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Oxidative stress modulates carcinogenesis in the liver; however, direct evidence for metabolic control of oxidative stress during pathogenesis, particularly, of progression from cirrhosis to hepatocellular carcinoma (HCC), has been lacking. Deficiency of transaldolase (TAL), a rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway (PPP), restricts growth and predisposes to cirrhosis and HCC in mice and humans. Here, we show that mitochondrial oxidative stress and progression from cirrhosis to HCC and acetaminophen-induced liver necrosis are critically dependent on NADPH depletion and polyol buildup by aldose reductase (AR), while this enzyme protects from carbon trapping in the PPP and growth restriction in TAL deficiency. Both TAL and AR are confined to the cytosol; however, their inactivation distorts mitochondrial redox homeostasis in opposite directions. The results suggest that AR acts as a rheostat of carbon recycling and NADPH output of the PPP with broad implications for disease progression from cirrhosis to HCC. In this study, Oaks and Patel et al. characterize the crosstalk between the pentose phosphate pathway and mitochondrial redox homeostasis in the context of aldose reductase and transaldolase deficiency and the contribution of pentose phosphate pathway mitochondria deregulation to the progression from cirrhosis to hepatocellular carcinoma.

Background:Patients with systemic lupus erythematosus (SLE) undergoing total hip arthroplasty and total knee arthroplasty (THA and TKA) experience higher complication rates than osteoarthritis (OA) patients.There are several molecular processes in SLE patients that may affect the response to the physiologic stresses of arthroplasty. Patients with SLE have been described to exhibit endothelial dysfunction, with excess secretion of soluble cell adhesion molecules, including intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), and these molecules are known to increase in plasma following arthroplasty. Excess Type 1 interferon (IFN) is a critical driver of SLE pathogenesis, and it may similarly affect the response to surgery as well as the postoperative healing process.We conducted a prospective study of SLE patients undergoing THA/TKA to investigate the role of these processes, performing comprehensive assessment of patients clinical and laboratory data, as well as biosample collection for assessment of endothelial cell dysfunction and IFN activity.Objectives:To characterize the degree of endothelial cell activation at baseline in SLE patients, as well as changes in this following THA/TKA by measuring plasma levels of soluble cell adhesion molecules ICAM-1 and VCAM-1.To characterize the difference in IFN activity in OA and SLE patients prior to and following THA/TKA.Methods:This prospective study enrolled 30 SLE patients with SLE satisfying either 2019 ACR/EULAR SLE classification criteria, or the 1997 modification of 1982 ACR SLE classification criteria. Additionally, 26 age-, sex-, and procedure-matched OA controls undergoing THA/TKA were enrolled. Demographics and risk stratification information was collected from all patients (BMI, medications, comorbidities, etc.). A rheumatologist (D.R.F., C.S.) evaluated SLE-specific disease activity on postoperative day 1 (POD1). Standard laboratory tests, as well as plasma and whole blood samples were collected from subjects at baseline, POD1, and six weeks postoperatively (6W). Plasma levels of soluble ICAM-1and VCAM-1 were measured, and whole blood RNA sequencing was performed from a subset of samples obtained at baseline, POD1, and 6W. Adverse events (AEs) were assessed at baseline, 1-, 6-, 12-, and 24-weeks. Descriptive statistics were performed and comparisons were made using Fisher’s exact test, Chi-square and Wilcoxon rank-sum test.Results:The SLE patients in our cohort generally had low disease activity, with an average Systemic Lupus Erythematosus Disease Activity Index-2K score of 4, in keeping with a population undergoing elective surgery. SLE patients experienced significantly more postoperative anemia, and were seen in the emergency department more often in the 24 weeks postoperatively, compared with OA patients (Table 1).There were no significant differences in plasma levels of soluble ICAM-1 or VCAM-1 between OA and SLE patients (Table 2) at baseline or during the postoperative period.The IFN score and the IFN module identified on weighted correlation network analysis were significantly elevated in SLE patients at all time points. The IFN score and IFN module expression fell in all groups on POD1, before returning to levels comparable to baseline by 6W. A module with transcripts associated with B cells was identified, and was significantly lower in SLE patients versus OA controls at all time points.Conclusion:This is the first prospective analysis of SLE patients undergoing arthroplasty, proving the feasibility of such studies. No significant difference was observed in soluble cell adhesion molecules at any time point. Differential expression in B Cell and IFN modules was seen between OA and SLE patients, with dynamic shifts occurring in the immediate perioperative period. Larger prospective studies may allow for better assessment of factors associated with adverse events in SLE patients after THA/TKA.REFERENCES:NIL.Acknowledgements:We would like to thank and acknowledge the support of the HSS Surgeon-in-Chief research grant.Disclosure of Interests:David R. Fernandez: None declared, Stephen Batter: None declared, Deanna Jannat-Khah AstraZeneca, Cytodyn, Pfizer, Wallgreens, Mikhail Olferiev: None declared, Insa Mannstadt: None declared, Mark Figgie HS2, Joint Effort ASO, Mekanika, Wishbone, Lima, Wishbone, Peter Sculco DePuy, EOS Imaging, Intellijoint, Intellijoint, Parvizi Surgical Innovation, DePuy, EOS Imaging, Intellijoint, Lima Corporate, Zimmer, Intellijoint, Jason Blevins Globus Medical, KCI, Lima Corporate, Caroline Siegel: None declared, Dina Greenman: None declared, Kyriakos Kirou: None declared, Susan Goodman UCB, Norvartis.

