Adjunctive pascolizumab in rifampicin-susceptible pulmonary tuberculosis: proof-of-concept, partially-randomised, double-blind, placebo-controlled, dose-escalation trial.

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 (humanised 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] non-randomised 0.05 mg/kg (n = 4); [2] non-randomised 0.5 mg/kg (n = 4); [3] randomised 2.5 mg/kg (n = 9) or placebo (n = 3); [4] randomised 10 mg/kg (n = 9) or placebo (n = 3). Co-primary safety outcome was study-drug-related grade 4 or serious adverse event (G4/SAE); in all cohorts (1-4). Co-primary efficacy outcome was week-8 sputum culture time-to-positivity (TTP); in randomised cohorts (3-4) combined. RESULTS: Pascolizumab levels exceeded IL-4 50% neutralising 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 = 0.185). Rate of TTP increase was greater with pascolizumab (difference from placebo 0.011 [95% Bayesian credible interval 0.006 to 0.015] log10TTP/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.

Prospective study of policies and use of therapies for COVID-19 among Australian health services during 2020.

BACKGROUND: The COVID-19 pandemic has generated significant debate about how emerging infections can be treated in the absence of evidence-based therapies to combat disease. In particular, the use of off-label therapies outside of a clinical trial setting has been controversial. AIM: To longitudinally study policies and prescribing practices pertaining to therapies for COVID-19 in Australian health services during 2020. METHODS: Prospective data were collected from participating Australian health services who may care for patients with COVID-19 via an electronic portal. A single informant from each health service was emailed a survey link at regular intervals. Information was sought regarding changes to COVID-19 policy at their service and use of therapies for COVID-19. RESULTS: Overall, 78 hospitals were represented from 39 respondents with longitudinal data collection from May to December 2020. All Australian states/territories were represented with the majority (34/39; 87%) of respondents located in a major city. Just over half (20/39) of respondents had a written policy for COVID-19 therapy use at their health service at survey enrolment and policies changed frequently throughout the pandemic. Therapy use outside of a clinical trial was reported in 54% of health services, most frequently in Victoria, correlating with higher numbers of COVID-19 cases. At study commencement, hydroxychloroquine was most frequently used, with corticosteroids and remdesivir use increasingly throughout the study period. CONCLUSION: Our results reflect the reactive nature of prescribing of therapies for COVID-19 and highlight the importance of evidence-based guidelines to assist prescribers.

Remdesivir in Coronavirus Disease 2019 (COVID-19) treatment: a review of evidence.

COVID-19 is an infectious disease caused by a novel ß-coronavirus, belonging to the same subgenus as the Severe Acute Respiratory Syndrome (SARS) virus. Remdesivir, an investigational broad-spectrum antiviral agent has previously demonstrated in vitro activity against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), and in vivo efficacy against other related coronaviruses in animal models. Its safety profile has been tested in a compassionate use setting for patients with COVID-19. The current therapeutic studies demonstrate clinical effectiveness of remdesivir in COVID-19 patients by shortening time to clinical recovery, and hospital stay. In this review, we critically analyze the current evidence of remdesivir against COVID-19 and dissect the aspects over its safety and efficacy. Based on existing data, remdesivir can be regarded as a potential therapeutic agent against COVID-19. Further large-scale, randomized placebo-controlled clinical trials are, however, awaited to validate these findings.

Oral vs Intravenous Antibiotics for Patients With Klebsiella pneumoniae Liver Abscess: A Randomized, Controlled Noninferiority Study.

