Igor Hisashi Murai

Background: Identifying and addressing long-term health and societal challenges after COVID-19 is a research priority. Objectives: To create an international, multidisciplinary COVID-19 database, and synthesise long-term outcomes, predictors and costs. Design: Systematic identification of COVID-19 data sets and meta-analysis of individual participant data on long-term outcomes after COVID-19. Setting: Contributed data were collected in clinical, community and research settings. Interventions: Interventions from original studies were included as covariates in models. Data sources: MEDLINE, Cochrane Central Register of Controlled Trials, EMBASE, Web of Science, PsycInfo ^® (American Psychological Association, Washington, DC, USA), Cumulative Index to Nursing and Allied Health Literature, World Health Organization Global Index Medicus, Epistemonikos, LitCOVID; World Health Organization International Clinical Trials Registry Platform; ClinicalTrials.gov and supplementary searches for studies (November 2019–November 2021) were searched for studies on > 10 people from cohort, case-control, survey or randomised controlled trial studies, across any setting, describing validated assessment instruments, symptoms, hospitalisation, discharge destination or mortality beyond 28-days after COVID-19 onset. Data were extracted by two independent reviewers. Methods: Principal investigators contributed fully anonymised individual participant data. Demography, equity and symptoms were described. Assessment instruments were mapped to the International Classification of Functioning, Disability and Health. Factors associated with outcomes at 3–6 months, 9–12 months and beyond 12 months of index infection, for n > 500 individual participant data and > 1 data set were described using ratio of difference, point estimates, odds ratio and 95% confidence interval, as appropriate. The Mixed Methods Appraisal Tool described study quality; models were appraised using a Grading of Recommendations Assessment, Development and Evaluation-informed approach; heterogeneity was described using I ² . Outcome measures: Included overall perception of health, multidomain cognitive function, anxiety, depression, stress, post-traumatic stress disorder, fatigue, strength, walking ability, mobility, coping with daily life, breathlessness, mortality, later hospitalisation and health-related quality of life. Results: PRECIOUS collated 116 data sets from 40 countries (individual participant data = 62,849), comprising 20 randomised controlled trials, 13 case-control, 60 cohort 2 longitudinal, 1 survey and 20 other study types. Participants’ median age was 58 years interquartile range (45–68); 34,185 (54.4%) were female; 158 unique symptoms and 137 unique assessment instruments were captured, predominantly describing International Classification of Function, Disability and Health-body functions. Women had poorer outcomes across 30/37 models, compared with men. In 15/37 models, pre-existing lung disease and increasing age were associated with poorer outcomes; hospitalisation, diabetes and chronic kidney disease were each associated with poorer outcomes in 8/37 models. Initial hospitalisation resulted in lower health-related quality of life that did not recover for up to 2 years after initial infection. Heterogeneity was low in 34/37 models; 22/37 models were of moderate and 11/37 were of low quality. Limitations: Use of secondary data limits available covariates, outcomes and time points to those included in primary data sets; evidence was primarily based on high-income countries. There was a lack of data on longer-term healthcare resource use to estimate the costs to the healthcare system. Conclusions: PRECIOUS contributes to the overall picture of long-term COVID-19 outcomes beyond the long-COVID condition and highlights poorer long-term outcomes in women and people with pre-existing comorbidities. Future work: Evidence gaps included healthcare resource use, isolation, loneliness, societal participation and return to work outcomes. Data are needed on the role of health inequity on long-term outcomes. Study registration: This study is registered as PROSPERO (CRD42020224323, IRAS ID: 293578). Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: NIHR132895) and is published in full in Health and Social Care Delivery Research ; Vol. 14, No. 29. See the NIHR Funding and Awards website for further award information.

Background The acute exercise-mediated changes in metabolic, immunomodulatory, and gut hormones are blunted by excessive adiposity. We investigated whether bariatric surgery improves the acute postprandial exercise response in terms of glucose metabolism, gut hormones, and inflammatory markers in women with severe obesity. Methods Thirteen women (age: 37 ± 7; BMI: 47.6 ± 5.6) underwent an exercise session (resistance training plus aerobic exercise) before and 3 months after surgery. Blood samples were collected at baseline, immediately and 30 min after exercise to analyze glucose, insulin, inflammatory markers, and gut hormones. Results Post-surgery, glucose levels decreased immediately (P = 0.0011) and 30 min after exercise (P = 0.0160), but AUC remained similar (181.0 vs. 166.8 mg/dL x min⁻¹, P = 0.1980) between conditions. Insulin response to postprandial exercise did not change after surgery (all P > 0.05), but AUC was reduced post-surgery (60.7 vs. 26.3 µU/mL x min⁻¹, P = 0.0457). No changes occurred in Glucagon-Like Peptide-1 (GLP-1) and Peptide YY (PYY) pre-surgery exercise (all P > 0.05); however, both parameters were increased immediately (P = 0.0180 and P = 0.0020, respectively) and 30 min post-exercise (P = 0.0380 and P = 0.0360, respectively) after surgery. AUC for GLP-1 (2.3 vs. 14.5 pg/mL x min⁻¹, P = 0.0075) and PYY (9.9 vs. 224.2 pg/mL x min⁻¹, P = 0.0004) were increased post-surgery. Surgery did not affect Pancreatic Polypeptide (PP) or Gastric Inhibitory Polypeptide (GIP) responses to postprandial exercise. Both parameters were elevated immediately (all P < 0.05) and 30 min post-exercise (all P < 0.05), regardless of surgery. PP (549.6 vs. 261.7 pg/mL x min⁻¹, P = 0.0457) and GIP (610.6 vs. 429.1 pg/mL x min⁻¹, P = 0.0260) AUC was lower post- vs. pre-surgery. No changes were observed for ghrelin levels and inflammatory markers (all P > 0.05). Conclusions Bariatric surgery improves the secretion of GLP-1 and PYY in response to postprandial acute exercise in parallel with enhanced peripheral insulin response.

