IMPORTANCEThe efficacy of vitamin D 3 supplementation in coronavirus disease 2019 remains unclear.OBJECTIVE To investigate the effect of a single high dose of vitamin D 3 on hospital length of stay in patients with COVID-19. DESIGN, SETTING, AND PARTICIPANTSThis was a multicenter, double-blind, randomized, placebo-controlled trial conducted in 2 sites in Sao Paulo, Brazil. The study included 240 hospitalized patients with COVID-19 who were moderately to severely ill at the time of enrollment from June 2, 2020, to August 27, 2020. The final follow-up was on October 7, 2020.INTERVENTIONS Patients were randomly assigned to receive a single oral dose of 200 000 IU of vitamin D 3 (n = 120) or placebo (n = 120). MAIN OUTCOMES AND MEASURESThe primary outcome was length of stay, defined as the time from the date of randomization to hospital discharge. Prespecified secondary outcomes included mortality during hospitalization; the number of patients admitted to the intensive care unit; the number of patients who required mechanical ventilation and the duration of mechanical ventilation; and serum levels of 25-hydroxyvitamin D, total calcium, creatinine, and C-reactive protein. RESULTSOf 240 randomized patients, 237 were included in the primary analysis (mean [SD] age, 56.2 [14.4] years; 104 [43.9%] women; mean [SD] baseline 25-hydroxyvitamin D level, 20.9 [9.2] ng/mL). Median (interquartile range) length of stay was not significantly different between the vitamin D 3 (7.0 [4.0-10.0] days) and placebo groups (7.0 [5.0-13.0] days) (log-rank P = .59; unadjusted hazard ratio for hospital discharge, 1.07 [95% CI, 0.82-1.39]; P = .62). The difference between the vitamin D 3 group and the placebo group was not significant for in-hospital mortality (7.6% vs 5.1%; difference, 2.5% [95% CI, -4.1% to 9.2%]; P = .43), admission to the intensive care unit (16.0% vs 21.2%; difference, -5.2% [95% CI, -15.1% to 4.7%]; P = .30), or need for mechanical ventilation (7.6% vs 14.4%; difference, -6.8% [95% CI, -15.1% to 1.2%]; P = .09). Mean serum levels of 25-hydroxyvitamin D significantly increased after a single dose of vitamin D 3 vs placebo (44.4 ng/mL vs 19.8 ng/mL; difference, 24.1 ng/mL [95% CI, 19.5-28.7]; P < .001). There were no adverse events, but an episode of vomiting was associated with the intervention.CONCLUSIONS AND RELEVANCE Among hospitalized patients with COVID-19, a single high dose of vitamin D 3 , compared with placebo, did not significantly reduce hospital length of stay. The findings do not support the use of a high dose of vitamin D 3 for treatment of moderate to severe COVID-19.

ObjectiveTo determine the immunogenicity of the third dose of CoronaVac vaccine in a large population of patients with autoimmune rheumatic diseases (ARD) and the factors associated with impaired response.MethodsAdult patients with ARD and age-balanced/sex-balanced controls (control group, CG) previously vaccinated with two doses of CoronaVac received the third dose at D210 (6 months after the second dose). The presence of anti-SARS-CoV-2 S1/S2 IgG and neutralising antibodies (NAb) was evaluated previously to vaccination (D210) and 30 days later (D240). Patients with controlled disease suspended mycophenolate mofetil (MMF) for 7 days or methotrexate (MTX) for 2 weekly doses after vaccination.ResultsARD (n=597) and CG (n=199) had comparable age (p=0.943). Anti-S1/S2 IgG seropositivity rates significantly increased from D210 (60%) to D240 (93%) (p<0.0001) in patients with ARD. NAb positivity also increased: 38% (D210) vs 81.4% (D240) (p<0.0001). The same pattern was observed for CG, with significantly higher frequencies for both parameters at D240 (p<0.05). Multivariate logistic regression analyses in the ARD group revealed that older age (OR=0.98, 95% CI 0.96 to 1.0, p=0.024), vasculitis diagnosis (OR=0.24, 95% CI 0.11 to 0.53, p<0.001), prednisone ≥5 mg/day (OR=0.46, 95% CI 0.27 to 0.77, p=0.003), MMF (OR=0.30, 95% CI 0.15 to 0.61, p<0.001) and biologics (OR=0.27, 95% CI 0.16 to 0.46, p<0.001) were associated with reduced anti-S1/S2 IgG positivity. Similar analyses demonstrated that prednisone ≥5 mg/day (OR=0.63, 95% CI 0.44 to 0.90, p=0.011), abatacept (OR=0.39, 95% CI 0.20 to 0.74, p=0.004), belimumab (OR=0.29, 95% CI 0.13 to 0.67, p=0.004) and rituximab (OR=0.11, 95% CI 0.04 to 0.30, p<0.001) were negatively associated with NAb positivity. Further evaluation of COVID-19 seronegative ARD at D210 demonstrated prominent increases in positivity rates at D240 for anti-S1/S2 IgG (80.5%) and NAb (59.1%) (p<0.0001).ConclusionsWe provide novel data on a robust response to the third dose of CoronaVac in patients with ARD, even in those with prevaccination COVID-19 seronegative status. Drugs implicated in reducing immunogenicity after the regular two-dose regimen were associated with non-responsiveness after the third dose, except for MTX.Trial registration numberNCT04754698.

