Mutations, substitutions, and selection: Linking mutagenic processes to cancer using evolutionary theory.

Cancers are the product of evolutionary events, where molecular variation occurs and accumulates in tissues and tumors. Sequencing of this molecular variation informs not only which variants are driving tumorigenesis, but also the mechanisms behind what is fueling mutagenesis. Both of these details are crucial for preventing premature deaths due to cancer, whether it is by targeting the variants driving the cancer phenotype or by measures to prevent exogenous mutations from contributing to somatic evolution. Here, we review tools to determine both molecular signatures and cancer drivers, and avenues by which these metrics may be linked.

Long-term outcomes of great saphenous vein harvest techniques for infrainguinal arterial bypass in a Medicare-matched registry database.

OBJECTIVE: Long-term outcomes for harvesting techniques for great saphenous vein (GSV) and its impact on the outcomes of infrainguinal arterial bypass remains largely unknown. Endoscopic GSV harvesting (EVH) has emerged as a less invasive alternative to conventional open techniques. Using the Vascular Quality initiative Vascular Implant Surveillance & Interventional Outcomes Network (VQI-VISION) database, we compared the long-term outcomes of infrainguinal arterial bypass using open and endoscopic GSV harvest techniques. METHODS: Patients who underwent infrainguinal GSV bypass between 2010 and 2019 were identified in the VQI-VISION Medicare linked database. Long-term outcomes of major/minor amputations, and reinterventions up to 5 years of follow-up were compared between continuous incisions, skip incision, and EVH, with continuous incisions being the reference group. Secondary outcomes included 30- and 90-day readmission, in addition to surgical site infections and patency rates at 6 months to 2 years postoperatively. Survival analysis using Kaplan-Meier curves and Cox regression hazard models were utilized to compare outcomes between groups. To adjust for multiple comparisons between the study groups, a P value of 2.5% was considered significant. RESULTS: Among the 8915 patients included in the study, continuous and skip vein harvest techniques were used in 44.4% and 43.4% of cases each, whereas 12.3% underwent EVH. The utilization of EVH remained relatively stable at around 12% throughout the study period. Compared with GSV harvest using continuous incisions, EVH was associated with higher rates of reintervention at 1 year (46.5% vs 41.3%; adjusted hazard ratio [aHR], 1.22; 95% confidence interval [CI], 1.06-1.41; P = .01]. However, no significant difference was observed between EVH and continuous incisions, and between skip and continuous incisions in terms of long-term reintervention or major and minor amputations on adjusted analysis. Compared with continuous incision vein harvest, both EVH and skip incisions were associated with lower surgical site infection rates within the first 6 months post-bypass (aHR, 0.53; 95% CI, 0.35-0.82 and aHR, 0.68; 95% CI, 0.53-0.87, respectively). Loss of primary, primary-assisted, and secondary patency was higher after EVH compared with continuous incision vein harvest. Among surgeons performing EVH, comparable long-term outcomes were observed regardless of low (<4 cases/year), medium (4-7 cases/year), or high procedural volumes (>7 cases/year). CONCLUSIONS: Despite higher 1-year reintervention rates, EVH for infrainguinal arterial bypass is not associated with a significant difference in long-term reintervention or amputation rates compared with other harvesting techniques. These outcomes are not influenced by procedural volumes for EVH technique.

How multidisciplinary clinics may mitigate socioeconomic barriers to care for chronic limb-threatening ischemia.