This study implemented two spectral wave models, namely WAVEWATCH III and WAM, to render wave hindcasts around the globe at 1° × 1° grid resolution, and thereby to statistically evaluate their performance. The models used six-hourly spatially and temporally interpolated OSCAT wind data as input for the months of June and December in 2010. Global validation of WAM and WWIII hindcasts was achieved using satellite measurements (AVISO and Jason-2 wave data) and NDBC buoy data, which yielded an accurate statistical assessment. Both models were shown to reproduce the seasonal variability in wave height and wave period quite realistically at the buoy locations and along the selected global transects, albeit with different magnitudes. The statistical assessment and wave spectra validation showed that OSCAT winds are highly skilful in sea state prediction, even during a storm event such as the Boxing Day storm, 2010. The skill assessment of the models based on the boreal summer and winter revealed minor random errors and generally high correlations coefficients. It was noted that the performance of the two models was comparable during June 2010 using OSCAT winds. However, an exception was reported for the WAM model during December 2010, where it exhibited slightly better performance.

Anxious depression is a prevalent disease with devastating consequences and a poor prognosis. Nevertheless, the neurobiological mechanisms underlying this mood disorder remain poorly characterized. The LPA1 receptor is one of the six characterized G protein-coupled receptors (LPA1–6) through which lysophosphatidic acid acts as an intracellular signalling molecule. The loss of this receptor induces anxiety and several behavioural and neurobiological changes that have been strongly associated with depression. In this study, we sought to investigate the involvement of the LPA1 receptor in mood. We first examined hedonic and despair-like behaviours in wild-type and maLPA1 receptor null mice. Owing to the behavioural response exhibited by the maLPA1-null mice, the panic-like reaction was assessed. In addition, c-Fos expression was evaluated as a measure of the functional activity, followed by interregional correlation matrices to establish the brain map of functional activation. maLPA1-null mice exhibited anhedonia, agitation and increased stress reactivity, behaviours that are strongly associated with the psychopathological endophenotype of depression with anxiety features. Furthermore, the functional brain maps differed between the genotypes. The maLPA1-null mice showed increased limbic-system activation, similar to that observed in depressive patients. Antidepressant treatment induced behavioural improvements and functional brain normalisation. Finally, based on validity criteria, maLPA1-null mice are proposed as an animal model of anxious depression. Here, for we believe the first time, we have identified a possible relationship between the LPA1 receptor and anxious depression, shedding light on the unknown neurobiological basis of this subtype of depression and providing an opportunity to explore new therapeutic targets for the treatment of mood disorders, especially for the anxious subtype of depression.