Background The modulating effect of vitamin D on cytokine levels in severe coronavirus disease 2019 (COVID-19) remains unknown. Objectives To investigate the effect of a single high-dose of vitamin D3 on cytokines, chemokines, and growth factor in hospitalized patients with moderate to severe COVID-19. Methods This is a post-hoc, ancillary and exploratory analysis from a multicenter, double-blind, placebo-controlled, randomized clinical trial registered in ClinicalTrials.gov, NCT04449718. Patients with moderate to severe COVID-19 were recruited from two hospitals in Sao Paulo, Brazil. Of 240 randomized patients, 200 were assessed in this study and randomly assigned to receive a single oral dose of 200 000 IU of vitamin D3 (n = 101) or placebo (n = 99). The primary outcome was hospital length of stay, that has been published in our previous study. The prespecified secondary outcomes were serum levels of interleukin-1β, interleukin-6, interleukin-10, tumor necrosis factor alpha (TNF-α) and 25-hydroxyvitamin D. The post-hoc exploratory secondary outcomes were interleukin-4, interleukin-12p70, interleukin-17A, interferon gamma (IFN-γ), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-8, interferon-inducible protein-10 (IP-10), macrophage inflammatory protein-1 beta (MIP-1β), monocyte chemoattractant protein-1 (MCP-1), growth factor vascular endothelial (VEGF), and leukocytes count. Generalized estimating equations (GEE) for repeated measures, with Bonferroni's adjustment, were used for testing all outcomes. Results The study included 200 patients with a mean (SD) age 55.5 (14.3) years and body mass index (BMI) 32.2 (7.1) kg/m2, of which 109 (54.5%) were male. GM-CSF levels showed a significant group by time interaction effect (P = 0.04), although between-group difference at post-intervention after Bonferroni's adjustment was not significant. No significant effects were observed for the other outcomes. Conclusions The findings do not support the use of a single dose of 200 000 IU of vitamin D3, compared to placebo, for the improvement of cytokines, chemokines, and growth factor in hospitalized patients with moderate to severe COVID-19. Clinical Trial Registration: ClinicalTrials.gov, NCT04449718.

Background Creatine supplementation could be a nonexpensive, safe, and effective dietary intervention to counteract bone loss. The aim of this study was to investigate whether long-term creatine supplementation can improve bone health in older, postmenopausal women. Methods A double-blind, placebo-controlled, parallel-group, randomized trial was conducted between November 2011 and December 2017 in Sao Paulo, Brazil. Two hundred postmenopausal women with osteopenia were randomly allocated to receive either creatine monohydrate (3 g/d) or placebo for 2 years. At baseline and after 12 and 24 months, we assessed areal bone mineral density (aBMD; primary outcome), lean and fat mass (through dual X-ray absorptiometry), volumetric BMD and bone microarchitecture parameters, biochemical bone markers, physical function and strength, and the number of falls and fractures. Possible adverse effects were self-reported. Results Lumbar spine (p &lt; .001), femoral neck (p &lt; .001), and total femur aBMD (p = .032) decreased across time; however, no interaction effect was observed (all p &gt; .050). Bone markers, microarchitecture parameters, and the number of falls/fractures were not changed with creatine (all p &gt; .050). Lean mass and appendicular skeletal muscle mass increased throughout the intervention (p &lt; .001), with no additive effect of creatine (p = .731 and p = .397, respectively). Creatine did not affect health-related laboratory parameters. Conclusion Creatine supplementation more than 2 years did not improve bone health in older, postmenopausal women with osteopenia, nor did it affect lean mass or muscle function in this population. This refutes the long-lasting notion that this dietary supplement alone has osteogenic or anabolic properties in the long run. Clinical trial registry Clinicaltrials.gov: NCT: 01472393.