OBJECTIVE: Although multidisciplinary clinics improve outcomes in chronic limb-threatening ischemia (CLTI), their role in addressing socioeconomic disparities is unknown. Our institution treats patients with CLTI at both traditional general vascular clinics and a multidisciplinary Limb Preservation Program (LPP). The LPP is in a minority community, providing expedited care at a single facility by a consistent team. We compared outcomes within the LPP with our institution's traditional clinics and explored patients' perspectives on barriers to care to evaluate if the LPP might address them. METHODS: All patients undergoing index revascularization for CLTI from 2014 to 2023 at our institution were stratified by clinic type (LPP or traditional). We collected clinical and socioeconomic variables, including Area Deprivation Index (ADI). Patient characteristics were compared using χ2, Student t, or Mood median tests. Outcomes were compared using log-rank and multivariable Cox analysis. We also conducted semi-structured interviews to understand patient-perceived barriers. RESULTS: From 2014 to 2023, 983 limbs from 871 patients were revascularized; 19.5% of limbs were treated within the LPP. Compared with traditional clinic patients, more LPP patients were non-White (43.75% vs 27.43%; P < .0001), diabetic (82.29% vs 61.19%; P < .0001), dialysis-dependent (29.17% vs 13.40%; P < .0001), had ADI in the most deprived decile (29.38% vs 19.54%; P = .0061), resided closer to clinic (median 6.73 vs 28.84 miles; P = .0120), and had worse Wound, Ischemia, and foot Infection (WIfI) stage (P < .001). There were no differences in freedom from death, major adverse limb event (MALE), or patency loss. Within the most deprived subgroup (ADI >90), traditional clinic patients had earlier patency loss (P = .0108) compared with LPP patients. Multivariable analysis of the entire cohort demonstrated that increasing age, heart failure, dialysis, chronic obstructive pulmonary disease, and increasing WIfI stage were independently associated with earlier death, and male sex was associated with earlier MALE. Ten traditional clinic patients were interviewed via convenience sampling. Emerging themes included difficulty understanding their disease, high visit frequency, transportation barriers, distrust of the health care system, and patient-physician racial discordance. CONCLUSIONS: LPP patients had worse comorbidities and socioeconomic deprivation yet had similar outcomes to healthier, less deprived non-LPP patients. The multidisciplinary clinic's structure addresses several patient-perceived barriers. Its proximity to disadvantaged patients and ability to conduct multiple appointments at a single visit may address transportation and visit frequency barriers, and the consistent team may facilitate patient education and improve trust. Including these elements in a multidisciplinary clinic and locating it in an area of need may mitigate some negative impacts of socioeconomic deprivation on CLTI outcomes.

French early nationwide idecabtagene vicleucel chimeric antigen receptor T-cell therapy experience in patients with relapsed/refractory multiple myeloma (FENIX): A real-world IFM study from the DESCAR-T registry.

Idecabtagene vicleucel (ide-cel), a chimeric antigen receptor T-cell therapy targeting B-cell maturation antigen (BCMA), received early access program (EAP) authorization in France in April 2021 for relapsed/refractory multiple myeloma (RRMM). We conducted a real-world registry-based multicentre observational study in 11 French hospitals to evaluate ide-cel outcomes. Data from 176 RRMM patients who underwent apheresis between June 2021 and November 2022 were collected from the French national DESCAR-T registry. Of these, 159 patients (90%) received ide-cel. Cytokine release syndrome occurred in 90% with 2% grade ≥3, and neurotoxicity occurred in 12% with 3% grade ≥3. Over the first 6 months, the best overall response and ≥complete response rates were 88% and 47% respectively. The median progression-free survival (PFS) from the ide-cel infusion was 12.5 months, the median overall survival (OS) was 20.8 months and the estimated OS rate at 12 months was 73.3%. Patients with extra-medullary disease (EMD) had impaired PFS (6.2 months vs. 14.8 months). On multivariable analysis, EMD and previous exposure to BCMA-targeted immunoconjugate or T-cell-redirecting GPRC5D bispecific antibody were associated with inferior PFS. Our study supports ide-cel's feasibility, safety and efficacy in real-life settings, emphasizing the importance of screening for EMD and considering prior treatments to optimize patient selection.

Socio-economic association of alcohol use disorder and cardiovascular and alcohol-associated liver disease from 2010 to 2019.

BACKGROUNDS AND AIMS: Alcohol use leads to disabilities and deaths worldwide. It not only harms the liver but also causes alcohol use disorder (AUD) and heart disease. Additionally, alcohol consumption contributes to health disparities among different socio-economic groups. METHODS: We estimated global and regional trends in the burden of AUD, liver disease, and cardiovascular disease from alcohol using the methodology of the Global Burden of Disease study. RESULTS: In 2019, the highest disability-adjusted life years rate per 100,000 population was due to AUD (207.31 [95% Uncertainty interval (UI) 163.71-261.66]), followed by alcohol-associated liver disease (ALD) (133.31 [95% UI 112.68-156.17]). The prevalence rate decreased for AUD (APC [annual percentage change] -0.38%) and alcohol-induced cardiomyopathy (APC -1.85%) but increased for ALD (APC 0.44%) and liver cancer (APC 0.53%). Although the mortality rate for liver cancer from alcohol increased (APC 0.30%), mortality rates from other diseases decreased. Between 2010 and 2019, the burden of alcohol-associated complications increased in countries with low and low-middle sociodemographic index (SDI), contributing more significantly to the global burden. CONCLUSION: The global burden of AUD, liver, and cardiovascular disease has been high and increasing over the past decade, particularly for liver complications. Lower SDI countries are contributing more to this global burden. There is a pressing need for effective strategies to address this escalating burden.