BACKGROUND: Klebsiella pneumoniae liver abscess (KLA) is emerging worldwide due to hypermucoviscous strains with a propensity for metastatic infection. Treatment includes drainage and prolonged intravenous antibiotics. We aimed to determine whether oral antibiotics were noninferior to continued intravenous antibiotics for KLA. METHODS: This noninferiority, parallel group, randomized, clinical trial recruited hospitalized adults with liver abscess and K. pneumoniae isolated from blood or abscess fluid who had received ≤7 days of effective antibiotics at 3 sites in Singapore. Patients were randomized 1:1 to oral (ciprofloxacin) or intravenous (ceftriaxone) antibiotics for 28 days. If day 28 clinical response criteria were not met, further oral antibiotics were prescribed until clinical response was met. The primary endpoint was clinical cure assessed at week 12 and included a composite of absence of fever in the preceding week, C-reactive protein <20 mg/L, and reduction in abscess size. A noninferiority margin of 12% was used. RESULTS: Between November 2013 and October 2017, 152 patients (mean age, 58.7 years; 25.7% women) were recruited, following a median 5 days of effective intravenous antibiotics. A total of 106 (69.7%) underwent abscess drainage; 71/74 (95.9%) randomized to oral antibiotics met the primary endpoint compared with 72/78 (92.3%) randomized to intravenous antibiotics (risk difference, 3.6%; 2-sided 95% confidence interval, -4.9% to 12.8%). Effects were consistent in the per-protocol population. Nonfatal serious adverse events occurred in 12/72 (16.7%) in the oral group and 13/77 (16.9%) in the intravenous group. CONCLUSIONS: Oral antibiotics were noninferior to intravenous antibiotics for the early treatment of KLA. CLINICAL TRIALS REGISTRATION: NCT01723150.

A blood RNA transcript signature for TB exposure in household contacts.

BACKGROUND: Current tools for diagnosing latent TB infection (LTBI) detect immunological memory of past exposure but are unable to determine whether exposure is recent. We sought to identify a whole-blood transcriptome signature of recent TB exposure. METHODS: We studied household contacts of TB patients; healthy volunteers without recent history of TB exposure; and patients with active TB. We performed whole-blood RNA sequencing (in all), an interferon gamma release assay (IGRA; in contacts and healthy controls) and PET/MRI lung scans (in contacts only). We evaluated differentially-expressed genes in household contacts (log2 fold change ≥1 versus healthy controls; false-discovery rate < 0.05); compared these to differentially-expressed genes seen in the active TB group; and assessed the association of a composite gene expression score to independent exposure/treatment/immunological variables. RESULTS: There were 186 differentially-expressed genes in household contacts (n = 26, age 22-66, 46% male) compared with healthy controls (n = 5, age 29-38, 100% male). Of these genes, 141 (76%) were also differentially expressed in active TB (n = 14, age 27-69, 71% male). The exposure signature included genes from inflammatory response, type I interferon signalling and neutrophil-mediated immunity pathways; and genes such as BATF2 and SCARF1 known to be associated with incipient TB. The composite gene-expression score was higher in IGRA-positive contacts (P = 0.04) but not related to time from exposure, isoniazid prophylaxis, or abnormalities on PET/MRI (all P > 0.19). CONCLUSIONS: Transcriptomics can detect TB exposure and, with further development, may be an approach of value for epidemiological research and targeting public health interventions.

Perceptions and Acceptability of Digital Interventions Among Tuberculosis Patients in Cambodia: Qualitative Study of Video-Based Directly Observed Therapy.

BACKGROUND: Despite the development of effective drugs for treatment, tuberculosis remains one of the leading causes of death from an infectious disease worldwide. One of the greatest challenges to tuberculosis control is patient adherence to treatment. Recent research has shown that video-based directly observed therapy is a feasible and effective approach to supporting treatment adherence in high-income settings. However, few studies have explored the potential for such a solution in a low- or middle-income country setting. Globally, these countries' rapidly rising rate of mobile penetration suggests that the potential for translation of these results may be high. OBJECTIVE: We sought to examine patient perceptions related to the use of mobile health, and specifically video-based directly observed therapy, in a previously unstudied patient demographic: patients with tuberculosis in a low-income country setting (Cambodia). METHODS: We conducted a cross-sectional qualitative study in urban and periurban areas in Cambodia, consisting of 6 focus groups with tuberculosis patients who were receiving treatment (standard directly observed therapy) through a nongovernmental organization. RESULTS: Familiarity with mobile technology and apps was widespread in this population, and overall willingness to consider a mobile app for video-based directly observed therapy was high. However, we identified potential challenges. First, patients very much valued their frequent in-person interactions with their health care provider, which may be reduced with the video-based directly observed therapy intervention. Second, there may be technical issues to address, including how to make the app suitable for illiterate participants. CONCLUSIONS: While video-based directly observed therapy is a promising technology, even in country settings where mobile penetration is reportedly almost universal, it should be introduced with caution. However, the results were generally promising and yielded important insights that not only will be translated into the further adaptation of key features of video-based directly observed therapy for tuberculosis patients in Cambodia, but also can inform the future design and successful implementation of video-based directly observed therapy interventions in low- and middle-income settings more generally.

