Sustainable varicose vein therapy using functionalized hydrogels derived solely from livestock waste

Developing sustainable and effective treatments for chronic venous insufficiency (CVI) is crucial. In this study, we propose an innovative restorative approach utilizing hydrogels derived from the decellularized extracellular matrix (dECM) of cadaveric vascular tissues, adipose-derived stem cells (ADSCs), and gold nanoparticles (AuNPs). This therapeutic method leverages waste valorization by repurposing discarded cadaveric tissues from slaughterhouse livestock. The dECM hydrogels, enriched with ADSCs and AuNPs, offer a biocompatible scaffold that supports cellular differentiation and vascular integrity. Our approach addresses the limitations of current allo-, auto-, and xenograft methods by enhancing integration and functionality while potentially reducing costs through sustainable practices. This study explores functionalized hydrogel formulation solely generated from agri-food waste, gelation mechanisms, and preliminary cost-effectiveness, presenting a promising new avenue for treating early-stage varicose veins that can ultimately be translated to human models using discarded tissues

Multicenter, prospective cohort study of oesophageal injuries and related clinical outcomes (MUSOIC study)

Objective: To identify prognostic factors associated with 90-day mortality in patients with oesophageal perforation (OP), and characterize the specific timeline from presentation to intervention, and its relation to mortality. Background: OP is a rare gastro-intestinal surgical emergency with a high mortality rate. However, there is no updated evidence on its outcomes in the context of centralized esophago-gastric services; updated consensus guidelines; and novel non-surgical treatment strategies. Methods: A multi-center, prospective cohort study involving eight high-volume esophago-gastric centers (January 2016 to December 2020) was undertaken. The primary outcome measure was 90-day mortality. Secondary measures included length of hospital and ICU stay, and complications requiring re-intervention or re-admission. Mortality model training was performed using random forest, support-vector machines, and logistic regression with and without elastic net regularisation. Chronological analysis was performed by examining each patient’s journey timepoint with reference to symptom onset. Results: The mortality rate for 369 patients included was 18.9%. Patients treated conservatively, endoscopically, surgically, or combined approaches had mortality rates of 24.1%, 23.7%, 8.7%, and 18.2%, respectively. The predictive variables for mortality were Charlson comorbidity index, haemoglobin count, leucocyte count, creatinine levels, cause of perforation, presence of cancer, hospital transfer, CT findings, whether a contrast swallow was performed, and intervention type. Stepwise interval model showed that time to diagnosis was the most significant contributor to mortality. Conclusion: Non-surgical strategies have better outcomes and may be preferred in selected cohorts to manage perforations. Outcomes can be significantly improved through better risk-stratification based on afore-mentioned modifiable risk factors

LAsting Symptoms after Oesophageal Resectional Surgery (LASORS): multicentre validation cohort study

BackgroundLong-term symptom burden and health-related quality-of-life outcomes after curative oesophageal cancer treatment are poorly understood. Existing tools are cumbersome and do not address the post-treatment population specifically. The aim of this study was to validate the six-symptom LASORS tool for identifying patients after curative oesophageal cancer treatment with poor health-related quality of life and to assess its clinical utility.MethodsBetween 2015 and 2019, patients from 15 UK centres who underwent curative-intent oesophageal cancer treatment, and were disease-free at least 1 year after surgery, were invited to participate in the study and complete LASORS and European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-OG25 questionnaires. Receiver operating characteristic curve analysis was used to examine the accuracy of the LASORS tool for identifying patients with poor health-related quality of life.ResultsA total of 263 patients completed the questionnaire. Four of the six LASORS symptoms were associated with poor health-related quality of life: reduced energy (OR 2.13 (95% c.i. 1.45 to 3.13)); low mood (OR 1.86 (95% c.i. 1.20 to 2.88)); diarrhoea more than three times a day unrelated to eating (OR 1.48 (95% c.i. 1.06 to 2.07)); and bloating or cramping after eating (OR 1.35 (95% c.i. 1.03 to 1.77)). The LASORS tool showed good diagnostic accuracy with an area under the receiver operating characteristic curve of 0.858 for identifying patients with poor health-related quality of life.ConclusionThe six-symptom LASORS tool generated a reliable model for identification of patients with poor health-related quality of life after curative treatment for oesophageal cancer. This is the first tool of its kind to be prospectively validated in the post-esophagectomy population. Clinical utility lies in identification of patients at risk of poor health-related quality of life, ease of use of the tool, and in planning survivorship services

Patient-specific cancer genes contribute to recurrently perturbed pathways and establish therapeutic vulnerabilities in esophageal adenocarcinoma

Abstract: The identification of cancer-promoting genetic alterations is challenging particularly in highly unstable and heterogeneous cancers, such as esophageal adenocarcinoma (EAC). Here we describe a machine learning algorithm to identify cancer genes in individual patients considering all types of damaging alterations simultaneously. Analysing 261 EACs from the OCCAMS Consortium, we discover helper genes that, alongside well-known drivers, promote cancer. We confirm the robustness of our approach in 107 additional EACs. Unlike recurrent alterations of known drivers, these cancer helper genes are rare or patient-specific. However, they converge towards perturbations of well-known cancer processes. Recurrence of the same process perturbations, rather than individual genes, divides EACs into six clusters differing in their molecular and clinical features. Experimentally mimicking the alterations of predicted helper genes in cancer and pre-cancer cells validates their contribution to disease progression, while reverting their alterations reveals EAC acquired dependencies that can be exploited in therapy

The development and validation of a scoring tool to predict the operative duration of elective laparoscopic cholecystectomy.