PNPLA3 risk allele is associated with risk of hepatocellular carcinoma but not decompensation in compensated cirrhosis.

BACKGROUND: The PNPLA3-rs738409-G, TM6SF2-rs58542926-T, and HSD17B13-rs6834314-A polymorphisms have been associated with cirrhosis, hepatic decompensation, and HCC. However, whether they remain associated with HCC and decompensation in people who already have cirrhosis remains unclear, which limits the clinical utility of genetics in risk stratification as HCC is uncommon in the absence of cirrhosis. We aimed to characterize the effects of PNPLA3, TM6SF2, and HSD17B13 genotype on hepatic decompensation, HCC, and liver-related mortality or liver transplant in patients with baseline compensated cirrhosis. METHODS: We conducted a single-center retrospective study of patients in the Michigan Genomics Initiative who underwent genotyping. The primary predictors were PNPLA3, TM6SF2, and HSD17B13 genotypes. Primary outcomes were either hepatic decompensation, HCC, or liver-related mortality/transplant. We conducted competing risk Fine-Gray analyses on our cohort. RESULTS: We identified 732 patients with baseline compensated cirrhosis. During follow-up, 50% of patients developed decompensation, 13% developed HCC, 24% underwent liver transplant, and 27% died. PNPLA3-rs738409-G genotype was associated with risk of incident HCC: adjusted subhazard hazard ratio 2.42 (1.40-4.17), p=0.0015 for PNPLA3-rs738409-GG vs. PNPLA3-rs738409-CC genotype. The 5-year cumulative incidence of HCC was higher in PNPLA3-rs738409-GG carriers than PNPLA3-rs738409-CC/-CG carriers: 15.6% (9.0%-24.0%) vs. 7.4% (5.2%-10.0%), p<0.001. PNPLA3 genotype was not associated with decompensation or the combined outcome of liver-related mortality or liver transplant. TM6SF2 and HSD17B13 genotypes were not associated with decompensation or HCC. CONCLUSIONS: The PNPLA3-rs738409-G allele is associated with an increased risk of HCC among patients with baseline compensated cirrhosis. People with cirrhosis and PNPLA3-rs738409-GG genotype may warrant more intensive HCC surveillance.

Educating Trainees to Treat Peripheral Arterial Disease: Challenges and Opportunities.

Educating trainees to treat Peripheral Artery Disease (PAD) carries specific contemporary challenges. The national increase of the prevalence of PAD combined with a significant shortage of vascular surgeons creates a need for concern for future management of this complex disease. Over the past 2 decades, traditional (5 + 2) and integrated (0 + 5) paradigms have fostered trainee annual growth and comparable case distribution and volumes in endovascular and open surgical treatment options have been maintained. Close evaluation into not only the absolute numbers of surgical cases, but the level of trainee involvement in each logged case is recommended. Future implementation of the Entrustable Professional Activity (EPA) modules will hopefully assist in ensuring linear development of surgical skill and judgment. Additionally, advances in individual and systems level techniques to enhance skill acquisition in the form of "off-the job training" and simulation-based training may provide an enhancement to traditional technical training methods. Finally, the possibility and role of artificial intelligence in vascular surgery skill training must not be ignored, but carefully explored and utilized to modernize cognitive and technical skill preparation for trainees in the and delivery of care for PAD patients. Overall, the training residents for the treatment of PAD patients will be associated with new challenges that vascular surgery must embrace and surmount to advance our specialty.

Mpox outbreak in Rio de Janeiro, Brazil: A translational approach.