Sub-clinical abnormalities detected by PET/MRI in household tuberculosis contacts.

BACKGROUND: The understanding of early events following TB exposure is limited by traditional tests that rely on detection of an immune response to infection, which is delayed, or on imaging tests with low sensitivity for early disease. We investigated for evidence of lung abnormalities in heavily exposed TB contacts using PET/MRI. METHODS: 30 household contacts of 20 index patients underwent clinical assessment, IGRA testing, chest x-ray and PET/MRI scan using 18-F-FDG. MRI images were examined by a radiology/nuclear medicine dual-qualified physician using a standardised report form, while PET/MRI images were examined independently by another radiology/nuclear medicine dual-qualified physician using a similar form. Standardised uptake value (SUV) was quantified for each abnormal lesion. RESULTS: IGRA was positive in 40%. PET/MRI scan was abnormal in 30%, predominantly FDG uptake in hilar or mediastinal lymph nodes and lung apices. We did not identify any relationship between PET/MRI findings and degree of exposure or IGRA status. CONCLUSION: PET-based imaging may provide important insights into the natural history following exposure to TB that may not be available from traditional tests of TB immune response or imaging. The clinical significance of the abnormalities is uncertain and merits further investigation in longitudinal studies.

A Novel Approach to CT, MR, and PET Examination of Patients with Infections Requiring Stringent Airborne Precautions.

PURPOSE: To investigate the feasibility of using a modified portable isolation chamber, which conforms to Centers for Disease Control and Prevention (CDC) isolation requirements, in the imaging of infectious patients. MATERIALS AND METHODS: This study was approved by the ethics committee, and all participants gave written informed consent. In this prospective study, the isolation chamber was assessed for computed tomographic (CT), magnetic resonance (MR), and positron emission tomographic (PET) image uniformity and noise by using uniform phantoms. For each modality, equivalent phantom examinations were performed without the isolation chamber. Paired analyses of the differences from these baseline values were conducted by finding the mean difference in the matched sections for each image quality parameter. A potential increase in CT patient dose was assessed, and MR radiofrequency (RF) interference was monitored. Eight participants with active pulmonary tuberculosis (mean age, 48.1 years; age range, 26-88 years; five men, three women) were then examined within a hybrid PET/MR imager. The 95% confidence intervals for the difference in the two matched population means were determined by using the two-sided t distribution for each of the phantom study imaging modalities. RESULTS: Phantom images were evaluated for image uniformity and noise. Increased image noise can affect low contrast resolution, which has the potential to mimic or mask abnormalities when the differences between healthy and diseased tissues are small; clinically, CT image noise is maintained at a constant level with dose modulation. Increased attenuation of annihilation photons, when not corrected for, could lead to photopenic areas on the PET image; PET image nonuniformity complied with guidelines. Artifacts on the MR image due to RF noise spikes could mask abnormalities; paired analysis of variations in MR imaging mean signal-to-noise ratio and uniformity from baseline were within 5% for both gradient-echo and spin-echo sequences. In the eight participants who underwent imaging, the increased radiation dose for the attenuation of the isolation chamber would have resulted in a mean increase in patient size-specific dose estimate of 0.32 mGy ± 0.04 (standard deviation). The RF noise assessment revealed no prominent increase at any frequency band. The eight participants were examined within the isolation chamber without incident. CONCLUSION A modified portable isolation chamber, which conforms to CDC infection control guidelines, was found to be feasible within the confines of CT, MR imaging, and PET environments.

