Portuguese Recommendations for the management of Raynaud's phenomenon and digital ulcers in systemic sclerosis and other connective tissue diseases.

OBJECTIVE: To develop evidence-based recommendations for the non-pharmacological and pharmacological management of Raynaud's phenomenon (RP) and digital ulcers (DUs) in patients with systemic sclerosis and other immune-mediated connective tissue diseases (CTDs). METHODS: A task force comprising 21 rheumatologists, two surgeons (vascular and plastic), two nurses, and one patient representative was established. Following a systematic literature review performed to inform the recommendations, statements were formulated and discussed during two meetings (one online and one in-person). Levels of evidence, grades of recommendation (GoR), and level of agreement (LoA) were determined. RESULTS: Five overarching principles and 13 recommendations were developed. GoR ranged from A to D. The mean ± standard difference (SD) LoA with the overarching principles and recommendations ranged from 7.8±2.1 to 9.8±0.4. Briefly, the management of RP and DUs in patients with CTDs should be coordinated by a multidisciplinary team and based on shared decisions with patients. Nifedipine should be used as first-line therapy for RP and/or DUs. Sildenafil, tadalafil, and/or iloprost IV are second-line options for severe and/or refractory patients with RP and/or DUs. Sildenafil, tadalafil and/or Iloprost IV, should be prescribed for healing and prevention (also including bosentan) of DUs. In patients with RP and/or DUs, non-pharmacological interventions might be considered as add-ons, but there is limited quality and quantity of scientific evidence supporting their use. CONCLUSIONS: These recommendations will inform rheumatologists, specialist nurses, other healthcare professionals, and patients about a comprehensive and personalized management of RP and DUs. A research agenda was developed to address unmet needs, particularly for non-pharmacologic interventions.

Trends and Missing Links in (De)Hydration Research: A Narrative Review.

Despite decades of literature on (de)hydration in healthy individuals, many unanswered questions remain. To outline research and policy priorities, it is fundamental to recognize the literature trends on (de)hydration and identify current research gaps, which herein we aimed to pinpoint. From a representative sample of 180 (de)hydration studies with 4350 individuals, we found that research is mainly limited to small-scale laboratory-based sample sizes, with high variability in demographics (sex, age, and level of competition); to non-ecological (highly simulated and controlled) conditions; and with a focus on recreationally active male adults (e.g., Tier 1, non-athletes). The laboratory-simulated environments are limiting factors underpinning the need to better translate scientific research into field studies. Although, consistently, dehydration is defined as the loss of 2% of body weight, the hydration status is estimated using a very heterogeneous range of parameters. Water is the most researched hydration fluid, followed by alcoholic beverages with added carbohydrates (CHO). The current research still overlooks beverages supplemented with proteins, amino acids (AA), and glycerol. Future research should invest more effort in "real-world" studies with larger and more heterogeneous cohorts, exploring the entire available spectrum of fluids while addressing hydration outcomes more harmoniously.

Human SARS-CoV-2 challenge uncovers local and systemic response dynamics.

The COVID-19 pandemic is an ongoing global health threat, yet our understanding of the dynamics of early cellular responses to this disease remains limited1. Here in our SARS-CoV-2 human challenge study, we used single-cell multi-omics profiling of nasopharyngeal swabs and blood to temporally resolve abortive, transient and sustained infections in seronegative individuals challenged with pre-Alpha SARS-CoV-2. Our analyses revealed rapid changes in cell-type proportions and dozens of highly dynamic cellular response states in epithelial and immune cells associated with specific time points and infection status. We observed that the interferon response in blood preceded the nasopharyngeal response. Moreover, nasopharyngeal immune infiltration occurred early in samples from individuals with only transient infection and later in samples from individuals with sustained infection. High expression of HLA-DQA2 before inoculation was associated with preventing sustained infection. Ciliated cells showed multiple immune responses and were most permissive for viral replication, whereas nasopharyngeal T cells and macrophages were infected non-productively. We resolved 54 T cell states, including acutely activated T cells that clonally expanded while carrying convergent SARS-CoV-2 motifs. Our new computational pipeline Cell2TCR identifies activated antigen-responding T cells based on a gene expression signature and clusters these into clonotype groups and motifs. Overall, our detailed time series data can serve as a Rosetta stone for epithelial and immune cell responses and reveals early dynamic responses associated with protection against infection.

