Differential Patterns by Area-Level Social Determinants of Health in Coronavirus Disease 2019 (COVID-19)-Related Mortality and Non-COVID-19 Mortality: A Population-Based Study of 11.8 Million People in Ontario, Canada.

BACKGROUND: Social determinants of health (SDOH) have been associated with coronavirus disease 2019 (COVID-19) outcomes. We examined patterns in COVID-19-related mortality by SDOH and compared these patterns to those for non-COVID-19 mortality. METHODS: Residents of Ontario, Canada, aged ≥20 years were followed from 1 March 2020 to 2 March 2021. COVID-19-related death was defined as death within 30 days following or 7 days prior to a positive COVID-19 test. Area-level SDOH from the 2016 census included median household income; proportion with diploma or higher educational attainment; proportion essential workers, racially minoritized groups, recent immigrants, apartment buildings, and high-density housing; and average household size. We examined associations between SDOH and COVID-19-related mortality, and non-COVID-19 mortality using cause-specific hazard models. RESULTS: Of 11 810 255 individuals, we observed 3880 COVID-19-related deaths and 88 107 non-COVID-19 deaths. After accounting for demographics, baseline health, and other area-level SDOH, the following were associated with increased hazards of COVID-19-related death (hazard ratio [95% confidence interval]: lower income (1.30 [1.04-1.62]), lower educational attainment (1.27 [1.07-1.52]), higher proportions essential workers (1.28 [1.05-1.57]), racially minoritized groups (1.42 [1.08-1.87]), apartment buildings (1.25 [1.07-1.46]), and large vs medium household size (1.30 [1.12-1.50]). Areas with higher proportion racially minoritized groups were associated with a lower hazard of non-COVID-19 mortality (0.88 [0.84-0.92]). CONCLUSIONS: Area-level SDOH are associated with COVID-19-related mortality after accounting for demographic and clinical factors. COVID-19 has reversed patterns of lower non-COVID-19 mortality among racially minoritized groups. Pandemic responses should include strategies to address disproportionate risks and inequitable coverage of preventive interventions associated with SDOH.

Rapid antigen-based and rapid molecular tests for the detection of SARS-CoV-2: a rapid review with network meta-analysis of diagnostic test accuracy studies.

BACKGROUND: The global spread of COVID-19 created an explosion in rapid tests with results in < 1 hour, but their relative performance characteristics are not fully understood yet. Our aim was to determine the most sensitive and specific rapid test for the diagnosis of SARS-CoV-2. METHODS: Design: Rapid review and diagnostic test accuracy network meta-analysis (DTA-NMA). ELIGIBILITY CRITERIA: Randomized controlled trials (RCTs) and observational studies assessing rapid antigen and/or rapid molecular test(s) to detect SARS-CoV-2 in participants of any age, suspected or not with SARS-CoV-2 infection. INFORMATION SOURCES: Embase, MEDLINE, and Cochrane Central Register of Controlled Trials, up to September 12, 2021. OUTCOME MEASURES: Sensitivity and specificity of rapid antigen and molecular tests suitable for detecting SARS-CoV-2. Data extraction and risk of bias assessment: Screening of literature search results was conducted by one reviewer; data abstraction was completed by one reviewer and independently verified by a second reviewer. Risk of bias was not assessed in the included studies. DATA SYNTHESIS: Random-effects meta-analysis and DTA-NMA. RESULTS: We included 93 studies (reported in 88 articles) relating to 36 rapid antigen tests in 104,961 participants and 23 rapid molecular tests in 10,449 participants. Overall, rapid antigen tests had a sensitivity of 0.75 (95% confidence interval 0.70-0.79) and specificity of 0.99 (0.98-0.99). Rapid antigen test sensitivity was higher when nasal or combined samples (e.g., combinations of nose, throat, mouth, or saliva samples) were used, but lower when nasopharyngeal samples were used, and in those classified as asymptomatic at the time of testing. Rapid molecular tests may result in fewer false negatives than rapid antigen tests (sensitivity: 0.93, 0.88-0.96; specificity: 0.98, 0.97-0.99). The tests with the highest sensitivity and specificity estimates were the Xpert Xpress rapid molecular test by Cepheid (sensitivity: 0.99, 0.83-1.00; specificity: 0.97, 0.69-1.00) among the 23 commercial rapid molecular tests and the COVID-VIRO test by AAZ-LMB (sensitivity: 0.93, 0.48-0.99; specificity: 0.98, 0.44-1.00) among the 36 rapid antigen tests we examined. CONCLUSIONS: Rapid molecular tests were associated with both high sensitivity and specificity, while rapid antigen tests were mainly associated with high specificity, according to the minimum performance requirements by WHO and Health Canada. Our rapid review was limited to English, peer-reviewed published results of commercial tests, and study risk of bias was not assessed. A full systematic review is required. REVIEW REGISTRATION: PROSPERO CRD42021289712.

