Methyl-donor supplementation in women with systemic lupus erythematosus with different nutritional status: the protocol for a randomised, double-blind, placebo-controlled trial.

INTRODUCTION: DNA hypomethylation in patients with systemic lupus erythematosus (SLE) has been recently documented in the literature. Low levels of DNA methylation have been observed globally and in genes associated with immune and inflammatory pathways in SLE's CD4+T lymphocytes. Given that certain micronutrients can either donate methyl groups within one-carbon metabolism pathways or serve as cofactors for enzymes involved in the DNA methylation process, this randomised, double-blind, placebo-controlled trial aims to investigate whether a 3-month supplementation of folic acid and vitamin B12 will modulate the DNA methylation profile in subcutaneous adipose tissue (primary outcome) of women with SLE and normal weight or excess body weight. As secondary objectives, we will assess gene expression, telomere length and phenotypic characteristics (ie, clinical parameters, body weight and composition, abdominal circumference, food intake and disordered eating attitude, physical activity, lipid profile, serum concentrations of leptin, adiponectin, and cytokines). METHODS AND ANALYSIS: Patients will be classified according to their nutritional status by body mass index in normal weight or excess body weight. Subsequently, patients in each group will be randomly assigned to either a placebo or an intervention group (folic acid (400 mcg) and vitamin B12 (2000 mcg) supplementation). Endpoint evaluations will be conducted using both intention-to-treat and per-protocol analyses. This study has the potential to design new personalised nutritional approaches as adjunctive therapy for patients with SLE. ETHICS AND DISSEMINATION: This study has been reviewed and approved by the Ethical Committee from Clinical Hospital of the School of Medicine of the University of Sao Paulo, Brazil (CAAE.: 47317521.8.0000.0068). TRIAL REGISTRATION NUMBER: NCT05097365 (first version).

Acute Effects of Citrulline Malate Supplementation on Nocturnal Blood Pressure Dipping After Exercise in Hypertensive Patients: A Randomized, Placebo-Controlled Trial.

BACKGROUND: Citrulline malate (CM), especially when used in conjunction with physical exercise, has demonstrated potential as a non-pharmacological adjunct in the management of hypertension. Nevertheless, its impact on nocturnal blood pressure dipping remains unexplored. OBJECTIVE: Evaluate the impact of a single dose of CM on nocturnal blood pressure dipping after exercise in hypertensive individuals. METHODS: In a double-blind, placebo-controlled, parallel-group clinical trial, twenty hypertensive adults (55 ± 16 years) were randomly assigned to either a CM (6 g) or placebo (6 g of corn starch) group (PLA). Resting blood pressure was measured after a 20-min period of comfortable seating in a calm environment. Both groups underwent 40 min of treadmill running/walking at an intensity of 60-70% of their reserve heart rate, 120 min after ingesting the substances. Ambulatory blood pressure monitoring was employed to measure blood pressure over 24 h. RESULTS: No significant differences in systolic blood pressure values were observed between the CM and PLA groups at rest, during wakefulness, sleep, or over a 24-h period. However, CM exhibited a significant reduction in diastolic blood pressure in several metrics: delta 24 h (-14 mmHg vs -6 mmHg, p = 0.047), delta wakefulness (-12 mmHg vs -4 mmHg, p = 0.024), percent delta 24 h (-16% vs -6%, p = 0.024), and percent delta wakefulness (-14% vs -4%, p = 0.013). No significant differences were found between CM and PLA in terms of systolic and diastolic nocturnal absolute reductions (-13 mmHg vs -12 mmHg, p = 0.808, and -13 mmHg vs -8 mmHg, p = 0.273, respectively) or nocturnal percentage decrease (-9.9% vs -9.4%, p = 0.844, and -15.3% vs -11.7%, p = 0.399, respectively). CONCLUSIONS: The study found no significant changes in the post-exercise nocturnal blood pressure dip following a single dose of CM supplementation. However, a notable reduction in diastolic blood pressure was observed during the waking period and over the average 24-h monitoring period. CLINICAL TRIAL REGISTRY NUMBER AND WEBSITE: ClinicalTrials.gov platform (NCT03378596).

[Therapeutic effect of vitamin D supplementation in mexican patients with allergic rhinitis]. / Efecto de la suplementación con vitamina D en pacientes mexicanos con rinitis alérgica.

