Latent class evaluation of the performance of serological tests for exposure to Brucella spp. in cattle, sheep, and goats in Tanzania

Background: Brucellosis is a neglected zoonosis endemic in many countries, including regions of sub-Saharan Africa. Evaluated diagnostic tools for the detection of exposure to Brucella spp. are important for disease surveillance and guiding prevention and control activities. Methods and findings: Bayesian latent class analysis was used to evaluate performance of the Rose Bengal plate test (RBT) and a competitive ELISA (cELISA) in detecting Brucella spp. exposure at the individual animal-level for cattle, sheep, and goats in Tanzania. Median posterior estimates of RBT sensitivity were: 0.779 (95% Bayesian credibility interval (BCI): 0.570–0.894), 0.893 (0.636–0.989), and 0.807 (0.575–0.966), and for cELISA were: 0.623 (0.443–0.790), 0.409 (0.241–0.644), and 0.561 (0.376–0.713), for cattle, sheep, and goats, respectively. Sensitivity BCIs were wide, with the widest for cELISA in sheep. RBT and cELISA median posterior estimates of specificity were high across species models: RBT ranged between 0.989 (0.980–0.998) and 0.995 (0.985–0.999), and cELISA between 0.984 (0.974–0.995) and 0.996 (0.988–1). Each species model generated seroprevalence estimates for two livestock subpopulations, pastoralist and non-pastoralist. Pastoralist seroprevalence estimates were: 0.063 (0.045–0.090), 0.033 (0.018–0.049), and 0.051 (0.034–0.076), for cattle, sheep, and goats, respectively. Non-pastoralist seroprevalence estimates were below 0.01 for all species models. Series and parallel diagnostic approaches were evaluated. Parallel outperformed a series approach. Median posterior estimates for parallel testing were ≥0.920 (0.760–0.986) for sensitivity and ≥0.973 (0.955–0.992) for specificity, for all species models. Conclusions: Our findings indicate that Brucella spp. surveillance in Tanzania using RBT and cELISA in parallel at the animal-level would give high test performance. There is a need to evaluate strategies for implementing parallel testing at the herd- and flock-level. Our findings can assist in generating robust Brucella spp. exposure estimates for livestock in Tanzania and wider sub-Saharan Africa. The adoption of locally evaluated robust diagnostic tests in setting-specific surveillance is an important step towards brucellosis prevention and control

Latent class evaluation of the performance of serological tests for exposure to Brucella spp. in cattle, sheep, and goats in Tanzania

BACKGROUND : Brucellosis is a neglected zoonosis endemic in many countries, including regions of sub-Saharan Africa. Evaluated diagnostic tools for the detection of exposure to Brucella spp. are important for disease surveillance and guiding prevention and control activities. METHODS AND FINDINGS : Bayesian latent class analysis was used to evaluate performance of the Rose Bengal plate test (RBT) and a competitive ELISA (cELISA) in detecting Brucella spp. exposure at the individual animal-level for cattle, sheep, and goats in Tanzania. Median posterior estimates of RBT sensitivity were: 0.779 (95% Bayesian credibility interval (BCI): 0.570–0.894), 0.893 (0.636–0.989), and 0.807 (0.575–0.966), and for cELISA were: 0.623 (0.443–0.790), 0.409 (0.241–0.644), and 0.561 (0.376–0.713), for cattle, sheep, and goats, respectively. Sensitivity BCIs were wide, with the widest for cELISA in sheep. RBT and cELISA median posterior estimates of specificity were high across species models: RBT ranged between 0.989 (0.980–0.998) and 0.995 (0.985–0.999), and cELISA between 0.984 (0.974–0.995) and 0.996 (0.988–1). Each species model generated seroprevalence estimates for two livestock subpopulations, pastoralist and non-pastoralist. Pastoralist seroprevalence estimates were: 0.063 (0.045–0.090), 0.033 (0.018–0.049), and 0.051 (0.034–0.076), for cattle, sheep, and goats, respectively. Non-pastoralist seroprevalence estimates were below 0.01 for all species models. Series and parallel diagnostic approaches were evaluated. Parallel outperformed a series approach. Median posterior estimates for parallel testing were ≥0.920 (0.760-0.986) for sensitivity and ≥0.973 (0.955-0.992) for specificity, for all species models. CONCLUSIONS : Our findings indicate that Brucella spp. surveillance in Tanzania using RBT and cELISA in parallel at the animal-level would give high test performance. There is a need to evaluate strategies for implementing parallel testing at the herd- and flock-level. Our findings can assist in generating robust Brucella spp. exposure estimates for livestock in Tanzania and wider sub-Saharan Africa. The adoption of locally evaluated robust diagnostic tests in setting-specific surveillance is an important step towards brucellosis prevention and control.The UK Biotechnology and Biological Sciences Research Council (BBSRC), Department for International Development (DFID), the Economic & Social Research Council (ESRC), the Medical Research Council (MRC), the Natural Environment Research Council (NERC) and the Defence Science & Technology Laboratory under the Zoonoses and Emerging Livestock Systems programme, Zoonoses and Emerging Livestock Systems – Associated Studentship programme, US National Institutes of Health-National (NIH) Science Foundation Ecology and Evolution of Infectious Disease program, UK BBSRC , the US NIH, National Institute of Allergy and Infectious Diseases through Investigating Febrile Deaths in Tanzania (INDITe) and the BBSRC Institute Strategic Programme Grants.https://journals.plos.org/plosntdspm2022Veterinary Tropical Disease

