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Abstract Follicular lymphoma (FL) exhibits considerable variability in biological features and clinical trajectories across patients. To dissect the diversity of FL, we utilized a Bernoulli mixture model to identify genetic subtypes in 713 pre-treatment tumor tissue samples. Our analysis revealed the existence of five subtypes with unique genetic profiles that correlated with clinicopathological characteristics. The clusters were enriched in specific mutations as follows: CS (CREBBP and STAT6), TT (TNFAIP3 and TP53), GM (GNA13 and MEF2B), Q (quiescent, for low mutation burden), and AR (mutations of mTOR pathway-related genes). The subtype Q was enriched for patients with stage I disease and associated with a lower proliferative history than the other subtypes. The AR subtype was unique in its enrichment for IgM-expressing FL cases and was associated with advanced-stage and more than 4 nodal sites. The existence of subtypes was validated in an independent cohort of 418 samples from the GALLIUM trial. Notably, patients assigned to the TT subtype consistently experienced inferior progression-free survival when treated with immunochemotherapy. Our findings offer insight into core pathways distinctly linked with each FL cluster and are expected to be informative in the era of targeted therapies.

Abstract Background Government interest in investing in commercial physical activity apps has increased with little evidence of their cost-effectiveness. This is the first study to our knowledge to examine the cost-effectiveness of a commercial physical activity app (Carrot Rewards) despite there being over 100,000 in the major app stores. Methods A cost-effectiveness analysis was performed to calculate the incremental cost-effectiveness ratio (ICER) of the app compared to a no-intervention reference scenario using a five-year time horizon. Primary data was collected between 2016 and 2017. Data synthesis, model creation, and statistical analyses were conducted between 2019 and 2020. An age-, sex-, and geography-dependent Markov model was developed assuming a public healthcare payer perspective. A closed cohort (n = 38,452) representing the population reached by Carrot Rewards in two Canadian provinces (British Columbia, Newfoundland & Labrador) at the time of a 12-month prospective study was used. Costs and effects were both discounted at 1.5% and expressed in 2015 Canadian dollars. Subgroup analyses were conducted to compare ICERs between provinces, sexes, age groups, and engagement levels. Results Carrot Rewards had an ICER of $11,113 CAD per quality adjusted life year (QALY), well below a $50,000 CAD per QALY willingness-to-pay (WTP) threshold. Subgroup analyses revealed that the app had lower ICERs for British Columbians, females, highly engaged users, and adults aged 35-64 yrs., and was dominant for older adults (65 + yrs). Deterministic sensitivity analyses revealed that the ICER was most influenced by the relative risk of diabetes. Probabilistic sensitivity analyses revealed varying parameter estimates predominantly resulted in ICERs below the WTP threshold. Conclusions The Carrot Rewards app was cost-effective, and dominant for older adults. These results provide, for the first time, rigorous health economic evidence for a commercial physical activity app as part of public health programming.

Autoimmune bullous diseases (AIBDs) are a group of skin-related disorders that involve damage to structures maintaining cell-cell adhesion, such as desmosomes and hemidesmosomes. Key autoimmune bullous diseases include pemphigus related diseases, pemphigoid related conditions, acquired epidermolysis bullosa (EBA), and dermatitis herpetiformis (DH). Each group of conditions exhibits characteristic clinical lesion patterns and is associated with specific autoantibodies targeting epidermal and dermal structures involved in cell-cell adhesion and skin integrity. Pemphigus diseases primarily target desmoglein (Dsg) 3 and Dsg1 proteins but several non-desmoglein autoantibodies have also been linked to pemphigus. Pemphigoid diseases typically target BP (bullous pemphigoid)180 and BP230; EBA is associated with antibodies directed against anti-type VII collagen; and DH by IgA autoantibodies against tissue transglutaminase and deaminated gliadin. Investigation into the serological biomarkers found in autoimmune bullous diseases have allowed the development of diagnostic assessments (ie. tissue antibody detection and serological testing) based on the unique autoantibody profiles of a particular disease group. The methods for the detection and quantification of disease-associated autoantibodies continue to evolve and improve.

Background Surgical site infections (SSIs) are morbid and costly complications after elective colorectal surgery. SSI prevention bundles have been shown to reduce SSI in colorectal surgery, but their impact on organ space infections (OSI) is variable. Adoption of an evidence-based practice without an implementation strategy is often unsuccessful. Our aim was to successfully implement an OSI prevention bundle and to achieve a cost-effective reduction in OSI following elective left-sided colorectal operations.Methods The Translating Research into Practice model was used to implement an OSI prevention bundle in all patients undergoing elective left-sided colorectal resections by a single unit from November 2018 to September 2019. The new components included oral antibiotics with mechanical bowel preparation, when required, and use of impermeable surgical gowns. Other standardised components included alcoholic chlorhexidine skin preparation, glove change after bowel handling prior to wound closure with clean instruments. The primary outcome was OSI. Secondary outcomes included bundle compliance, unintended consequences and total patient costs. Outcomes were compared with all patients undergoing elective left-sided colorectal resections at the same institution in 2017.Results Elective colorectal resections were performed in 173 patients across two cohorts. The compliance rate with bundle items was 63% for all items and 93% for one omitted item. There was a reduction in OSI from 12.9% (11 of 85) to 3.4% (3 of 88, p