OBJETIVES: To evaluate the impact of cholecalciferol (D3) supplementation using clinical and paraclinical variables in patients with RA and vitamin D insufficiency and deficiency. METHODS: A randomized, double-blind, placebo-controlled study included patients from 5 to 40 years with a diagnosis of RA and vitamin D insufficiency and deficiency. They were supplemented for 8 weeks with 4000 or 5000 IU, depending on age. Total nasal symptoms score (TNSS) was measured monthly and 25(OH)D3 levels at baseline and at the end of the study. RESULTS: A total of 31 patients were included, with a mean age of 18.19 years. In the active group, there was a significant improvement in symptomatology with respect to the TNSS score and an increase in serum vitamin D levels (p < 0.01). There were no adverse reactions with cholecalciferol or placebo. CONCLUSIONS: Supplementing patients with vitamin D3, at the evaluated dose, together with conventional treatent for allergic rhinitis results in symptoms and quality of life improvement in patients with this disease.

OBJETIVOS: Evaluar el impacto de la suplementación con colecalciferol (D3) mediante variables clínicas y paraclínicas en pacientes con RA e insuficiencia y deficiencia de vitamina D. MÉTODOS: Estudio aleatorio, doble ciego, placebo controlado, en el que se incluyeron pacientes de 5 a 40 años, con diagnóstico de RA e insuficiencia y deficiencia de vitamina D. Fueron suplementados con 4000 o 5000 UI, dependiendo de la edad, durante 8 semanas. Mensualmente se midió la puntuación total síntomas nasales (TNSS) y las concentraciones de 25(OH)D3 al inicio y al final del estudio. RESULTADOS: Se incluyeron 31 pacientes, con una edad promedio de 18.19 años. En el grupo activo existió una mejoría significativa en la sintomatología respecto a la puntación de TNSS y un incremento en los niveles séricos de vitamina D (p < 0.01). No se presentaron reacciones adversas con la ingesta de colecalciferol o placebo. CONCLUSIONES: Suplementar a los pacientes con vitamina D3, a la dosis evaluada, junto con el tratamiento convencional para la rinitis alergica resulta en una mejoría sintomática y en la calidad de vida de los pacientes con esta enfermedad.

The effect of fiber supplementation with agave fructans or psyllium plantago in symptoms of constipation and its relation with whole and regional transit time and pH.

BACKGROUND: Supplementation with the Agave tequilana Weber blue variety fructans is a feasible treatment option for functional constipation (FC). However, its effects on colonic function have not yet been studied. This study assessed whole gut transit time (WGTT) and regional transit time using a wireless motility capsule (WMC) before and after supplementation with different fiber treatments in patients with FC. METHODS: A secondary analysis was performed on data collected from a randomized, double-blind clinical trial comparing agave fructans with psyllium plantago. WGTT, regional transit time, contractility, and pH were measured using WMC before and after fiber supplementation. Comparisons were performed using nonparametric tests. KEY RESULTS: Twenty patients with FC were evaluated, with a median age of 39 (25-54 years), and 18 (90%) were women. Five patients were included in each intervention group. There were no changes in WGTT or regional transit times between the groups (p > 0.05). Similarly, there were no differences in the changes experienced by regional or general contractility among the groups (p > 0.05). The cecal pH profile did not differ between the groups before and after fiber supplementation (p > 0.05). The percentages of clinical responses and consistency of bowel movements between the groups were similar. CONCLUSIONS & INFERENCES: FC presents a clinical response to a fiber challenge, regardless of the administered intervention. However, this response was not associated with improvement in contractility or regional transit time. We speculate that there are other mechanisms by which fiber consumption may improve FC.

Effect of spirulina on risk of hospitalization among patients with COVID-19: the TOGETHER randomized trial.

BACKGROUND: Algae-derived nutraceuticals, such as spirulina, have been reported to have biological activities that may minimize clinical consequences to COVID-19 infections. OBJECTIVES: This study aimed to determine whether spirulina is an effective treatment for high-risk patients with early COVID-19 in an outpatient setting. METHODS: The TOGETHER trial is a placebo-controlled, randomized, platform trial conducted in Brazil. Eligible participants were symptomatic adults with a positive rapid test for SARS-CoV-2 older than 50 y or with a known risk factor for disease severity. Patients were randomly assigned to receive placebo or spirulina (1 g twice daily for 14 d). The primary end point was hospitalization defined as either retention in a COVID-19 emergency setting for >6 h or transfer to tertiary hospital owing to COVID-19 at 28 d. Secondary outcomes included time-to-hospitalization, mortality, and adverse drug reactions. We used a Bayesian framework to compare spirulina with placebo. RESULTS: We recruited 1126 participants, 569 randomly assigned to spirulina and 557 to placebo. The median age was 49.0 y, and 65.3% were female. The primary outcome occurred in 11.2% in the spirulina group and 8.1% in the placebo group (odds ratio [OR]: 1.24; 95% credible interval: 0.84, 1.86). There were no differences in emergency department visit (OR: 1.21; 95% credible interval: 0.81, 1.83), nor time to symptom relief (hazard ratio: 0.90; 95% credible interval: 0.79, 1.03). Spirulina also not demonstrate important treatment effects in the prespecified subgroups defined by age, sex, BMI, days since symptom onset, or vaccination status. CONCLUSIONS: Spirulina has no any clinical benefits as an outpatient therapy for COVID-19 compared with placebo with respect to reducing the retention in an emergency setting or COVID-19-related hospitalization. There are no differences between spirulina and placebo for other secondary outcomes. This trial was registered at clinicaltrials.gov as NCT04727424.