Low Prevalence of Late Myocardial Injury on Cardiac MRI Following COVID-19 Infection.

BACKGROUND: The prevalence of abnormal cardiac magnetic resonance imaging (MRI) findings indicative of myocardial injury in patients who recovered from coronavirus disease 2019 (COVID-19) is currently unclear, with a high variability in the reported prevalence. PURPOSE: To assess the prevalence of myocardial injury after a COVID-19 infection. STUDY TYPE: Prospective, bicentric study. SUBJECTS: Seventy consecutive patients who recovered from COVID-19 and were previously hospitalized. Mean age was 57 years and 39% of the patients were female. Ten healthy controls and a comparator group of 75 nonischemic cardiomyopathy (NICM) patients were employed. FIELD STRENGTH/SEQUENCE: 1.5-T, steady-state free precession (SSFP) gradient-echo sequence, modified Look-Locker inversion recovery sequence with balanced SSFP readout, T2-prepared spiral readout sequence and a T1-weighted inversion recovery fast gradient-echo sequence was acquired ~4-5 months after recovery from COVID-19. ASSESSMENT: The SSFP sequence was utilized for the calculation of left and right ventricular volumes and ejection fractions (LVEF and RVEF) following manual endocardial contouring. T1 and T2 mapping was performed by pixel-wise exponential fitting, and T1 and T2 values were computed by manual contouring of the left ventricular endocardial and epicardial walls. Late gadolinium enhancement (LGE) images were graded qualitatively as LGE present or absent. STATISTICAL TESTS: T-tests and the χ2 or Fisher's exact tests were used to compare continuous and categorical variables respectively between the COVID-19 and NICM groups. Inter-rater agreement was evaluated by the intraclass correlation coefficient for continuous variables and Cohen's kappa test for LGE. RESULTS: Reduced RVEF occurred in 10%, LGE and elevated native T1 in 9%, reduced LVEF in 4%, and elevated T2 in 3% of COVID-19 patients, respectively. Patients with NICM had lower mean LVEF (41.6% ± 6% vs. 60% ± 7%), RVEF (46% ± 5% vs. 61% ± 9%), and a significantly higher prevalence of LGE (27% vs. 9%) when compared to those post-COVID-19. DATA CONCLUSION: Abnormal cardiac MRI findings may show a low prevalence in patients who recovered from COVID-19 and were previously hospitalized. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Maternal Benzodiazepines and Z-Drugs Use during Pregnancy and Adverse Birth and Neurodevelopmental Outcomes in Offspring: A Population-Based Cohort Study.

INTRODUCTION: The use of benzodiazepines and/or z-drugs in women of childbearing age has increased. OBJECTIVE: The aim of the study was to evaluate whether gestational benzodiazepine and/or z-drug exposure is associated with adverse birth and neurodevelopmental outcomes. METHODS: A population-based cohort including mother-child pairs from 2001 to 2018 in Hong Kong was analysed to compare gestationally exposed and nonexposed children on the risk of preterm birth, small for gestational age, autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD) through logistic/Cox proportional hazards regression with a 95% confidence interval (CI). Sibling-matched analyses and negative control analyses were applied. RESULTS: When comparing gestationally exposed with gestationally nonexposed children, the weighted odds ratio (wOR) was 1.10 (95% CI = 0.97-1.25) for preterm birth and 1.03 (95% CI = 0.76-1.39) for small for gestational age, while the weighted hazard ratio (wHR) was 1.40 (95% CI = 1.13-1.73) for ASD and 1.15 (95% CI = 0.94-1.40) for ADHD. Sibling-matched analyses showed no association between gestationally exposed children and their gestationally nonexposed siblings for all outcomes (preterm birth: wOR = 0.84, 95% CI = 0.66-1.06; small for gestational age: wOR = 1.02, 95% CI = 0.50-2.09; ASD: wHR = 1.10, 95% CI = 0.70-1.72; ADHD: wHR = 1.04, 95% CI = 0.57-1.90). Similarly, no significant differences were observed when comparing children whose mothers took benzodiazepines and/or z-drugs during pregnancy to children whose mothers took benzodiazepines and/or z-drugs before but not during pregnancy for all outcomes. CONCLUSIONS: The findings do not support a causal relationship between gestational benzodiazepines and/or z-drugs exposure and preterm birth, small for gestational age, ASD, or ADHD. Clinicians and pregnant women should carefully balance the known risks of benzodiazepines and/or z-drugs use against those of untreated anxiety and sleep problems.

