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Adjunctive rosuvastatin for rifampicin-susceptible pulmonary tuberculosis (rs-PTB) shows no effect on microbiological or radiological outcomes in a phase IIb randomised, controlled trial (NCT04504851). We explore the impact of adjunctive rosuvastatin on 18F-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT) imaging in a sub-study of 24 participants. Changes in standardised uptake value (SUVmax, SUVmean), Total Metabolic Volume, (TMV), Total Lesion Glycolysis (TLG), cavity diameter and volume, between week 0 and week 8 post-randomisation, are evaluated. Here we show no evidence of difference in the reduction in TLG [median 65.8% for the rosuvastatin group (Q1, Q3 38.6, 94.5) vs 64.3% for standard tuberculosis treatment group (Q1, Q3 -20.0, 81.7), P = 0.32], reduction in cavity volume on CT [median 3.2 cm 3 (IQR 11.1, 0.5) for rosuvastatin, 2.2 cm 3 (IQR 4.6, 0.7) for control (p = 0.72)], or any other PET-CT parameter measured. We show that the first 8-weeks of standard tuberculosis treatment results in a reduction in the volumetric indices (TLG and TMV), but had little change in SUVmax or SUVmean. Change in TLG and TMV holds promise as biomarkers of tuberculosis treatment response: future PET-CT studies should evaluate their role in predicting relapse-free cure, and the overall role of 18F-FDG-PET-CT as a tool for early-phase tuberculosis clinical trials., Competing Interests: Competing interests: The authors declare the following competing interests: Dr. Jim O’Doherty is employed by Siemens Medical Solutions. However, Siemens Medical Solutions had no role in the conception, design, execution, data analysis, manuscript preparation, or the decision to submit this study for publication. The views expressed in this study are solely those of the authors and do not necessarily reflect those of Siemens Medical Solutions. All other authors declare no financial or non-financial competing interests., (© 2024. The Author(s).)

Background: Interleukin 4 (IL-4), increased in tuberculosis infection, may impair bacterial killing. Blocking IL-4 confers benefit in animal models. We evaluated safety and efficacy of pascolizumab (humanized anti-IL-4 monoclonal antibody) as adjunctive tuberculosis treatment., Methods: Participants with rifampicin-susceptible pulmonary tuberculosis received a single intravenous infusion of pascolizumab or placebo, and standard 6-month tuberculosis treatment. Pascolizumab dose increased in successive cohorts: (1) nonrandomized 0.05 mg/kg (n = 4); (2) nonrandomized 0.5 mg/kg (n = 4); (3) randomized 2.5 mg/kg (n = 9) or placebo (n = 3); and (4) randomized 10 mg/kg (n = 9) or placebo (n = 3). Coprimary safety outcome was study-drug-related grade 4 or serious adverse event (G4/SAE) in all cohorts (1-4). Coprimary efficacy outcome was week 8 sputum culture time-to-positivity (TTP) in randomized cohorts (3-4) combined., Results: Pascolizumab levels exceeded IL-4 50% neutralizing dose for 8 weeks in 78%-100% of participants in cohorts 3-4. There were no study-drug-related G4/SAEs. Median week-8 TTP was 42 days in pascolizumab and placebo groups (P = .185). Rate of TTP increase was greater with pascolizumab (difference from placebo 0.011 log10 TTP/day; 95% Bayesian credible interval 0.006 to 0.015 log10 TTP/day)., Conclusions: There was no evidence to suggest blocking IL-4 was unsafe. Preliminary efficacy findings are consistent with animal models. This supports further investigation of adjunctive anti-IL-4 interventions for tuberculosis in larger phase 2 trials., Clinical Trials Registration: NCT01638520., Competing Interests: Potential conflicts of interest. J. A. G. was an employee of GSK at the time of the study. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Positron emission tomography-computed tomography (PET-CT) has the potential to revolutionize research in infectious diseases, as it has done with cancer. There is growing interest in it as a biomarker in the setting of early-phase tuberculosis clinical trials, particularly given the limitations of current biomarkers as adequate predictors of sterilizing cure for tuberculosis. PET-CT is a real-time tool that provides a 3-dimensional view of the spatial distribution of tuberculosis within the lung parenchyma and the nature of lesions with uptake (ie, whether nodular, consolidative, or cavitary). Its ability to provide functional data on changes in metabolism, drug penetration, and immune control of tuberculous lesions has the potential to facilitate drug development and regimen selection for advancement to phase 3 trials in tuberculosis. In this narrative review, we discuss the role that PET-CT may have in evaluating responses to drug therapy in active tuberculosis treatment and the challenges in taking PET-CT forward as predictive biomarker of relapse-free cure in the setting of phase 2 clinical trials., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