Background/aims Prediabetes and diabetes disproportionately impact Latino youth, yet few diabetes prevention programs have prioritized inclusion of this underrepresented population. This report describes the recruitment process, yields, associated costs, and phenotypic characteristics of Latino youth with obesity and prediabetes enrolled in a randomized controlled diabetes prevention study in the USA. Methods Recruitment efforts included referrals from clinics, community outlets, local media, and word of mouth with the goal of enrolling 120 Latino adolescents aged 12–16 with obesity (BMI >  95th percentile) and prediabetes. Prediabetes eligibility was determined by any of the following: HbA1c between 5.7 and 6.5%, fasting glucose between 100 and 125 mg/dL, or a 2-h glucose between 120 and 199 mg/dL following a 75-g oral glucose tolerance test (OGTT), but not meeting any of the diagnostic criteria for diabetes. Eligible participants were randomized 2:1 to either a 6-month community-based lifestyle intervention that included group nutrition and health education classes (1 day/week) and group exercise classes (2 days/week) or usual care control arm. Recruitment yields were determined by review of referral source in the study screening database. Recruitment costs were determined by an after-the-fact financial review of actual and in-kind costs. Participant phenotypic characteristics (i.e., demographics, anthropometrics, and biochemical data) were compared by recruitment strategy using a one-way ANOVA. Results Recruitment efforts covered 160 mile 2 (414 km 2 ) across 26 ZIP codes (postcode) in the Phoenix Metropolitan Area and yielded 655 referrals from clinics ( n  = 344), community ( n  = 143), media ( n  = 137), and word-of-mouth ( n  = 31). From this pool, 26% ( n  = 167) did not meet general, pre-screening eligibility criteria; 29% ( n  = 187) declined participation; and 10% ( n  = 64) were unable to be contacted. A total of 237 youth were invited to the clinical research unit to determine final eligibility. Following the OGTT, 52% ( n  = 122) met prediabetes criteria and 117 were subsequently randomized. Clinical recruitment yielded the highest number of referrals (53%; n  = 344) while word-of-mouth yielded the highest proportion (35%; n  = 11) of randomized participants per referred youth. There were no significant differences in anthropometric or biochemical measures among youth by recruitment strategy. Based upon final enrollment numbers, community recruitment was the costliest approach ($486/randomized participant) followed by clinical ($248/randomized participant) and media ($236/randomized participant). Conclusions The ability to meet enrollment goals for a clinical trial of an underrepresented population required multiple recruitment strategies. Although strategies vary in yields and costs, it appears they produce similar phenotypical risk profiles of eligible youth. Trial registration ClinicalTrials.gov NCT02615353 . Registered on 26 November 2015

Nearly 3 decades have passed since Hofstede (1980) collected the data used to classify countries by their underlying work-related value structures. The present study, in which recent data from 9 countries in 4 continents was collected, is a reexamination of his country classifications. The results suggest that many shifts have occurred since Hofstede's study in 1980. These shifts are related to some of the major environmental changes that have occurred.

•REAC-TAVI 2 will study the effects of aspirin vs. low-dose ticagrelor post-TAVI.•The study will randomize patients with high ischemic risk post-TAVI to aspirin vs. ticagrelor.•REAC-TAVI 2 will assess subclinical valve thrombosis at 3 and 12 months after TAVI.•All bleeding events at 12 months post-TAVI will be assessed according to BARC criteria. Patients undergoing transcatheter aortic valve implantation (TAVI) frequently experience life-threatening ischemic and bleeding complications. However, management of antithrombotic therapy after TAVI in patients without oral anticoagulation (OAC), particularly in patients with high burden for subsequent ischemic events, has limited evidence from randomized controlled trials. The REAC TAVI2 trial is a prospective, multicenter, open-label, phase III randomized trial (NCT05283356). A total of 1206 patients undergoing TAVI with high ischemic risk (defined as concomitant coronary artery disease, diabetes mellitus or peripheral vascular disease) will be randomized in a 1:1 ratio to single antiplatelet therapy with aspirin (100 mg once daily) or low-dose ticagrelor (60 mg twice daily). The primary endpoint is the incidence of a net adverse clinical event (NACE) at 1-year after TAVI. NACE is defined as a composite of all-cause mortality, cerebrovascular events, myocardial infarction, progressive angina leading to emergency evaluation, rehospitalization or new coronary angiogram, clinical valve thrombosis, acute limb ischemia leading to hospitalization, and type 2, 3, or 5 bleeding. The secondary endpoint is the incidence of subclinical valve thrombosis detected by hypo-attenuated leaflet thickening and reduced leaflet motion at 3 and 12 months post-TAVI assessed by 4-dimensional computed tomography. In patients undergoing TAVI without an indication for OAC, there is a need for antiplatelet therapy that provides protection against ischemic events without increasing bleeding, particularly in the subset of patients at heightened risk of ischemic events. The REAC-TAVI 2 is a randomized multicenter clinical trial designed to study the effect of single antiplatelet therapy with aspirin compared to low-dose ticagrelor on a composite outcome of all-cause mortality, ischemic, and bleeding events after TAVI.