Systematic Examination of Antigen-Specific Recall T Cell Responses to SARS-CoV-2 versus Influenza Virus Reveals a Distinct Inflammatory Profile.

There is a pressing need for an in-depth understanding of immunity to SARS-CoV-2. In this study, we investigated human T cell recall responses to fully glycosylated spike trimer, recombinant N protein, as well as to S, N, M, and E peptide pools in the early convalescent phase and compared them with influenza-specific memory responses from the same donors. All subjects showed SARS-CoV-2-specific T cell responses to at least one Ag. Both SARS-CoV-2-specific and influenza-specific CD4+ T cell responses were predominantly of the central memory phenotype; however SARS-CoV-2-specific CD4+ T cells exhibited a lower IFN-γ to TNF ratio compared with influenza-specific memory responses from the same donors, independent of disease severity. SARS-CoV-2-specific T cells were less multifunctional than influenza-specific T cells, particularly in severe cases, potentially suggesting exhaustion. Most SARS-CoV-2-convalescent subjects also produced IFN-γ in response to seasonal OC43 S protein. We observed granzyme B+/IFN-γ+, CD4+, and CD8+ proliferative responses to peptide pools in most individuals, with CD4+ T cell responses predominating over CD8+ T cell responses. Peripheral T follicular helper (pTfh) responses to S or N strongly correlated with serum neutralization assays as well as receptor binding domain-specific IgA; however, the frequency of pTfh responses to SARS-CoV-2 was lower than the frequency of pTfh responses to influenza virus. Overall, T cell responses to SARS-CoV-2 are robust; however, CD4+ Th1 responses predominate over CD8+ T cell responses, have a more inflammatory profile, and have a weaker pTfh response than the response to influenza virus within the same donors, potentially contributing to COVID-19 disease.

Trends of polypharmacy among older people in Asia, Australia and the United Kingdom: a multinational population-based study.

BACKGROUND: Polypharmacy among older people represents a global challenge due to its association with adverse drug events. The reported prevalence of polypharmacy varies widely across countries, and is particularly high in Asian countries. However, there is no multinational study using standardised measurements exploring variations in prescribing trends. OBJECTIVE: To compare polypharmacy trends in older people in Asia, Australia and the United Kingdom. DESIGN: Multinational, retrospective, time-trend, observational study using a common study protocol. SETTING: Outpatient and community settings. SUBJECTS: All individuals aged ≥ 65 years between 2013 and 2016. METHODS: We defined polypharmacy as the concomitant use of ≥5 medications for ≥45 days per year. We estimated the annual prevalence of polypharmacy and calculated average annual percentage change (AAPC) to assess the time trends. RESULTS: A total of 1.62 million individuals were included in this study. The highest prevalence of polypharmacy was observed in Hong Kong (46.4%), followed by Taiwan (38.8%), South Korea (32.0%), the United Kingdom (23.5%) and Australia (20.1%) in 2016. For the time trend, the Asian region showed a steady increase, particularly in Hong Kong and South Korea (AAPC: Hong Kong, 2.7%; South Korea, 1.8%; Taiwan, 1.0%). However, Australia and the United Kingdom showed a decreasing trend (Australia, -4.9%; the United Kingdom, -1.1%). CONCLUSIONS: Polypharmacy prevalence in older people was higher in Hong Kong, Taiwan and South Korea, with an increasing trend over time, compared with Australia and the United Kingdom. Our findings underline the necessity to monitor polypharmacy among older people in Asia by conducting government-level interventions and introducing medicine-optimisation strategies.