BACKGROUND: The value, speed of completion and robustness of the evidence generated by TB treatment trials could be improved by implementing standards for best practice. METHODS: A global panel of experts participated in a Delphi process, using a 7-point Likert scale to score and revise draft standards until consensus was reached. RESULTS: Eleven standards were defined: Standard 1, high quality data on TB regimens are essential to inform clinical and programmatic management; Standard 2, the research questions addressed by TB trials should be relevant to affected communities, who should be included in all trial stages; Standard 3, trials should make every effort to be as inclusive as possible; Standard 4, the most efficient trial designs should be considered to improve the evidence base as quickly and cost effectively as possible, without compromising quality; Standard 5, trial governance should be in line with accepted good clinical practice; Standard 6, trials should investigate and report strategies that promote optimal engagement in care; Standard 7, where possible, TB trials should include pharmacokinetic and pharmacodynamic components; Standard 8, outcomes should include frequency of disease recurrence and post-treatment sequelae; Standard 9, TB trials should aim to harmonise key outcomes and data structures across studies; Standard 10, TB trials should include biobanking; Standard 11, treatment trials should invest in capacity strengthening of local trial and TB programme staff. CONCLUSION: These standards should improve the efficiency and effectiveness of evidence generation, as well as the translation of research into policy and practice.