Effect of Motor Interference Therapy on Distress Related to Traumatic Memories: A Randomized, Double-Blind, Controlled Feasibility Trial.

INTRODUCTION: Traumatic memories (TM) are a core feature of stress-related disorders, including posttraumatic stress disorder (PTSD). Treatment is often difficult, and specific pharmacological interventions are lacking. We present a novel non-pharmacological intervention called motor interference therapy (MIT) as a promising alternative for these symptoms. AIMS: To determine the feasibility of MIT, a brief, audio-delivered, and non-pharmacological intervention that uses cognitive and motor tasks to treat TM. METHODS: We designed a randomized, double-blind trial. Twenty-eight participants from an outpatient clinic with at least one TM were included to receive either MIT or progressive muscle relaxation (PMR). Spanish versions of the PTSD symptom severity scale (EGS), visual analog scale for TM (TM-VAS), and quality of life (EQ-VAS) were applied prior to intervention, 1 week, and 1 month following intervention. RESULTS: Mean scores on all measures improved from baseline to posttest for both groups. MIT participants showed significantly more positive scores at 1 week and 1 month (TM-VAS baseline: 9.8 ± 0.4; immediate: 6.0 ± 2.0; 1 week: 3.8 ± 3.1 [d = 1.57]; 1 month 2.9 ± 2.8 [d = 1.93]) than PMR participants on measures of distress due to TM, trauma re-experiencing, anxiety, and a composite measure of PTSD. CONCLUSION: MIT is a simple, effective, and easy-to-use tool for treating TM and other stress-related symptoms. It requires relatively few resources and could be adapted to many contexts. The results provide proof-of-principle support for conducting future research with larger cohorts and controls to improve clinical effectiveness and research on brief interventions. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03627078.

EFFICACY AND SAFETY OF THE PROPOSED BIOSIMILAR AFLIBERCEPT, SDZ-AFL, IN PATIENTS WITH NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: 52-Week Results From the Phase 3 Mylight Study.

PURPOSE: The Phase 3 Mylight study was designed to confirm clinical equivalence of proposed biosimilar aflibercept (SOK583A1; Sandoz [proposed biosimilar aflibercept, SDZ-AFL]) to its reference biologic (Eylea; Regeneron Pharmaceuticals, Inc; Bayer AG [reference aflibercept, Ref-AFL]). METHOD: Mylight was a prospective, double-masked, 2-arm, parallel Phase 3 study. Participants with neovascular age-related macular degeneration were randomized 1:1 to receive eight injections of SDZ-AFL (n = 244) or Ref-AFL (n = 240) over 48 weeks. The primary endpoint was mean change in best-corrected visual acuity score from baseline to Week 8. Secondary endpoints included anatomical outcomes, best-corrected visual acuity at Weeks 24 and 52, safety, and pharmacokinetics. RESULTS: Similarity in mean change in best-corrected visual acuity score was established between SDZ-AFL (n = 235) and Ref-AFL (n = 226) at Week 8 (difference: -0.3 [90% CI, -1.5 to 1.0]) and Week 52. No clinically meaningful differences occurred between groups in anatomical outcomes. Safety profiles were similar, with comparable incidences of treatment-related adverse events (SDZ-AFL: 2.5%; Ref-AFL: 2.9%). The incidence of anti-drug antibodies was similar between groups. Systemic free aflibercept concentrations 24 hours postdose were low and comparable between SDZ-AFL and Ref-AFL. CONCLUSION: Proposed biosimilar aflibercept matched reference aflibercept in efficacy, safety, and pharmacokinetics in participants with neovascular age-related macular degeneration. Therefore, this Phase 3 study confirmed biosimilarity of SDZ-AFL to Ref-AFL.

Evaluation of enteral and parenteral hyaluronic acid in induced ischemic skin flaps in rats: a double-blinded and randomized study.