Eight Weeks of Intermittent Exercise in Hypoxia, with or without a Low-Carbohydrate Diet, Improves Bone Mass and Functional and Physiological Capacity in Older Adults with Type 2 Diabetes.

In an increasingly aging and overweight population, osteoporosis and type 2 diabetes (T2DM) are major public health concerns. T2DM patients experience prejudicial effects on their bone health, affecting their physical capacity. Exercise in hypoxia (EH) and a low-carbohydrate diet (LCD) have been suggested for therapeutic benefits in T2DM, improving bone mineral content (BMC) and glycemic control. This study investigated the effects of EH combined with an LCD on body composition and functional and physiologic capacity in T2DM patients. Older T2DM patients (n = 42) were randomly assigned to the following groups: (1) control group: control diet + exercise in normoxia; (2) EH group: control diet + EH; (3) intervention group: LCD + EH. Cardiopulmonary tests (BRUCE protocol), body composition (DEXA), and functional capacity (6MWT, handgrip strength) were evaluated. Body mass index (kg/m2) and body fat (%) decreased in all groups (p < 0.001). BMC (kg) increased in all groups (p < 0.001) and was significantly higher in the EH and EH + LCD groups (p < 0.001). VO2peak improved in all groups (p < 0.001), but more so in the hypoxia groups (p = 0.019). Functional capacity was increased in all groups (p < 0.001), but more so in the EH group in 6MWT (p = 0.030). EH with and without an LCD is a therapeutic strategy for improving bone mass in T2DM, which is associated with cardiorespiratory and functional improvements.

The effect of menthol rinsing before intermittent exercise on physiological, physical, and thermo-behavioral responses of male football referees in hot and humid environment.

Introduction: In the current experiment, we aimed to evaluate whether eliciting pre-exercise non-thermal cooling sensations would alter perceptual measures, and physical and physiological responses in football referees. Methods: Nine highly trained male football referees undertook two 45-minute intermittent exercise protocols in hot and humid conditions (34.2 ± 0.6°C, 62.5 ± 1.0% relative humidity). In a randomized counterbalanced crossover design, 1 of 2 beverages were given before the warm-up: a 0.01% menthol solution or a placebo noncaloric solution. Physical performance was quantified as total distance covered in each of the three 15-minute exercise blocks. Core temperature, heart rate, thermal sensation and thermal comfort were measured at rest and after each exercise block. Results: No changes were observed between trials and over time for distance covered. No main effect of mouth rinse was observed for core temperature and heart rate, but both increased over time in all conditions (P < 0.001). Thermal sensation and thermal comfort were significantly improved with menthol after mouth-rinsing (P < 0.05), but with no differences at any other time-point. Discussion: These results indicate that non-thermal cooling oral stimuli provide immediate behavioral changes but may not influence physiological or physical responses in football referees, during intermittent exercise in hot and humid environments. Clinical Trial Registration: www.clinicaltrials.gov, identifier NCT05632692.

Anxiety and depression in patients with giant cell arteritis.

Objectives: To compare the prevalence of anxiety and depression in patients with GCA with that in the general population, using the Hospital Anxiety and Depression Scale (HADS), and to identify independent predictors of these psychiatric manifestations in patients with GCA. Methods: We conducted a cross-sectional study including all patients diagnosed with GCA followed during 1 year in a vasculitis outpatient clinic. The HADS and 36-item Short Form (SF-36) questionnaires were prospectively collected. Patients' HADS results were compared with an age- and gender-matched control group. HADS anxiety (HADS-A) and HADS depression (HADS-D) scores between 8 and 10 defined possible anxiety and depression and ≥11 defined probable anxiety and depression, respectively. Results: We included 72 patients and 288 controls. Compared with controls, patients with GCA had a statistically significant higher prevalence of HADS-A ≥8 (48.6% vs 26.4%), HADS-A ≥11 (30.6% vs 12.2%) and HADS-D ≥11 (33.3% vs 18.1%). GCA was an independent predictor of HADS-A ≥8 [odds ratio (OR) 3.3 (95% CI 1.9, 5.9)], HADS-A ≥11 [OR 3.8 (95% CI 2.0, 7.4)] and HADS-D ≥11 [OR 2.6 (95% CI 1.4, 4.7)]. Among patients with GCA, a negative correlation was observed between HADS-A/D and SF-36 mental health scores (r = -0.780 and r = -0.742, respectively). Glucocorticoid therapy was a predictor of HADS-A ≥8 [OR 10.4 (95% CI 1.2, 94.2)] and older age of HADS-D ≥8 [OR 1.2 (95% CI 1.1, 1.3)] and HADS-D ≥11 [OR 1.1 (95% CI 1.0, 1.2)]. Conclusions: Compared with the general population, patients with GCA have a higher prevalence of anxiety and depression and GCA is an independent predictor of these symptoms. Glucocorticoid treatment and older age are predictors of anxiety and depression, respectively, in patients with GCA.