Background: Shorter treatments are needed for drug-susceptible tuberculosis. Adjunctive statins increase bactericidal activity in preclinical tuberculosis models. We investigated the safety and efficacy of adjunctive rosuvastatin in people with tuberculosis. We tested the hypothesis that adjunctive rosuvastatin accelerates sputum culture conversion within the first 8 weeks of treatment of rifampicin-susceptible tuberculosis., Methods: This phase 2b, randomised, open-label, multicentre trial conducted in five hospitals or clinics in three countries with high tuberculosis burden (ie, the Philippines, Viet Nam, and Uganda) enrolled adult participants aged 18-75 years with sputum smear or Xpert MTB/RIF positive, rifampicin-susceptible tuberculosis who had received less than 7 days of previous tuberculosis treatment. Participants were randomly assigned via a web-based system to receive either 10 mg rosuvastatin once per day for 8 weeks plus standard tuberculosis therapy (rifampicin, isoniazid, pyrazinamide, and ethambutol; rosuvastatin group) or standard tuberculosis therapy alone (control group). Randomisation was stratified by trial site, history of diabetes, and HIV co-infection. Laboratory staff and central investigators involved in data cleaning and analysis were masked to treatment allocation, but study participants and site investigators were not. Both groups continued standard treatment to week 24. Sputum samples were collected once per week for the first 8 weeks after randomisation, and then at weeks 10, 12, and 24. The primary efficacy outcome was time to culture conversion (TTCC; days) in liquid culture by week 8, assessed in randomised participants who had microbiological confirmation of tuberculosis, took at least one dose of rosuvastatin, and who did not show resistance to rifampicin (modified intention-to-treat population), for which groups were compared with the Cox proportional hazards model. The main safety outcome was grade 3-5 adverse events by week 24, assessed in the intention-to-treat population, for which groups were compared with Fisher's exact test. All participants completed 24 weeks of follow-up. This trial is registered with ClinicalTrials.gov (NCT04504851)., Findings: Between Sept 2, 2020, and Jan 14, 2021, 174 participants were screened and 137 were randomly assigned to the rosuvastatin group (70 participants) or control group (67 participants). In the modified intention-to-treat population of 135 participants, 102 (76%) were men and 33 (24%) were women. Median TTCC in liquid media was 42 days (95% CI 35-49) in the rosuvastatin group (68 participants) and 42 days (36-53) in the control group (67 participants; hazard ratio 1·30 [0·88-1·91], p=0·19). Grade 3-5 adverse events occurred in six (9%) of 70 in the rosuvastatin group (none were considered related to rosuvastatin) and four (6%) of 67 in the control group (p=0·75). There were no serious adverse events that were considered to be related to rosuvastatin., Interpretation: Adjunctive rosuvastatin at 10 mg once per day was safe but did not produce substantive benefits on culture conversion in the overall study population. Future trials could explore the safety and efficacy of higher doses of adjunctive rosuvastatin., Funding: National Medical Research Council, Singapore., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objectives: In the early months of the COVID-19 pandemic in Singapore, the vast majority of infected persons were migrant workers living in dormitories who had few medical comorbidities. In 2021, with the Delta and Omicron waves, this shifted to the more vulnerable, elderly population within the local community. We examined evolving trends among the hospitalised cases of COVID-19., Methods: All patients with polymerase chain reaction-positive SARS-CoV-2 admitted from February 2020 to October 2021 were included and subsequently stratified by their year of admission (2020 or 2021). We compared the baseline clinical characteristics, clinical course, and outcomes., Results: A majority of cases were seen in 2020 (n = 1359), compared with 2021 (n = 422), due to the large outbreaks in migrant worker dormitories. Nevertheless, the greater proportion of locally transmitted cases outside of dormitories in 2021 (78.7% vs 12.3%) meant a significantly older population with more medical comorbidities had COVID-19. This led to an observably higher proportion of patients with severe disease presenting with raised inflammatory markers, need for therapeutics, supplemental oxygenation, and higher mortality., Conclusion: Changing demographics and the characteristics of the exposed populations are associated with distinct differences in clinical presentation and outcomes. Older age remained consistently associated with adverse outcomes., Competing Interests: Declarations of competing interest The authors have no competing interests to declare., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Patients with preexisting kidney disease or acute kidney injury had poorer outcomes in coronavirus disease 2019 (COVID-19) illness. Lymphopenia was associated with more severe illness. Risk stratification with simple laboratory tests may help appropriate site patients in a cost-effective manner and ease the burden on healthcare systems. We examined a ratio of serum creatinine level to absolute lymphocyte count at presentation (creatinine-lymphocyte ratio, CLR) in predicting outcomes in hospitalized patients with COVID-19. We analyzed 553 consecutive polymerase chain reaction-positive SARS-COV-2 hospitalized patients. Patients with end-stage kidney disease were excluded. Serum creatinine and full blood count (FBC) examination were obtained within the first day of admission. We examined the utility of CLR in predicting adverse clinical outcomes (requiring intensive care, mechanical ventilation, acute kidney injury requiring renal replacement therapy or death). An optimized cutoff of CLR > 77 was derived for predicting adverse outcomes (72.2% sensitivity, and 83.9% specificity). Ninety-seven patients (17.5%) fell within this cut off. These patients were older and more likely to have chronic medical conditions. A higher proportion of these patients had adverse outcomes (13.4% vs 1.1%, P < .001). On receiver operating curve analyses, CLR predicted patients who had adverse outcomes well (area under curve [AUC] = 0.82, 95%CI 0.72-0.92), which was comparable to other laboratory tests like serum ferritin, C-reactive protein and lactate dehydrogenase. Elevated CLR on admission, which may be determined by relatively simple laboratory tests, was able to reasonably discriminate patients who had experienced adverse outcomes during their hospital stay. This may be a simple and cost-effective means of risk stratification and triage., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Coronavirus Disease 2019 (COVID-19) serology has an evolving role in the diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, its use in hospitalized patients with acute respiratory symptoms remains unclear. Hospitalized patients with acute respiratory illness admitted to an isolation ward were recruited. All patients had negative nasopharyngeal swab polymerase chain reaction (PCR) for SARS-CoV-2. Serological studies using four separate assays (cPass: surrogate neutralizing enzyme-linked immunosorbent assay [ELISA]; Elecsys: N-antigen based chemiluminescent assay; SFB: S protein flow-based; epitope peptide-based ELISA) were performed on stored plasma collected from patients during the initial hospital stay, and a convalescent visit 4-12 weeks later. Of the 51 patients studied (aged 54, interquartile range 21-84; 62.7% male), no patients tested positive on the Elecsys or cPass assays. Out of 51 patients, 5 had antibodies detected on B-cell Epitope Assay and 3/51 had antibodies detected on SFB assay. These 8 patients with positive serological test to COVID-19 were more likely to have a high-risk occupation (p = 0.039), bacterial infection (p = 0.028), and neutrophilia (p = 0.013) during their initial hospital admission. Discrepant COVID-19 serological findings were observed among those with recent hospital admissions and bacterial infections. The positive serological findings within our cohort raise important questions about the interpretation of sero-epidemiology during the current pandemic., (© 2022 Wiley Periodicals LLC.)