Mpox is a zoonotic disease historically reported in Africa. Since 2003, limited outbreaks have occurred outside Africa. In 2022, the global spread of cases with sustained interhuman transmission and unusual disease features raised public health concerns. We explore the mpox outbreak in Rio de Janeiro (RJ) state, Brazil, in an observational study of mpox-suspected cases from June to December 2022. Data collection relied on a public healthcare notification form. Diagnosis was determined by MPXV-PCR. In 46 confirmed cases, anti-OPXV IgG was determined by ELISA, and seven MPXV genomes were sequenced. A total of 3095 cases were included, 816 (26.3%) with positive MPXV-PCR results. Most positive cases were men in their 30 s and MSM. A total of 285 (34.9%) MPXV-PCR+ patients live with HIV. Eight were coinfected with varicella-zoster virus. Anogenital lesions and adenomegaly were associated with the diagnosis of mpox. Females and individuals under 18 represented 9.4% and 5.4% of all confirmed cases, respectively, showing higher PCR cycle threshold (Ct) values and fewer anogenital lesions compared to adult men. Anti-OPXV IgG was detected in 29/46 (63.0%) patients. All analyzed sequences belonged to clade IIb. In RJ state, mpox presented a diverse clinical picture, represented mainly by mild cases with low complication rates and prominent genital involvement. The incidence in females and children was higher than usually reported. The observation of a bimodal distribution of Ct values, with few positive results, may suggest the need to review the diagnostic criteria in these groups.

A p85 isoform switch enhances PI3K activation on endosomes by a MAP4- and PI3P-dependent mechanism.

Phosphatidylinositol 3-kinase α (PI3Kα) is a heterodimer of p110α catalytic and p85 adaptor subunits that is activated by agonist-stimulated receptor tyrosine kinases. Although p85α recruits p110α to activated receptors on membranes, p85α loss, which occurs commonly in cancer, paradoxically promotes agonist-stimulated PI3K/Akt signaling. p110α localizes to microtubules via microtubule-associated protein 4 (MAP4), facilitating its interaction with activated receptor kinases on endosomes to initiate PI3K/Akt signaling. Here, we demonstrate that in response to agonist stimulation and p85α knockdown, the residual p110α, coupled predominantly to p85ß, exhibits enhanced recruitment with receptor tyrosine kinases to endosomes. Moreover, the p110α C2 domain binds PI3-phosphate, and this interaction is also required to recruit p110α to endosomes and for PI3K/Akt signaling. Stable knockdown of p85α, which mimics the reduced p85α levels observed in cancer, enhances cell growth and tumorsphere formation, and these effects are abrogated by MAP4 or p85ß knockdown, underscoring their role in the tumor-promoting activity of p85α loss.

Nuclear phosphoinositide signaling promotes YAP/TAZ-TEAD transcriptional activity in breast cancer.

The Hippo pathway effectors Yes-associated protein 1 (YAP) and its homolog TAZ are transcriptional coactivators that control gene expression by binding to TEA domain (TEAD) family transcription factors. The YAP/TAZ-TEAD complex is a key regulator of cancer-specific transcriptional programs, which promote tumor progression in diverse types of cancer, including breast cancer. Despite intensive efforts, the YAP/TAZ-TEAD complex in cancer has remained largely undruggable due to an incomplete mechanistic understanding. Here, we report that nuclear phosphoinositides function as cofactors that mediate the binding of YAP/TAZ to TEADs. The enzymatic products of phosphoinositide kinases PIPKIα and IPMK, including phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and phosphatidylinositol 3,4,5-trisphosphate (P(I3,4,5)P3), bridge the binding of YAP/TAZ to TEAD. Inhibiting these kinases or the association of YAP/TAZ with PI(4,5)P2 and PI(3,4,5)P3 attenuates YAP/TAZ interaction with the TEADs, the expression of YAP/TAZ target genes, and breast cancer cell motility. Although we could not conclusively exclude the possibility that other enzymatic products of IPMK such as inositol phosphates play a role in the mechanism, our results point to a previously unrecognized role of nuclear phosphoinositide signaling in control of YAP/TAZ activity and implicate this pathway as a potential therapeutic target in YAP/TAZ-driven breast cancer.

Incidence of liver cancer in young adults according to the Global Burden of Disease database 2019.