Pain assessment tools in paediatric palliative care: A systematic review of psychometric properties and recommendations for clinical practice.

BACKGROUND: Assessing pain in infants, children and young people with life-limiting conditions remains a challenge due to diverse patient conditions, types of pain and often a reduced ability or inability of patients to communicate verbally. AIM: To systematically identify pain assessment tools that are currently used in paediatric palliative care and examine their psychometric properties and feasibility and make recommendations for clinical practice. DESIGN: A systematic literature review and evaluation of psychometric properties of pain assessment tools of original peer-reviewed research published from inception of data sources to April 2021. DATA SOURCES: PsycINFO via ProQuest, Web of Science Core, Medline via Ovid, EMBASE, BIOSIS and CINAHL were searched from inception to April 2021. Hand searches of reference lists of included studies and relevant reviews were performed. RESULTS: From 1168 articles identified, 201 papers were selected for full-text assessment. Thirty-four articles met the eligibility criteria and we examined the psychometric properties of 22 pain assessment tools. Overall, the Faces Pain Scale-Revised (FPS-R) had high cross-cultural validity, construct validity (hypothesis testing) and responsiveness; while the Faces, Legs, Activity, Cry and Consolability (FLACC) scale and Paediatric Pain Profile (PPP) had high internal consistency, criterion validity, reliability and responsiveness. The number of studies per psychometric property of each pain assessment tool was limited and the methodological quality of included studies was low. CONCLUSION: Balancing aspects of feasibility and psychometric properties, the FPS-R is recommended for self-assessment, and the FLACC scale/FLACC Revised and PPP are the recommended observational tools in their respective age groups.

Using Virtual Care to Facilitate Direct Hospital Admissions in Outpatients with Worsening COVID-19 Infection.

Recognizing emergency department overcrowding during the COVID-19 pandemic, a pathway to facilitate direct admissions for outpatients with worsening COVID-19 infection was created using the COVID-19 expansion to outpatients (COVIDEO) virtual care program. Outpatients appropriate for direct admission had oxygen saturations consistently <92% without severe respiratory distress. Pulse oximeters were proactively delivered to high-risk patients, and patients contacted the program in the event of worsening symptoms or desaturation persistently <92%. Over a 15-month period, 9,116 outpatients were managed by the program, 164 of whom were hospitalized, and 83 of those hospitalized (50.6%) were directly admitted through this pathway. Of those directly admitted, 10 (12.0%) patients required ICU admission, occurring a median of 4 days from hospital admission. The mortality rate among directly admitted patients was 3.6% (3/83). Implementation of a virtual care program to facilitate direct admissions in outpatients with COVID-19 created a safe, efficient, and patient-centered pathway of care.

Antifungal Combinations for Treatment of Cryptococcal Meningitis in Africa.

BACKGROUND: Cryptococcal meningitis accounts for more than 100,000 human immunodeficiency virus (HIV)-related deaths per year. We tested two treatment strategies that could be more sustainable in Africa than the standard of 2 weeks of amphotericin B plus flucytosine and more effective than the widely used fluconazole monotherapy. METHODS: We randomly assigned HIV-infected adults with cryptococcal meningitis to receive an oral regimen (fluconazole [1200 mg per day] plus flucytosine [100 mg per kilogram of body weight per day] for 2 weeks), 1 week of amphotericin B (1 mg per kilogram per day), or 2 weeks of amphotericin B (1 mg per kilogram per day). Each patient assigned to receive amphotericin B was also randomly assigned to receive fluconazole or flucytosine as a partner drug. After induction treatment, all the patients received fluconazole consolidation therapy and were followed to 10 weeks. RESULTS: A total of 721 patients underwent randomization. Mortality in the oral-regimen, 1-week amphotericin B, and 2-week amphotericin B groups was 18.2% (41 of 225), 21.9% (49 of 224), and 21.4% (49 of 229), respectively, at 2 weeks and was 35.1% (79 of 225), 36.2% (81 of 224), and 39.7% (91 of 229), respectively, at 10 weeks. The upper limit of the one-sided 97.5% confidence interval for the difference in 2-week mortality was 4.2 percentage points for the oral-regimen group versus the 2-week amphotericin B groups and 8.1 percentage points for the 1-week amphotericin B groups versus the 2-week amphotericin B groups, both of which were below the predefined 10-percentage-point noninferiority margin. As a partner drug with amphotericin B, flucytosine was superior to fluconazole (71 deaths [31.1%] vs. 101 deaths [45.0%]; hazard ratio for death at 10 weeks, 0.62; 95% confidence interval [CI], 0.45 to 0.84; P=0.002). One week of amphotericin B plus flucytosine was associated with the lowest 10-week mortality (24.2%; 95% CI, 16.2 to 32.1). Side effects, such as severe anemia, were more frequent with 2 weeks than with 1 week of amphotericin B or with the oral regimen. CONCLUSIONS: One week of amphotericin B plus flucytosine and 2 weeks of fluconazole plus flucytosine were effective as induction therapy for cryptococcal meningitis in resource-limited settings. (ACTA Current Controlled Trials number, ISRCTN45035509 .).