Background/introduction: There are little data on outcomes of COVID-19 patients with the presence of fever compared to the presence of symptoms., Aim: We examined the associations between symptomology, presence of fever and outcomes of a COVID-19 cohort., Design and Methods: Between 23 January and 30 April 2020, 554 COVID-19 patients were admitted to a tertiary hospital in Singapore. They were allocated into four groups based on symptomology and fever-Group 1: asymptomatic and afebrile, Group 2: symptomatic but afebrile, Group 3: febrile but asymptomatic and Group 4: symptomatic and febrile. The primary outcomes were intensive care unit (ICU) admissions and mortality. The composite end-point included ICU admissions, mortality or any COVID-19 related end-organ involvement., Results: There were differences in ferritin (P=0.003), C-reactive protein (CRP) levels (P<0.001) and lymphopenia (P=0.033) across all groups, with the most favourable biochemical profile in Group 1, and the least in Group 4. Symptomatic groups (Groups 2 and 4) had higher ICU admissions (1.9% and 6.0%, respectively, P=0.003) than asymptomatic groups (Groups 1 and 3). Composite end-point was highest in Group 4 (24.0%), followed by Group 3 (8.6%), Group 2 (4.8%) and Group 1 (2.4%) (P<0.001). The presence of fever (OR 4.096, 95% CI 1.737-9.656, P=0.001) was associated with the composite end-point after adjusting for age, pulse rate, comorbidities, lymphocyte, ferritin and CRP. Presence of symptoms was not associated with the composite end-point., Discussion/conclusion: In this COVID-19 cohort, presence of fever was a predictor of adverse outcomes. This has implications on the management of febrile but asymptomatic COVID-19 patients., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Haematological markers such as absolute lymphopenia have been associated with severe COVID-19 infection. However, in the literature to date, the cohorts described have typically included patients who were moderate to severely unwell with pneumonia and who required intensive care stay. It is uncertain if these markers apply to a population with less severe illness. We sought to describe the haematological profile of patients with mild disease with COVID-19 admitted to a single centre in Singapore., Methods: We examined 554 consecutive PCR positive SARS-COV-2 patients admitted to a single tertiary healthcare institution from Feb 2020 to April 2020. In all patients a full blood count was obtained within 24 h of presentation., Results: Patients with pneumonia had higher neutrophil percentages (66.5 ± 11.6 vs 55.2 ± 12.6%, p  < 0.001), lower absolute lymphocyte count (1.5 ± 1.1 vs 1.9 ± 2.1 x109/L, p  < 0.011) and absolute eosinophil count (0.2 ± 0.9 vs 0.7 ± 1.8 × 109/L, p  = 0.002). Platelet counts (210 ± 56 vs 230 ± 61, p  = 0.020) were slightly lower in the group with pneumonia. We did not demonstrate significant differences in the neutrophil-lymphocyte ratio, monocyte-lymphocyte ratio and platelet-lymphocyte ratio in patients with or without pneumonia. Sixty-eight patients (12.3%) had peripheral eosinophilia. This was more common in migrant workers living in dormitories., Conclusion: Neutrophilia and lymphopenia were found to be markers associated with severe COVID-19 illness. We did not find that combined haematological parameters: neutrophil-lymphocyte ratio, monocyte-lymphocyte ratio and platelet-lymphocyte ratio, had any association with disease severity in our cohort of patients with mild-moderate disease. Migrant workers living in dormitories had eosinophilia which may reflect concurrent chronic parasitic infection.

Background: Several specific risk scores for Coronavirus disease 2019 (COVID-19) involving clinical and biochemical parameters have been developed from higher-risk patients, in addition to validating well-established pneumonia risk scores. We compared multiple risk scores in predicting more severe disease in a cohort of young patients with few comorbid illnesses. Accurately predicting the progression of COVID-19 may guide triage and therapy., Methods: We retrospectively examined 554 hospitalised COVID-19 patients in Singapore. The CURB-65 score, Pneumonia Severity Index (PSI), ISARIC 4C prognostic score (4C), CHA 2 DS 2 -VASc score, COVID-GRAM Critical Illness risk score (COVID-GRAM), Veterans Health Administration COVID-19 index for COVID-19 Mortality (VACO), and the "rule-of-6" score were compared for three performance characteristics: the need for supplemental oxygen, intensive care admission and mechanical ventilation., Results: A majority of patients were young (≤ 40 years, n = 372, 67.1%). 57 (10.3%) developed pneumonia, with 16 (2.9% of study population) requiring supplemental oxygen. 19 patients (3.4%) required intensive care and 2 patients (0.5%) died. The clinical risk scores predicted patients who required supplemental oxygenation and intensive care well. Adding the presence of fever to the CHA 2 DS 2 -VASc score and 4C score improved the ability to predict patients who required supplemental oxygen (c-statistic 0.81, 95% CI 0.68-0.94; and 0.84, 95% CI 0.75-0.94 respectively)., Conclusion: Simple scores including well established pneumonia risk scores can help predict progression of COVID-19. Adding the presence of fever as a parameter to the CHA 2 DS 2 -VASc or the 4C score improved the performance of these scores in a young population with few comorbidities., (© 2021. The Author(s).)

