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Early weaning in intensive pig production induces stress, compromising gastrointestinal health. Poor fat digestion results from the piglets’ underdeveloped digestive system. Dietary emulsifiers can enhance fat utilization, and glyceryl polyethylene glycol ricinoleate (GPGR) has been shown to improve pig performance. This study evaluated GPGR’s effects on intestinal health in weaned piglets in a commercial production farm. A total of 380 just weaned (21 days old) piglets were divided in two groups of 190 animals each (in four replicates) that received either a basal diet (control) or a basal diet + 350 g/ton GPGR pharmaceutical formulation as top dress. Blood samples were collected at pre-established days, and intestinal sampling occurred 15 days post-weaning. Plasma cortisol, citrulline, intestinal morphology, mucus quality, enzymatic activity, volatile fatty acids (VFAs), and cecal microbiota were analyzed. GPGR did not alter plasma cortisol but increased citrullinemia (P: 0.024), suggesting greater enterocyte functional mass. GPGR piglets showed improved intestinal morphology (greater villus height, villus height:crypt depth ratio, and intestinal absorption area, p < 0.05) and higher enzymatic maltase activity (p ≤ 0.014). VFAs, bacterial adherence to mucus, and goblet cell counts were unaffected. Dietary GPGR increased Firmicutes and Actinobacteria (P: 0.014 and P: 0.045, respectively) while reducing Proteobacteria (p < 0.001). In conclusion, dietary GPGR promotes intestinal health in weaned piglets by improving epithelial structure, digestive function, and microbiota balance, representing a promising strategy to support piglets in overcoming the early nursery phase.

Mechanoelectrical transduction is a cellular signalling pathway where physical stimuli are converted into electro-chemical signals by mechanically activated ion channels. We describe here the presence of mechanically activated currents in melanoma cells that are dependent on TMEM87a, which we have renamed Elkin1. Heterologous expression of this protein in PIEZO1-deficient cells, that exhibit no baseline mechanosensitivity, is sufficient to reconstitute mechanically activated currents. Melanoma cells lacking functional Elkin1 exhibit defective mechanoelectrical transduction, decreased motility and increased dissociation from organotypic spheroids. By analysing cell adhesion properties, we demonstrate that Elkin1 deletion is associated with increased cell-substrate adhesion and decreased homotypic cell-cell adhesion strength. We therefore conclude that Elkin1 supports a PIEZO1-independent mechanoelectrical transduction pathway and modulates cellular adhesions and regulates melanoma cell migration and cell-cell interactions. When cells receive signals about their surrounding environment, this initiates a chain of signals which generate a response. Some of these signalling pathways allow cells to sense physical and mechanical forces via a process called mechanotransduction. There are different types of mechanotransduction. In one pathway, mechanical forces open up specialized channels on the cell surface which allow charged particles to move across the membrane and create an electrical current. Mechanoelectrical transduction plays an important role in the spread of cancer: as cancer cells move away from a tumour they use these signalling pathways to find their way between cells and move into other parts of the body. Understanding these pathways could reveal ways to stop cancer from spreading, making it easier to treat. However, it remains unclear which molecules regulate mechanoelectrical transduction in cancer cells. Now, Patkunarajah, Stear et al. have studied whether mechanoelectrical transduction is involved in the migration of skin cancer cells. To study mechanoelectrical transduction, a fine mechanical input was applied to the skin cancer cells whilst measuring the flow of charged molecules moving across the membrane. This experiment revealed that a previously unknown protein named Elkin1 is required to convert mechanical forces into electrical currents. Deleting this newly found protein caused skin cancer cells to move more slowly and dissociate more easily from tumour-like clusters of cells. These findings suggest that Elkin1 is part of a newly identified mechanotransduction pathway that allows cells to sense mechanical forces from their surrounding environment. More work is needed to determine what role Elkin1 plays in mechanoelectrical transduction and whether other proteins are also involved. This could lead to new approaches that prevent cancer cells from dissociating from tumours and spreading to other body parts.