PURPOSE: To evaluate exogenous hyaluronic acid (HA) derived from bacterial fermentation through enteral and parenteral routes in ischemic skin flaps induced in rats, using clinical and histological exams; and interleukins (IL) as tissue inflammatory biomarkers. METHODS: Sixty-four male adults Wistar rats with ischemic skin flaps on the dorsum were randomized into four groups, based on the treatment protocol: subcutaneous administration of saline solution (0.9%) (GI); oral administration of distilled water (GII); subcutaneous administration of HA (0.3%) (GIII); and oral administration of HA (1%) (GIV). Flaps of all groups were comparable regarding clinical and macroscopic evaluation, histological examination, pro-inflammatory cytokines (IL-1ß, IL-6, and tumor necrosis factor-α) and anti-inflammatory cytokine IL-10. RESULTS: A lower percentage of necrosis was identified in flaps treated with subcutaneous administration of HA (0.3%). The pro- and anti-inflammatory cytokines, epidermis thickness, blood vessels, and inflammatory cells showed statistically significant inter-group and intra-group differences (p < 0.05). CONCLUSIONS: High molecular HA (1,400 ~ 2,000 kDa) administrated by subcutaneous or oral route exhibited beneficial effects in ischemic skin flaps of rats. However, subcutaneous administration of HA (0.3%) showed better results in terms of the percentage of necrosis and epithelialization.

No Combined Effect of Caffeinated Chewing Gum and Priming Exercise on Oxygen Uptake and Muscle Near-Infrared Spectroscopy-Derived Kinetics: A Double-Blind Randomized Crossover Placebo-Controlled Trial in Cyclists.

This study aimed to investigate the effects of caffeine ingestion by chewing gum (GUMCAF) combined with priming exercise on pulmonary oxygen uptake (V˙O2) and near-infrared spectroscopy-derived muscle oxygen extraction (HHb + Mb) kinetics during cycling performed in a severe-intensity domain. Fifteen trained cyclists completed four visits: two under a placebo gum (GUMPLA) and two under GUMCAF ingestion. Each visit consisted of two square-wave cycling bouts at Δ70 intensity (70% of difference between the V˙O2 at first ventilatory threshold and V˙O2max) with duration of 6 min each and 5 min of passive rest between the bouts. The GUMPLA or GUMCAF (400 mg) was chewed for 5 min, 12 min before the first Δ70 bout in a randomized double-blind procedure. The fundamental phase and slow component of HHb + Mb and V˙O2 kinetics were evaluated. For HHb + Mb kinetics, regardless of ingested gum, priming exercise effects occurred on the time constant (GUMCAF 16.0 ± 4.0 vs. 13.9 ± 2.9 s; GUMPLA 15.7 ± 6.1 vs. 13.2 ± 2.5 s), amplitude, slow component, time delay, and mean response time parameters (p ≤ .032). For V˙O2 kinetics, there were significant effects of bouts on the amplitude, slow component, end V˙O2, and the gain kinetics parameters (p < .017). Baseline V˙O2 was higher during GUMCAF than GUMPLA (p = .020). No significant effects occurred for the interaction between gum and bout in any parameter of V˙O2 or HHb + Mb kinetics. Therefore, unlike the priming exercise in severe-intensity exercise, GUMCAF is not an effective strategy for improving V˙O2 or HHb + Mb kinetics acceleration.

Antisense therapy to block the Kallikrein-kinin pathway in COVID-19: The ASKCOV randomized controlled trial.

PURPOSE: To assess the effect of antisense therapy to block kallikrein-kinin pathway in COVID-19 patients. MATERIAL AND METHODS: Randomized, placebo-controlled, double blind, controlled trial enrolling hospitalized COVID-19 patients that required supplementary oxygen to sustain peripheral oxygen saturation. Key exclusion criteria included use of mechanical ventilation or vasopressors, and patients with more than 10 days since symptom onset or more than 48 h of oxygen use. Patients were randomized to either one subcutaneous dose of ISIS721744, an antisense that blocks prekallikrein, or placebo. The primary outcome was the number of days alive and free of oxygen support up to 15 days (DAFOR15). Secondary endpoints included organ failure score, need and duration of mechanical ventilation up to 15 days, and all-cause mortality at 30 days. Exploratory endpoints included physiological parameters, biomarkers, and quality of life. RESULTS: From October 10, 2020, to December 09, 2020, 111 patients were randomized at thirteen sites in Brazil (56 to treatment and 55 to control group). Average age was 57.5 years, and most patients were male (68.5%). There were no significant differences in DAFOR15 between groups (5.9 ± 5.2 days for the intervention arm and 7.7 ± 5.1 for the control group; mean difference - 0.65, 95% confidence intervals from -2.95 to 1.36, p = 0.520). CONCLUSION: Antisense therapy designed to block the kallikrein-kinin pathway did not demonstrate clinical benefits in increasing days-alive without respiratory support at 15 days in patients with COVID-19 during the first wave in 2020. GOV IDENTIFIER: NCT04549922.