Abstract: Liver dysfunction in patients with COVID-19 (coronavirus disease 2019) has been described. However, it is not clear if the presence of abnormal liver function tests at presentation was related to underlying undiagnosed liver disease, or a result of the viral infection.We retrospectively examined the first 554 consecutive polymerase chain reaction positive SARS-CoV-2 patients admitted from February 2020 to April 2020 to our academic medical centre. We reviewed their clinical data, chest radiography and laboratory studies obtained within 24 hour of admission.Despite similar hemodynamic parameters, we found significant aspartate transaminase elevation (64 ± 141 vs 35 ± 23 U/L, P < .001) in those with pneumonia compared to those without. Elevated liver enzymes were seen in 102 patients (18.4%). They presented with higher temperatures (38.5 ± 0.9 vs 37.5 ± 0.8 degC, P = .011), higher total white cell counts (6.95 ± 2.29 vs 6.39 ± 2.19 x109/L, P = .021), serum ferritin (240 ± 274 vs 165 ± 198 ng/ml, P = .002) and lactate dehydrogenase (632 ± 912 vs 389 ± 107 U/L, P < .001). These patients were more likely to require intensive care (6.9% vs 2.7% P = .036) and mechanical ventilation (5.9% vs 2.2%, P = .046). Migrant workers from dormitories had a higher rate of baseline liver function test abnormalities (88/425 vs 14/129, P = .01), which were more likely to persist at the time of discharge.Despite relatively mild COVID-19 disease, there was a significant prevalence of liver dysfunction, particularly amongst migrant workers. Elevated liver enzymes were associated with more severe disease, despite similar haemodynamic characteristics. Future studies should explore whether pre-existing liver disease may predispose to more severe COVID-19 disease., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: COVID-19 is a respiratory viral infection with unique features including a more chronic course and systemic disease manifestations including multiple organ involvement; and there are differences in disease severity between ethnic groups. The immunological basis for disease has not been fully characterised. Analysis of whole-blood RNA expression may provide valuable information on disease pathogenesis., Methods: We studied 45 patients with confirmed COVID-19 infection within 10 days from onset of illness and a control group of 19 asymptomatic healthy volunteers with no known exposure to COVID-19 in the previous 14 days. Relevant demographic and clinical information was collected and a blood sample was drawn from all participants for whole-blood RNA sequencing. We evaluated differentially-expressed genes in COVID-19 patients (log2 fold change ≥ 1 versus healthy controls; false-discovery rate < 0.05) and associated protein pathways and compared these to published whole-blood signatures for respiratory syncytial virus (RSV) and influenza. We developed a disease score reflecting the overall magnitude of expression of internally-validated genes and assessed the relationship between the disease score and clinical disease parameters., Results: We found 135 differentially-expressed genes in the patients with COVID-19 (median age 35 years; 82% male; 36% Chinese, 53% South Asian ethnicity). Of the 117 induced genes, 14 were found in datasets from RSV and 40 from influenza; 95 genes were unique to COVID-19. Protein pathways were mostly generic responses to viral infections, including apoptosis by P53-associated pathway, but also included some unique pathways such as viral carcinogenesis. There were no major qualitative differences in pathways between ethnic groups. The composite gene-expression score was correlated with the time from onset of symptoms and nasal swab qPCR CT values (both p < 0.01) but was not related to participant age, gender, ethnicity or the presence or absence of chest X-ray abnormalities (all p > 0.05)., Conclusions: The whole-blood transcriptome of COVID-19 has overall similarity with other respiratory infections but there are some unique pathways that merit further exploration to determine clinical relevance. The approach to a disease score may be of value, but needs further validation in a population with a greater range of disease severity.

