Sir Charles Gairdner Hospital

This propensity score-matched study utilized data from the MSBase registry to compare outcomes between patients discontinuing OCR due to safety concerns ("Switchers") and those continuing treatment ("Continuers"). Matching was performed using inverse probability of treatment weighting (IPTW) to balance treatment duration and baseline characteristics. Primary outcomes included annualized relapse rate (ARR), time to first relapse, 24-48 weeks confirmed disability worsening (CDW), and progression independent of relapse activity (PIRA). From an initial cohort of 310 Switchers and 1,315 Continuers, 66 patients who experienced at least one safety event and switched from OCR were matched with 66 Continuers. PS-IPTW analyses revealed higher ARR in Switchers (0.08, 95% CI: 0.05-0.14) versus Continuers (0.038, 95% CI: 0.02-0.07; p=0.040). Time to first relapse showed no significant difference (HR=2.23, 95% CI: 0.68-7.28; p=0.183). Trends toward increased CDW24 weeks risk (PS-IPTW HR=2.11, 95% CI: 0.93-4.75; p=0.073), while no significant difference was found at 48 weeks (HR=1.81, 95% CI: 0.83-3.30; p=0.201). PIRA risk showed a trend toward an increase in Switchers (HR=2.45, 95% CI: 0.95-6.29; p=0.063). In this propensity-score-matched analysis, OCR discontinuation due to safety concerns was associated with increased relapse activity and trends toward greater disability progression. These findings highlight the importance of maintaining therapeutic intensity and systematic monitoring during treatment transitions to mitigate safety risks Conclusion: Further research is needed to develop strategies for effectively managing adverse events to optimize patient outcomes.

BackgroundThe laboratory diagnosis of tuberculous pleuritis (TBP) is hindered by the paucibacillary nature of Mycobacterium tuberculosis in the pleural space, resulting in low sensitivity of microbiological culture and polymerase chain reaction–based analyses on pleural fluid. The use of metagenomic next-generation sequencing for diagnosing TBP may be limited by the background noise of DNA from nontuberculous mycobacteria.MethodsWe performed targeted sequencing to analyze M. tuberculosis DNA in paired pleural fluid and plasma from prospectively enrolled consecutive patients with new-onset pleural effusion. We used a bioinformatics alignment algorithm to the M. tuberculosis genome that was masked for regions with high sequence similarity to nontuberculous mycobacteria. Our primary outcome was a comparison of diagnostic sensitivity between M. tuberculosis sequencing as described above and culture using McNemar’s test.ResultsAmong the included 329 patients with pleural effusion, 34 patients with TBP were identified. Targeted sequencing detected M. tuberculosis DNA fragments in the pleural fluid of all TBP cases (median, 267.6 reads per 10 million [RP10M]; interquartile range [IQR], 30.8–2644.3) but absent in 288 out of 295 (97.6%) non-TBP samples (median, 0 RP10M; IQR, 0–0). Targeted sequencing of pleural fluid achieved a sensitivity of 97.1% for TBP detection at a cutoff of 2 RP10M, in contrast to 47.1% by M. tuberculosis culture (P<0.001, McNemar’s test). Sequencing yielded an area-under-the-curve value of 0.9996 (95% confidence interval, 0.9988–1.0000) for differentiating TBP and non-TBP. Plasma analysis by targeted sequencing with the same alignment algorithm reported an area-under-the-curve value of 0.9475 (95% confidence interval, 0.8929–1.0000).ConclusionsTargeted sequencing of pleural fluid with selectively masked M. tuberculosis genomic alignment accurately diagnosed TBP and outperformed conventional diagnostic tests. (Supported by InnoHK and the Hong Kong Tuberculosis, Chest and Heart Diseases Association; ClinicalTrials.gov number, NCT05397730.)