The modulating effect of vitamin D on cytokine concentrations in severe coronavirus disease 2019 (COVID-19) remains unknown. We aimed 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. This is a post hoc, ancillary, and exploratory analysis from a multicenter, double-blind, placebo-controlled, randomized clinical trial. Patients with moderate to severe COVID-19 were recruited from 2 hospitals in São Paulo, Brazil. Of 240 randomly assigned patients, 200 were assessed in this study and randomly assigned to receive a single oral dose of 200,000 IU vitamin D₃ (n = 101) or placebo (n = 99). The primary outcome was hospital length of stay, which has been published in our previous study. The prespecified secondary outcomes were serum concentrations of IL-1β, IL-6, IL-10, TNF-α, and 25-hydroxyvitamin D. The post hoc exploratory secondary outcomes were IL-4, IL-12p70, IL-17A, IFN-γ, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-8, IFN-inducible protein-10 (IP-10), macrophage inflammatory protein-1β (MIP-1β), monocyte chemoattractant protein-1 (MCP-1), vascular endothelial growth factor (VEGF), and leukocyte count. Generalized estimating equations for repeated measures, with Bonferroni's adjustment, were used for testing all outcomes. The study included 200 patients with a mean ± SD age of 55.5 ± 14.3 y and BMI of 32.2 ± 7.1 kg/m², of which 109 (54.5%) were male. GM-CSF concentrations showed a significant group-by-time interaction effect (P = 0.04), although the between-group difference at postintervention after Bonferroni's adjustment was not significant. No significant effects were observed for the other outcomes. The findings do not support the use of a single dose of 200,000 IU vitamin D₃, compared with placebo, for the improvement of cytokines, chemokines, and growth factor in hospitalized patients with moderate to severe COVID-19. This trial was registered at clinicaltrials.gov as NCT04449718.

In this ancillary analysis of a multicenter, double-blinded, randomized, placebo-controlled trial, we investigated the effect of a single high dose of vitamin D[3] on the length of hospital stay of patients with severe 25-hydroxyvitamin D deficiency ...

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. 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. 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: P = 0.120). Patients exhibiting 25(OH)D <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. Among hospitalized patients with moderate to severe COVID-19, those with severe 25(OH)D deficiency (<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.

Importance: Patients with COVID-19 may exhibit 25-hydroxyvitamin D deficiency, but the beneficial effects of vitamin D ₃ supplementation in this disease remain to be proven by randomized controlled trials. Objective: To investigate the efficacy and safety of vitamin D ₃ supplementation in patients with severe COVID-19. Design, Setting, and Participants: This is a multicenter, double-blind, randomized, placebo-controlled trial conducted in two centers (a quaternary hospital and a field hospital) in Sao Paulo, Brazil. The trial included 240 hospitalized patients with severe COVID-19. The study was conducted from June 2, 2020 to October 7, 2020. Interventions: Patients were randomly allocated (1:1 ratio) to receive either a single oral dose of 200,000 IU of vitamin D ₃ or placebo. Main Outcomes and Measures: The primary outcome was hospital length of stay, defined as hospital discharge from the date of randomization or death. Secondary outcomes were mortality, admission to ICU, mechanical ventilation requirement, and serum levels of 25-hydroxyvitamin D, creatinine, calcium, C-reactive protein, and D-dimer. Results: Of 240 randomized patients (mean age, 56 years; 56% men), 232 (96.7%) were included in the primary analysis. Log-rank test showed that hospital length of stay was comparable between the vitamin D ₃ supplementation and placebo groups (7.0 days [95% CI, 6.1 to 7.9] and 7.0 days [95% CI, 6.2 to 7.8 days]; hazard ratio, 1.12 [95% CI, 0.9 to 1.5]; P = .379; respectively). The rate of mortality (7.0% vs 5.1%; P = .590), admission to ICU (15.8% vs 21.2%; P = .314), and mechanical ventilation requirement (7.0% vs 14.4%; P = .090) did not significantly differ between groups. Vitamin D ₃ supplementation significantly increased serum 25-hydroxyvitamin D levels compared to placebo (difference, 24.0 ng/mL [95% CI, 21.0% to 26.9%]; P = .001). No adverse events were observed. Conclusions and Relevance: Among hospitalized patients with severe COVID-19, vitamin D ₃ supplementation was safe and increased 25-hydroxyvitamin D levels, but did not reduce hospital length of stay or any other relevant outcomes vs placebo. This trial does not support the use of vitamin D ₃ supplementation as an adjuvant treatment of patients with COVID-19. Key points: Question: Can vitamin D ₃ supplementation reduce hospital length of stay in hospitalized patients with severe COVID-19? Findings: In this double-blind, randomized, placebo-controlled trial involving 240 hospitalized patients with severe COVID-19, a single dose of 200,000 IU of vitamin D ₃ supplementation was safe and effective in increasing 25-hydroxyvitamin D levels, but did not significantly reduce hospital length of stay (hazard ratio, 1.12) or any other clinically-relevant outcomes compared with placebo. Meaning: Vitamin D ₃ supplementation does not confer therapeutic benefits among hospitalized patients with severe COVID-19.