Introduction: The gold standard for COVID-19 diagnosis is currently a real-time reverse transcriptase polymerase chain reaction (RT-PCR) to detect SARS-CoV-2. This is most commonly performed on respiratory secretions obtained via a nasopharyngeal swab. Due to supply chain limitations and high demand worldwide because of the COVID-19 pandemic, access to commercial nasopharyngeal swabs has not been assured. 3D printing methods have been used to meet the shortfall. For longer-term considerations, 3D printing may not compare well with injection molding as a production method due to the challenging scalability and greater production costs of 3D printing., Methods: To secure sufficient nasopharyngeal swab availability for our national healthcare system, we designed a novel injection molded nasopharyngeal swab (the IM2 swab). We performed a clinical diagnostic study comparing the IM2 swab to the Copan FLOQSwab. Forty patients with a known diagnosis of COVID-19 and 10 healthy controls were recruited. Paired nasopharyngeal swabs were obtained from the same nostril of each participant and tested for SARS-CoV-2 by RT-PCR., Results: When compared to the Copan FLOQswab, results from the IM2 swab displayed excellent overall agreement and positive percent agreement of 96.0% and 94.9%, respectively. There was no significant difference in mean RT-PCR cycle threshold values for the ORF1ab (28.05 vs. 28.03, p = 0.97) and E-gene (29.72 vs. 29.37, p = 0.64) targets, respectively. We did not observe any significant adverse events and there was no significant difference in patient-reported pain., Conclusion: In summary, the IM2 nasopharyngeal swab is a clinically safe, highly accurate option to commercial nasopharyngeal swabs.

Importance: Three-dimensionally printed nasopharyngeal swabs (3DP swabs) have been used to mitigate swab shortages during the coronavirus disease 2019 (COVID-19) pandemic. Clinical validation for diagnostic accuracy and consistency, as well as patient acceptability, is crucial to evaluate the swab's performance., Objective: To determine the accuracy and acceptability of the 3DP swab for identifying severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)., Design, Setting, and Participants: A diagnostic study was conducted from May to July 2020 at 2 tertiary care centers in Singapore with different reference swabs (FLOQSwab [COPAN Diagnostics] or Dacron swab [Deltalab]) and swab processing techniques (wet or dry) to evaluate the performance of the 3DP swab compared with traditional, standard-of-care nasopharyngeal swabs used in health care institutions. The participants were patients with COVID-19 in the first 2 weeks of illness and controls with acute respiratory illness with negative test results for SARS-CoV-2. Paired nasopharyngeal swabs were obtained from the same nostril and tested for SARS-CoV-2 by reverse-transcriptase polymerase chain reaction. The sequence of swabs was randomized based on odd and even participant numbers., Main Outcomes and Measures: Primary outcome measures were overall agreement (OA), positive percentage agreement (PPA), and negative percentage agreement of the 3DP swab compared with reference swabs. Secondary outcome measures were the correlation of cycle threshold (Ct) values of both swabs., Results: The mean (SD) age of participants was 45.4 (13.1) years, and most participants were men (87 of 89 [97.8%]), in keeping with the epidemiology of the COVID-19 pandemic in Singapore. A total of 79 patients with COVID-19 and 10 controls were recruited. Among the patients with COVID-19, the overall agreement and PPA of the 3DP swab was 91.1% and 93.5%, respectively, compared with reference swabs. The PPA was 100% for patients with COVID-19 who were tested within the first week of illness. All controls tested negative. The reverse-transcriptase polymerase chain reaction Ct values for the ORF1ab and E-gene targets showed a strong correlation (intraclass correlations coefficient, 0.869-0.920) between the 3DP and reference swab on independent testing at each institution despite differences in sample processing. Discordant results for both gene targets were observed only at high Ct values., Conclusions and Relevance: In this diagnostic study of 79 patients with COVID-19 and 10 controls, the 3DP swab performed accurately and consistently across health care institutions and could help mitigate strained resources in the escalating COVID-19 pandemic.

Objectives: The vast majority of COVID-19 cases in Singapore have occurred amongst migrant workers. This paper examined trends in the hospitalised cases and tested the assumption that the low severity of disease was related to the relatively young affected population., Methods: All patients with PCR-positive SARS-CoV-2 admitted from February to April 2020 were divided into: (i) imported cases, (ii) locally-transmitted cases outside migrant worker dormitories and (iii) migrant worker dormitory cases. They were examined for underlying comorbidities, clinical progress and outcomes., Results: Imported cases (n = 29) peaked in mid-March 2020, followed by local cases (n = 100) in mid-April 2020; migrant worker cases (n = 425) continued to increase in late April 2020. Migrant worker cases were younger, had few medical comorbidities and less severe disease. As the migrant worker cases increased, the proportion of patients with pneumonia decreased, whilst patients presenting earlier in their illness and asymptomatic disease became more common., Conclusion: Singapore experienced a substantial shift in the population at risk of severe COVID-19. Successful control in the community protected an aging population. Large migrant worker dormitory outbreaks occurred, but the disease incurred was less severe, resulting in Singapore having one of the lowest case fatality rates in the world., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The Coronavirus disease 2019 (COVID-19) pandemic is rapidly evolving and affecting healthcare systems across the world. Singapore has escalated its alert level to Disease Outbreak Response System Condition (DORSCON) Orange, signifying severe disease with community spread. We aimed to study the overall volume of AIS cases and the delivery of hyperacute stroke services during DORSCON Orange. This was a single-centre, observational cohort study performed at a comprehensive stroke centre responsible for AIS cases in the western region of Singapore, as well as providing care for COVID-19 patients. All AIS patients reviewed as an acute stroke activation in the Emergency Department (ED) from November 2019 to April 2020 were included. System processes timings, treatment and clinical outcome variables were collected. We studied 350 AIS activation patients admitted through the ED, 206 (58.9%) pre- and 144 during DORSCON Orange. Across the study period, number of stroke activations showed significant decline (p = 0.004, 95% CI 6.513 to - 2.287), as the number of COVID-19 cases increased exponentially, whilst proportion of activations receiving acute recanalization therapy remained stable (p = 0.519, 95% CI - 1.605 to 2.702). Amongst AIS patients that received acute recanalization therapy, early neurological outcomes in terms of change in median NIHSS at 24 h (-4 versus -4, p = 0.685) were largely similar between the pre- and during DORSCON orange periods. The number of stroke activations decreased while the proportion receiving acute recanalization therapy remained stable in the current COVID-19 pandemic in Singapore.