Vacuolar ATPase-mediated regulation of neutral lipid dynamics: Insights into lipid droplet homeostasis and stress response mechanisms.

This study explores the intricate relationship between the yeast vacuolar H+-ATPase (V-ATPase) and neutral lipid metabolism. We show that LD generation observed upon loss of V-ATPase activity is crucial for survival in lipotoxic conditions. Moreover, the study uncovers a link between V-ATPase function, inositol metabolism and the activation of the oxidative pentose phosphate pathway, highlighting its pivotal role in counteracting oxidative stress. This work provides foundational insights into metabolic adaptations triggered by V-ATPase dysfunction, shedding light on cellular adaptability under lipotoxic and oxidative stress conditions.

Combined low-carbohydrate diet and long-term exercise in hypoxia in type 2 diabetes: A randomized controlled trial protocol to assess glycemic control, cardiovascular risk factors and body composition.

Background: Cardiovascular disease is the leading cause of mortality associated with diabetes, which is characterized by chronic hyperglycemia. Low-carbohydrate diet has gained popularity as an intervention in patients with type 2 diabetes mellitus, acting to improve glycemic profile and serum lipids. In its turn, exercise in hypoxia induces specific adaptations, mostly modulated via hypoxia-induced transcription factor signaling cascade, which increases with exposure to altitude, and promotes angiogenesis, glycogen supply, glucose tolerance, and raises GLUT-4 expression. Aim: Given that hyperglycemia decreases HIF-1α and it is better controlled when following a low-carbohydrate diet, this study aims to examine the hypothesis that a combination of both low-carbohydrate diet and chronic exercise in hypoxia in type 2 diabetes mellitus is associated with improved glycemic control and cardiovascular parameters, whose protocol is described. Methods: Patients with type 2 diabetes mellitus (n = 48) will be recruited and randomized into one of the three groups: (a) Control group: Control diet (low-fat and moderate-carbohydrate diet) + exercise in normoxia; (2) exercise in hypoxia group: Control diet + exercise in hypoxia; (3) intervention group: Low-carbohydrate diet (low-carbohydrate and high-fat diet) + exercise in hypoxia. Before and after 8 weeks of interventions, cardiopulmonary tests (Bruce protocol), body composition and blood pressure will be evaluated. Blood samples will be collected to measure hypoxia-induced transcription factor, C-reactive protein, glycemic and lipid profiles. Summary: This will be the first trial to examine the isolated and combined effect of chronic exercise in hypoxia and low-carbohydrate diet in type 2 diabetes mellitus. This trial will help to fill a significant research gap, guide future research and contribute to the combined nutrition and exercise approach to type 2 diabetes mellitus.

Characteristics and outcome of ANCA-associated vasculitides induced by anti-thyroid drugs: a multicentre retrospective case-control study.