BACKGROUND AND AIMS: The worldwide burden of cancer is increasing in younger populations. However, the epidemiology of primary liver cancer remains understudied in young adults compared to other cancer forms. APPROACH AND RESULTS: This study analyzed data from the Global Burden of Disease study between 2010 and 2019 to assess the age-standardized incidence, mortality, and disability-adjusted life years associated with primary liver cancer in the young (15-49 y), stratified by region, nation, sociodemographic index, and sex. The study found a global estimate of 78,299 primary liver cancer cases, 60,602 deaths, and 2.90 million disability-adjusted life years in the young population. The Western Pacific region exhibited the highest burden in 2019, showing the most significant increase compared to other regions between 2010 and 2019. More than half of the countries worldwide have undergone an increase in primary liver cancer incidence rates in young adults. Around 12.51% of deaths due to primary liver cancer occur in young individuals. Throughout the study period, there was a significant decline in primary liver cancer mortality due to most etiologies, except for metabolic dysfunction-associated steatotic liver disease-attributable primary liver cancer (annual percentage change + 0.87%, 95% CI: 0.70%-1.05%) and alcohol-attributable primary liver cancer (annual percentage change + 0.21%, 95% CI: 0.01%-0.42%). The limitations of the Global Burden of Disease database include reliance on the quality of primary data and possible underestimation of alcohol consumption. CONCLUSIONS: Over the past decade, there has been a marked increase in the burden of primary liver cancer, especially that originating from steatotic liver disease. This trend calls for the development of urgent and comprehensive strategies to mitigate this rising burden globally.

Evaluating the impact of an interdisciplinary integrated limb preservation service operating concurrently with a single-specialty service.

BACKGROUND: This study examined the efficacy of an interdisciplinary limb preservation service (LPS) in improving surgical outcomes for diabetic foot ulcer (DFU) patients compared to traditional care. METHODS: Data from January 1, 2017 to September 30, 2020 were retrospectively reviewed. An interdisciplinary LPS clinic began on August 1, 2018, coexisting with a preexisting single specialty service. Primary outcomes were major/minor amputation rates and ratios and hospital length of stay. Surgical endpoints pre- and post-LPS launch were compared. RESULTS: Among 976 procedures for 731 unique DFU patients, most were male (80.4%) and Hispanic (89.3%). Patient demographics were consistent before and after LPS initiation. Major amputation rates decreased by 45.5% (15.4%-8.4%, p = 0.001), with outpatient procedures increasing over 5-fold (3.3% pre-LPS to 18.7% post-LPS, p < 0.001). Hospital stay reduced from 10.1 to 8.5 days post-LPS (p < 0.001). The major to minor amputation ratio declined from 22.4% to 12.7%. CONCLUSIONS: The interdisciplinary LPS improved patient outcomes, marked by fewer major amputations and reduced hospital stays, suggesting the model's potential for broader application.

Global and regional burden of alcohol-associated liver disease and alcohol use disorder in the elderly.

Background & Aims: Alcohol-associated liver diseases (ALDs) and alcohol use disorder (AUD) pose a global health risk. AUD is underrecognized in the elderly, and the burden of AUD complications, including ALD, may increase with aging populations and rising alcohol intake. However, there is a lack of epidemiological evidence on AUD and ALD in the elderly. Methods: Using the Global Burden of Disease Study 2019, we analyzed the prevalence, mortality, disability-adjusted life years (DALYs), age-standardized rates (ASRs), and temporal change from 2000 to 2019 of ALD and AUD in the overall population and the elderly (65-89 years). The findings were categorized by sex, region, nation, and sociodemographic index. Results: The prevalence rates of ALD in the elderly were higher than those in adolescents and young adults, whereas AUD levels were lower than those in adolescents and young adults. In 2019, there were 9.39 million cases (8.69% of cases in the overall population) of AUD, 3.23 million cases (21.8% of cases in the overall population) of alcohol-associated cirrhosis, and 68,468 cases (51.27% of cases in the overall population) of liver cancer from alcohol among the elderly. ASRs of the prevalence of ALD and AUD in the elderly increased in most regions; on the contrary, ASRs of death and DALYs decreased in most regions. Nevertheless, ASRs of death and DALYs from liver cancer from alcohol increased in many areas. Conclusions: Our findings highlighted the increased prevalence of ALD in the elderly, with a burden of AUD comparable with that in the overall population. Public health strategies on ALD and AUD targeting the elderly are urgently needed. Impact and implications: The burden of alcohol-associated liver disease (ALD) and alcohol use disorder (AUD) is increasing. Advances in healthcare and education have resulted in a remarkable spike in life expectancy and a consequential population aging. Nevertheless, little is known about the epidemiology of ALD and AUD in the elderly. Our study indicates the increasing burden of ALD and AUD in the elderly population, necessitating early detection, intervention, and tailored care to the unique needs and complexities faced by older individuals grappling with these conditions.