A severe case of swimmer's itch in Victoria, Australia with bullous eruption.

Abstract: We describe a severe case of swimmer's itch in Victoria with widespread bullous eruption, which is a rare manifestation of this condition and presented a diagnostic challenge. This is the first case reported in Victoria, having been previously reported in more northern parts of Australia; with climate change trends, swimmer's itch is likely to become increasingly common in southern parts of the region.

The global spread of healthcare-associated multidrug-resistant bacteria: a perspective from Asia.

Since antibiotics were first used, each new introduced class has been followed by a global wave of emergent resistance, largely originating in Europe and North America where they were first used. Methicillin-resistant Staphylococcus aureus spread from the United Kingdom and North America across Europe and then Asia over more than a decade. Vancomycin-resistant enterococci and Klebsiella pneumoniae carbapenemase-producing K. pneumoniae followed a similar path some 20 years later. Recently however, metallo-ß-lactamases have originated in Asia. New Delhi metallo-ß-lactamase-1 was found in almost every continent within a year of its emergence in India. Metallo-ß-lactamase enzymes are encoded on highly transmissible plasmids that spread rapidly between bacteria, rather than relying on clonal proliferation. Global air travel may have helped facilitate rapid dissemination. As the antibiotic pipeline offers little in the short term, our most important tools against the spread of antibiotic resistant organisms are intensified infection control, surveillance, and antimicrobial stewardship.

Cost-minimization analysis of oral versus intravenous antibiotic treatment for Klebsiella pneumoniae liver abscess.

A cost-minimization analysis was conducted for Klebsiella pneumoniae liver abscess (KLA) patients enrolled in a randomized controlled trial which found oral ciprofloxacin to be non-inferior to intravenous (IV) ceftriaxone in terms of clinical outcomes. Healthcare service utilization and cost data were obtained from medical records and estimated from self-reported patient surveys in a non-inferiority trial of oral ciprofloxacin versus IV ceftriaxone administered to 152 hospitalized adults with KLA in Singapore between November 2013 and October 2017. Total costs were evaluated by category and payer, and compared between oral and IV antibiotic groups over the trial period of 12 weeks. Among the subset of 139 patients for whom cost data were collected, average total cost over 12 weeks was $16,378 (95% CI, $14,620-$18,136) for the oral ciprofloxacin group and $20,569 (95% CI, $18,296-$22,842) for the IV ceftriaxone group, largely driven by lower average outpatient costs, as the average number of outpatient visits was halved for the oral ciprofloxacin group. There were no other statistically significant differences, either in inpatient costs or in other informal healthcare costs. Oral ciprofloxacin is less costly than IV ceftriaxone in the treatment of Klebsiella liver abscess, largely driven by reduced outpatient service costs.Trial registration: ClinicalTrials.gov Identifier NCT01723150 (7/11/2012).

A Randomized Trial of Nafamostat for Covid-19.