BCG vaccination of healthcare workers for protection against COVID-19: 12-month outcomes from an international randomised controlled trial.

OBJECTIVES: Bacille Calmette-Guérin (BCG) vaccine has immunomodulatory effects that may provide protection against unrelated infectious diseases. We aimed to determine whether BCG vaccination protects adults against COVID-19. DESIGN: Phase III double-blind randomised controlled trial. SETTING: Healthcare centres in Australia, Brazil, the Netherlands, Spain, and the United Kingdom during the COVID-19 pandemic. PARTICIPANTS: 3988 healthcare workers with no prior COVID-19 and no contraindication to BCG. INTERVENTION: Randomised 1:1 using a web-based procedure to receive a single 0.1 mL intradermal dose of BCG-Denmark (BCG group, n = 1999) or saline (placebo group, n = 1989). MAIN OUTCOME MEASURES: Difference in incidence of (i) symptomatic and (ii) severe COVID-19 during the 12 months following randomisation in the modified intention to treat (mITT) population (confirmed SARS-CoV-2 naïve at inclusion). RESULTS: Of the 3988 participants randomised, 3386 had a negative baseline SARS-CoV-2 test and were included in the mITT population. The 12-month adjusted estimated risk of symptomatic COVID-19 was higher in the BCG group (22.6%; 95% confidence interval [CI] 20.6 to 24.5%) compared with the placebo group (19.6%; 95% CI 17.6 to 21.5%); adjusted difference +3.0% points (95% CI 0.2 to 5.8%; p = 0.04). The 12-month adjusted estimated risk of severe COVID-19 (mainly comprising those reporting being unable to work for ≥3 consecutive days) was 11.0% in the BCG group (95% CI 9.5 to 12.4%) compared with 9.6% in the placebo group (95% CI 8.3 to 11.1%); adjusted difference +1.3% points (95% CI -0.7 to 3.3%, p = 0.2). Breakthrough COVID-19 (post COVID-19 vaccination) and asymptomatic SARS-CoV-2 infections were similar in the two groups. There were 18 hospitalisations due to COVID-19 (11 in BCG group, 7 in placebo group; adjusted hazard ratio 1.56, 95% CI 0.60 to 4.02, p = 0.4) and two deaths due to COVID-19, both in the placebo group. CONCLUSIONS: Compared to placebo, vaccination with BCG-Denmark increased the risk of symptomatic COVID-19 over 12 months among healthcare workers and did not decrease the risk of severe COVID-19 or post-vaccination breakthrough COVID-19. TRIAL REGISTRATION: ClinicalTrials.gov NCT04327206.

Repetitive Transcranial Magnetic Stimulation with Body Weight-supported Treadmill Training Enhances Independent Walking of Individuals with Chronic Incomplete Spinal Cord Injury: A Pilot Randomized Clinical Trial.

The purpose of this study is to evaluate the efficacy of repetitive transcranial magnetic stimulation (rTMS) combined with body weight-support treadmill training (BWSTT) for improving walking function of individuals with chronic incomplete spinal cord injury (iSCI). A 4-week, double-blinded, randomized, sham-controlled pilot study involved 12 sessions of real (10 Hz, 1800 pulses) or sham rTMS combined with BWSTT (15-20 min, moderate intensity). Walking independence was assessed using the Walking Index for Spinal Cord Injury II (WISCI-II). Lower extremity motor function (lower extremity motor score [LEMS]) and spasticity, sensory function, functional independence (Spinal Cord Injury Measure III [SCIM-III]), and quality of life were also assessed. Walking independence (WISCI-II) after the 6th session was higher in the BWSTT/rTMS real (n = 7) (median change (IQR): 3 (1.5 to 3.5)) than in the sham group (n = 8) (median change (IQR): 0 (0 to 0.25), but there was no difference between groups after 12th session (BWSTT/rTMS real median change (IQR): 4 (2 to 5); BWSSTT/rTMS sham median change (IQR): 0 (0 to 3.25). Compared to baseline, LEMS and SCIM-III mobility scores were increased after 12 sessions in the BWSTT/rTMS real but not in the sham group. Within- and between-group sensory function, functional independence, and quality of life remained similar. This preliminary result suggests that combining BWSTT with rTMS could lead to earlier gait improvement in patients with chronic iSCI.

Effect of vitamin D3 on antiphospholipid antibodies in hospitalized patients with moderate to severe COVID-19.