CrossFit® consists of workouts of the day (WODs) in which different exercises are conducted at high intensity with minimal or no rest periods. This study sought to quantify exercise intensity and muscular fatigue in the three CrossFit® session modalities: gymnastics (G), metabolic conditioning (M) and weightlifting (W). Thirty two, young, strength-trained, healthy men completed the three WODs: G (\"Cindy\"), M (double skip rope jumps) and W (power cleans). The variables measured in the sessions were: mean heart rate (HR), rate of perceived exertion (RPE), blood lactate [lactate], and jump height (H), average power (AP) and maximum take-off velocity (V ) in a counter movement jump test. In all three WODs, elevated HR values (≥90% of the theoretical HR ) were recorded at the time points mid-session and end-session. Mean RPEs were 17.6 ± 1.6 (G WOD), 16.0 ± 2.3 (M WOD), and 15.7 ± 2.0 (W WOD). Postexercise [lactate] was higher than 10 mmol·L for the three WODs. Following the G (\"Cindy\") and W (power cleans) WODs, respectively, significant muscular power losses were observed in H (7.3% and 8.1%), V (13.8% and 3.3%), AP relative (4.6% and 8.3%) and AP total (4.2% and 8.2%) while losses in the M WOD were not significant (p > 0.05). A vigorous intensity of exercise was noted in all three WODs, with greater mean HRs detected in the \"Cindy\" and skip rope WODs than power clean WOD. Muscular fatigue was produced in response to the \"Cindy\" and power clean WODs but not the skip rope WOD.

There is a lack of evidence about the ventilatory efficiency in resistance exercises despite the key role played in endurance exercises. This study aimed to compare the cardiorespiratory, metabolic responses and ventilatory efficiency between half-squat (HS) and cycle ergometer exercises during a constant-load test at the lactate threshold (LT) intensity. Eighteen healthy male participants were randomly assigned in a crossover design to carry out HS or cycle ergometer tests. For the three HS tests, a one repetition maximum (1RM) test was performed first to determine the load (kg) corresponding to the 1RM percentages. In the second test, the incremental HS exercise was carried out to establish the load (kg) at the LT intensity. Finally, a constant-load HS test was performed at the LT intensity. The first cycle ergometer test was incremental loading to determine the intensity in watts corresponding to the LT, followed by a constant-load test at the LT intensity. A recovery time of 48 hours between each test was established. During both constant-load test, cardiorespiratory and metabolic responses were monitored. A significant exercise mode x time interaction effect was only detected in oxygen uptake (VO2), heart rate, and blood lactate (p < 0.001). No differences were found between the two types of exercise in ventilatory efficiency (p >0.05). Ventilation (VE) and carbon dioxide were highly correlated (p <0.001) in the cycle ergometer (r = 0.892) and HS (r = 0.915) exercises. In the VO2 efficiency slope (OUES), similarly significant and high correlations (p <0.001) were found between VO2 and log10 VE in the cycle ergometer (r = 0.875) and in the HS (r = 0.853) exercise. Although the cardioventilatory responses were greater in the cycle ergometer test as compared to HS exercise, ventilatory efficiency was very similar between the two exercise modalities in a predominantly aerobic metabolism.

We estimated the prevalence of overall sexualized drug use (SDU) and of chemsex in particular, assessed patterns of drug use, and identified subpopulations of men who have sex with men (MSM) where SDU and chemsex are more frequent. Using data from an online survey of 9407 MSM recruited during 2016 in 7 European countries, we calculated the proportion of participants who reported SDU and chemsex (mephedrone, methamphetamine, and/or GHB/GBL) in the last 12 months. We grouped the different drug-use combinations in patterns and described sexual risk behaviors, sexually transmitted infections (STI), and HIV seropositivity for each one of them. Factors associated with SDU and chemsex were assessed with two logistic regression models. SDU was reported by 17.7% and chemsex by 5.2%. Risk indicators increased through the different SDU patterns but were higher within those including chemsex drugs. In the multivariate analysis, chemsex was independently associated with living in Slovenia. Both SDU and chemsex were independently associated with living in Spain; being < 50 years old; living in cities of > 500,000 inhabitants; being open about their sex life; reporting transactional sex; condomless anal intercourse; having received an STI diagnosis and with being HIV positive or having been tested ≤ 12 months ago. Magnitude of associations was higher in the chemsex model. One in five participants reported SDU, but prevalence of chemsex was notably lower. However, the risk profiles and higher prevalence of HIV/STIs among those involved in chemsex suggest the existence of a subpopulation of MSM that could be playing a relevant role in the HIV and STI epidemics, especially in very large cities of some countries.

