Enteropathy-associated T cell lymphoma subtypes are characterized by loss of function of SETD2

Enteropathy-associated T cell lymphoma (EATL) is a lethal, and the most common, neoplastic complication of celiac disease. Here, we defined the genetic landscape of EATL through whole-exome sequencing of 69 EATL tumors. SETD2 was the most frequently silenced gene in EATL (32% of cases). The JAK-STAT pathway was the most frequently mutated pathway, with frequent mutations in STAT5B as well as JAK1 , JAK3 , STAT3 , and SOCS1 . We also identified mutations in KRAS , TP53 , and TERT . Type I EATL and type II EATL (monomorphic epitheliotropic intestinal T cell lymphoma) had highly overlapping genetic alterations indicating shared mechanisms underlying their pathogenesis. We modeled the effects of SETD2 loss in vivo by developing a T cell–specific knockout mouse. These mice manifested an expansion of γδ T cells, indicating novel roles for SETD2 in T cell development and lymphomagenesis. Our data render the most comprehensive genetic portrait yet of this uncommon but lethal disease and may inform future classification schemes

The Genetic Basis of Hepatosplenic T-cell Lymphoma

Hepatosplenic T cell lymphoma (HSTL) is a rare and lethal lymphoma; the genetic drivers of this disease are unknown. Through whole exome sequencing of 68 HSTLs, we define recurrently mutated driver genes and copy number alterations in the disease. Chromatin modifying genes including SETD2, INO80 and ARID1B were commonly mutated in HSTL, affecting 62% of cases. HSTLs manifest frequent mutations in STAT5B (31%), STAT3 (9%), and PIK3CD (9%) for which there currently exist potential targeted therapies. In addition, we noted less frequent events in EZH2, KRAS and TP53. SETD2 was the most frequently silenced gene in HSTL. We experimentally demonstrated that SETD2 acts as a tumor suppressor gene. In addition, we found that mutations in STAT5B and PIK3CD activate critical signaling pathways important to cell survival in HSTL. Our work thus defines the genetic landscape of HSTL and implicates novel gene mutations linked to HSTL pathogenesis and potential treatment targets

Therapeutic Impact of Cytoreductive Surgery and Irradiation of Posterior Fossa Ependymoma in the Molecular Era: A Retrospective Multicohort Analysis

Posterior fossa ependymoma comprises two distinct molecular variants termed EPN_PFA and EPN_PFB that have a distinct biology and natural history. The therapeutic value of cytoreductive surgery and radiation therapy for posterior fossa ependymoma after accounting for molecular subgroup is not known

Validity and Validation in Social, Behavioral, and Health Sciences

XV, 327 p. 15 illus., 2 illus. in color.online re

Clinical and patient-reported outcomes of Chinese patients undergoing haemodialysis in hospital or in the community: A 1-year longitudinal study

© 2015 The Authors Nephrology published by Wiley Publishing Asia Pty Ltd on behalf of Asian Pacific Society of Nephrology Aim: Little is known about the effect of haemodialysis (HD) setting on outcomes of patients with end stage renal disease (ESRD). The study aimed at comparing clinical outcomes and patient-reported outcomes (PRO) of patients on community-based (CBHD) and hospital-based haemodialysis (HBHD). Methods: A prospective cohort of Chinese ESRD patients receiving HBHD (n = 89) or CBHD (n = 117) in Hong Kong were followed up for 12 months. Subjects were assessed on clinical outcomes of dialysis adequacy (Kt/V) and blood haemoglobin and PRO of health-related quality of life (SF-12v2), general health condition (Global Rating Scale (GRS)) and confidence to cope with their illness (Patient Enablement Instrument (PEI)). Differences between groups were analyzed by independent t-tests for the SF-12v2, GRS and PEI scores. Ï 2 tests were used to analyze the difference in proportion of patients reaching the targets of Kt/V and blood haemoglobin and with GRS > 0 and PEI > 0. Multiple linear and logistic regressions were performed to assess the adjusted difference-in-difference estimation. Results: The mean PEI and GRS scores of CBHD patients at 12 months were significantly higher than those of HBHD patients. CBHD patients had significantly greater improvement in self-efficacy and were more likely to be enabled after 12 months than the HBHD patients. Conclusion: The study showed similar clinical outcomes and PRO between CBHD and HBHD but CBHD was more effective than HBHD in promoting patient enablement over a 12-month period. The results suggest added value for patients receiving CBHD and support the transfer of HD care from the hospital to the community.Link_to_subscribed_fulltex

The comparative effects of metabolic surgery, SGLT2i, or GLP-1RA in patients with obesity and type 2 diabetes: a retrospective cohort study Corresponding

