Effectiveness of community-based oral antiviral treatments against severe COVID-19 outcomes in people 70 years and over in Victoria, Australia, 2022: an observational study.

Background: Oral Antiviral (OAV) COVID-19 treatments are widely used, but evidence for their effectiveness against the Omicron variant in higher risk, vaccinated individuals is limited. Methods: Retrospective study of two vaccinated cohorts of COVID-19 cases aged ≥70 years diagnosed during a BA.4/5 Omicron wave in Victoria, Australia. Cases received either nirmatrelvir-ritonavir or molnupiravir as their only treatment. Data linkage and logistic regression modelling was used to evaluate the association between treatment and death and hospitalisation and compared with no treatment. Findings: Of 38,933 individuals in the mortality study population, 13.5% (n = 5250) received nirmatrelvir-ritonavir, 51.3% (n = 19,962) received molnupiravir and 35.2% (n = 13,721) were untreated. Treatment was associated with a 57% (OR = 0.43, 95% CI 0.36-0.51) reduction in the odds of death, 73% (OR = 0.27, 95% CI 0.17-0.40) for nirmatrelvir-ritonavir and 55% (OR = 0.45, 95% CI 0.38-0.54) for molnupiravir. Treatment was associated with a 31% (OR = 0.69, 95% CI 0.55-0.86) reduction in the odds of hospitalisation, 40% (OR = 0.60, 95% CI 0.43-0.83) for nirmatrelvir-ritonavir and 29% (OR = 0.71, 95% CI 0.58-0.87) for molnupiravir. Cases treated within 1 day of diagnosis had a 61% reduction in the odds of death (OR = 0.39, 95% CI 0.33-0.46) compared with 33% reduction for a delay of 4 or more days (OR = 0.67, 95% CI 0.44-0.97). Interpretation: Treatment with both nirmatrelvir-ritonavir or molnupiravir was associated with a reduction in death and hospitalisation in vaccinated ≥70 years individuals during the Omicron era. Timely, equitable treatment with OAVs is an important tool in the fight against COVID-19. Funding: There was no funding for this study.

The importance of utilizing travel history metadata for informative phylogeographical inferences: a case study of early SARS-CoV-2 introductions into Australia.

Inferring the spatiotemporal spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) via Bayesian phylogeography has been complicated by the overwhelming sampling bias present in the global genomic dataset. Previous work has demonstrated the utility of metadata in addressing this bias. Specifically, the inclusion of recent travel history of SARS-CoV-2-positive individuals into extended phylogeographical models has demonstrated increased accuracy of estimates, along with proposing alternative hypotheses that were not apparent using only genomic and geographical data. However, as the availability of comprehensive epidemiological metadata is limited, many of the current estimates rely on sequence data and basic metadata (i.e. sample date and location). As the bias within the SARS-CoV-2 sequence dataset is extensive, the degree to which we can rely on results drawn from standard phylogeographical models (i.e. discrete trait analysis) that lack integrated metadata is of great concern. This is particularly important when estimates influence and inform public health policy. We compared results generated from the same dataset, using two discrete phylogeographical models: one including travel history metadata and one without. We utilized sequences from Victoria, Australia, in this case study for two unique properties. Firstly, the high proportion of cases sequenced throughout 2020 within Victoria and the rest of Australia. Secondly, individual travel history was collected from returning travellers in Victoria during the first wave (January to May) of the coronavirus disease 2019 (COVID-19) pandemic. We found that the implementation of individual travel history was essential for the estimation of SARS-CoV-2 movement via discrete phylogeography models. Without the additional information provided by the travel history metadata, the discrete trait analysis could not be fit to the data due to numerical instability. We also suggest that during the first wave of the COVID-19 pandemic in Australia, the primary driving force behind the spread of SARS-CoV-2 was viral importation from international locations. This case study demonstrates the necessity of robust genomic datasets supplemented with epidemiological metadata for generating accurate estimates from phylogeographical models in datasets that have significant sampling bias. For future work, we recommend the collection of metadata in conjunction with genomic data. Furthermore, we highlight the risk of applying phylogeographical models to biased datasets without incorporating appropriate metadata, especially when estimates influence public health policy decision making.

Prolonged Viral Shedding in Patients with Mild to Moderate COVID-19 Disease: A Regional Perspective.