Background: Preprint manuscripts, rapid publications and opinion pieces have been essential in permitting the lay press and public health authorities to preview data relating to coronavirus disease 2019 (COVID-19), including the range of clinical manifestations and the basic epidemiology early on in the pandemic. However, the rapid dissemination of information has highlighted some issues with communication of scientific results and opinions in this time of heightened sensitivity and global concern., Main Text: Rapid publication of COVID-19 literature through expedited review, preprint publications and opinion pieces are important resources for the medical scientific community. Yet the risks of unverified information loom large in times when the healthcare community is desperate for information. Information that has not been properly vetted, or opinion pieces without solid evidence, may be used to influence public health policy decisions. We discuss three examples of unverified information and the consequences in this time of high anxiety surrounding COVID-19., Conclusions: In an era when information can be widely and swiftly disseminated, it is important to ensure that the scientific community is not an inadvertent source of misinformation. This will require a multimodal approach, with buy-in from editors, publishers, preprint servers, authors and journalists. The landscape of medical publications has changed, and a collaborative approach is required to maintain a high standard of scientific communications.

Background: Waning measles immunity among vaccinated individuals may result in an attenuated illness. This study compares the epidemiological, clinical, and laboratory profile of measles cases with waning immunity with other measles cases., Methods: Polymerase chain reaction-positive (+) measles cases notified to Victoria's Department of Health and Human Services from 2008 to 2017 with immunoglobulin (Ig) M and IgG tested at diagnosis were classified according to serology at diagnosis: IgG negative (-) (nonimmune), IgM+/IgG+ (indeterminate), or IgM-/IgG+ (waning immunity)., Results: Between 2008 and 2017, 297 measles cases were notified, of whom 190 (64%) were included; 151 of 190 (79%) were nonimmune at diagnosis, 26 (14%) were indeterminate, and 13 (7%) had waning immunity. Between 2008-2013 and 2014-2017, the proportion of cases with waning immunity increased from 0 of 87 (0%) to 13 of 103 (13%) (P < .001) and the diagnostic sensitivity of initial IgM fell from 93% to 81% (P = .012), respectively. Seven (54%) waning immunity cases reported receiving measles-containing vaccines; 1 case had 2 documented doses. Compared with nonimmune and indeterminate cases, waning immunity cases were more likely to be male; less likely to report fever, coryza, and cough; and had lower burden of virus (higher cycle threshold values). Waning immunity cases had higher IgG titers than indeterminate cases (mean optical density values, 1.96 vs 0.71; P = .004). Onward transmission from 1 waning immunity case was documented., Conclusions: Waning immunity among measles cases, associated with secondary vaccine failure and modified clinical illness, is emerging in Victoria with transmission potential., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

We investigated the contribution of host immune cells to bacterial killing in a whole-blood bactericidal activity (WBA) assay, an ex vivo model used to test efficacy of drugs against mycobacterium tuberculosis (Mtb). We performed WBA assays with immuno-magnetic depletion of specific cell types, in the presence or absence of rifampicin. Innate immune cells decreased Mtb growth in absence of drug, but appeared to diminish the cidal activity of rifampicin, possibly attributable to intracellular bacterial sequestration. Adaptive immune cells had no effect with or without drug. The WBA assay may have potential for testing adjunctive host-directed therapies acting on phagocytic cells., Competing Interests: The authors have declared that no competing interests exist.