Individual and social determinants of SARS-CoV-2 testing and positivity in Ontario, Canada: a population-wide study.

BACKGROUND: Optimizing the public health response to reduce the burden of COVID-19 necessitates characterizing population-level heterogeneity of risks for the disease. However, heterogeneity in SARS-CoV-2 testing may introduce biased estimates depending on analytic design. We aimed to explore the potential for collider bias in a large study of disease determinants, and evaluate individual, environmental and social determinants associated with SARS-CoV-2 testing and diagnosis among residents of Ontario, Canada. METHODS: We explored the potential for collider bias and characterized individual, environmental and social determinants of being tested and testing positive for SARS-CoV-2 infection using cross-sectional analyses among 14.7 million community-dwelling people in Ontario, Canada. Among those with a diagnosis, we used separate analytic designs to compare predictors of people testing positive versus negative; symptomatic people testing positive versus testing negative; and people testing positive versus people not testing positive (i.e., testing negative or not being tested). Our analyses included tests conducted between Mar. 1 and June 20, 2020. RESULTS: Of 14 695 579 people, we found that 758 691 were tested for SARS-CoV-2, of whom 25 030 (3.3%) had a positive test result. The further the odds of testing from the null, the more variability we generally observed in the odds of diagnosis across analytic design, particularly among individual factors. We found that there was less variability in testing by social determinants across analytic designs. Residing in areas with the highest household density (adjusted odds ratio [OR] 1.86, 95% confidence interval [CI] 1.75-1.98), highest proportion of essential workers (adjusted OR 1.58, 95% CI 1.48-1.69), lowest educational attainment (adjusted OR 1.33, 95% CI 1.26-1.41) and highest proportion of recent immigrants (adjusted OR 1.10, 95% CI 1.05-1.15) were consistently related to increased odds of SARS-CoV-2 diagnosis regardless of analytic design. INTERPRETATION: Where testing is limited, our results suggest that risk factors may be better estimated using population comparators rather than test-negative comparators. Optimizing COVID-19 responses necessitates investment in and sufficient coverage of structural interventions tailored to heterogeneity in social determinants of risk, including household crowding, occupation and structural racism.

Addition of Flucytosine to Fluconazole for the Treatment of Cryptococcal Meningitis in Africa: A Multicountry Cost-effectiveness Analysis.

