which warrants further investigation

COVID-19 and the HIV care continuum in Uganda: minimising collateral damage

The novel coronavirus, SARS-CoV-2, has spread across the world within months of its first description in Wuhan, China in December 2019, resulting in an unprecedented global health emergency. Whilst Europe and North America are the current epicentres of infection, the global health community are preparing for the potential effects of this new disease on the African continent. Modelling studies predict that factors such as a youthful and rural population may be protective in mitigating the spread of COVID-19 in the World Health Organisation (WHO) African Region, however, with 220 million infections and 4.6 million hospitalisations predicted in the first year of the pandemic alone, fragile health systems could still be placed under significant strain. Furthermore, subsequent disruptions to the provision of services for people living with HIV, or at risk of acquiring HIV, are predicted to lead to an extra 500,000 adult HIV deaths and a 2-fold increase in mother to child transmission of HIV in sub-Saharan Africa in 2020-2021. Ignoring these predictions may have severe consequences and we risk �stepping back in time� in AIDS-related deaths to numbers seen over a decade ago. Reflecting on our current experience of the COVID-19 pandemic in Uganda, we explore the potential impact of public health measures implemented to mitigate spread of COVID-19 on the HIV care continuum, and suggest areas of focus for HIV services, policy makers and governments to urgently address in order to minimise the collateral damage

Improving wear time compliance with a 24-hour waist-worn accelerometer protocol in the International Study of Childhood Obesity, Lifestyle and the Environment (ISCOLE)

Background: We compared 24-hour waist-worn accelerometer wear time characteristics of 9-11 year old children in the International Study of Childhood Obesity, Lifestyle and the Environment (ISCOLE) to similarly aged U.S. children providing waking-hours waist-worn accelerometer data in the 2003-2006 National Health and Nutrition Examination Survey (NHANES). Methods: Valid cases were defined as having >= 4 days with >= 10 hours of waking wear time in a 24-hour period, including one weekend day. Previously published algorithms for extracting total sleep episode time from 24-hour accelerometer data and for identifying wear time (in both the 24-hour and waking-hours protocols) were applied. The number of valid days obtained and a ratio (percent) of valid cases to the number of participants originally wearing an accelerometer were computed for both ISCOLE and NHANES. Given the two surveys' discrepant sampling designs, wear time (minutes/day, hours/day) from U.S. ISCOLE was compared to NHANES using a meta-analytic approach. Wear time for the 11 additional countries participating in ISCOLE were graphically compared with NHANES. Results: 491 U.S. ISCOLE children (9.92 +/- 0.03 years of age [M +/- SE]) and 586 NHANES children (10.43 +/- 0.04 years of age) were deemed valid cases. The ratio of valid cases to the number of participants originally wearing an accelerometer was 76.7% in U.S. ISCOLE and 62.6% in NHANES. Wear time averaged 1357.0 +/- 4.2 minutes per 24-hour day in ISCOLE. Waking wear time was 884.4 +/- 2.2 minutes/day for U.S. ISCOLE children and 822.6 +/- 4.3 minutes/day in NHANES children (difference = 61.8 minutes/day, p <0.001). Wear time characteristics were consistently higher in all ISCOLE study sites compared to the NHANES protocol. Conclusions: A 24-hour waist-worn accelerometry protocol implemented in U.S. children produced 22.6 out of 24 hours of possible wear time, and 61.8 more minutes/day of waking wear time than a similarly implemented and processed waking wear time waist-worn accelerometry protocol. Consistent results were obtained internationally. The 24-hour protocol may produce an important increase in wear time compliance that also provides an opportunity to study the total sleep episode time separate and distinct from physical activity and sedentary time detected during waking-hours.Peer reviewe

