SummaryBackgroundWHO recommends Xpert MTB/RIF as initial diagnostic testing for tuberculous meningitis. However, diagnosis remains difficult, with Xpert sensitivity of about 50–70% and culture sensitivity of about 60%. We evaluated the diagnostic performance of the new Xpert MTB/RIF Ultra (Xpert Ultra) for tuberculous meningitis.MethodsWe prospectively obtained diagnostic cerebrospinal fluid (CSF) specimens during screening for a trial on the treatment of HIV-associated cryptococcal meningitis in Mbarara, Uganda. HIV-infected adults with suspected meningitis (eg, headache, nuchal rigidity, altered mental status) were screened consecutively at Mbarara Regional Referral Hospital. We centrifuged CSF, resuspended the pellet in 2 mL of CSF, and tested 0·5 mL with mycobacteria growth indicator tube culture, 1 mL with Xpert, and cryopreserved 0·5 mL, later tested with Xpert Ultra. We assessed diagnostic performance against uniform clinical case definition or a composite reference standard of any positive CSF tuberculous test.FindingsFrom Feb 27, 2015, to Nov 7, 2016, we prospectively evaluated 129 HIV-infected adults with suspected meningitis for tuberculosis. 23 participants were classified as probable or definite tuberculous meningitis by uniform case definition, excluding Xpert Ultra results. Xpert Ultra sensitivity was 70% (95% CI 47–87; 16 of 23 cases) for probable or definite tuberculous meningitis compared with 43% (23–66; 10/23) for Xpert and 43% (23–66; 10/23) for culture. With composite standard, we detected tuberculous meningitis in 22 (17%) of 129 participants. Xpert Ultra had 95% sensitivity (95% CI 77–99; 21 of 22 cases) for tuberculous meningitis, which was higher than either Xpert (45% [24–68]; 10/22; p=0·0010) or culture (45% [24–68]; 10/22; p=0·0034). Of 21 participants positive by Xpert Ultra, 13 were positive by culture, Xpert, or both, and eight were only positive by Xpert Ultra. Of those eight, three were categorised as probable tuberculous meningitis, three as possible tuberculous meningitis, and two as not tuberculous meningitis. Testing 6 mL or more of CSF was associated with more frequent detection of tuberculosis than with less than 6 mL (26% vs 7%; p=0·014).InterpretationXpert Ultra detected significantly more tuberculous meningitis than did either Xpert or culture. WHO now recommends the use of Xpert Ultra as the initial diagnostic test for suspected tuberculous meningitis.FundingNational Institute of Neurologic Diseases and Stroke, Fogarty International Center, National Institute of Allergy and Infectious Disease, UK Medical Research Council/DfID/Wellcome Trust Global Health Trials, Doris Duke Charitable Foundation.

BackgroundIn response to the COVID-19 pandemic, legislation and guidance were introduced in Scotland permitting medical abortion at home by telemedicine for pregnancies at less than 12 weeks’ gestation. Women had a telephone consultation with a clinician. Routine ultrasound was not performed. Medications and a low-sensitivity pregnancy test to confirm success of treatment were collected by or delivered to the woman, with telephone support provided as needed.MethodsA prospective cohort study of 663 women choosing medical abortion at home via the NHS Lothian telemedicine abortion service between 1 April and 9 July 2020. Interviewer-administered questionnaires were completed 4 and 14 days following treatment. Regional hospital databases were reviewed to verify abortion outcomes and complications within 6 weeks. Outcome measures included efficacy, complications and acceptability.ResultsAlmost all (642/663, 98.2%) the women were under 10 weeks’ gestation. For 522/663 (78.7%) women, gestation was determined using last menstrual period alone. Some 650/663 (98%) women had a complete abortion, 5 (0.8%) an ongoing pregnancy and 4 (0.6%) an incomplete abortion. No one was treated inadvertently beyond 12 weeks’ gestation, but one woman was never pregnant. One woman who had a pre-abortion ultrasound was later managed as a caesarean scar ectopic. There were two cases of haemorrhage and no severe infections. Some 123 (18.5%) women sought advice by telephone for a concern related to the abortion and 56 (8.4%) then attended a clinic for review. Most (628, 95%) women rated their care as very or somewhat acceptable.ConclusionsThis model of telemedicine abortion without routine ultrasound is safe, and has high efficacy and high acceptability among women.

Background: Identifying new antifungals for cryptococcal meningitis remains a priority given the inadequacy of current therapy. Sertraline has previously demonstrated in vitro and in vivo activity against Cryptococcus. We evaluated the efficacy of adjunctive sertraline for cryptococcal meningitis in a double-blind, randomised, placebo-controlled clinical trial. Methods: We assessed 18-week survival among HIV-infected Ugandan adults with cryptococcal meningitis enrolled from 09 March 2015 to 29 May 2017. Participants were randomly assigned to receive standard therapy with 7-14 days of amphotericin (0•7-1•0 mg/kg/day) + fluconazole (starting at 800 mg/day) with either adjunctive sertraline or placebo. Sertraline was administered at a dose of 400 mg/day for 2 weeks, followed by 200 mg/day for 12 weeks, then tapered off over 3 weeks. Randomisation in a 1:1 ratio was performed with variable block sizes of 2 and 4, with stratification by site (Kampala or Mbarara) and antiretroviral status (experienced or naïve). Analysis was by intention-to-treat. This study is registered with ClinicalTrials.gov, number .