BACKGROUND: Mortality from cryptococcal meningitis remains very high in Africa. In the Advancing Cryptococcal Meningitis Treatment for Africa (ACTA) trial, 2 weeks of fluconazole (FLU) plus flucytosine (5FC) was as effective and less costly than 2 weeks of amphotericin-based regimens. However, many African settings treat with FLU monotherapy, and the cost-effectiveness of adding 5FC to FLU is uncertain. METHODS: The effectiveness and costs of FLU+5FC were taken from ACTA, which included a costing analysis at the Zambian site. The effectiveness of FLU was derived from cohorts of consecutively enrolled patients, managed in respects other than drug therapy, as were participants in ACTA. FLU costs were derived from costs of FLU+5FC in ACTA, by subtracting 5FC drug and monitoring costs. The cost-effectiveness of FLU+5FC vs FLU alone was measured as the incremental cost-effectiveness ratio (ICER). A probabilistic sensitivity analysis assessed uncertainties and a bivariate deterministic sensitivity analysis examined the impact of varying mortality and 5FC drug costs on the ICER. RESULTS: The mean costs per patient were US $847 (95% confidence interval [CI] $776-927) for FLU+5FC, and US $628 (95% CI $557-709) for FLU. The 10-week mortality rate was 35.1% (95% CI 28.9-41.7%) with FLU+5FC and 53.8% (95% CI 43.1-64.1%) with FLU. At the current 5FC price of US $1.30 per 500 mg tablet, the ICER of 5FC+FLU versus FLU alone was US $65 (95% CI $28-208) per life-year saved. Reducing the 5FC cost to between US $0.80 and US $0.40 per 500 mg resulted in an ICER between US $44 and US $28 per life-year saved. CONCLUSIONS: The addition of 5FC to FLU is cost-effective for cryptococcal meningitis treatment in Africa and, if made available widely, could substantially reduce mortality rates among human immunodeficiency virus-infected persons in Africa.

One-year Mortality Outcomes From the Advancing Cryptococcal Meningitis Treatment for Africa Trial of Cryptococcal Meningitis Treatment in Malawi.

In Malawi, 236 participants from the Advancing Cryptococcal Meningitis Treatment for Africa trial were followed for 12 months. The trial outcomes reported at 10 weeks were sustained to 1 year. One-week amphotericin B plus flucytosine was associated with the lowest 1 year mortality (27.5% [95% confidence interval, 16.3 to 44.1]).

Access and Unmet Needs of Orphan Drugs in 194 Countries and 6 Areas: A Global Policy Review With Content Analysis.

OBJECTIVES: Three hundred million people living with rare diseases worldwide are disproportionately deprived of in-time diagnosis and treatment compared with other patients. This review provides an overview of global policies that optimize development, licensing, pricing, and reimbursement of orphan drugs. METHODS: Pharmaceutical legislation and policies related to access and regulation of orphan drugs were examined from 194 World Health Organization member countries and 6 areas. Orphan drug policies (ODPs) were identified through internet search, emails to national pharmacovigilance centers, and systematic academic literature search. Texts from selected publications were extracted for content analysis. RESULTS: One hundred seventy-two drug regulation documents and 77 academic publications from 162 countries/areas were included. Ninety-two of 200 countries/areas (46.0%) had documentation on ODPs. Thirty-four subthemes from content analysis were categorized into 6 policy themes, namely, orphan drug designation, marketing authorization, safety and efficacy requirements, price regulation, incentives that encourage market availability, and incentives that encourage research and development. Countries/areas with ODPs were statistically wealthier (gross national income per capita = $10 875 vs $3950, P < .001). Country/area income was also positively correlated with the scope of the respective ODP (correlation coefficient = 0.57, P < .001). CONCLUSIONS: Globally, the number of countries with an ODP has grown rapidly since 2013. Nevertheless, disparities in geographical distribution and income levels affect the establishment of ODPs. Furthermore, identified policy gaps in price regulation, incentives that encourage market availability, and incentives that encourage research and development should be addressed to improve access to available and affordable orphan drugs.

Healthcare Costs and Life-years Gained From Treatments Within the Advancing Cryptococcal Meningitis Treatment for Africa (ACTA) Trial on Cryptococcal Meningitis: A Comparison of Antifungal Induction Strategies in Sub-Saharan Africa.