Background: Beetroot juice (BJ) is rich in inorganic nitrates and has proved effective at increasing blood nitric oxide (NO) levels. When used as a supplement BJ has shown an ergogenic effect on cardiorespiratory resistance exercise modalities, yet few studies have examined its impact on high intensity efforts. Objective: To assess the effects of BJ intake on anaerobic performance in a Wingate test. Methods: Fifteen trained men (age 21.46 ± 1.72 years, height 1.78 ± 0.07 cm and weight 76.90 ± 8.67 kg) undertook a 30-s maximum intensity test on an inertial cycle ergometer after drinking 70 mL of BJ (5.6 mmol NO3−) or placebo. Results: Despite no impacts of BJ on the mean power recorded during the test, improvements were produced in peak power (6%) (p = 0.034), average power 0–15 s (6.7%) (p = 0.048) and final blood lactate levels (82.6%) (p < 0.001), and there was a trend towards a shorter time taken to attain peak power (−8.4%) (p = 0.055). Conclusions: Supplementation with BJ has an ergonomic effect on maximum power output and on average power during the first 15 s of a 30-s maximum intensity inertial cycle ergometer test.

Background Beetroot juice (BJ) is classified as a high-level supplement for improving sports performance. There is some controversy over the benefits of BJ supplementation for endurance exercise performance, especially when referring to well-trained athletes. This study examines the effects of acute BJ supplementation on cardioventilatory responses, exercise economy/efficiency, slow component of oxygen uptake, time trial performance, blood lactate, energy consumption, and carbohydrate and fat oxidation. Methods Twelve well-trained, male triathletes (aged 21–47 yr) were assigned in a randomized, double-blind, crossover design to receive 70 ml of BJ (6.5 mmol NO 3 − ) or placebo (PL). Three hours after taking the supplement, participants completed an endurance test on a cycle ergometer at a constant work rate (W) corresponding to first ventilatory threshold (VT1) (30 min) and second ventilatory threshold (VT2) time trial (~ 15 min). Results Maximal oxygen uptake was 54.78 ± 3.13 mL·min − 1 ·kg − 1 , and gross efficiency was > 22% at each load intensity and experimental condition. No significant interaction effect (supplement*intensity) was observed on any of the cardioventilatory variables, efficiency/economy, VT2 time trial, energy expenditure, carbohydrate oxidation and fat oxidation ( p  > 0.05). Conclusion Our findings do not support an improvement in the variables examined in response to acute BJ supplementation. Probably, higher doses are needed for improving time trial performance in male triathletes during a cycle ergometer test conducted at a load intensity equivalent to the first and second ventilatory threshold.

To evaluate the safety of thiopurines in patients with inflammatory bowel disease. To identify predictive factors associated with the development of thiopurine-induced adverse events. Long-term incidence of adverse events was estimated in patients from a prospectively maintained Spanish nationwide database using Kaplan-Meier analysis. Cox regression analysis was performed to identify potential predictive factors of adverse events. Three thousand nine hundred and thirty-one patients were included. Ninety-five percent of patients were on azathioprine. The median follow-up with thiopurines was 44 months (range, 0-420). Adverse events occurred at a median of 1 month after starting treatment. The cumulative incidence of adverse events was 26%, with an annual risk of 7% per patient-year of treatment. Most frequent adverse events were nausea (8%), hepatotoxicity (4%), myelotoxicity (4%), and pancreatitis (4%). Four patients had lymphoma. Female and Crohn's disease increased the risk of having nausea. The risk of hepatotoxicity was lower in females and higher in Crohn's disease. The risk of myelotoxicity was significantly higher in patients treated with mercaptopurine and in females. The risk of pancreatitis was higher in Crohn's disease. Overall, 17% of patients discontinued thiopurine treatment due to adverse events. Thirty-seven percent of these patients started thiopurines again and 40% of them had adverse events again. As many as 1 of 4 patients on thiopurine therapy had adverse events during follow-up. A relatively high proportion of patients (17%) had to discontinue the treatment with thiopurines due to adverse events. However, more than half of patients that restarted thiopurine treatment after its discontinuation due to adverse events tolerated it. Several predictive factors for some adverse events have been identified.