Peer reviewe

Sex differences in oncogenic mutational processes.

Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research

CXCR5⁺ follicular cytotoxic T cells control viral infection in B cell follicles

During unresolved infections, some viruses escape immunological control and establish a persistant reservoir in certain cell types, such as human immunodeficiency virus (HIV), which persists in follicular helper T cells (TFH cells), and Epstein-Barr virus (EBV), which persists in B cells. Here we identified a specialized group of cytotoxic T cells (TC cells) that expressed the chemokine receptor CXCR5, selectively entered B cell follicles and eradicated infected TFH cells and B cells. The differentiation of these cells, which we have called 'follicular cytotoxic T cells' (TFC cells), required the transcription factors Bcl6, E2A and TCF-1 but was inhibited by the transcriptional regulators Blimp1, Id2 and Id3. Blimp1 and E2A directly regulated Cxcr5 expression and, together with Bcl6 and TCF-1, formed a transcriptional circuit that guided TFC cell development. The identification of TFC cells has far-reaching implications for the development of strategies to control infections that target B cells and TFH cells and to treat B cell–derived malignancies

Evacetrapib and Cardiovascular Outcomes in High-Risk Vascular Disease

BACKGROUND: The cholesteryl ester transfer protein inhibitor evacetrapib substantially raises the high-density lipoprotein (HDL) cholesterol level, reduces the low-density lipoprotein (LDL) cholesterol level, and enhances cellular cholesterol efflux capacity. We sought to determine the effect of evacetrapib on major adverse cardiovascular outcomes in patients with high-risk vascular disease. METHODS: In a multicenter, randomized, double-blind, placebo-controlled phase 3 trial, we enrolled 12,092 patients who had at least one of the following conditions: an acute coronary syndrome within the previous 30 to 365 days, cerebrovascular atherosclerotic disease, peripheral vascular arterial disease, or diabetes mellitus with coronary artery disease. Patients were randomly assigned to receive either evacetrapib at a dose of 130 mg or matching placebo, administered daily, in addition to standard medical therapy. The primary efficacy end point was the first occurrence of any component of the composite of death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina. RESULTS: At 3 months, a 31.1% decrease in the mean LDL cholesterol level was observed with evacetrapib versus a 6.0% increase with placebo, and a 133.2% increase in the mean HDL cholesterol level was seen with evacetrapib versus a 1.6% increase with placebo. After 1363 of the planned 1670 primary end-point events had occurred, the data and safety monitoring board recommended that the trial be terminated early because of a lack of efficacy. After a median of 26 months of evacetrapib or placebo, a primary end-point event occurred in 12.9% of the patients in the evacetrapib group and in 12.8% of those in the placebo group (hazard ratio, 1.01; 95% confidence interval, 0.91 to 1.11; P=0.91). CONCLUSIONS: Although the cholesteryl ester transfer protein inhibitor evacetrapib had favorable effects on established lipid biomarkers, treatment with evacetrapib did not result in a lower rate of cardiovascular events than placebo among patients with high-risk vascular disease. (Funded by Eli Lilly; ACCELERATE ClinicalTrials.gov number, NCT01687998 .)

Burdens of type 2 diabetes and cardiovascular disease attributable to sugar-sweetened beverages in 184 countries

The consumption of sugar-sweetened beverages (SSBs) is associated with type 2 diabetes (T2D) and cardiovascular diseases (CVD). However, an updated and comprehensive assessment of the global burden attributable to SSBs remains scarce. Here we estimated SSB-attributable T2D and CVD burdens across 184 countries in 1990 and 2020 globally, regionally and nationally, incorporating data from the Global Dietary Database, jointly stratified by age, sex, educational attainment and urbanicity. In 2020, 2.2 million (95% uncertainty interval 2.0-2.3) new T2D cases and 1.2 million (95% uncertainty interval 1.1-1.3) new CVD cases were attributable to SSBs worldwide, representing 9.8% and 3.1%, respectively, of all incident cases. Globally, proportional SSB-attributable burdens were higher among men versus women, younger versus older adults, higher- versus lower-educated adults, and adults in urban versus rural areas. By world region, the highest SSB-attributable percentage burdens were in Latin America and the Caribbean (T2D: 24.4%; CVD: 11.3%) and sub-Saharan Africa (T2D: 21.5%; CVD: 10.5%). From 1990 to 2020, the largest proportional increases in SSB-attributable incident T2D and CVD cases were in sub-Saharan Africa (+8.8% and +4.4%, respectively). Our study highlights the countries and subpopulations most affected by cardiometabolic disease associated with SSB consumption, assisting in shaping effective policies and interventions to reduce these burdens globally.The GDD estimates that underlie this research were supported by the Gates Foundation (grant OPP1176682 to D.M.). This analysis was further supported by the American Heart Association (grant 903679 to L.L.-C.) and Consejo Nacional de Ciencia y Tecnología in Mexico (to L.L.-C.). We acknowledge the Tufts University High Performance Computing Cluster (https://it.tufts.edu/high-performance-computing), which was used for the research reported in this paper. This cluster is based on work supported by the National Science Foundation (grant 2018149) and is under active development by Research Technology, Tufts Technology Services. The funding agencies had no role in the design of the study; collection, management, analysis or interpretation of the data; preparation, review or approval of the paper; or decision to submit for publication.Scopu