BACKGROUND: The risk of transmission of Coronavirus Disease 2019 (COVID-19) is increasingly understood to be greatest early after symptom onset, however, factors associated with prolonged and increased risk of transmission remain unclear. In settings where COVID-19 prevalence is low, there may be a benefit of extending the period that patients are isolated to decrease the risk of transmission. This study explored the duration of viral shedding in such a location, in patients with mild-moderate COVID-19 disease in Ballarat, Australia. METHODS: Patients diagnosed with COVID-19 disease using a real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay from oropharyngeal and bilateral deep nasopharyngeal sampling and managed through Ballarat Health Services between March 1 and May 1, 2020 were included. Patients were retested if they were afebrile for >72 hours, asymptomatic and >14 days since symptom onset. If positive on retesting, patients were tested every 3 to 7 days thereafter. RESULTS: Patients underwent testing a median of 4 days (range 1-12) after initial symptom onset. Duration of symptoms ranged from 1 to 36 days. Positive tests were recorded up to a median of day 21 (range 6-38). Cycle thresholds were inversely correlated with time since symptom onset (P < .0001). Median time to the first negative test was 25 days (range 12-32). Two patients who had remained asymptomatic for >7 days after initial symptom onset had recrudescence of mild symptoms on day 13 and 14; both tested positive on follow-up tests at this time. CONCLUSIONS: This study demonstrates prolonged shedding of COVID-19 in patients with mild-moderate disease. It suggests that some patients with mild disease may have recrudescence of symptoms a week or more after their initial symptoms resolved.

Outcomes with a shorter multidrug-resistant tuberculosis regimen from Karakalpakstan, Uzbekistan.

BACKGROUND: In 2016, World Health Organization guidelines conditionally recommended standardised shorter 9-12-month regimens for multidrug-resistant (MDR) tuberculosis (TB) treatment. We conducted a prospective study of a shorter standardised MDR-TB regimen in Karakalpakstan, Uzbekistan. METHODS: Consecutive adults and children with confirmed rifampicin-resistant pulmonary TB were enrolled between September 1, 2013 and March 31, 2015; exclusions included prior treatment with second-line anti-TB drugs, and documented resistance to ofloxacin or to two second-line injectable agents. The primary outcome was recurrence-free cure at 1 year following treatment completion. RESULTS: Of 146 enrolled patients, 128 were included: 67 female (52.3%), median age 30.1 (interquartile range 23.8-44.4) years. At the end of treatment, 71.9% (92 out of 128) of patients achieved treatment success, with 68% (87 out of 128) achieving recurrence-free cure at 1 year following completion. Unsuccessful outcomes during treatment included 22 (17.2%) treatment failures with fluoroquinolone-resistance amplification in 8 patients (8 out of 22, 36.4%); 12 (9.4%) lost to follow-up; and 2 (1.5%) deaths. Recurrence occurred in one patient. Fourteen patients (10.9%) experienced serious adverse events. Baseline resistance to both pyrazinamide and ethambutol (adjusted OR 6.13, 95% CI 2.01; 18.63) and adherence <95% (adjusted OR 5.33, 95% CI 1.73; 16.36) were associated with unsuccessful outcome in multivariable logistic regression. CONCLUSIONS: Overall success with a standardised shorter MDR-TB regimen was moderate with considerable treatment failure and amplification of fluoroquinolone resistance. When introducing standardised shorter regimens, baseline drug susceptibility testing and minimising missed doses are critical. High rates globally of pyrazinamide, ethambutol and ethionamide resistance raise questions of continued inclusion of these drugs in shorter regimens in the absence of drug susceptibility testing-confirmed susceptibility.

Case Report: Japanese Encephalitis Associated with Chorioretinitis after Short-Term Travel to Bali, Indonesia.

Japanese encephalitis (JE) virus is a mosquito-borne flavivirus endemic throughout Asia. Incidence in non-endemic countries is rare, with an estimate of less than one case per one million travelers. Most human JE infections are asymptomatic or cause a mild, nonspecific febrile illness. Neurological involvement, if present, is usually severe and associated with high mortality or ongoing neurological sequelae in survivors. Ocular manifestations are rare with JE, but uveitis has been described to be associated with other flavivirus infections, including West Nile virus. We report the first probable case of JE chorioretinitis acquired by a 45-year-old Australian traveler to Bali. This case highlights the importance of a detailed ocular examination when there is clinical suspicion of JE.

Six hundred years of South American tree rings reveal an increase in severe hydroclimatic events since mid-20th century.

South American (SA) societies are highly vulnerable to droughts and pluvials, but lack of long-term climate observations severely limits our understanding of the global processes driving climatic variability in the region. The number and quality of SA climate-sensitive tree ring chronologies have significantly increased in recent decades, now providing a robust network of 286 records for characterizing hydroclimate variability since 1400 CE. We combine this network with a self-calibrated Palmer Drought Severity Index (scPDSI) dataset to derive the South American Drought Atlas (SADA) over the continent south of 12°S. The gridded annual reconstruction of austral summer scPDSI is the most spatially complete estimate of SA hydroclimate to date, and well matches past historical dry/wet events. Relating the SADA to the Australia-New Zealand Drought Atlas, sea surface temperatures and atmospheric pressure fields, we determine that the El Niño-Southern Oscillation (ENSO) and the Southern Annular Mode (SAM) are strongly associated with spatially extended droughts and pluvials over the SADA domain during the past several centuries. SADA also exhibits more extended severe droughts and extreme pluvials since the mid-20th century. Extensive droughts are consistent with the observed 20th-century trend toward positive SAM anomalies concomitant with the weakening of midlatitude Westerlies, while low-level moisture transport intensified by global warming has favored extreme rainfall across the subtropics. The SADA thus provides a long-term context for observed hydroclimatic changes and for 21st-century Intergovernmental Panel on Climate Change (IPCC) projections that suggest SA will experience more frequent/severe droughts and rainfall events as a consequence of increasing greenhouse gas emissions.