Background: New antidiabetic agents (sodium-glucose cotransporter-2 inhibitor [SGLT2i] and glucagon-like peptide-1 receptor agonist [GLP-1RA]) and metabolic surgery have protective effects on metabolic syndromes. Objectives: To compare the changes of metabolic parameters and costs among patients with obesity and type 2 diabetes undergoing metabolic surgery and initiating new antidiabetic agents over 12 months. Setting: Hong Kong Hospital Authority database from 2006 to 2017. Methods: This is a population-wide retrospective cohort study consisting of 2,616 patients (1,810 SGLT2i, 528 GLP-1RA, 278 metabolic surgery). Inverse probability treatment weighting of propensity score was applied to balance baseline covariates of patients with obesity and type 2 diabetes who underwent metabolic surgery, or initiated SGLT2i or GLP-1RA. Metabolic parameters and direct medical costs were measured and compared from baseline to 12 months in bariatric surgery, SGLT2i, and GLP-1RA groups. Results: Patients in all 3 groups had improved metabolic parameters over a 12-month period. Patients with metabolic surgery achieved significantly better outcomes in BMI (-5.39, -0.56, -0.40 kg/m2, p<0.001), % total weight loss (15.16%, 1.34%, 1.63%, p<0.001), systolic (-2.21, -0.59, 1.28 mmHg, p<0.001) and diastolic (-1.16, 0.50, -0.13 mmHg, p<0.001) blood pressure, HbA1c (-1.80%, -0.77%, -0.80%, p<0.001), triglycerides (-0.64, -0.11, -0.09 mmol/L, p<0.001), and estimated glomerular filtration rate (3.08, -1.37, -0.41 ml/min/1.73m2, p<0.001) after 12-month compared with patients with SGLT2i and GLP1-RA. Although the metabolic surgery group incurred the greatest direct medical costs (US$33,551, US$10,945, US$10,627, p<0.001), largely due to the surgery itself, the total monthly direct medical expenditure of metabolic surgery group became lower than that of SGLT2i and GLP1RA groups at 7 months. Conclusions: Beneficial weight loss and metabolic outcomes at 12-months were observed in all 3 groups, among which the metabolic surgery group showed the most remarkable effects but incurred the greatest medical costs. However, studies with a longer follow-up period are warranted to show long-term outcomes

Risk of autoimmune diseases following COVID-19 and the potential protective effect from vaccination: a population-based cohort studyResearch in context

Summary: Background: Case reports suggest that SARS-CoV-2 infection could lead to immune dysregulation and trigger autoimmunity while COVID-19 vaccination is effective against severe COVID-19 outcomes. We aim to examine the association between COVID-19 and development of autoimmune diseases (ADs), and the potential protective effect of COVID-19 vaccination on such an association. Methods: A retrospective cohort study was conducted in Hong Kong between 1 April 2020 and 15 November 2022. COVID-19 was confirmed by positive polymerase chain reaction or rapid antigen test. Cox proportional hazard regression with inverse probability of treatment weighting was applied to estimate the risk of incident ADs following COVID-19. COVID-19 vaccinated population was compared against COVID-19 unvaccinated population to examine the protective effect of COVID-19 vaccination on new ADs. Findings: The study included 1,028,721 COVID-19 and 3,168,467 non-COVID individuals. Compared with non-COVID controls, patients with COVID-19 presented an increased risk of developing pernicious anaemia [adjusted Hazard Ratio (aHR): 1.72; 95% Confidence Interval (CI): 1.12–2.64]; spondyloarthritis [aHR: 1.32 (95% CI: 1.03–1.69)]; rheumatoid arthritis [aHR: 1.29 (95% CI: 1.09–1.54)]; other autoimmune arthritis [aHR: 1.43 (95% CI: 1.33–1.54)]; psoriasis [aHR: 1.42 (95% CI: 1.13–1.78)]; pemphigoid [aHR: 2.39 (95% CI: 1.83–3.11)]; Graves' disease [aHR: 1.30 (95% CI: 1.10–1.54)]; anti-phospholipid antibody syndrome [aHR: 2.12 (95% CI: 1.47–3.05)]; immune mediated thrombocytopenia [aHR: 2.1 (95% CI: 1.82–2.43)]; multiple sclerosis [aHR: 2.66 (95% CI: 1.17–6.05)]; vasculitis [aHR: 1.46 (95% CI: 1.04–2.04)]. Among COVID-19 patients, completion of two doses of COVID-19 vaccine shows a decreased risk of pemphigoid, Graves' disease, anti-phospholipid antibody syndrome, immune-mediated thrombocytopenia, systemic lupus erythematosus and other autoimmune arthritis. Interpretation: Our findings suggested that COVID-19 is associated with an increased risk of developing various ADs and the risk could be attenuated by COVID-19 vaccination. Future studies investigating pathology and mechanisms would be valuable to interpreting our findings. Funding: Supported by RGC Collaborative Research Fund (C7154-20GF)

Cost-effectiveness of an early assessment service for young people with early psychosis in Hong Kong

Objective: The Early Assessment Service for Young People with Early Psychosis (EASY) was developed in Hong Kong in 2001 to provide a comprehensive and integrated approach for early detection and intervention for young people suffering from first episode psychosis. The present study examined the cost-effectiveness of the service over a period of 24 months compared to standard care. Method: This is a historical control study. Sixty-five patients who presented to the EASY service in 2001 with first episode psychosis were individually matched (on age, sex and diagnosis) with 65 patients who received standard psychiatric care in a precursor service (pre-EASY) between 1999 and 2000. A retrospective cost-effectiveness analysis was conducted over a period of 24 months. The overall average cost of service utilization per patient and the effects on hospitalization rate were compared using bootstrapping analysis. Cost per point improvement in Positive and Negative Syndrome Scale (PANSS) was also computed with sensitivity analysis. Only direct costs were analysed in the current study. Results: There was no significant difference in service utilization between the EASY and pre-EASY standard care groups. The cost-effectiveness acceptability curve, which was used to explore uncertainty in estimates of cost and effects, suggested that there was a probability of at least 94% that the EASY model was more cost-effective than the pre-EASY service in reducing psychiatric inpatient admissions. EASY patients also showed superior results in average cost per unit improvement in PANSS. Conclusions: EASY is likely to be more cost-effective in improving outcomes, particularly in reducing hospitalization and improving clinical symptoms among young people with first episode psychosis. This study provides a perspective from the east Asian region, and supports further development of similar services, particularly in the local setting. However, further studies with a longer follow up period and larger sample size are required to verify these findings. © 2011 The Royal Australian and New Zealand College of Psychiatrists.link_to_subscribed_fulltex