Anti-disialoganglioside (GD2) antibody therapy has provided clinical benefit to patients with neuroblastoma however efficacy is likely impaired by the immunosuppressive tumor microenvironment. We have previously defined a link between intratumoral copper levels and immune evasion. Here, we report that adjuvant copper chelation potentiates anti-GD2 antibody therapy to confer durable tumor control in immunocompetent models of neuroblastoma. Mechanistic studies reveal copper chelation creates an immune-primed tumor microenvironment through enhanced infiltration and activity of Fc-receptor-bearing cells, specifically neutrophils which are emerging as key effectors of antibody therapy. Moreover, we report copper sequestration by neuroblastoma attenuates neutrophil function which can be successfully reversed using copper chelation to increase pro-inflammatory effector functions. Importantly, we repurpose the clinically approved copper chelating agent Cuprior as a non-toxic, efficacious immunomodulatory strategy. Collectively, our findings provide evidence for the clinical testing of Cuprior as an adjuvant to enhance the activity of anti-GD2 antibody therapy and improve outcomes for patients with neuroblastoma. Anti-disialoganglioside (GD2) antibody therapy has proven beneficial to neuroblastoma patients and intra-tumoral copper levels have been associated with immune evasion. Here the authors show that copper chelation potentiates anti-GD2 immunotherapy through improved infiltration and function of Fc receptor bearing neutrophils.

ObjectivesTo determine factors associated with COVID-19-related death in people with rheumatic diseases.MethodsPhysician-reported registry of adults with rheumatic disease and confirmed or presumptive COVID-19 (from 24 March to 1 July 2020). The primary outcome was COVID-19-related death. Age, sex, smoking status, comorbidities, rheumatic disease diagnosis, disease activity and medications were included as covariates in multivariable logistic regression models. Analyses were further stratified according to rheumatic disease category.ResultsOf 3729 patients (mean age 57 years, 68% female), 390 (10.5%) died. Independent factors associated with COVID-19-related death were age (66–75 years: OR 3.00, 95% CI 2.13 to 4.22; >75 years: 6.18, 4.47 to 8.53; both vs ≤65 years), male sex (1.46, 1.11 to 1.91), hypertension combined with cardiovascular disease (1.89, 1.31 to 2.73), chronic lung disease (1.68, 1.26 to 2.25) and prednisolone-equivalent dosage >10 mg/day (1.69, 1.18 to 2.41; vs no glucocorticoid intake). Moderate/high disease activity (vs remission/low disease activity) was associated with higher odds of death (1.87, 1.27 to 2.77). Rituximab (4.04, 2.32 to 7.03), sulfasalazine (3.60, 1.66 to 7.78), immunosuppressants (azathioprine, cyclophosphamide, ciclosporin, mycophenolate or tacrolimus: 2.22, 1.43 to 3.46) and not receiving any disease-modifying anti-rheumatic drug (DMARD) (2.11, 1.48 to 3.01) were associated with higher odds of death, compared with methotrexate monotherapy. Other synthetic/biological DMARDs were not associated with COVID-19-related death.ConclusionAmong people with rheumatic disease, COVID-19-related death was associated with known general factors (older age, male sex and specific comorbidities) and disease-specific factors (disease activity and specific medications). The association with moderate/high disease activity highlights the importance of adequate disease control with DMARDs, preferably without increasing glucocorticoid dosages. Caution may be required with rituximab, sulfasalazine and some immunosuppressants.