Case Manifestations and Public Health Response for Outbreak of Meningococcal W Disease, Central Australia, 2017.

Neisseria meningitidis serogroup W has emerged as an increasingly common cause of invasive meningococcal disease worldwide; the average case-fatality rate is 10%. In 2017, an unprecedented outbreak of serogroup W infection occurred among the Indigenous pediatric population of Central Australia; there were 24 cases over a 5-month period. Among these cases were atypical manifestations, including meningococcal pneumonia, septic arthritis, and conjunctivitis. The outbreak juxtaposed a well-resourced healthcare system against unique challenges related to covering vast distances, a socially disadvantaged population, and a disease process that was rapid and unpredictable. A coordinated clinical and public health response included investigation of and empiric treatment for 649 febrile children, provision of prophylactic antimicrobial drugs for 465 close contacts, and implementation of a quadrivalent meningococcal ACWY conjugate vaccine immunization program. The response contained the outbreak within 6 months; no deaths and only 1 case of major illness were recorded.

Version 4 of the CRU TS monthly high-resolution gridded multivariate climate dataset.

CRU TS (Climatic Research Unit gridded Time Series) is a widely used climate dataset on a 0.5° latitude by 0.5° longitude grid over all land domains of the world except Antarctica. It is derived by the interpolation of monthly climate anomalies from extensive networks of weather station observations. Here we describe the construction of a major new version, CRU TS v4. It is updated to span 1901-2018 by the inclusion of additional station observations, and it will be updated annually. The interpolation process has been changed to use angular-distance weighting (ADW), and the production of secondary variables has been revised to better suit this approach. This implementation of ADW provides improved traceability between each gridded value and the input observations, and allows more informative diagnostics that dataset users can utilise to assess how dataset quality might vary geographically.

Isolation of a Halogen-Bonded Complex Formed between Methane and Chlorine Monofluoride and Characterisation by Rotational Spectroscopy and Ab Initio Calculations.

A halogen-bonded complex formed between methane and chlorine monofluoride has been isolated in the gas phase before the reaction between the components and has been characterised through its rotational spectrum, which is of the symmetric-top type but only exhibits K = 0 type transitions at the low effective temperature of the pulsed-jet experiment. Spectroscopic constants for two low-lying states that result from internal rotation of the CH4 subunit were detected for each of the two isotopic varieties H4C···35ClF and H4C···37ClF and were analysed to show that ClF lies on the symmetry axis with Cl located closer than F to the C atom, at the distance r0(C···Cl) ≅ 3.28 Å and with an intermolecular stretching force constant kσ ≅ 4 N m-1. Ab initio calculations at the explicitly correlated level CCSD(T)(F12c)/cc-pVTZ-F12 show that in the equilibrium geometry, the ClF molecule lies along a C3 axis of CH4 and Cl is involved in a halogen bond. The Cl atom points at the nucleophilic region identified on the C3 axis, opposite the unique C-H bond and somewhere near the C atom and the tetrahedron face centre, with re(C···Cl) = 3.191 Å. Atoms-in-molecules (AIM) theory shows a bond critical point between Cl and C, confirming the presence of a halogen bond. The energy that is required to dissociate the complex from the equilibrium conformation into its CH4 and ClF components is only De ≅ 5 kJ mol-1. A likely path for the internal rotation of the CH4 subunit is identified by calculations at the same level of theory, which also provide the variation of the energy of the system as a function of the motion along that path. The barrier to the motion along the path is only ≅ 20 cm-1.

Office Based Endovenous Radiofrequency Ablation of Truncal Veins: A Case for Moving Varicose Vein Treatment out of Operating Theatres.