ABSTRACT Introduction Overweight and obesity are increasing rapidly in most countries. Underweight body mass index (BMI), though much less common, is also associated with adverse health outcomes. There is poor understanding of the implications of BMI in lymphoma patients. Recent international guidelines indicate that curative‐intent cancer treatment should not be modified for obesity alone, with no specific recommendations for low BMI patients. Our aim was to examine the impact of BMI on outcomes in a contemporary cohort of lymphoma patients. Methods We examined BMI in relation to baseline clinical features and outcomes in an Australasian cohort of 4686 lymphoma cases from the national registry. Results Patients with an overweight or obese BMI had no significant decrement in overall survival (OS) or progression free survival (PFS) compared to those with a normal BMI for any of the histological subtypes examined in this study. However, the minority of patients with underweight BMI demonstrated inferior OS for Hodgkin lymphoma (adjHR = 2.55, 95% CI = 1.05–6.19, p = 0.04) and OS (adjHR = 1.54, 95% CI = 1.02–2.32, p = 0.04) in diffuse large B‐cell lymphoma compared to patients with a normal BMI. Conclusion These findings support continued standard dosing in overweight and obese patients and identify poor outcomes requiring careful management in underweight populations. Trial Registration The authors have confirmed clinical trial registration is not needed for this submission.

Biologic and small-molecule therapies are increasingly used in dermatology for conditions such as psoriasis and atopic dermatitis. Live and live-attenuated vaccines are traditionally avoided in patients receiving these agents due to concerns regarding vaccine-strain infection. We conducted a systematic review to evaluate the safety of live and live-attenuated vaccines in patients receiving biologic or small-molecule therapies used in dermatologic practice. PubMed, Embase (Ovid) and the Cochrane Library were searched from January 2010 to February 2025 for human studies reporting safety or immunogenicity outcomes following live vaccine administration in patients receiving relevant therapies. Of 1104 records identified, nine studies met inclusion criteria, comprising one randomised controlled trial, three cohort studies, three retrospective case series, one cross-sectional observational study and one case report. Vaccines evaluated included measles-mumps-rubella, measles-mumps-rubella-varicella, varicella, live zoster and yellow fever vaccines. Across studies, no cases of vaccine-strain infection or disseminated vaccine-related disease were reported. Mild and self-limiting post-vaccination reactions were described in several cohorts. Where assessed, immunogenicity responses were generally preserved, although data were limited and inconsistently reported. Most included studies involved patients receiving biologic or small-molecule monotherapy, though some cohorts permitted background conventional immunomodulatory therapy. The available evidence, although limited and predominantly observational, suggests that selected live and live-attenuated vaccines may be administered without serious adverse outcomes in carefully chosen patients receiving biologic or small-molecule therapies. Larger prospective studies are needed to better define safety and immunogenicity across newer targeted agents.

Tenofovir alafenamide (TAF) is widely used for the treatment of chronic hepatitis B virus (HBV) infection and has been considered resistant to clinically significant antiviral resistance. We describe a 32-year-old woman with genotype C8 chronic HBV infection who had persistently elevated HBV DNA viral load despite documented adherence to entecavir and subsequent TAF therapy. After an initial virologic response to TAF, HBV DNA viral load rebounded to pretreatment levels. Whole genome sequencing (WGS) of HBV obtained before and after TAF exposure identified multiple putative resistance associated mutations (RAMs) within the reverse transcriptase region (Y9H, H126Y, and A317S) previously associated with reduced susceptibility to tenofovir, together with deletions involving the basal core promoter and PreS1 regions. No RAMs to entecavir or other nucleos(t)ide analogues were detected. These findings provide genomic evidence of TAF treatment failure in the presence of combined putative tenofovir RAMs within the reverse transcriptase region and structural viral deletions.