BACKGROUND: Nafamostat mesylate is a potent in vitro antiviral agent that inhibits the host transmembrane protease serine 2 enzyme used by severe acute respiratory syndrome coronavirus 2 for cell entry. METHODS: This open-label, pragmatic, randomized clinical trial in Australia, New Zealand, and Nepal included noncritically ill hospitalized patients with coronavirus disease 2019 (Covid-19). Participants were randomly assigned to usual care or usual care plus nafamostat. The primary end point was death (any cause) or receipt of new invasive or noninvasive ventilation or vasopressor support within 28 days after randomization. Analysis was with a Bayesian logistic model in which an adjusted odds ratio <1.0 indicates improved outcomes with nafamostat. Enrollment was closed due to falling numbers of eligible patients. RESULTS: We screened 647 patients in 21 hospitals (15 in Australia, 4 in New Zealand, and 2 in Nepal) and enrolled 160 participants from May 2021 to August 2022. In the intention-to-treat population, the primary end point occurred in 8 (11%) of 73 patients with usual care and 4 (5%) of 82 with nafamostat. The median adjusted odds ratio for the primary end point for nafamostat was 0.40 (95% credible interval, 0.12 to 1.34) with a posterior probability of effectiveness (adjusted odds ratio <1.0) of 93%. For usual care compared with nafamostat, hyperkalemia occurred in 1 (1%) of 67 and 7 (9%) of 78 participants, respectively, and clinically relevant bleeding occurred in 1 (1%) of 73 and 7 (8%) of 82 participants. CONCLUSIONS: Among hospitalized patients with Covid-19, there was a 93% posterior probability that nafamostat reduced the odds of death or organ support. Prespecified stopping criteria were not met, precluding definitive conclusions. Hyperkalemia and bleeding were more common with nafamostat. (Funded by ASCOT and others; ClinicalTrials.gov number, NCT04483960.)

Favipiravir in early symptomatic COVID-19, a randomised placebo-controlled trial.

Background: Well tolerated antivirals administered early in the course of COVID-19 infection when the viremia is highest could prevent progression to severe disease. Favipiravir inhibits SARS-CoV-2 viral replication in vitro with evidence of clinical benefit in open label trials. Placebo controlled studies of people with early symptomatic COVID-19 with regular assessments of SARS-CoV-2 viral load can determine if it has an antiviral effect and improves clinical outcomes. Methods: People with PCR-confirmed COVID-19 and 5 days or less of symptoms were randomised 1:1 to favipiravir 1800 mg on day 1, then 800 mg twice daily or matched placebo for 14 days. SARS-CoV-2 viral load was quantitated from second daily self-collected nose-throat swabs while receiving study drug. The primary endpoint was time to virological cure defined as 2 successive swabs negative for SARS-CoV-2 by PCR and secondary outcomes were progression of disease severity, symptom resolution and safety. Findings: Between 31 July 2020 and 19 September 2021, 200 people were enrolled (199 in the community, 1 in hospital) with 190 receiving one or more doses of drug (modified intention to treat [mITT] population). There was no difference in time to virological cure (Log-rank p=0.6 comparing Kaplan Meier curves), progression to hospitalisation (14 favipiravir, 9 placebo; p=0.38), time to symptom resolution (cough, fever, sore throat) and there were no deaths. 51 people related an adverse event that was possibly drug related, but these were evenly distributed (n=24 favipiravir, n=27 placebo). Sensitivity analyses where the definition of virological cure was changed to: a single negative PCR, exclude datapoints based on the presence or absence of human DNA in the swab, a SARS-CoV-2 viral load < 300 copies/mL being considered negative all demonstrated no difference between arms. Interpretation: Favipiravir does not improve the time to virological cure or clinical outcomes and shows no evidence of an antiviral effect when treating early symptomatic COVID-19 infection. Funding: The study was supported in part by grants from the Commonwealth Bank Australia, the Lord Mayor's Charitable Foundation, Melbourne Australia and the Orloff Family Charitable Trust, Melbourne, Australia. JHM is supported by the Medical Research Future Fund, AYP, JT are supported by the Australian National Health and Medical Research Council.

Stool metagenome analysis of patients with Klebsiella pneumoniae liver abscess and their domestic partners.

OBJECTIVES: Hypermucoviscous Klebsiella pneumoniae is an emerging cause of community-acquired liver abscess. The aim of this study was to investigate whether hypermucoviscous strains could be shared among households. METHODS: The clinical K. pneumoniae isolates from a cohort of 24 patients with Klebsiella liver abscess were genotyped, and the stool metagenomes of the index patients and their cohabiting domestic partners were analyzed. RESULTS: K. pneumoniae was identified in 33% of index patient stools, and one index patient's clinical isolate was identified in their domestic partner's stool. CONCLUSIONS: This could represent a transmission event or could represent exposure to a common environmental source.