OBJECTIVES: This study aims to assess the efficacy and outcomes at one year after office based endovenous radiofrequency ablation (OBEVRFA) as a standalone procedure for varicose veins under local anaesthesia. METHODS: A retrospective study of prospectively collected data of all OBEVRFAs done in the vascular unit from April 2014 to June 2016 was performed. The demographics, clinical findings, initial venous duplex ultrasound (DUS) findings, the vein ablated, and immediate complications were recorded. Patients were reviewed at six weeks and again if necessary with or without a repeat DUS. The follow up period ranged from 12 to 38 months. Patients undergoing further procedures for symptomatic residual veins within the follow up period were recorded. Average cost and income were obtained from the hospital Patient Level Information and Costing Systems data. RESULTS: A total of 523 limbs were listed for OBEVRFA during the study period. Ninety-four (18%) were cancelled on the day of surgery for various reasons. A total of 429 procedures in 394 patients were performed. There were 35 bilateral cases; each limb performed on separate occasions. The female to male ratio was 1.2:1. The median age was 54 years (range 17-88 years). The CEAP (Clinical, Etiologic, Anatomic and Pathophysiologic) classification was C2 to C3, 291 (68%); C4 to C5, 11 (26%), and C6, 26 (6%). Forty-seven (11%) recurrent varicose veins were treated. There were three recorded cases of endovenous heat induced thrombosis (EHIT). Sixty (14%) patients were lost to follow up. One hundred and five (29%) patients underwent repeat DUS for persistent symptoms. In the follow up period, only 86 patients (23%) needed further multiple avulsions. CONCLUSIONS: OBEVRFAs of the truncal veins for the treatment of varicose veins is safe and effective and could be performed in all suitable patients to free up theatre capacity.

Clearance of infant vancomycin-resistant Enterococcus faecium carriage after a neonatal inpatient outbreak.

A follow-up cohort study was undertaken to document clearance of fecal vancomycin-resistant Enterococcus faecium carriage in 19 infants colonized during a hospital outbreak. By the conclusion of the 14-month study period, all participants had returned terminal negative fecal specimens, supporting the hypothesis that carriage is transient in this population.

Outbreak of vanB vancomycin-resistant Enterococcus faecium colonization in a neonatal service.

OBJECTIVE: To describe successful termination of an outbreak of vancomycin-resistant Enterococcus faecium (VREfm) colonization within a neonatal service. SETTING: Multisite neonatal intensive care unit and special care nurseries within a single health care service. PARTICIPANTS: Forty-four cases of VREfm-colonized neonatal inpatients-including 2 clinical isolates (eye swab and catheter-urine specimen) and 42 screening isolates. INTERVENTIONS: Active surveillance cultures, patient isolation, contact precautions, enhanced environment cleaning, and staff and parent education. Whole genome sequencing and multilocus sequence typing were used to characterize the outbreak and refine infection control procedures. RESULTS: Peak prevalence of VREfm colonization across all sites was 31% upon discovery of the outbreak. Subsequent to the intervention, transmission was halted within 8 weeks and no further isolates of the outbreak strain have been detected as of 12 months following outbreak cessation. Environmental swabs revealed VREfm colonization of baby-weighing scales, a baby bath, and a pharmacy refrigerator within the neonatal intensive care unit. All isolates were of a single multilocus sequence type (sequence type 796) and highly clonal at the core genome level. CONCLUSIONS: Bundled infection control interventions were effective in rapidly terminating a clonal outbreak of sequence type 796 VREfm colonization within a neonatal inpatient service. Strain-typing and active surveillance cultures were critical in guiding the management of this outbreak. The closed environment of a neonatal unit likely facilitated eradication of the patient and environment reservoirs of VREfm colonization.

Mismatch repair deficiency does not mediate clinical resistance to temozolomide in malignant glioma.

PURPOSE: A major mechanism of resistance to methylating agents, including temozolomide, is the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (AGT). Preclinical data indicates that defective DNA mismatch repair (MMR) results in tolerance to temozolomide regardless of AGT activity. The purpose of this study was to determine the role of MMR deficiency in mediating resistance in samples from patients with both newly diagnosed malignant gliomas and those who have failed temozolomide therapy. EXPERIMENTAL DESIGN: The roles of AGT and MMR deficiency in mediating resistance in glioblastoma multiforme were assessed by immunohistochemistry and microsatellite instability (MSI), respectively. The mutation status of the MSH6 gene, a proposed correlate of temozolomide resistance, was determined by direct sequencing and compared with data from immunofluorescent detection of MSH6 protein and reverse transcription-PCR amplification of MSH6 RNA. RESULTS: Seventy percent of newly diagnosed and 78% of failed-therapy glioblastoma multiforme samples expressed nuclear AGT protein in > or = 20% of cells analyzed, suggesting alternate means of resistance in 20% to 30% of cases. Single loci MSI was observed in 3% of patient samples; no sample showed the presence of high MSI. MSI was not shown to correlate with MSH6 mutation or loss of MSH6 protein expression. CONCLUSIONS: Although high AGT levels may mediate resistance in a portion of these samples, MMR deficiency does not seem to be responsible for mediating temozolomide resistance in adult malignant glioma. Accordingly, the presence of a fraction of samples exhibiting both low AGT expression and MMR proficiency suggests that additional mechanisms of temozolomide resistance are operational in the clinic.