Phosphonate-based iron complex for a cost-effective and long cycling aqueous iron redox flow battery.

A promising metal-organic complex, iron (Fe)-NTMPA2, consisting of Fe(III) chloride and nitrilotri-(methylphosphonic acid) (NTMPA), is designed for use in aqueous iron redox flow batteries. A full-cell testing, where a concentrated Fe-NTMPA2 anolyte (0.67 M) is paired with a Fe-CN catholyte, demonstrates exceptional cycling stability over 1000 charge/discharge cycles, and noteworthy performances, including 96% capacity utilization, a minimal capacity fade rate of 0.0013% per cycle (1.3% over 1,000 cycles), high Coulombic efficiency and energy efficiency near 100% and 87%, respectively, all achieved under a current density of 20 mA·cm-². Furthermore, density functional theory unveils two potential coordination structures for Fe-NTMPA2 complexes, improving the understanding between the ligand coordination environment and electron transfer kinetics. When paired with a high redox potential Fe-Dcbpy/CN catholyte, 2,2'-bipyridine-4,4'-dicarboxylic (Dcbpy) acid and cyanide (CN) ligands, Fe-NTMPA2 demonstrates a notably elevated cell voltage of 1 V, enabling a practical energy density of up to 9 Wh/L.

Effect of virtual reality hypnosis on intraoperative sedation needs and functional recovery in knee arthroplasty: a prospective randomized clinical trial.

BACKGROUND AND OBJECTIVES: Perioperative psychological stress and pharmacological anxiolysis can negatively affect the quality of recovery after total knee arthroplasty. We aimed to assess whether hypnosis combined with virtual reality could reduce intraoperative pharmacological sedation and improve quality of recovery after total knee arthroplasty surgery. METHODS: In this prospective randomized clinical trial, 60 patients scheduled for total knee arthroplasty with spinal anesthesia were randomly divided into 2 groups of 30 patients each. Intraoperatively, intermittent boluses of midazolam 1 mg were administered at 5 min intervals at the patient's request, with a maximum driven by the clinical assessment of sedation depth. During surgery, patients received standard care (group control) or virtual reality hypnosis (group VRH). An unblinded observer recorded the total dose of midazolam administered during surgery, and changes in the Quality-of-Recovery 15-item score, comfort, fatigue, pain and anxiety before and 1, 3 and 7 days after surgery. RESULTS: Patients in the VRH group required a lower dose of midazolam (mg; median (range)) intraoperatively (group VRH: 0 (0-4) and group control: 2 (0-9), p<0.001). Quality-of-Recovery 15-item, anxiety, and pain were similar between groups. CONCLUSIONS: In total knee arthroplasty with spinal anesthesia, VRH reduces the requirement for intraoperative pharmacological sedation, without a change in the quality of recovery. TRIAL REGISTRATION NUMBER: NCT05707234.

Secondary interventions following open vs endovascular revascularization for chronic limb threatening ischemia in the BEST-CLI trial.

OBJECTIVES: Patients undergoing revascularization for chronic limb-threatening ischemia experience a high burden of target limb reinterventions. We analyzed data from the Best Endovascular versus Best Surgical Therapy in Patients with Critical Limb Ischemia (BEST-CLI) randomized trial comparing initial open bypass (OPEN) and endovascular (ENDO) treatment strategies, with a focus on reintervention-related study endpoints. METHODS: In a planned secondary analysis, we examined the rates of major reintervention, any reintervention, and the composite of any reintervention, amputation, or death by intention-to-treat assignment in both trial cohorts (cohort 1 with suitable single-segment great saphenous vein [SSGSV], n = 1434; cohort 2 lacking suitable SSGSV, n = 396). We also compared the cumulative number of major and all index limb reinterventions over time. Comparisons between treatment arms within each cohort were made using univariable and multivariable Cox regression models. RESULTS: In cohort 1, assignment to OPEN was associated with a significantly reduced hazard of a major limb reintervention (hazard ratio [HR], 0.37; 95% confidence interval [CI], 0.28-0.49; P < .001), any reintervention (HR, 0.63; 95% CI, 0.53-0.75; P < .001), or any reintervention, amputation, or death (HR, 0.68; 95% CI, 0.60-0.78; P < .001). Findings were similar in cohort 2 for major reintervention (HR, 0.53; 95% CI, 0.33-0.84; P = .007) or any reintervention (HR, 0.71; 95% CI, 0.52-0.98; P = .04). In both cohorts, early (30-day) limb reinterventions were notably higher for patients assigned to ENDO as compared with OPEN (14.7% vs 4.5% of cohort 1 subjects; 16.6% vs 5.6% of cohort 2 subjects). The mean number of major (mean events per subject ratio [MR], 0.45; 95% CI, 0.34-0.58; P < .001) or any target limb reinterventions (MR, 0.67; 95% CI, 0.57-0.80; P < .001) per year was significantly less in the OPEN arm of cohort 1. The mean number of reinterventions per limb salvaged per year was lower in the OPEN arm of cohort 1 (MR, 0.45; 95% CI, 0.35-0.57; P < .001 and MR, 0.66; 95% CI, 0.55-0.79; P < .001 for major and all, respectively). The majority of index limb reinterventions occurred during the first year following randomization, but events continued to accumulate over the duration of follow-up in the trial. CONCLUSIONS: Reintervention is common following revascularization for chronic limb-threatening ischemia. Among patients deemed suitable for either approach, initial treatment with open bypass, particularly in patients with available SSGSV conduit, is associated with a significantly lower number of major and minor target limb reinterventions.