BACKGROUND: Mortality from cryptoccocal meningitis remains high. The ACTA trial demonstrated that, compared with 2 weeks of amphotericin B (AmB) plus flucystosine (5FC), 1 week of AmB and 5FC was associated with lower mortality and 2 weeks of oral flucanozole (FLU) plus 5FC was non-inferior. Here, we assess the cost-effectiveness of these different treatment courses. METHODS: Participants were randomized in a ratio of 2:1:1:1:1 to 2 weeks of oral 5FC and FLU, 1 week of AmB and FLU, 1 week of AmB and 5FC, 2 weeks of AmB and FLU, or 2 weeks of AmB and 5FC in Malawi, Zambia, Cameroon, and Tanzania. Data on individual resource use and health outcomes were collected. Cost-effectiveness was measured as incremental costs per life-year saved, and non-parametric bootstrapping was done. RESULTS: Total costs per patient were US $1442 for 2 weeks of oral FLU and 5FC, $1763 for 1 week of AmB and FLU, $1861 for 1 week of AmB and 5FC, $2125 for 2 weeks of AmB and FLU, and $2285 for 2 weeks of AmB and 5FC. Compared to 2 weeks of AmB and 5FC, 1 week of AmB and 5FC was less costly and more effective and 2 weeks of oral FLU and 5FC was less costly and as effective. The incremental cost-effectiveness ratio for 1 week of AmB and 5FC versus oral FLU and 5FC was US $208 (95% confidence interval $91-1210) per life-year saved. CLINICAL TRIALS REGISTRATION: ISRCTN45035509. CONCLUSIONS: Both 1 week of AmB and 5FC and 2 weeks of Oral FLU and 5FC are cost-effective treatments.

Adjunctive Dexamethasone in HIV-Associated Cryptococcal Meningitis.

BACKGROUND: Cryptococcal meningitis associated with human immunodeficiency virus (HIV) infection causes more than 600,000 deaths each year worldwide. Treatment has changed little in 20 years, and there are no imminent new anticryptococcal agents. The use of adjuvant glucocorticoids reduces mortality among patients with other forms of meningitis in some populations, but their use is untested in patients with cryptococcal meningitis. METHODS: In this double-blind, randomized, placebo-controlled trial, we recruited adult patients with HIV-associated cryptococcal meningitis in Vietnam, Thailand, Indonesia, Laos, Uganda, and Malawi. All the patients received either dexamethasone or placebo for 6 weeks, along with combination antifungal therapy with amphotericin B and fluconazole. RESULTS: The trial was stopped for safety reasons after the enrollment of 451 patients. Mortality was 47% in the dexamethasone group and 41% in the placebo group by 10 weeks (hazard ratio in the dexamethasone group, 1.11; 95% confidence interval [CI], 0.84 to 1.47; P=0.45) and 57% and 49%, respectively, by 6 months (hazard ratio, 1.18; 95% CI, 0.91 to 1.53; P=0.20). The percentage of patients with disability at 10 weeks was higher in the dexamethasone group than in the placebo group, with 13% versus 25% having a prespecified good outcome (odds ratio, 0.42; 95% CI, 0.25 to 0.69; P<0.001). Clinical adverse events were more common in the dexamethasone group than in the placebo group (667 vs. 494 events, P=0.01), with more patients in the dexamethasone group having grade 3 or 4 infection (48 vs. 25 patients, P=0.003), renal events (22 vs. 7, P=0.004), and cardiac events (8 vs. 0, P=0.004). Fungal clearance in cerebrospinal fluid was slower in the dexamethasone group. Results were consistent across Asian and African sites. CONCLUSIONS: Dexamethasone did not reduce mortality among patients with HIV-associated cryptococcal meningitis and was associated with more adverse events and disability than was placebo. (Funded by the United Kingdom Department for International Development and others through the Joint Global Health Trials program; Current Controlled Trials number, ISRCTN59144167.).

Anti-Ebola therapy for patients with Ebola virus disease: a systematic review.

BACKGROUND: Management of Ebola virus disease (EVD) has historically focused on infection prevention, case detection and supportive care. Several specific anti-Ebola therapies have been investigated, including during the 2014-2016 West African outbreak. Our objective was to conduct a systematic review of the effect of anti-Ebola virus therapies on clinical outcomes to guide their potential use and future evaluation. METHODS: We searched PubMed, EMBASE, Global Health, Cochrane Library, African Index Medicus, WHOLIS (inception-9 April 2018), and trial registries for observational studies or clinical trials, in any language, that enrolled patients with confirmed EVD who received therapy targeting Ebola virus and reported on mortality, symptom duration, or adverse effects. RESULTS: From 11,257 citations and registered trials, we reviewed 55 full-text citations, of which 35 met eligibility criteria (1 randomized clinical trial (RCT), 8 non-randomized comparative studies, 9 case series and 17 case reports) and collectively examined 21 anti-Ebola virus agents. The 31 studies performed during the West African outbreak reported on 4.8% (1377/28616) of all patients with Ebola. The only RCT enrolled 72 patients (0.25% of all patients with Ebola) and compared the monoclonal antibody ZMapp vs. standard care (mortality, 22% vs. 37%; 95% confidence interval for risk difference, - 36 to 7%). Studies of convalescent plasma, interferon-ß-1a, favipiravir, brincidofovir, artesunate-amodiaquine and TKM-130803 were associated with at least moderate risk of bias. CONCLUSIONS: Research evaluating anti-Ebola virus agents has reached very few patients with EVD, and inferences are limited by non-randomized study designs. ZMapp has the most promising treatment signal.