OBJECTIVE: To investigate the effect of a single oral dose of 200,000 IU of vitamin D3 on antiphospholipid antibodies in hospitalized patients with moderate to severe COVID-19. METHODS: This is a post-hoc, exploratory analysis from a double-blind, placebo-controlled, randomized clinical trial performed in two centers in Sao Paulo, Brazil. Hospitalized patients with COVID-19 were randomly assigned to receive either vitamin D3 (n = 97) or placebo (n = 97). In this post-hoc analysis, the endpoints were titers and frequency of anti-ß2-Glycoprotein-I (aß2-GP) and Anticardiolipin (aCL) antibodies [Immunoglobulin G, M and A (IgG, IgM and IgA)]. RESULTS: Overall mean (SD) age was 55.3 (13.9) years, Body Mass Index (BMI) was 32.2 (7.1 kg/m2), and 106 participants (54.6 %) were male. There was a significant group by time interaction (p = 0.046) for frequency of aCL IgG, with increased values from baseline to discharge in the placebo group [n (%), from 13 (13.4) to 25 (25.8)] compared to the vitamin D3 [from 25 (25.8) to 29 (29.9)]. However, the frequency of aCL IgG did not change between the groups on discharge. No significant differences between vitamin D3 and placebo groups were found for any other autoantibodies. CONCLUSION: These findings do not support the use of a single oral dose of 200,000 IU of vitamin D3 to modulate autoantibodies in hospitalized patients with moderate to severe COVID-19.

Development of a new accurate lateral flow immunoassay for diagnosis of human leptospirosis.

PURPOSE: The current diagnostic methods for leptospirosis diagnosis are technically complex and expensive, with limited applicability to specialized laboratories. Furthermore, they lack diagnostic accuracy in the acute stage of the disease, which coincides with a period when antibiotics are highly effective. New simple and accurate tests are mandatory to decentralize and improve diagnosis. Here, we introduced a new lateral flow immunoassay (Lepto-LF) for human leptospirosis. METHODS: We conducted a double-blinded assay using 104 serum samples from patients with confirmed or discarded diagnosis for leptospirosis. The diagnostic performance of Lepto-LF was estimated across different ranges of days from onset of symptoms (dpo), considering the diagnostic algorithm as reference standard. Additionally, it was compared with the screening methods enzyme-linked immunosorbent assay (IgM-ELISA) and the slide agglutination test using temperature-resistant antigen (SATR). RESULTS: Lepto-LF exhibited perfect diagnostic performance with a Youden´s index J = 1 from 6 dpo in the acute phase. IgM-ELISA gave slightly lower accuracy with J = 0.91 and 95.5% of both sensitivity and specificity; while SATR showed a markedly inferior yield (J = 0.41, sensitivity = 95.5%, specificity = 45.5%). The performances remained consistent in the convalescence phase of the disease (> 10 dpo). CONCLUSION: Lepto-LF was found to be a reliable test for simple, rapid and early diagnosis of leptospirosis, resulting a promising tool for decentralizing leptospirosis diagnosis and enabling timely treatment of patients. In addition, Lepto-LF may be employed as confirmatory test, especially in remote areas and vulnerable contexts where the standard MAT is not available.

Efficacy and safety of Butantan-DV in participants aged 2-59 years through an extended follow-up: results from a double-blind, randomised, placebo-controlled, phase 3, multicentre trial in Brazil.

BACKGROUND: A single-dose dengue vaccine that protects individuals across a wide age range and regardless of dengue serostatus is an unmet need. We assessed the safety and efficacy of the live, attenuated, tetravalent Butantan-dengue vaccine (Butantan-DV) in adults, adolescents, and children. We previously reported the primary and secondary efficacy and safety endpoints in the initial 2 years of follow-up. Here we report the results through an extended follow-up period, with an average of 3·7 years of follow-up. METHODS: In this double-blind, randomised, placebo-controlled, phase 3, multicentre trial in Brazil, healthy participants (aged 2-59 years) who had not previously received a dengue vaccine were enrolled and randomly assigned 2:1 (stratified by age 18-59 years, 7-17 years, and 2-6 years) using a central electronic randomisation system to receive 0·5 mL of Butantan-DV (containing approximately 103 plaque-forming units of each of the four vaccine virus strains) or placebo, administered subcutaneously. Syringes containing vaccine or placebo were prepared by an unmasked trial pharmacist who was not involved in any subsequent participant assessments; other site staff and the participants remained unaware of the group allocations. Vaccine efficacy was calculated with the accrual of virologically confirmed dengue (VCD) cases (by RT-PCR) at least 28 days after vaccination up until the cutoff (at least 2 years of follow-up from the last participant enrolled). The primary endpoint was vaccine efficacy against VCD after day 28 by any dengue virus (DENV) serotype regardless of dengue serostatus at baseline in the per-protocol population. The primary and secondary safety endpoints up until day 21 were previously reported; secondary safety endpoints include the frequency of unsolicited vaccine-related adverse events after day 22. Safety analyses were done on all participants as treated. This trial is registered with ClinicalTrials.gov (NCT02406729) and is ongoing. FINDINGS: Of 16 363 participants assessed for eligibility, 16 235 were randomly assigned between Feb 22, 2016, and July 5, 2019, and received single-dose Butantan-DV (10 259 participants) or placebo (5976 participants). 16 162 participants (Butantan-DV n=10 215; placebo n=5947) were included in the per-protocol population and 16 235 (Butantan-DV n=10 259; placebo n=5976) in the safety population. At the data cutoff (July 13, 2021), participants had 2-5 years of follow-up (mean 3·7 years [SD 1·0], median 4·0 years [IQR 3·2-4·5]). 356 VCD cases were captured through the follow-up (128 in the vaccine group and 228 in the placebo group). Vaccine efficacy against VCD caused by any DENV serotype was 67·3% (95% CI 59·4-73·9); cases caused by DENV-3 or DENV-4 were not observed. The proportions of participants who had serious adverse events were similar between treatment groups (637 [6·2%] in the vaccine group and 395 [6·6%] in the placebo group) up until the cutoff. INTERPRETATION: A single dose of Butantan-DV was generally well tolerated and efficacious against symptomatic VCD (caused by DENV-1 and DENV-2) for a mean of 3·7 years. These findings support the continued development of Butantan-DV to prevent dengue disease in children, adolescents, and adults regardless of dengue serostatus. FUNDING: Instituto Butantan and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co. TRANSLATIONS: For the Spanish and Portuguese translations of the abstract see Supplementary Materials section.