Disparities among ethnic groups in mortality and outcomes among adults with MASLD: A multicenter study.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease and 10%-20% occurs in lean individuals. There is little data in the literature regarding outcomes in an ethnically-diverse patient populations with MASLD. Thus, we aim to investigate the natural history and ethnic disparities of MASLD patients in a diverse population, and stratified by body mass index categories. METHODS: We conducted a retrospective multicenter study on patients with MASLD at the Banner Health System from 2012 to 2022. Main outcomes included mortality and incidence of cirrhosis, cardiovascular disease, diabetes mellitus (DM), liver-related events (LREs), and cancer. We used competing risk and Cox proportional hazard regression analysis for outcome modelling. RESULTS: A total of 51 452 (cross-sectional cohort) and 37 027 (longitudinal cohort) patients were identified with 9.6% lean. The cohort was 63.33% European ancestry, 27.96% Hispanic ancestry, 3.45% African ancestry, and 2.31% Native American/Alaskan ancestry. Median follow-up was 45.8 months. After adjusting for confounders, compared to European individuals, Hispanic and Native American/Alaskan patients had higher prevalence of cirrhosis and DM, and individuals of Hispanic, African, and Native American/Alaskan ancestry had higher mortality and incidence of LREs and DM. Lean patients had higher mortality and incidence of LREs compared with non-lean patients. CONCLUSION: Native American/Alaskan, Hispanic, and African patients had higher mortality and incidence of LREs and DM compared with European patients. Further studies to explore the underlying disparities and intervention to prevent LREs in lean patients, particularly several ethnic groups, may improve clinical outcomes.

Oral as compared to intravenous tranexamic acid to limit peri-operative blood loss associated with primary total hip arthroplasty: A randomised noninferiority trial.

BACKGROUND: Oral as compared to intravenous tranexamic acid (TXA) is an attractive option, in terms of cost and safety, to reduce blood loss and transfusion in total hip arthroplasty. Exclusion criteria applied in the most recent randomised trials may have limited the generalisability of oral tranexamic acid in this indication. Larger and more inclusive studies are needed to definitively establish oral administration as a credible alternative to intravenous administration. OBJECTIVES: To assess the noninferiority of oral to intravenous TXA at reducing intra-operative and postoperative total blood loss (TBL) in primary posterolateral approached total hip arthroplasty (PLTHA). DESIGN: Noninferiority, single centre, randomised, double-blind controlled study. SETTING: Patients scheduled for primary PLTHA. Data acquisition occurred between May 2021 and November 2022 at the University Hospital of Liège, Belgium. PATIENTS: Two hundred and twenty-eight patients, randomised in a 1 : 1 ratio from a computer-generated list, completed the trial. INTERVENTIONS: Administration of 2 g of oral TXA 2 h before total hip arthroplasty and 4 h after incision (Group oral) was compared to the intravenous administration of 1 g of TXA 30 min before surgery and 4 h after incision (Group i.v.). MAIN OUTCOME MEASURES: TBL (measured intra-operative and drainage blood loss up to 48 h after surgery, primary outcome), decrease in haemoglobin concentration, D-Dimer at day 1 and day 3, transfusion rate (secondary outcomes). RESULTS: Analyses were performed on 108 out of 114 participants (Group i.v.) and 104 out of 114 participants (Group oral). Group oral was noninferior to Group i.v. with regard to TBL, with a difference between medians (95% CI) of 35 ml (-103.77 to 33.77) within the noninferiority margins. Median [IQR] of estimated TBL was 480 ml [350 to 565] and 445 ml [323 to 558], respectively. No significant interaction between group and time was observed regarding the evolution of TBL and haemoglobin over time. CONCLUSIONS: TXA as an oral premedication before PLTHA is noninferior to its intravenous administration regarding peri-operative TBL. TRIAL REGISTRATION: European Clinical Trial Register under EudraCT-number 2020-004167-29 ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-004167-29/BE ).