Exercise seems to enhance the beneficial effect of bariatric (Roux-en-Y gastric bypass [RYGB]) surgery on insulin resistance. We hypothesized that skeletal muscle extracellular matrix (ECM) remodeling may underlie these benefits. Women were randomized to either a combined aerobic and resistance exercise training program following RYGB (RYGB + ET) or standard of care (RYGB). Insulin sensitivity was assessed by oral glucose tolerance test. Muscle biopsy specimens were obtained at baseline and 3 and 9 months after surgery and subjected to comprehensive phenotyping, transcriptome profiling, molecular pathway identification, and validation in vitro. Exercise training improved insulin sensitivity beyond surgery alone (e.g., Matsuda index: RYGB 123% vs. RYGB + ET 325%; P ≤ 0.0001). ECM remodeling was reduced by surgery alone, with an additive benefit of surgery and exercise training (e.g., collagen I: RYGB −41% vs. RYGB + ET −76%; P ≤ 0.0001). Exercise and RYGB had an additive effect on enhancing insulin sensitivity, but surgery alone did not resolve insulin resistance and ECM remodeling. We identified candidates modulated by exercise training that may become therapeutic targets for treating insulin resistance, in particular, the transforming growth factor-β1/SMAD 2/3 pathway and its antagonist follistatin. Exercise-induced increases in insulin sensitivity after bariatric surgery are at least partially mediated by muscle ECM remodeling.

Igor Hisashi Murai, Hamilton Roschel, Bruno Gualano; Response to Letter to the Editor: “Exercise mitigates bone loss in women with severe obesity after Roux-en

Context: Bone loss after bariatric surgery potentially could be mitigated by exercise.Objective: To investigate the role of exercise training (ET) in attenuating bariatric surgery–induced bone loss.Design: Randomized, controlled trial.Setting: Referral center for bariatric surgery.Patients: Seventy women with severe obesity, aged 25 to 55 years, who underwent Roux-en-Y gastric bypass (RYGB).Intervention: Supervised, 6-month, ET program after RYGB vs. standard of care (RYGB only).Outcomes: Areal bone mineral density (aBMD) was the primary outcome. Bone microarchitecture, bone turnover, and biochemical markers were secondary outcomes.Results: Surgery significantly decreased femoral neck, total hip, distal radius, and whole body aBMD (P < 0.001); and increased bone turnover markers, including collagen type I C-telopeptide (CTX), procollagen type I N-propeptide (P1NP), sclerostin, and osteopontin (P < 0.05). Compared with RYGB only, exercise mitigated the percent loss of aBMD at femoral neck [estimated mean difference (EMD), −2.91%; P = 0.007;], total hip (EMD, −2.26%; P = 0.009), distal radius (EMD, −1.87%; P = 0.038), and cortical volumetric bone mineral density at distal radius (EMD, −2.09%; P = 0.024). Exercise also attenuated CTX (EMD, −0.20 ng/mL; P = 0.002), P1NP (EMD, −17.59 ng/mL; P = 0.024), and sclerostin levels (EMD, −610 pg/mL; P = 0.046) in comparison with RYGB. Exercise did not affect biochemical markers (e.g., 25(OH)D, calcium, intact PTH, phosphorus, and magnesium).Conclusion: Exercise mitigated bariatric surgery–induced bone loss, possibly through mechanisms involving suppression in bone turnover and sclerostin. Exercise should be incorporated in postsurgery care to preserve bone mass.