BackgroundIncreased antiretroviral therapy (ART) availability has been associated with more patients developing cryptococcosis after ART initiation. Despite this changing epidemiology, data regarding cryptococcal meningitis in those already receiving ART are limited. We compared clinical presentations and outcomes among ART-naïve and ART-experienced Ugandans.MethodsWe prospectively enrolled 605 HIV-infected persons with first-episode cryptococcal meningitis from August 2013 to May 2017 who received amphotericin-based combination therapy. We classified participants by ART status and ART duration and compared groups for 2-week survival.ResultsOverall, 46% (281/605) of participants were receiving ART at presentation. Compared with those not receiving ART, those receiving ART had higher CD4 counts (P < .001) and lower cerebrospinal fluid fungal burdens (P < .001). Of those receiving ART, 56% (156/281) initiated ART within 6 months, and 18% (51/281) initiated ART within 14 days. Two-week mortality did not differ by ART status (27% in both ART-naïve and ART-experienced%; P > .99). However, 47% (24/51) of those receiving ART for ≤14 days died within 2 weeks, compared with 19% (20/105) of those receiving ART for 15–182 days and 26% (32/125) of those receiving ART for >6 months (P < .001). Among persons receiving ART for >6 months, 87% had HIV viral loads >1000 copies/mL.ConclusionsCryptococcosis after ART initiation is common in Africa. Patients initiating ART who unmask cryptococcal meningitis are at a high risk of death. Immune recovery in the setting of central nervous system infection is detrimental, and management of this population requires further study. Implementing pre-ART cryptococcal antigen screening is urgently needed to prevent cryptococcal meningitis after ART initiation.

No abstract

Background: Valvular calcification is central to the pathogenesis and progression of aortic stenosis, with pre-clinical and observational studies suggesting that bone turnover and osteoblastic differentiation of valvular interstitial cells are important contributory mechanisms. We aimed to establish whether inhibition of these pathways with denosumab or alendronic acid could reduce disease progression in aortic stenosis. Methods: In a single-centre parallel group double-blind randomized controlled trial, patients over 50 years of age with calcific aortic stenosis (peak aortic jet velocity >2.5 m/s) were randomized 2:1:2:1 to denosumab (60 mg every 6 months), placebo injection, alendronic acid (70 mg once weekly) or placebo capsule. Participants underwent serial assessments with Doppler echocardiography, computed tomography aortic valve calcium scoring and 18F-sodium fluoride positron emission tomography and computed tomography. The primary endpoint was the calculated 24-month change in aortic valve calcium score. Results: One-hundred and fifty patients (mean age 72±8 years; 21% female) with calcific aortic stenosis (peak aortic jet velocity 3.36 [2.93 to 3.82] m/s; aortic valve calcium score 1152 [655 to 2065] Agatston Units) were randomized and received the allocated trial intervention: denosumab (n=49), alendronic acid (n=51) and placebo (injection n=25, capsule n=25; pooled for analysis). Serum C-terminal telopeptide, a measure of bone turnover, halved from baseline to 6 months with denosumab (0.23 [0.18 to 0.33] to 0.11 [0.08 to 0.17] µg/L) and alendronic acid (0.20 [0.14 to 0.28] to 0.09 [0.08 to 0.13] µg/L) but was unchanged with placebo (0.23 [0.17 to 0.30] to 0.26 [0.16 to 0.31] µg/L). There were no differences in 24-month change in aortic valve calcium score between denosumab and placebo (343 [198 to 804] AU versus 354 [76 to 675] AU, p=0.41), or alendronic acid and placebo (326 [138 to 813] AU versus 354 [76 to 675] AU, p=0.49). Similarly, there were no differences in change in peak aortic jet velocity or 18F-sodium fluoride aortic valve uptake. Conclusions: Neither denosumab nor alendronic acid affected progression of aortic valve calcification in patients with calcific aortic stenosis. Alternative pathways and mechanisms need to be explored to identify disease-modifying therapies for the growing population of patients with this potentially fatal condition. Clinical Trial Registration: https://www.clinicaltrials.gov Unique Identifier: NCT02132026.

Background In cryptococcal meningitis phase 2 clinical trials, early fungicidal activity (EFA) of Cryptococcus clearance from cerebrospinal fluid (CSF) is used as a surrogate endpoint for all-cause mortality. The Food and Drug Administration allows for using surrogate endpoints for accelerated regulatory approval, but EFA as a surrogate endpoint requires further validation. We examined the relationship between rate of CSF Cryptococcus clearance (EFA) and mortality through 18 weeks. Methods We pooled individual-level CSF data from 3 sequential cryptococcal meningitis clinical trials conducted during 2010–2017. All 738 subjects received amphotericin + fluconazole induction therapy and had serial quantitative CSF cultures. The log10-transformed colony-forming units (CFUs) per mL CSF were analyzed by general linear regression versus day of culture over the first 10 days. Results Mortality through 18 weeks was 37% for EFA &gt; = 0.60 (n = 170), 36% for 0.40–0.59 (n = 182), 39% for 0.30–0.39 (n = 112), 35% for 0.20–0.29 (n = 87), and 50% for those with EFA &lt; 0.20 CFU/mL/day (n = 187). The hazard ratio for 18-week mortality, comparing those with EFA &lt; 0.20 to those with EFA &gt; = 0.20, was 1.60 (95% confidence interval, 1.25, 2.04; P = .002). The lowest EFA group had lower median CD4 T-cell counts (P &lt; .01) and lower proportion of patients with CSF pleocytosis (P &lt; .001). Conclusions EFA is associated with all-cause mortality in cryptococcal meningitis. An EFA threshold of &gt; = 0.20 log10 CFU/mL/day was associated with similar 18-week mortality (37%) compared to 50% mortality with EFA &lt; 0.20. This EFA threshold may be considered a target for a surrogate endpoint. This builds upon existing studies to validate EFA as a surrogate endpoint.

No abstract