Aesthetic Radiofrequency Associated with Rosmarinus officinalis Supplementation is Safe and Reduces Oxidative Stress in Women: Randomized, and Double-Blind Clinical Trial.

The objective were to evaluate the effects of supplementation of standardized dry extract of Rosmarinus officinalis (RO) and the application of aesthetic radiofrequency on the oxidative stress markers catalase (CAT), superoxide dismutase (SOD), non-protein thiols (NP-SH), and thiobarbituric acid reactive species (TBARS) and the biochemical markers triglycerides, total cholesterol, high density lipoprotein (HDL) cholesterol, glutamic-oxaloacetic transaminase (TGO/AST), pyruvic-glutamic transaminase (TGP/ALT), gamma glutamyl transpeptidase (gamma-GT), and creatinine. This study included 32 women received the aesthetic therapy to reduce localized fat. They were divided into the control group (n = 8) receiving placebo capsules and the intervention group (n = 24) subdivided into Group A, B, and C, each with eight members receiving supplementation with 100, 500, and 1000 mg/day of standardized dry extract of RO, respectively. The Universal Trial Number (UTN) - U1111-1274-6255. Supplementation with RO (500 mg/day) demonstrated a reduction in oxidative stress (quantified with through a significant increase in NP-SH and a reduction in SOD and CAT enzymes). The radiofrequency aesthetic treatment did not promote an increase in oxidative stress; however, it caused significant changes in total cholesterol, HDL cholesterol, and creatinine. RO is a plant with antioxidant effects and its oral consumption is safe in selected women subjects in hepatic and renal markers.

Investigating the efficacy of transcranial direct current stimulation on chronic pain management in endometriosis patients: A randomized controlled trial protocol.

INTRODUCTION: Similar to chronic pain conditions, individuals with endometriosis can be affected by central sensitization syndrome (CSS), which is characterized by a loss of analgesia and central amplification of pain. Transcranial direct current stimulation (tDCS) has shown potential as an effective intervention to improve pain generated by other chronic pain conditions impacted by CSS, such as fibromyalgia and chronic pelvic issues. This study aims to evaluate the effectiveness of tDCS on pain, fatigue, and quality of life among patients affected by endometriosis. METHODS: This is a single-center, parallel, double-blinded, randomized, controlled clinical trial protocol study. We aim to recruit 40 participants affected by endometriosis (active group, n = 20; sham group, n = 20). Anodal tDCS will be delivered at an intensity of 2mA, applied over the primary motor cortex for 20 minutes per day for 10 consecutive days. There will be four assessment times: 1 week before beginning the intervention; on the 10th day following the last tDCS session; and 1 and 2 months after the last tDCS session. Pain evaluated by the algometry will be the primary outcome. Pain intensity, quality of life, fatigue, and global perception of change will be the secondary outcomes. We will calculate the effects of the active versus sham stimulation on primary and secondary outcomes by using generalized estimated equations or mixed model analysis. The effect size calculation will represent the effect measure. We expect that only the active group show reductions in pain, fatigue, and quality of life. The results of this trial will produce an important first step in providing evidence on the effectiveness of neuromodulation for the management of pain and will provide data to support new studies on tDCS. REGISTRATION: Brazilian Clinical Trials Registry (RBR-4q69573).