Background Vitamin D acts as a mediator in the immune system regulating antiviral mechanisms and inflammatory processes. Vitamin D insufficiency has been suggested as a potential risk factor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, although its impact on the prognosis of hospitalized patients with coronavirus disease 2019 (COVID-19) remains unclear. Objective This multicenter prospective cohort study was designed to investigate whether serum 25-hydroxyvitamin D [25(OH)D] concentration is associated with hospital length of stay and prognosis in hospitalized patients with COVID-19. Methods Patients with moderate to severe COVID-19 (n = 220) were recruited from 2 hospitals in Sao Paulo, Brazil. Serum 25(OH)D concentrations were categorized as follows: &lt;10 ng/mL, 10 to &lt;20 ng/mL, 20 to &lt;30 ng/mL, and ≥30 ng/mL, and &lt;10 ng/mL and ≥10 ng/mL. The primary outcome was hospital length of stay and the secondary outcomes were the rate of patients who required invasive mechanical ventilation and mortality. Results There were no significant differences in hospital length of stay when the 4 25(OH)D categories were compared (P = 0.120). Patients exhibiting 25(OH)D &lt;10 ng/mL showed a trend (P = 0.057) for longer hospital length of stay compared with those with 25(OH)D ≥10 ng/mL [9.0 d (95% CI: 6.4, 11.6 d) vs. 7.0 d (95% CI: 6.6, 7.4 d)]. The multivariable Cox proportional hazard models showed no significant associations between 25(OH)D and primary or secondary outcomes. Conclusions Among hospitalized patients with moderate to severe COVID-19, those with severe 25(OH)D deficiency (&lt;10 ng/mL) exhibited a trend for longer hospital length of stay compared with patients with higher 25(OH)D concentrations. This association was not significant in the multivariable Cox regression model. Prospective studies should test whether correcting severe 25(OH)D deficiency could improve the prognosis of patients with COVID-19.

Background Regular physical activity (PA) has been postulated to improve, or at least maintain, immunity across the life span. However, the link between physical (in)activity and coronavirus disease-2019 (COVID-19) remains to be established. This small-scale prospective cohort study is nested within a randomized controlled trial aimed to investigate the possible associations between PA levels and clinical outcomes among hospitalized patients with moderate to severe COVID-19. Methods Hospitalized patients with COVID-19 (mean age: 54.9 years) were recruited from the Clinical Hospital of the School of Medicine of the University of Sao Paulo (a quaternary referral teaching hospital) and from Ibirapuera Field Hospital, both located in Sao Paulo, Brazil. PA level was assessed using the Baecke Questionnaire of Habitual Physical Activity. The primary outcome was hospital length of stay. The secondary outcomes were mortality, admission to the intensive care unit (ICU), and mechanical ventilation requirement. Results Median hospital length of stay was 7.0 ± 4.0 days; 3.3% of patients died, 13.8% were admitted to ICU, and 8.6% required mechanical ventilation. Adjusted linear regression models showed that PA indices were not associated with hospital length of stay (work index: β = -0.57 (95%CI: -1.80 to 0.65), p = 0.355; sport index: β = 0.43 (95%CI: -0.94 to 1.80), p = 0.536; leisure-time index: β = 1.18 (95%CI: -0.22 to 2.59), p = 0.099; total activity index: β = 0.20 (95%CI: -0.48 to 0.87), p = 0.563). None of the PA indices were associated with mortality, admission to ICU, or mechanical ventilation requirement (all p > 0.05). Conclusion Among hospitalized patients with COVID-19, PA did not independently associate with hospital length of stay or any other clinically relevant outcomes. These findings should be interpreted as meaning that, among already hospitalized patients with more severe forms of COVID-19, being active is a potential protective factor likely outweighed by a cluster of comorbidities (e.g., type 2 diabetes, hypertension, weight excess) and older age, suggesting that the benefit of PA against the worsening of COVID-19 may vary across stages of the disease.