Preliminary Effects of a Mobile Interactive Supervised Therapy Intervention on People Living With HIV: Pilot Randomized Controlled Trial.

BACKGROUND: As people living with HIV infection require lifelong treatment, nonadherence to medication will reduce their chance of maintaining viral suppression and increase the risk of developing drug resistance and HIV transmission. OBJECTIVE: This study aimed to evaluate the efficacy of a mobile app, Mobile Interactive Supervised Therapy (MIST), for improving adherence to oral HIV medications among HIV-infected adults in Singapore. METHODS: We conducted a two-group pilot randomized controlled trial (RCT) with a process evaluation, in which 40 HIV-infected participants with once-daily medication regimes were recruited from a public tertiary hospital in Singapore and randomly assigned equally to either the intervention (receiving MIST and routine care) or control (receiving routine care only) groups. The intervention lasted for 2 months. The outcome of antiretroviral therapy (ART) adherence was measured by a 7-day recall self-report (SR), pill count (PC), an electronic medical device-Medication Event Monitoring System (MEMS)-and a mobile app-MIST (for the intervention group only). In total, 20 participants from the intervention group were interviewed at the end of the intervention to assess the acceptability of MIST. Data were collected at baseline and at 1-month and 2-month postintervention. RESULTS: All participants had excellent medication adherence at baseline (median 100, IQR 100-100). The use of MIST did not result in a significant improvement in ART adherence when measured by the SR, PC, and MEMS, as compared with the control group at 1-month (P values >.99, .86, and .74, respectively) and 2-month (P values=.80, .84, and .82, respectively) postintervention. ART adherence also did not improve in each group over the same period. MIST was perceived to be a beneficial tool based on the process evaluation results. CONCLUSIONS: Although MIST did not enhance medication adherence to HIV treatments, mainly owing to the ceiling effect, it was perceived to be beneficial among the participants of this study. Our process evaluation provided useful data to further develop MIST for bigger and long-term mobile phone app-assisted intervention RCTs in the future. TRIAL REGISTRATION: ClinicalTrials.gov NCT03794648; https://clinicaltrials.gov/ct2/show/NCT03794648.

Endogenous endophthalmitis in Klebsiella pneumoniae pyogenic liver abscess: Systematic review and meta-analysis.

BACKGROUND: Endogenous endophthalmitis (EE) is a devastating complication that develops as a metastatic infection in patients with Klebsiella pneumoniae pyogenic liver abscess (KPPLA). The existing data are heterogeneous and the actual disease burden and risk factors for the development of EE among patients with KPPLA have not been systematically examined. We performed a systematic review and meta-analysis to examine the incidence of EE, temporal trend of EE, and risk factors for EE in patients with KPPLA. METHODOLOGY: The MEDLINE, EMBASE, Web of Science, and Cochrane Library databases were searched for articles published from inception to 2020 that evaluated the incidence of EE among patients with KPPLA. By a random-effects method, a pooled estimate of its incidence with 95% confidence intervals was estimated along with examination of its temporal and geographic variations. Pooled odds ratios were calculated for risk factors. RESULTS: Fifteen retrospective studies reporting data on 11889 patients with KPPLA met the inclusion criteria and were analyzed. With 217 patients developing EE, the pooled incidence of EE was 4.5% (95% confidence interval 2.4% to 8.2%). The heterogeneity was considerable and significant (Cochran's Q 243.5, p < 0.001, I2 = 94.2%). CONCLUSION: This meta-analysis estimates the actual incidence of EE among patients with KPPLA, where EE is reported in about 1 of 22 patients with KPPLA. Infection caused by K1 capsular serotype was an independent risk factor.

