Citations

Abstract Background and Aims Truncating variants in the TTN gene (TTNtv) are the most common genetic cause of dilated cardiomyopathy (DCM) but also occur as incidental findings in the general population. This study investigated factors associated with the clinical manifestation of TTNtv. Methods An international multicentre retrospective observational study was performed in families with TTNtv-related DCM. Shared frailty models were used to estimate associations of variant characteristics with lifetime risk of DCM, and logistic regression to estimate odds ratios (ORs) for individual-level clinical risk factor profiles (cardiac conditions, cardiovascular comorbidities, lifestyle) and DCM. Results A total of 3158 subjects in 1043 families with TTNtv-related DCM were studied. TTNtv-positive subjects were 21-fold more likely to develop DCM [OR, 21.21; 95% confidence interval (CI), 14.80–30.39]. Disease onset was earlier in males, but was similar for TTNtv of different types and locations. The presence of clinical risk factors was associated with earlier DCM onset (OR, 3.41; 95% CI, 2.06–5.64), with a prior history of atrial fibrillation having a two-fold increased odds of DCM (OR, 2.05; 95% CI, 1.27–3.32). The prevalence of clinical risk factors increased with age; however, the strength of the DCM association was greatest for young-onset (<30 years) disease (OR, 4.75; 95% CI, 2.35–9.60). Administration of beta-adrenergic receptor or renin-angiotensin system-blocking drugs prior to overt DCM was associated with 87% reduced odds of DCM (OR, .13; 95% CI, .08–.23). Conclusions Disease onset in TTNtv-associated familial DCM is dependent on individual patient context and is potentially modifiable by risk factor management and prophylactic therapeutic intervention.

This consensus by the Society of Abdominal Radiology Inflammatory Bowel Disease Disease Focused Panel provides an updated imaging-based definition of small bowel Crohn disease stricture for CT and MR enterography.

Abstract Background Indigenous populations worldwide experience unjust inequities in surgical outcomes. In Aotearoa New Zealand, Indigenous Māori experience poorer health outcomes, including higher rates of postoperative mortality. The aim of this study was to quantify ethnic disparities in ‘failure to rescue’ (FTR), complications, and mortality following gastrointestinal cancer surgery and to analyse trends over time. Methods A retrospective national population-based cohort study of patients undergoing resection for gastrointestinal and hepatopancreatobiliary cancers from 2005 to 2020 was conducted. Self-reported ethnicity data were collected at the time of surgery. The primary outcome was FTR, defined as mortality following a complication within 90 days of surgery. Results In total, 31 185 patients were included; 2479 (7.9%) were Māori, 46.5% were female, and the median age was 71 (interquartile range 62–78) years. Māori patients were younger and had higher levels of socio-economic deprivation and co-morbidity. Māori had higher age-standardized rates of mortality (5.9% versus 3.2%), complications (52.9% versus 42.4%), and FTR (10.8% versus 7.2%), compared with European/Other. Multivariable regression demonstrated higher odds of mortality (adjusted OR (aOR) 1.45 (95% c.i. 1.15–1.82)), complications (aOR 1.30 (95% c.i. 1.17–1.45)), and FTR (aOR 1.29 (95% c.i. 1.01–1.62)) for Māori. Analysis over time showed a significant improvement in risk-adjusted rates of mortality (6.2% in 2005–2008 versus 3.4% in 2017–2020) and FTR (7.3% in 2005–2008 versus 4.0% in 2017–2020) for European/Other, but no change for Māori (rates of mortality were 6.6% in 2005–2008 versus 5.4% in 2017–2020 and rates of FTR were 7.8% in 2005–2008 versus 6.3% in 2017–2020). Conclusion Widening inequities in FTR have worsened disparities in postoperative mortality for Māori patients. ‘Complication rescue’ is a target to reduce inequities and improve perioperative care for Māori patients.

ABSTRACT Knowledge of Treponema pallidum subspecies pallidum ( TPA ) outer membrane protein (OMP) sequence variability is essential for understanding spirochete proliferation within endemic populations as well as the design of a globally effective syphilis vaccine. Our group has identified extracellular loops (ECLs) of TPA BamA (TP0326) and members of the FadL family (TP0548, TP0856, TP0858, TP0859, and TP0865) as potential components of a multivalent vaccine cocktail. As part of a consortium to explore TPA strain diversity, we mapped the variability of BamA and FadL orthologs in 186 TPA strains from Malawi, China, and Colombia onto predicted 3D structures. The 186 genomes fell into eight subclades (five Nichols- and three SS14-lineage) with substantial geographic restriction. Single nucleotide variants accounted for the large majority of proteoforms, with variability notably higher within the Nichols-lineage strains. Most mutations were in regions of the proteins predicted to be extracellular and harboring B cell epitopes. We observed a striking difference in the degree of variability between the six OMPs, suggesting that these proteins are following divergent evolutionary paths. Concatenation of OMP sequences recapitulated the phylogenetic structure of the TPA strains, effectively segregating within clades and largely clustering by subclades. Finally, we noted that BamA and FadL candidate ECL vaccinogens, previously shown to elicit antibodies that kill treponemes during in vitro cultivation, are well conserved. Taken as a whole, our study establishes a structural-phylogenetic approach for analyzing the forces shaping the host-pathogen interface in syphilis within endemic populations while informing the selection of vaccine targets. IMPORTANCE Syphilis remains a major global health concern, reinforcing the need for a safe and effective vaccine. Understanding the variability of TPA OMPs is essential for tracking pathogen evolution and informing vaccine design. Here, we analyzed the variability of six TPA OMPs in 186 strains from Malawi, China, and Colombia, identifying protein-specific evolutionary patterns. Most mutations were localized in extracellular regions and, notably, appeared to correlate with the phylogenetic structure of TPA . Despite OMP heterogeneity, several candidate vaccinogens remained highly conserved, reinforcing their potential as globally effective vaccine targets. Our study establishes a structural-phylogenetic framework for dissecting the forces shaping the host-spirochete interface within endemic populations and provides a foundation for designing a globally effective syphilis vaccine.