OBJECTIVE: Data on ANCA-associated vasculitis (AAV) induced by anti-thyroid drugs (ATD) are scarce. We aimed to describe the characteristics and outcome of these patients in comparison to primary AAV. METHODS: We performed a retrospective multicentre study including patients with ATD-induced AAV. We focused on ATD-induced microscopic polyangiitis (MPA) and compared them with primary MPA by matching each case with four controls by gender and year of diagnosis. RESULTS: Forty-five patients with ATD-induced AAV of whom 24 MPA were included. ANCA were positive in 44 patients (98%), including myeloperoxidase (MPO)-ANCA in 21 (47%), proteinase 3 (PR3)-ANCA in six (13%), and double positive MPO- and PR3-ANCA in 15 (33%). Main clinical manifestations were skin involvement (64%), arthralgia (51%) and glomerulonephritis (20%). ATD was discontinued in 98% of cases, allowing vasculitis remission in seven (16%). All the remaining patients achieved remission after glucocorticoids, in combination with rituximab in 11 (30%) or cyclophosphamide in four (11%). ATD were reintroduced in seven cases (16%) without any subsequent relapse. Compared with 96 matched primary MPA, ATD-induced MPA were younger at diagnosis (48 vs 65 years, P < 0.001), had more frequent cutaneous involvement (54 vs 25%, P = 0.007), but less frequent kidney (38 vs 73%, P = 0.02), and a lower risk of relapse (adjusted HR 0.07; 95% CI 0.01, 0.65, P = 0.019). CONCLUSION: ATD-induced AAV were mainly MPA with MPO-ANCA, but double MPO- and PR3-ANCA positivity was frequent. The most common manifestations were skin and musculoskeletal manifestations. ATD-induced MPA were less severe and showed a lower risk of relapse than primary MPA.

Hepatitis B vaccination associated with low response in patients with rheumatic diseases treated with biologics.

BACKGROUND: Hepatitis B virus (HBV) vaccination is recommended for non-immunised patients with rheumatic diseases starting biological disease-modifying antirheumatic drugs (bDMARDs). There is some evidence that HBV vaccination is effective in patients under conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), but it is currently unclear whether this also applies to bDMARDs. OBJECTIVES: To assess the efficacy and safety of HBV vaccination in patients with inflammatory arthritides treated with bDMARDs. METHODS: A prospective cohort with inflammatory arthritides treated with bDMARDs, negative for anti-HBs and anti-HBc and never vaccinated for HBV was recruited. Engerix B was administered at 0, 1 and 6 months and anti-HBs was reassessed ≥1 month after last dose. Response was defined as anti-HBs≥10 IU/L and compared against vaccinated healthy controls. Disease flare, serious adverse events and immune-related disorders not previously present were recorded. RESULTS: 62 patients, most treated with TNF inhibitors (TNFi), and 38 controls were recruited. Most patients were taking csDMARDs (67.7%) and were in remission/low disease activity (59.4%). Only 20/62 patients (32.3%) had a positive response to vaccination, in comparison to 36/38 age-matched controls (94.7%, p<0.001). Response was seen in 19/51 patients treated with TNFi (37.3%) and in 1/11 (9.1%) patients treated with non-TNFi (p=0.07), including 1/6 treated with tocilizumab (16.7%). Among TNFi, response rates ranged from 4/22 (18.2%) for infliximab to 8/14 (57.1%) for etanercept. No relevant safety issues were identified. CONCLUSIONS: HBV vaccination response in patients with rheumatic diseases treated with bDMARDs was poorer than expected. Our data reinforce the recommendation for vaccination prior to starting bDMARDs.

Early human lung immune cell development and its role in epithelial cell fate.

Studies of human lung development have focused on epithelial and mesenchymal cell types and function, but much less is known about the developing lung immune cells, even though the airways are a major site of mucosal immunity after birth. An unanswered question is whether tissue-resident immune cells play a role in shaping the tissue as it develops in utero. Here, we profiled human embryonic and fetal lung immune cells using scRNA-seq, smFISH, and immunohistochemistry. At the embryonic stage, we observed an early wave of innate immune cells, including innate lymphoid cells, natural killer cells, myeloid cells, and lineage progenitors. By the canalicular stage, we detected naive T lymphocytes expressing high levels of cytotoxicity genes and the presence of mature B lymphocytes, including B-1 cells. Our analysis suggests that fetal lungs provide a niche for full B cell maturation. Given the presence and diversity of immune cells during development, we also investigated their possible effect on epithelial maturation. We found that IL-1ß drives epithelial progenitor exit from self-renewal and differentiation to basal cells in vitro. In vivo, IL-1ß-producing myeloid cells were found throughout the lung and adjacent to epithelial tips, suggesting that immune cells may direct human lung epithelial development.