Combined Impact of Creatine, Caffeine, and Variable Resistance on Repeated Sprint Ability in Young Soccer Players.

There is evidence that both intra-serial variable resistance (I-sVR), as pre-activation within the post-activation performance enhancement cycle (PAPE), and creatine and caffeine supplementation increase athletic performance in isolation. However, the effect of the three conditioning factors on 30 m repeated sprint ability (RSA) performance in young soccer players is unknown. This study determined the summative and isolation effect of ergogenic aids and pre-activation in half-back squats (HBSs) with I-sVR on performance in an RSA test in young soccer players. Twenty-eight young soccer players were randomly assigned to either EG1 (n = 7, creatine + caffeine + I-sVR), EG2 (n = 7, creatine + placebo2 + I-sVR), EG3 (n = 7, placebo1 + caffeine + I-sVR), or EG4 (n = 7, placebo1 + placebo2 + I-sVR), using a factorial, four-group-matched, double-blind, placebo-controlled design. Creatine supplementation included 0.3 g/kg/day for 14 days, caffeine supplementation included 0.3 mg/kg per day, and pre-activation in HBS with I-sVR (1 × 5 at 30% 1RM [1.0-1.1 m/s] + 1 × 4 at 60% 1RM [0.6-0.7 m/s]). The RSA test and HBS outcomes were evaluated. Three-way ANOVA showed non-significant differences for the RSA test and HBS outcomes (p > 0.05). At the end of this study, it was found that the three ergogenic aids, together, do not generate a summative effect on the physical performance of young soccer players. However, it is important to analyze individual responses to these specific protocols.

Efficacy, immunogenicity and safety of CoronaVac® in children and adolescents aged 6 months to 17 years: a multicenter, randomized, double-blind, placebo-controlled phase III clinical trial.

Safe and effective vaccines against COVID-19 for children and adolescents are needed. This international multicenter, randomized, double-blind, placebo-controlled, phase III clinical trial assessed the efficacy, immunogenicity, and safety of CoronaVac® in children and adolescents (NCT04992260). The study was carried out in Chile, South Africa, Malaysia, and the Philippines. The enrollment ran from September 10, 2021 to March 25, 2022. For efficacy assessment, the median follow-up duration from 14 days after the second dose was 169 days. A total of 11,349 subjects were enrolled. Two 3-µg injections of CoronaVac® or placebo were given 28 days apart. The primary endpoint was the efficacy of the CoronaVac®. The secondary endpoints were the immunogenicity and safety. The vaccine efficacy was 21.02% (95% CI: 1.65, 36.67). The level of neutralizing antibody in the vaccine group was significantly higher than that in the placebo group (GMT: 390.80 vs. 62.20, P <0.0001). Most adverse reactions were mild or moderate. All the severe adverse events were determined to be unrelated to the investigational products. In conclusion, in the Omicron-dominate period, a two-dose schedule of 3 µg CoronaVac® was found to be safe and immunogenic, and showed potential against symptomatic COVID-19 in healthy children and adolescents.

Effect of music on hemodynamic fluctuations in women during induction of general anesthesia: A prospective randomized controlled multicenter trial.

BACKGROUND: The authors aim to investigate the effect of music on hemodynamic fluctuations during induction of general anesthesia and reducing preoperative anxiety for women who underwent elective non-cardiac surgery. METHODS: It is a multicenter, double-blind, randomized, parallel-group clinical trial. Patients were randomized 1:1 to either a Music Intervention group (MI) or a Control group (Control). The MI participants listened to their preferred music for more than 30 minutes in the waiting area. The State-Trait Anxiety Inventory (STAI) was used to measure anxiety levels in the groups, and hemodynamic parameters (Heart Rate [HR], Mean Arterial Pressure [MAP]) were continuously recorded before induction (T0), at loss of consciousness (T1), immediately before intubation (T2), and after intubation (T3). Intubation-related adverse events were also recorded. The primary outcome was the incidence of MAP changes more than 20 % above baseline during T0-T2. RESULTS: A total of 164 patients were included in the final analyses. The incidence of MAP instability during T0-T2 was lower in the MI, and the 95 % Confidence Interval for the rate difference demonstrated the superiority of MI. HR instability was less frequent in MI participants both in T0-T2 and T2-T3. The overall incidence of preoperative anxiety was 53.7 % (88/164). After the music intervention, the mean score of STAI was significantly lower in the MI than in the Control, with a between-group difference of 8.01. CONCLUSIONS: Preoperative music intervention effectively prevented hemodynamic instability during anesthesia induction and significantly reduced preoperative anxiety in women undergoing elective non-cardiac surgery.