Predictive value of C-reactive protein for tuberculosis, bloodstream infection or death among HIV-infected individuals with chronic, non-specific symptoms and negative sputum smear microscopy.

BACKGROUND: C-reactive protein (CRP) is an inflammatory biomarker that may identify patients at risk of infections or death. Mortality among HIV-infected persons commencing antiretroviral therapy (ART) is often attributed to tuberculosis (TB) or bloodstream infections (BSI). METHODS: In two district hospitals in southern Malawi, we recruited HIV-infected adults with one or more unexplained symptoms present for at least one month (weight loss, fever or diarrhoea) and negative expectorated sputum microscopy for TB. CRP determination for 452 of 469 (96%) participants at study enrolment was analysed for associations with TB, BSI or death to 120 days post-enrolment. RESULTS: Baseline CRP was significantly elevated among patients with confirmed or probable TB (52), BSI (50) or death (60) compared to those with no identified infection who survived at least 120 days (269). A CRP value of >10 mg/L was associated with confirmed or probable TB (adjusted odds ratio 5.7; 95% CI 2.6, 14.3; 87% sensitivity) or death by 30 days (adjusted odds ratio 9.2; 95% CI 2.2, 55.1; 88% sensitivity). CRP was independently associated with TB, BSI or death, but the prediction of these endpoints was enhanced by including haemoglobin (all outcomes), CD4 count (BSI, death) and whether ART was started (death) in logistic regression models. CONCLUSION: High CRP at the time of ART initiation is associated with TB, BSI and early mortality and so has potential utility for stratifying patients for intensified clinical and laboratory investigation and follow-up. They may also be considered for empirical treatment of opportunistic infections including TB.

Task shifting of triage to peer expert informal care providers at a tertiary referral HIV clinic in Malawi: a cross-sectional operational evaluation.

BACKGROUND: HIV treatment models in Africa are labour intensive and require a high number of skilled staff. In this context, task-shifting is considered a feasible alternative for ART service delivery. In 2006, a lay health cadre of expert patients (EPs) at a tertiary referral HIV clinic in Zomba, Malawi was capacitated. There are few evaluations of EP program efficacy in this setting. Triage is the process of prioritizing patients in terms of the severity of their condition and ensures that no harmful delays occur to treatment and care. This study evaluates the safety of task-shifting triage, in an ambulatory low resource setting, to EPs. METHODS: As a quality improvement exercise in April 2010, formal triage training was conducted by adapting the World Health Organization Emergency Triage Assessment and Treatment Triage Module Guidelines. A cross sectional observation study was conducted 2 years after the intervention. Triage assessments performed by EPs were repeated by a clinical officer (gold standard) to assess sensitivities, specificities, positive and negative predictive values for EP triage scores. Proportions were calculated for categories of disposition by stratifying by EP and clinician triage scores. RESULTS: A total of 467 patients were triaged by 7 EPs and re-triaged by clinical officers. With combined triage scores for emergency and priority patients we report a sensitivity of 85% and specificity of 74% for the EP scoring, with a low positive predictive value (41%) and a high negative predictive value (96%). We calculate a serious miss rate of EP scoring (i.e. missed priority or emergency patients) as 2.2%. Admission rates to hospital were highest among those patients triaged as emergency cases either by the EP's (21%) or the clinicians (83%). Fewer patients triaged as priority by either EPs (5%) or clinicians (15%) were admitted to hospital, however these patients had the highest prevalence of same day lab testing and/or specialty referral. CONCLUSIONS: Our study provides reassurance that in the context of adequate training and ongoing supervision, task-shifting triage to lay health care workers does not necessarily lead to less accurate triaging. EPs have a tendency to be more conservative in over-triaging patients.