Effects of firsthand tobacco smoking on retinal vessel caliber: a systematic review and meta-analysis.

PURPOSE: To review the effects of firsthand tobacco smoking on central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE) of firsthand tobacco smokers. METHODS: We performed a search on EMBASE and PubMed for studies up to 15th July 2022. Two independent reviewers selected studies with baseline data of CRAE and CRVE of current smokers, nonsmokers, and former smokers. Initial search identified 893 studies, of which 10 were included in the meta-analysis. Two independent reviewers extracted data from the included studies. The quality of studies was assessed by the Newcastle-Ottawa Scale. RESULTS: In this meta-analysis, 7431 nonsmokers, 2448 current smokers and 5786 former smokers, as well as 7404 nonsmokers, 2430 current smokers and 5763 former smokers were included in CRAE and CRVE analysis respectively. Nonsmokers had narrower CRVE (Weighted mean difference [WMD], -12.15; 95% CI, -17.33 - -6.96) and CRAE (WMD, -4.77; 95% CI, -7.96 - -1.57) than current smokers, and narrower CRVE (WMD, -3.08; 95% CI, -6.06 - -0.11) than former smokers. Current smokers had wider CRVE (WMD, 10.42; 95% CI, 7.80 - 13.04) and CRAE (WMD, 7.05; 95% CI, 6.65 - 7.46) than former smokers. Subgroup analysis and sensitivity analysis were performed. CONCLUSION: Firsthand tobacco smoking resulted in wider CRAE and CRVE in current and former smokers, particularly in CRVE, and such changes may not be reversible after smoking cessation. Therefore, retinal vessel caliber may reflect the effects of firsthand tobacco smoking and be used to estimate the risk of cardiovascular diseases.

Associations between metabolic hyperferritinaemia, fibrosis-promoting alleles and clinical outcomes in steatotic liver disease.

BACKGROUND & AIMS: Ferritin has been investigated as a biomarker for liver fibrosis and iron in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). However, whether metabolic hyperferritinaemia predicts progression of liver disease remains unknown. In this study, we sought to understand associations between hyperferritinaemia and (1) adverse clinical outcomes and (2) common genetic variants related to iron metabolism and liver fibrosis. METHODS: This was a retrospective analysis of adults with MASLD seen at the University of Michigan Health System, where MASLD was defined by hepatic steatosis on imaging, biopsy or vibration-controlled transient elastography, plus metabolic risk factors in the absence of chronic liver diseases other than hemochromatosis. The primary predictor was serum ferritin level, which was dichotomized based on a cut-off of 300 or 450 mcg/L for women or men. Primary outcomes included (1) incident cirrhosis, liver-related events, congestive heart failure (CHF), and mortality and (2) distribution of common genetic variants associated with hepatic fibrosis and hereditary hemochromatosis. RESULTS: Of 7333 patients with MASLD, 1468 (20%) had elevated ferritin. In multivariate analysis, ferritinaemia was associated with increased mortality (HR 1.68 [1.35-2.09], p < .001) and incident liver-related events (HR 1.92 [1.11-3.32], p = .019). Furthermore, elevated ferritin was associated with carriage of cirrhosis-promoting alleles including PNPLA3-rs738409-G allele (p = .0068) and TM6SF2-rs58542926-T allele (p = 0.0083) but not with common HFE mutations. CONCLUSIONS: In MASLD patients, metabolic hyperferritinaemia was associated with increased mortality and higher incidence of liver-related events, and cirrhosis-promoting alleles but not with iron overload-promoting HFE mutations.