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

Background: Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies. We aimed to evaluate the safety and efficacy of convalescent plasma therapy in patients admitted to hospital with COVID-19. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. The trial is underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00, 95% CI 0·93–1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99, 95% CI 0·94–1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of 5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93–1·05; p=0·79). Interpretation: In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Background: In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Findings: Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

The effect of the magnitude of weight loss on non-alcoholic fatty liver disease: a systematic review and meta-analysis

Background Trials show that weight loss interventions improve biomarkers of non-alcoholic fatty liver disease (NAFLD), but it is unclear if a dose-response relationship exists. Objective We aimed to quantify the dose-response relationship between the magnitude of weight loss and improvements in NAFLD. Methods Nine databases and trial registries were searched until October 2020. Single-arm, non-randomized comparative, or randomized trials of weight loss interventions (behavioral weight loss programs [BWLPs], pharmacotherapy, or bariatric surgery) in people with NAFLD were eligible for inclusion if they reported an association between changes in weight and changes in blood, radiological, or histological biomarkers of liver disease. The review followed Cochrane methods and the risk of bias was assessed using the Newcastle-Ottawa scale. Pooled unstandardized b coefficients were calculated using random-effect meta-analyses. Results Forty-three studies (BWMPs: 26, pharmacotherapy: 9, surgery: 8) with 2809 participants were included. The median follow-up was 6 (interquartile range: 6) months. The direction of effect was generally consistent but the estimates imprecise. Every 1 kg of weight lost was associated with a 0.83-unit (95% CI: 0.53 to 1.14, p < 0.0001, I2 = 92%, n = 18) reduction in alanine aminotransferase (U/L), a 0.56-unit (95% CI: 0.32 to 0.79, p < 0.0001, I2 = 68%, n = 11) reduction in aspartate transaminase (U/L), and a 0.77 percentage point (95% CI: 0.51 to 1.03, p < 0.0001, I2 = 72%, n = 11) reduction in steatosis assessed by radiology or histology. There was evidence of a dose-response relationship with liver inflammation, ballooning, and resolution of NAFLD or NASH, but limited evidence of a dose-response relationship with fibrosis or NAFLD activity score. On average, the risk of bias for selection and outcome was medium and low, respectively. Conclusion Clinically significant improvements in NAFLD are achieved even with modest weight loss, but greater weight loss is associated with greater improvements. Embedding support for formal weight loss programs as part of the care pathway for the treatment of NAFLD could reduce the burden of disease. PROSPERO: CRD42018093676.</p