The BREAK study protocol: Effects of intermittent energy restriction on adaptive thermogenesis during weight loss and its maintenance.

BACKGROUND: Adaptive thermogenesis, defined as the decrease in the energy expenditure components beyond what can be predicted by changes in body mass stores, has been studied as a possible barrier to weight loss and weight maintenance. Intermittent energy restriction (IER), using energy balance refeeds, has been pointed out as a viable strategy to reduce adaptive thermogenesis and improve weight loss efficiency (greater weight loss per unit of energy deficit), as an alternative to a continuous energy restriction (CER). Following a randomized clinical trial design, the BREAK Study aims to compare the effects of IER versus CER on body composition and in adaptive thermogenesis, and understand whether participants will successfully maintain their weight loss after 12 months. METHODS: Seventy-four women with obesity and inactive (20-45 y) will be randomized to 16 weeks of CER or IER (8x2 weeks of energy restriction interspersed with 7x1 week in energy balance). Both groups will start with 2 weeks in energy balance before energy restriction, followed by 16 weeks in energy restriction, then 8 weeks in energy balance and finally a 12-month weight maintenance phase. Primary outcomes are changes in fat-mass and adaptive thermogenesis after weight loss and weight maintenance. Secondary outcomes include weight loss, fat-free mass preservation, alterations in energy expenditure components, and changes in hormones (thyroid function, insulin, leptin, and cortisol). DISCUSSION: We anticipate that The BREAK Study will allow us to better understand adaptive thermogenesis during weight loss and weight maintenance, in women with obesity. These findings will enable evidence-based decisions for obesity treatment. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05184361.

Menthol mouth rinsing and performance in elite football referees in the heat: A study protocol for a randomized crossover trial.

Background: Within professional European competitions, matches can be played in extreme environmental temperatures, ranging from -5 °C to +30 °C in different countries. Furthermore, the World Cups are usually played in the summer months, when temperatures can exceed 35 °C, increasing physiological stress. Practical and cost-effective cooling strategies may be implemented to help players and referees to cope with exercising in the heat. No study has evaluated the effect of non-thermal internal cooling techniques regarding performance responses on elite football referees, so far. This study aims to analyse the effects of a menthol mouth rinse regarding physical, physiological, and perceptual performance in elite male football referees, during a 90-min football protocol in the heat. Methods: At least thirteen male football referees will be recruited to perform two intermittent football protocols, separated by no less than 7 days. After passing the eligibility criteria, the participants will be randomly assigned to 1 of 2 beverages: (1) intervention - menthol solution 0.01% and (2) placebo - noncaloric berry-flavored solution, both at room temperature. The beverages will be given before warm-up (pre-cooling) and at the half-time (per-cooling). The trials will follow a randomized counterbalanced crossover design, single blinded, and will take place in indoor facilities, with Wet Bulb Globe Temperature (WBGT) > 30 °C, at the same time of the day to control for circadian variations. Impact of the project: The results of this study are expected to determine whether mouth rinsing a menthol solution before and during a football exercise protocol performed in the heat will alter perceptual measures and help ease physiological strain and attenuate performance decrements in elite male football referees, comparing to a non-cooling strategy. Thus, we can be closer to defining nutritional strategies of internal cooling that may be an advantage for the performance of the football referees in the heat. Trial registration: www.ClinicalTrials.gov NCT05632692 registered on 20 November 2022.

Perspectives and practices of nutritionists on dietary supplements for elite soccer teams: a cross-sectional survey study.