In asthma, augmented airway wall smooth muscle (ASM) bulk is a major remodeling feature, promoted by increased transforming growth factor (TGF)-β1 and connective tissue growth factor (CTGF). Runt-related transcription factor-2 (RUNX2) represses TGF-β1-induced CTGF through interactions with SMAD3. This study aimed to investigate the expression and role of RUNX2 in asthmatic and nonasthmatic ASM cells. mRNA and protein were detected by microarray, PCR, and western blot in nonasthmatic and asthmatic ASM cells. Immunohistochemistry identified RUNX2 in lung tissues from asthmatic patients and nonasthmatic subjects. Different RUNX2 isoforms were transfected into immortalized-asthmatic ASM cells, and markers of inflammation and airway remodeling were measured. RUNX2 alternatively spliced forms were examined in bronchial biopsies from asthmatic and healthy subjects. The abundance of RUNX2 was decreased in isolated ASM cells from asthmatic compared with nonasthmatic subjects. The ASM layer around airways in lung tissue sections from asthmatic and nonasthmatic patients had a heterogeneous pattern of RUNX2 protein detection. TGF-β1 stimulation increased RUNX2/RUNX2 variant 1 mRNA in nonasthmatic but not asthmatic ASM cells, facilitating SMAD3 activation and nuclear translocation in asthmatic ASM cells. RUNX2 isoform overexpression in immortalized asthmatic ASM cells failed to alter markers of inflammation (IL-6) but significantly reduced markers of remodeling (CTGF), ASM cell hypertrophy (GSK-3β and desmin), and proliferation (pSer795 Rb and α-tubulin). In bronchial biopsies, RUNX2 mRNA splicing was higher in asthmatic patients compared with healthy subjects. These data suggest RUNX2 plays a role in the homeostasis of healthy airways. Restoring RUNX2 may provide a new therapeutic approach for asthma.

This study investigated relationships between sleep quality, sleep apnoea and depression during pregnancy, focusing on their associations and potential bidirectional effects. Data from 193 pregnant women enrolled in a longitudinal study across pregnancy and postpartum were included. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). Sleep apnoea was measured using home sleep studies (Apnoea-Hypopnoea Index, AHI≥5). Depressive symptoms were evaluated using the Edinburgh Postnatal Depression Scale (EPDS ≥ 13). Repeat assessments of sleep quality, apnoea and depressive symptoms were undertaken in early and late pregnancy. Clinical depression was diagnosed using the Structured Clinical Interview for DSM in early pregnancy and six months postpartum. Women with depression diagnosed in early-mid pregnancy had poorer self-reported sleep quality, higher self-reported depressive symptoms and increased incidence of postnatal depression. Depression in early pregnancy was associated with poorer sleep quality concurrently (OR: 1.25 [1.10-1.41]) and in late pregnancy (OR: 1.19 [1.04-1.36]). Cross-lagged panel modelling showed early depressive symptoms predicted poorer sleep in late pregnancy, but not vice versa. Sleep apnoea (severity or diagnosis) was not associated with depression or depressive symptoms. Depressive symptoms in early pregnancy predicted poorer self-reported sleep quality in later pregnancy, but not the reverse. Treating depression early in pregnancy may improve subsequent sleep. Sleep apnoea and depression may require distinct management approaches. Persistent sleep issues in pregnant women with depression or depressive symptoms should prompt screening for underlying sleep disorders, with sleep-focused interventions or medication adjustments considered if none are identified.

To describe 5-year outcomes of chronic kidney disease (CKD) in a large, population-based cohort in Western Australia, including rates of progression, regression, kidney failure and death. CKD is a major public health challenge associated with increased morbidity and mortality, yet the natural history of early-stage disease in population settings remains poorly defined. We conducted a retrospective cohort study using linked pathology and hospital data for adults with incident CKD between 2006 and 2022. CKD stage was defined by two estimated glomerular filtration rate (eGFR) values ≥ 3 and < 12 months apart: mild (45-59), moderate (30-44) and severe (15-29) mL/min/1.73 m2. Outcomes were assessed over 5 years using a competing risks framework. Among 153 527 individuals with incident CKD during the study period (mean age 75.6 years, 52.6% women) 118 248 had mild, 58 323 moderate and 20 322 severe CKD. At 5 years, death occurred in 16.8% (mild), 26.7% (moderate) and 30.5% (severe); kidney failure occurred in 0.6%, 2.5% and 30.0%, respectively. CKD progression was more common than regression in mild (20.1% vs. 11.8%) and moderate (18.9% vs. 14.5%) disease. Albuminuria testing was recorded in < 35% of patients. People with early-stage CKD face substantial risks of progression, kidney failure and death within 5 years. The low rate of albuminuria testing suggests missed opportunities for early identification of high-risk individuals and timely intervention. Enhancing CKD detection and monitoring in primary care may improve outcomes.