Self-rated health (SRH) is an independent determinant for all-cause mortality. We aimed to examine the independent and combined associations of components of physical fitness with SRH at baseline (cross-sectional) and two years later (longitudinal) in children and adolescents. Spanish youth (N = 1378) aged 8 to 17.9 years participated at baseline. The dropout rate at 2-year follow-up was 19.5% (n = 270). Participants were categorized as either children (8 to 11.9 years age) or adolescents (12 to 17.9 years age). The ALPHA health- related fitness test battery for youth was used to assess physical fitness, and SRH was measured by a single-item question. Cumulative link, ANOVA and ANCOVA models were fitted to analyze the data. Cardiorespiratory fitness, relative upper body isometric muscular strength, muscular strength score, and global physical fitness were positively associated with SRH in children (OR, 1.048; 95% CI, 1.020–1.076; OR, 18.921; 95% CI, 3.47–104.355; OR, 1.213; 95% CI, 1.117–1.319, and OR, 1.170; 95% CI, 1.081–1.266, respectively; all p < 0.001) and adolescents (OR, 1.057; 95% CI, 1.037–1.076; OR, 5.707; 95% CI, 1.122–29.205; OR, 1.169; 95% CI, 1.070–1.278, and OR, 1.154 95% CI, 1.100–1.210, respectively; all p < 0.001); and motor fitness was positively associated with SRH only in adolescents at baseline (OR, 1.192; 95% CI, 1.066–1.309; p < 0.01). Cardiorespiratory fitness and global physical fitness were positively associated with SRH in children two years later (OR, 1.056; 95% CI, 1.023–1.091; p < 0.001; and OR, 1.082; 95% CI, 1.031–1.136; p < 0.01; respectively). Only cardiorespiratory fitness was independently associated with SRH in children and adolescents at baseline (OR, 1.059; 95% CI, 1.029–1.090; and OR, 1.073; 95% CI, 1.050–1.097, respectively; both p < 0.001) and two years later (OR, 1.075; 95% CI, 1.040–1.112; p < 0.001; and OR, 1.043; 95% CI, 1.014–1.074; p < 0.01, respectively). A high level of cardiorespiratory fitness at baseline or maintaining high levels of cardiorespiratory fitness from the baseline to 2-year follow-up were associated with a higher level of SRH at 2-year follow-up in children (p < 0.01) and adolescents (p < 0.05). These findings emphasize the importance of cardiorespiratory fitness as strong predictor of present and future SRH in youth. Intervention programs to enhance cardiorespiratory fitness level of the youth population are urgently needed for present and future youth’s health.

Cricothyrotomy is a complex procedure with a high rate of complications including failure to cannulate and injury to adjacent anatomy. The Control-Cric™ System and QuickTrach II™ represent two novel devices designed to optimize success and minimize complications with this procedure. This study compares these two devices against a standard open surgical technique. We conducted a randomized crossover study of United States Army combat medics using a synthetic cadaver model. Participants performed a surgical cricothyrotomy using the standard open surgical technique, Control-Cric™ System, and QuickTrach II™ device in a random order. The primary outcome was time to successful cannulation. The secondary outcome was first-attempt success. We also surveyed participants after performing the procedures as to their preferences. Of 70 enrolled subjects, 65 completed all study procedures. Of those that successfully cannulated, the mean times to cannulation were comparable for all three methods: standard 51.0s (95% CI 45.2–56.8), QuickTrach II™ 39.8s (95% CI 31.4–48.2) and the Cric-Control™ 53.6 (95% CI 45.7–61.4). Cannulation failure rates were not significantly different: standard 6.2%, QuickTrach II™ 13.9%, Cric-Control™ 18.5% (p=0.106). First pass success rates were also similar (93.4%, 91.1%, 88.7%, respectively, p=0.670). Of respondents completing the post-study survey, a majority (52.3%) preferred the QuickTrach II™ device. We identified no significant differences between the three cricothyrotomy techniques with regards to time to successful cannulation or first-pass success.