Abstract Background At low levels, carbon monoxide (CO) has been shown to have beneficial effects on multiple organs and tissues through its potential anti-inflammatory, anti-apoptotic, and anti-proliferative properties. However, the effect of CO-releasing molecule (CORM)-3, a water-soluble CORM, on ischemic stroke and its mechanism of action are still unclear. Methods We investigated the role of CORM-3 in the mouse model of transient middle cerebral artery occlusion (tMCAO). CORM-3 or saline was administered to mice by retro-orbital injection at the time of reperfusion after 1-h tMCAO or at 1 h after sham surgery. We assessed infarct volume and brain water content at 24 and 72 h after ischemia, blood-brain barrier permeability at 6 and 72 h after ischemia, and neurologic deficits on days 1, 3, 7, and 14. Results Among mice that underwent tMCAO, those that received CORM-3 had significantly smaller infarct volume and greater expression of neuronal nuclear antigen (NeuN) and microtubule-associated protein 2 than did saline-treated mice. CORM-3-treated mice had significantly fewer activated microglia in the peri-infarction zone than did control mice and exhibited downregulated expression of ionized calcium-binding adapter molecule (Iba)-1, tumor necrosis factor-α, and interleukin 1β. CORM-3-treated mice had significantly lower brain water content and enhanced neurologic outcomes on days 3, 7, and 14 post-tMCAO. Lastly, CORM-3 treatment reduced Evans blue leakage; increased expression of platelet-derived growth factor receptor-β, tight junction protein ZO-1, and matrix protein laminin; and decreased protein level of matrix metalloproteinase-9. Conclusion CORM-3 treatment at the time of reperfusion reduces ischemia-reperfusion-induced brain injury by suppressing neuroinflammation and alleviating blood-brain barrier disruption. Our data suggest that CORM-3 may provide an effective therapy for ischemic stroke.

Language impairment is a core difficulty in fragile X syndrome (FXS), and yet standardized measures lack the sensitivity to assess developmental changes in the nature of these impairments. Expressive Language Sampling Narrative (ELS-N) has emerged as a promising new measure with research demonstrating its usefulness in a wide range of ages in developmental disabilities and typical development. We examined ELS-N results in FXS and age-matched typically developing (TD) controls along with cognitive, adaptive, and clinical measures. We found the groups differed significantly on all ELS-N variables. Cognitive abilities were related to lexical diversity, syntactic complexity, and unintelligibility for the FXS group, but only verbal abilities were related to syntactic complexity in TD. Autism spectrum disorder (ASD) symptomatology was related to less intelligibility in speech. Measures of hyperactivity were related to increased talkativeness and unintelligibility. In addition, FXS males in comparison to FXS females were more impaired in cognitive ability, ASD symptoms, hyperactivity, and anxiety. This study extends the previous ELS research, supporting its use in FXS research as a measure to characterize language abilities. It also demonstrates the relationships between ELS-N variables and measures of cognitive, adaptive, ASD symptoms, and clinical symptoms.

Objective We investigated the diagnostic performance of semi-quantitative hyperintensity on T2-weighted short-tau-inversion-recovery black-blood (T2W-STIR-BB) images in identifying active cardiac sarcoidosis (CS) in patients, and compared it with that of 18F-fluoro-2-deoxyglucose positron emission tomography (FDG-PET).Methods This retrospective study included 40 steroid-naive patients (age 63.1±12.9 years, 20 men) diagnosed with CS who underwent both cardiac MRI and FDG-PET imaging. Active CS cases were defined as satisfying at least one of the following criteria for conventional indices: exacerbation of ventricular arrhythmia, newly identified advanced atrioventricular block, greater than 5% decrease in left ventricular ejection fraction on echocardiography, positive finding on gallium-scintigraphy or elevated levels of sarcoidosis-related serum biomarkers. T2W-STIR-BB images were semi-quantitatively analysed using a myocardium-to-spleen ratio (MSR). The diagnostic performance of T2W-STIR-BB and FDG-PET imaging for detecting active CS was investigated.Results Thirty-three patients satisfied at least one criterion and were considered as having active CS. Thirty patients (75%) tested positive with T2W-STIR-BB imaging, and 25 patients (63%) tested positive with FDG-PET. The sensitivity, specificity, accuracy, and positive and negative predictive values for identifying active CS by semi-quantitative MSR on T2W-STIR-BB images were 79%, 43%, 73%, 87% and 30%, respectively. These results were statistically comparable to those of FDG-PET (70%, 71%, 70%, 92% and 33%, respectively).Conclusions When using conventional diagnostic indices for active CS as the gold standard, T2W-STIR-BB imaging demonstrated comparable diagnostic performance to that of FDG-PET. The semi-quantitative analysis of high signal intensity on T2W-STIR-BB images using MSR was useful for detection of active CS.