A model for presenting accelerometer paradata in large studies : ISCOLE

Background: We present a model for reporting accelerometer paradata (process-related data produced from survey administration) collected in the International Study of Childhood Obesity Lifestyle and the Environment (ISCOLE), a multi-national investigation of >7000 children (averaging 10.5 years of age) sampled from 12 different developed and developing countries and five continents. Methods: ISCOLE employed a 24-hr waist worn 7-day protocol using the ActiGraph GT3X+. Checklists, flow charts, and systematic data queries documented accelerometer paradata from enrollment to data collection and treatment. Paradata included counts of consented and eligible participants, accelerometers distributed for initial and additional monitoring (site specific decisions in the face of initial monitoring failure), inadequate data (e.g., lost/malfunction, insufficient wear time), and averages for waking wear time, valid days of data, participants with valid data (>= 4 valid days of data, including 1 weekend day), and minutes with implausibly high values (>= 20,000 activity counts/min). Results: Of 7806 consented participants, 7372 were deemed eligible to participate, 7314 accelerometers were distributed for initial monitoring and another 106 for additional monitoring. 414 accelerometer data files were inadequate (primarily due to insufficient wear time). Only 29 accelerometers were lost during the implementation of ISCOLE worldwide. The final locked data file consisted of 6553 participant files (90.0% relative to number of participants who completed monitoring) with valid waking wear time, averaging 6.5 valid days and 888.4 minutes/day (14.8 hours). We documented 4762 minutes with implausibly high activity count values from 695 unique participants (9.4% of eligible participants and Conclusions: Detailed accelerometer paradata is useful for standardizing communication, facilitating study management, improving the representative qualities of surveys, tracking study endpoint attainment, comparing studies, and ultimately anticipating and controlling costs.Peer reviewe

Clinical impact of genomic testing in patients with suspected monogenic kidney disease

Purpose: To determine the diagnostic yield and clinical impact of exome sequencing (ES) in patients with suspected monogenic kidney disease. Methods: We performed clinically accredited singleton ES in a prospectively ascertained cohort of 204 patients assessed in multidisciplinary renal genetics clinics at four tertiary hospitals in Melbourne, Australia. Results: ES identified a molecular diagnosis in 80 (39%) patients, encompassing 35 distinct genetic disorders. Younger age at presentation was independently associated with an ES diagnosis (p < 0.001). Of those diagnosed, 31/80 (39%) had a change in their clinical diagnosis. ES diagnosis was considered to have contributed to management in 47/80 (59%), including negating the need for diagnostic renal biopsy in 10/80 (13%), changing surveillance in 35/80 (44%), and changing the treatment plan in 16/80 (20%). In cases with no change to management in the proband, the ES result had implications for the management of family members in 26/33 (79%). Cascade testing was subsequently offered to 40/80 families (50%). Conclusion: In this pragmatic pediatric and adult cohort with suspected monogenic kidney disease, ES had high diagnostic and clinical utility. Our findings, including predictors of positive diagnosis, can be used to guide clinical practice and health service design

Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers

Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2 x 10(53)). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2 x 10(-20)). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management

Cerebrospinal Fluid Bacillary Load by Xpert MTB/RIF Ultra Polymerase Chain Reaction Cycle Threshold Value Predicts 2-Week Mortality in Human Immunodeficiency Virus-Associated Tuberculous Meningitis.

BACKGROUND: The World Health Organization recommends GeneXpert MTB/RIF Ultra (Xpert Ultra), a fully automated polymerase chain reaction (PCR) assay, as the initial tuberculous meningitis (TBM) diagnostic test. The assay's PCR cycle threshold (Ct) values represent the number of PCR cycles required for probe signal to be detected (low Ct value = high bacillary load) and may approximate tuberculosis (TB) bacillary load. We measured the relationship between cerebrospinal fluid (CSF) TB bacillary load with mortality. METHODS: We prospectively enrolled 102 human immunodeficiency virus (HIV)-positive Ugandans with probable or definite TBM from April 2015 to August 2019. Xpert Ultra Ct tertiles and semi-quantitative categories were separately analyzed as predictors of 2-week mortality. We investigated associations between Ct and baseline clinical and CSF parameters. RESULTS: Subjects with Ct values in the low tertile (ie, high bacillary load) had 57% 2-week mortality-worse than the intermediate (17%) and high (25%) Ct tertiles and Xpert Ultra-negative (30%) probable TBM cases (P = .01). In contrast, the reported semi-quantitative Xpert Ultra categorization was less precise; with the medium to low category trending toward worse 2-week survival (42%) compared with very low (28%), trace (26%), and negative (30%) categories (P = .48). Ct tertile was significantly associated with baseline CSF lactate (P = .03). CONCLUSIONS: High CSF TB bacillary load, as measured by Xpert Ultra Ct tertile, is associated with an almost 2-fold higher 2-week mortality in HIV-associated TBM and is a better predictor than the reported Xpert Ultra semi-quantitative category. Xpert Ultra Ct values could identify TBM patients at increased risk of death who may benefit from enhanced supportive care