Introduction and objectives: Dietary supplements are part of the nutritional strategies frequently applied in sports performance support. With growing research on this subject and high demand from athletes, nutritionists need to keep up to date with the latest evidence and utility of dietary supplements, particularly in real-world contexts. As information about the use of dietary supplements among elite soccer players is still scarce, this work aimed to know how nutritionists working with elite soccer teams perceive and use these substances in their daily practice. Methods: A questionnaire previously used to describe nutritionists' beliefs and attitudes regarding the use of dietary supplements in a clinical context was adapted for this study. The online questionnaire was addressed to nutritionists working with elite soccer teams from six European Leagues and Brazil, between November 2022 and February 2023. Results: Overall, the participants considered themselves well-trained (76.9%), knowledgeable (95.4%), and interested in dietary supplements (95.4%). The majority (70.8%) of the participants agreed or strongly agreed to recommend dietary supplements to soccer players. Personal usage of dietary supplements was associated with recommending supplements (p < 0.001), but no relationships were found with years of experience and academic level. Discussion: Nutritionists working with elite soccer players consider the use of dietary supplements for performance-enhancement purposes and not only to compensate for nutritional deficits, which might contribute to their higher interest, training and perceived knowledge about this topic. Participants recognize players' interest in dietary supplements, and are mindful of the safety and efficacy of these products. The present study suggests that nutritionists working with elite soccer teams are among the highest prescribers of dietary supplements, although personal usage is lower than that of nutritionists working in a clinical context.

Disturbances of the Lung Glutathione System in Adult Guinea Pigs Following Neonatal Vitamin C or Cysteine Deficiency.

In premature infants receiving parenteral nutrition, oxidative stress is a trigger for the development of bronchopulmonary dysplasia, which is an important factor in the development of adult lung diseases. Neonatal vitamin C and glutathione deficiency is suspected to induce permanent modification of redox metabolism favoring the development of neonatal and adult lung diseases. A total of 64 3-day-old guinea pigs were fed an oral diet that was either complete or deficient in vitamin C (VCD), cysteine (CD) (glutathione-limiting substrate) or both (DD) for 4 days. At 1 week of age, half of the animals were sacrificed while the other started a complete diet until 12 weeks of age. At 1 week, the decrease in lung GSH in all deficient groups was partially explained by the oxidation of liver methionine-adenosyltransferase. mRNA levels of kelch-like ECH-associated protein 1 (Keap1), glutathione-reductase (Gsr) and glutaredoxin-1 (Glrx) were significantly lower only in CD but not in DD. At 12 weeks, glutathione levels were increased in VCD and CD. Keap1, Gsr and Glrx mRNA were increased, while glutathione-reductase and glutaredoxin proteins were lower in CD, favoring a higher glutathionylation status. Both neonatal deficiencies result in a long-term change in glutathione metabolism that could contribute to lung diseases' development.

Effects of dietary supplements on athletic performance in elite soccer players: a systematic review.

Dietary supplements are widely used among athletes, and soccer players are no exception. Nevertheless, evidence supporting the use of dietary supplements aiming to enhance performance in soccer is somewhat contradictory, scarce, or even nonexistent. Thus, the present study aimed to systematically review and synthesize the effects of dietary supplements on athletic performance (e.g. distance covered, sprinting, jump performance) in elite soccer players. Studies enrolling highly trained, elite, and world-class soccer players using dietary supplements were searched in MEDLINE/PubMed, Web of Science, Scopus, and EBSCO databases in June 2022. In total, 1043 studies were identified, and 18 met the eligibility criteria. The studies evaluated the impacts on athletic performance of several dietary supplements, including caffeine, creatine, protein, beverages with carbohydrates and electrolytes, tart cherry juice, nitrate-rich beetroot juice, sodium bicarbonate with minerals, yohimbine, and a proprietary nutraceutical blend. Caffeine supplementation in doses between 3 and 6 mg/kg of body mass may improve jump height and sprint ability, particularly in female players, but individual response to caffeine must be considered. Creatine may improve sprint, agility, and in female players, jump performance. Protein supplementation can improve sprint and jump performance between matches, especially if protein ingested from food is not up to recommendations. Beverages containing carbohydrates and electrolytes can be used as part of the strategies to achieve carbohydrate intake during training and match-days but used alone do not benefit athletic performance. Tart cherry juice might be useful for maintaining athletic performance after matches that produce higher force loss and exercise-induced muscle damage, although polyphenols from the diet might attenuate the effects of tart cherry supplementation. Nitrate-rich beetroot concentrate can attenuate performance decrease in the days following matches. Further investigation with sodium bicarbonate alone is necessary, as supplementation protocols with elite players included other substances. Finally, the available data does not support yohimbine supplementation or the use of Resurgex Plus® to improve athletic performance in elite soccer players. Still, more well-designed research with elite soccer players is needed to improve support and advice regarding the use of dietary supplements for athletic performance enhancement.