An 85-year-old man with a history of aortic valve replacement presented with lower limb cramps. He was initially diagnosed with degenerative disc disease, but was found to have Lactococcus garvieae infective endocarditis with septic embolic strokes causing a central poststroke pain syndrome. Cardiothoracic surgery was deemed too high risk and the patient completed 6 weeks of intravenous antimicrobials as well as prolonged inpatient rehabilitation. Lactococcus garvieae is an aquaculture pathogen which typically affects elderly and immunocompromised patients. Atypical presentations of endocarditis in the elderly can lead to delays in diagnosis.

A 10-year review of disseminated Mycobacterium avium complex (MAC) infection and MAC-immune reconstitution inflammatory syndrome in HIV-positive patients (2004-2014) at a state-wide tertiary referral HIV service demonstrates that despite advances in antiretroviral therapy, MAC infection remains a therapeutic challenge, particularly intra-abdominal disease.

Background: Shoulder injury related to vaccine administration (SIRVA) is a previously described phenomenon that is the result of improper vaccine delivery. Appropriate injection technique for administration of intramuscular vaccinations can reduce the risk of shoulder injury., Objective: In this article, we describe the cases of two patients who developed SIRVA. A literature review was conducted to find and describe other cases of shoulder injury that developed post-vaccination., Discussion: SIRVA has previously been described in the world literature. Seventeen cases in women and five cases in men were found. Pain and reduction in the range of movement within a few hours of vaccination were cardinal signs of a shoulder injury. This included injuries to the soft tissues of the shoulder as well as injuries to bone and joint. SIRVA can be avoided with correct vaccination technique as described.

We report a case of disseminated Mycobacterium haemophilum osteomyelitis in a patient with advanced HIV infection, who later developed recurrent immune reconstitution inflammatory syndrome after commencement of antiretroviral therapy. We review previous reports of M. haemophilum bone and joint infection associated with HIV infection and describe the management of M. haemophilum-associated immune reconstitution inflammatory syndrome, including the role of surgery as an adjunctive treatment modality and the potential drug interactions between antiretroviral and antimycobacterial agents., (© The Author(s) 2015.)

Background: The incidence and characteristics of tuberculosis (TB) in remote areas of Papua New Guinea (PNG) are largely unknown. The purpose of our study was to determine the incidence of TB in the Gulf Province of PNG and describe disease characteristics, co-morbidities and drug resistance profiles that could impact on disease outcomes and transmission., Methods: Between March 2012 and June 2012, we prospectively collected data on 274 patients presenting to Kikori Hospital with a presumptive diagnosis of TB, and on hospital inpatients receiving TB treatment during the study period. Sputum was collected for microscopy, GeneXpert analysis, culture and genotyping of isolates., Results: We estimate the incidence of TB in Kikori to be 1290 per 100,000 people (95% CI 1140 to 1460) in 2012. The proportion of TB patients co-infected with HIV was 1.9%. Three of 32 TB cases tested were rifampicin resistant. Typing of nine isolates demonstrated allelic diversity and most were related to Beijing strains., Conclusions: The incidence of TB in Kikori is one of the highest in the world and it is not driven by HIV co-infection. The high incidence and the presence of rifampicin resistant warrant urgent attention to mitigate substantial morbidity in the region.

Objective: To examine the performance in tropical northern Australia of SMART-COP, a simple scoring system developed in temperate Australia to predict the need for intensive respiratory or vasopressor support (IRVS) in pneumonia patients., Design, Setting and Patients: A prospective observational study of patients admitted to Royal Darwin Hospital in the Northern Territory with sepsis between August 2007 and May 2008. Chest x-rays were reviewed to confirm pneumonia, and each patient's SMART-COP score was assessed against the need for IRVS., Results: Of 206 patients presenting with radiologically confirmed pneumonia, 184 were eligible for inclusion. The mean age of patients was 50.1 years, 65% were Indigenous and 56% were men. Overall, 38 patients (21%) required IRVS, and 18 patients (10%) died by Day 30. A SMART-COP score of >or= 3 had a sensitivity of only 71% for predicting the need for IRVS and 67% for 30-day mortality. As the variables most strongly associated with IRVS were serum albumin level < 35 g/L (odds ratio, 6.8) and Indigenous status (odds ratio, 2.3), we tested a modified scoring system (SMART-COP) that used a higher weighting for albumin and included Indigenous status. A SMART-COP score of >or= 3 had a sensitivity of 97% for IRVS and 100% for 30-day mortality., Conclusions: The SMART-COP score underestimates the severity of pneumonia in tropical northern Australia, but can be improved by using locally relevant additions.