Health Systems and Sustainability: Doctors and Consumers Differ on Threats and Solutions

Background: Healthcare systems face the problem of insufficient resources to meet the needs of ageing populations and increasing demands for access to new treatments. It is unclear whether doctors and consumers agree on the main challenges to health system sustainability. Methodology: We conducted a mail survey of Australian doctors (specialists and general practitioners) and a computer assisted telephone interview (CATI) of consumers to determine their views on contributors to increasing health care costs, rationing of services and involvement in health resource allocation decisions. Differences in responses are reported as odds ratios (OR) and 99% confidence intervals (CI). Results: Of 2948 doctors, 1139 (38.6%) responded; 533 of 826 consumers responded (64.5% response). Doctors were more concerned than consumers with the effects of an ageing population (OR 3.0; 99% CI 1.7, 5.4), and costs of new drugs and technologies (OR 5.1; CI 3.3, 8.0), but less likely to consider pharmaceutical promotional activities as a cost driver (OR 0.29, CI 0.22, 0.39). Doctors were more likely than consumers to view ‘community demand’ for new technologies as a major cost driver, (OR 1.6; 1.2, 2.2), but less likely to attribute increased costs to patients failing to take responsibility for their own health (OR 0.35; 0.24, 0.49). Like doctors, the majority of consumers saw a need for public consultation in decisions about funding for new treatments. Conclusions: Australian doctors and consumers hold different views on the sustainability of the healthcare system, and a number of key issues relating to costs, cost drivers, roles and responsibilities. Doctors recognise their dual responsibility to patients and society, see an important role for physicians in influencing resource allocation, and acknowledge their lack of skills in assessing treatments of marginal value. Consumers recognise cost pressures on the health system, but express willingness to be involved in health care decision making

High-Dose Oral and Intravenous Rifampicin for the Treatment of Tuberculous Meningitis in Predominantly Human Immunodeficiency Virus (HIV)-Positive Ugandan Adults: A Phase II Open-Label Randomized Controlled Trial.

BACKGROUND: High-dose rifampicin may improve outcomes of tuberculous meningitis (TBM). Little safety or pharmacokinetic (PK) data exist on high-dose rifampicin in human immunodeficiency virus (HIV) coinfection, and no cerebrospinal fluid (CSF) PK data exist from Africa. We hypothesized that high-dose rifampicin would increase serum and CSF concentrations without excess toxicity. METHODS: In this phase II open-label trial, Ugandan adults with suspected TBM were randomized to standard-of-care control (PO-10, rifampicin 10 mg/kg/day), intravenous rifampicin (IV-20, 20 mg/kg/day), or high-dose oral rifampicin (PO-35, 35 mg/kg/day). We performed PK sampling on days 2 and 14. The primary outcomes were total exposure (AUC0-24), maximum concentration (Cmax), CSF concentration, and grade 3-5 adverse events. RESULTS: We enrolled 61 adults, 92% were living with HIV, median CD4 count was 50 cells/µL (interquartile range [IQR] 46-56). On day 2, geometric mean plasma AUC0-24hr was 42.9·h mg/L with standard-of-care 10 mg/kg dosing, 249·h mg/L for IV-20 and 327·h mg/L for PO-35 (P < .001). In CSF, standard of care achieved undetectable rifampicin concentration in 56% of participants and geometric mean AUC0-24hr 0.27 mg/L, compared with 1.74 mg/L (95% confidence interval [CI] 1.2-2.5) for IV-20 and 2.17 mg/L (1.6-2.9) for PO-35 regimens (P < .001). Achieving CSF concentrations above rifampicin minimal inhibitory concentration (MIC) occurred in 11% (2/18) of standard-of-care, 93% (14/15) of IV-20, and 95% (18/19) of PO-35 participants. Higher serum and CSF levels were sustained at day 14. Adverse events did not differ by dose (P = .34). CONCLUSIONS: Current international guidelines result in sub-therapeutic CSF rifampicin concentration for 89% of Ugandan TBM patients. High-dose intravenous and oral rifampicin were safe and respectively resulted in exposures ~6- and ~8-fold higher than standard of care, and CSF levels above the MIC