To test whether high circulating insulin concentrations influence the transport of β-alanine into skeletal muscle at either saturating or subsaturating β-alanine concentrations, we conducted two experiments whereby β-alanine and insulin concentrations were controlled. In experiment 1, 12 men received supraphysiological amounts of β-alanine intravenously (0.11 g·kg−1·min−1 for 150 min), with or without insulin infusion. β-Alanine and carnosine were measured in muscle before and 30 min after infusion. Blood samples were taken throughout the infusion protocol for plasma insulin and β-alanine analyses. β-Alanine content in 24-h urine was assessed. In experiment 2, six men ingested typical doses of β-alanine (10 mg/kg) before insulin infusion or no infusion. β-Alanine was assessed in muscle before and 120 min following ingestion. In experiment 1, no differences between conditions were shown for plasma β-alanine, muscle β-alanine, muscle carnosine and urinary β-alanine concentrations (all P > 0.05). In experiment 2, no differences between conditions were shown for plasma β-alanine or muscle β-alanine concentrations (all P > 0.05). Hyperinsulinemia did not increase β-alanine uptake by skeletal muscle cells, neither when substrate concentrations exceed the Vmax of β-alanine transporter TauT nor when it was below saturation. These results suggest that increasing insulin concentration is not necessary to maximize β-alanine transport into muscle following β-alanine intake.

To evaluate premenopausal women with longstanding rheumatoid arthritis (RA) for potential associations between parameters of localized bone involvement and parameters of systemic bone involvement in the affected joints.Methods. Eighty consecutively evaluated premenopausal women with RA were included in the study, along with 160 healthy female control subjects who were matched to the patients by age and body mass index. Volumetric bone mineral density (vBMD), bone microarchitecture, and finite elements of biomechanical bone strength (bone stiffness and estimated failure load) at the distal radius and distal tibia were analyzed by high-resolution peripheral quantitative computed tomography (HR-pQCT) in patients with RA compared to healthy controls. In addition, in patients with RA, localized bone involvement in the metacarpophalangeal and proximal interphalangeal joints was analyzed by HR-pQCT, to identify bone erosions and osteophytes.Results. Among the 80 premenopausal women with longstanding RA, the mean AE SD age was 39.4 AE 6.7 years and mean AE SD disease duration was 9.8 AE 5.3 years. Trabecular and cortical bone parameters and bone strength at the distal radius and distal tibia were all impaired in patients with RA compared to healthy controls (each P < 0.05). In total, 75% of RA patients had evidence of bone erosions, and 41.3% of RA patients had detectable osteophytes on HR-pQCT. RA patients with bone erosions, as compared to RA patients without bone erosions, had lower cortical vBMD (at the distal radius, mean AE SD 980 AE 72 mg HA/cm 3 versus 1,021 AE 47 mg HA/cm 3 [P = 0.03]; at the distal tibia, 979 AE 47 mg HA/cm 3 versus 1,003 AE 34 mg HA/cm 3 [P = 0.04]) and higher cortical bone porosity (at the distal radius, mean AE SD 2.8 AE 2.5% versus 1.8 AE 1.6% [P = 0.04]; at the distal tibia, 3.7 AE 1.6% versus 2.7 AE 1.6% [P = 0.01]). In patients with RA, osteophyte volume at the distal radius was positively correlated with trabecular vBMD (r = 0.392, P = 0.02), trabecular number (r = 0.381, P = 0.03), and trabecular stiffness (r = 0.411, P = 0.02), and negatively correlated with trabecular separation (r = À0.364, P = 0.04), as determined by Pearson's or Spearman's correlation test.Conclusion. The findings show that premenopausal women with longstanding RA have systemic bone fragility at peripheral joint sites. Moreover, the presence of bone erosions is mainly associated with cortical bone fragility at the distal radius and tibia, and presence of osteophytes is associated with repair of trabecular bone at the distal radius.