An adaptive randomised placebo controlled phase II trial of antivirals for COVID-19 infection (VIRCO): A structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: Primary objective: To determine the efficacy of a candidate antiviral on time to virological cure compared to standard of care within 14 days of randomisation Secondary objectives: • To determine the safety of the antiviral • To determine the clinical benefit of the antiviral over placebo according to the WHO 7-point ordinal scale • To determine the clinical benefit of the antiviral over placebo on time to resolution of clinical symptoms • To determine the effect of the antiviral over placebo on biomarkers of inflammation and immune activation TRIAL DESIGN: This is a multi-centre, triple-blind, randomised placebo controlled phase II, 2-arm trial with parallel-group design with allocation ratio 1:1. PARTICIPANTS: Inclusion Criteria: • Provision of informed consent by the participant • Age ≥18 years • Confirmed SARS-CoV-2 by nucleic acid testing in the past 5 days • COVID-19 related symptom initiation within 5 days • Female patients of childbearing potential must have a negative pregnancy test at Screening. Female patients of childbearing potential and fertile male patients who are sexually active with a female of childbearing potential must use highly effective methods of contraception throughout the study and for 1 week following the last dose of study treatment. EXCLUSION CRITERIA: • Known allergy to the study medication • Is on another clinical trial investigating an antiviral treatment for COVID-19 • Pregnancy • Patients with severe hepatic dysfunction equivalent to Grade C in the Child-Pugh classification • Patients with renal impairment requiring dialysis • Is deemed by the Investigator to be ineligible for any reason Participants will be recruited from, and the study visits will take place at Alfred Hospital, Monash Health, Austin Health in Victoria, Australia for hospitalised participants as well as recruitment in the community in participants homes for eligible people not requiring hospitalisation. INTERVENTION AND COMPARATOR: The first candidate antiviral is favipiravir Arm 1: Favipiravir 1800 mg favipiravir BD on Day 1 followed by 800 mg BD favipiravir for the next 13 days. Arm 2: Placebo MAIN OUTCOMES: Primary outcome: Time to virological cure as defined by 2 successive throat (or combined nose/throat) swabs negative for SARS-CoV-2 by nucleic acid testing during the 14 days after enrolment. RANDOMISATION: Randomisation performed at the Alfred Hospital Clinical Trials Pharmacy using computer generated block-randomisation lists with 6 participants per block. Within each block half of the participants will be randomised to the candidate antiviral and the other half to placebo. Randomisation is stratified by study site, with participants enrolled in the community considered as a study site. BLINDING (MASKING): Study participants, study investigators and the study statistician will be blinded to treatment allocation. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The study aims to recruit 190 people (95/arm) with the first candidate antiviral favipiravir TRIAL STATUS: Protocol version 2.0 Dated 31-Jul-2020. Recruitment will take place between July 2020 and December 2020. TRIAL REGISTRATION: clinicaltrials.gov NCT04445467 First posted 24-Jun-2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Dengue virus not detected in human semen.

Zika and Ebola viruses can persist in semen and pose a risk for sexual transmission. To determine if dengue virus, another flavivirus, is similarly detectable in semen, we performed dengue PCR on semen in five patients with acute dengue virus infection. All five tested negative, suggesting that dengue does not pose a risk for sexual transmission.

Population genomics of hypervirulent Klebsiella pneumoniae clonal-group 23 reveals early emergence and rapid global dissemination.

Severe liver abscess infections caused by hypervirulent clonal-group CG23 Klebsiella pneumoniae have been increasingly reported since the mid-1980s. Strains typically possess several virulence factors including an integrative, conjugative element ICEKp encoding the siderophore yersiniabactin and genotoxin colibactin. Here we investigate CG23's evolutionary history, showing several deep-branching sublineages associated with distinct ICEKp acquisitions. Over 80% of liver abscess isolates belong to sublineage CG23-I, which emerged in ~1928 following acquisition of ICEKp10 (encoding yersiniabactin and colibactin), and then disseminated globally within the human population. CG23-I's distinguishing feature is the colibactin synthesis locus, which reportedly promotes gut colonisation and metastatic infection in murine models. These data show circulation of CG23 K. pneumoniae decades before the liver abscess epidemic was first recognised, and provide a framework for future epidemiological and experimental studies of hypervirulent K. pneumoniae. To support such studies we present an open access, completely sequenced CG23-I human liver abscess isolate, SGH10.