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Background Among individuals with vitamin D deficiency, daily vitamin D supplementation appears to lower risk of acute respiratory infection. However, recent trials, in different populations and using different regimens, have yielded null results. We investigated the effect of daily vitamin D supplementation (vs placebo) on risk of upper respiratory infection (URI) in older adults. Methods The VITamin D and OmegA-3 TriaL (VITAL) is a randomized, double-blind, placebo-controlled trial of supplemental vitamin D and/or omega-3 fatty acids in generally healthy men (age ≥50 years) and women (age ≥55 years). This prespecified analysis focuses on vitamin D3 (2000 IU/day) versus placebo in the 15 804 (61%) participants with baseline serum total 25-hydroxyvitamin D level. The primary outcome was self-report of a recent URI at 1-year follow-up. Results Participants had a mean age of 68 years and 51% were women; 76% were non-Hispanic White, 16% Black, and 8% other race/ethnicity. The mean 25-hydroxyvitamin D level at baseline was 31 (standard deviation, 10) ng/mL, with <12 ng/mL in 2.4%. The overall effect of vitamin D supplementation on recent URI was nonsignificant (odds ratio [OR], 0.96 [95% confidence interval {CI},.86–1.06]). In the prespecified subgroup of primary interest (<12 ng/mL and denied taking concurrent vitamin D), which had only 255 participants, vitamin D supplementation was nonsignificant (OR, 0.60 [95% CI,.28–1.30]). Statistical power to assess effect modification in other subgroups was limited. Conclusions In older adults not selected for vitamin D deficiency, supplemental vitamin D did not lower URI risk overall. Whether effects differ in subgroups requires further study. Clinical Trials Registration. NCT01169259. [ABSTRACT FROM AUTHOR]

Objectives To assess eligibility criteria that either explicitly or implicitly exclude older patients from randomized controlled trials (RCTs) in RA. Methods Our analysis included RCTs of pharmacological interventions registered with ClinicalTrials.gov and started between 2013 and 2022. Co-primary outcomes were proportions of trials with an upper age limit and the eligibility criteria indirectly increasing risk of the exclusion of older adults. Results A total of 143/290 (49%) trials had an upper age limit of 85 years or less. Multivariable analysis showed that the odds of an upper age limit were significantly lower in trials performed in the USA [adjusted odds ratio (aOR), 0.34; CI, 0.12–0.99; P  = 0.04] and intercontinental trials (aOR, 0.4; CI, 0.18–0.87; P  = 0.02). In total, 154/290 (53%) trials had at least one eligibility criterion implicitly excluding older adults. These included specific comorbidities (n  = 114; 39%), compliance concerns (n  = 67; 23%), and broad and vague exclusion criteria (n  = 57; 20%); however, we found no significant associations between these criteria and trial characteristics. Overall, 217 (75%) trials either explicitly or implicitly excluded older patients; we also noted a trend towards increasing proportion of these trials over time. Only one trial (0.3%) enrolled solely patients aged 65 and older. Conclusion Older adults are commonly excluded from RCTs in RA based on both age limits and other eligibility criteria. This seriously limits the evidence base for the treatment of older patients in clinical practice. Given the growing prevalence of RA in older adults, relevant RCTs should be more inclusive to them. [ABSTRACT FROM AUTHOR]

Background Recurrent Clostridioides difficile infection (rCDI) occurs frequently, and concomitant antibiotic (CA) during the initial episode for treatment of non-CDI is a major risk factor. We sought to address the comparative efficacy of fidaxomicin versus vancomycin in the setting of CA during the initial CDI episode. Methods We conducted a randomized, controlled, open-label trial at 2 hospitals in Ann Arbor, Michigan. We consecutively consented and enrolled hospitalized patients ≥18 years old with diarrhea, a positive test for C. difficile , and ≥1 qualifying CA. Complicated CDI, CDI treatment for >24 hours prior to enrollment, and planned long-term (>12 weeks) CA use were notable exclusions. Clinical cure was defined as resolution of diarrhea for 2 consecutive days maintained until 2 days after therapy, and rCDI as recurrent diarrhea with positive testing ≤30 days after initial treatment. Patients were randomized to fidaxomicin or vancomycin. Results Baseline characteristics were similar in the 2 groups of 144 patients. Rates of clinical cure (73% vs 62.9%, P =.195) and rCDI (3.3% vs 4.0%; P >.99) were similar for fidaxomicin and vancomycin in the intention-to-treat and per-protocol cohorts, respectively. Only 4 patients developed rCDI. Conclusions In this study of patients with CDI receiving CA, a numerically higher proportion were cured with fidaxomicin versus vancomycin, but this result did not reach statistical significance. Overall recurrence was lower than anticipated in both arms compared with previous studies that did not extend duration of CDI treatment during CA. Clinical Trials Registration www.clinicaltrials.gov (NCT02692651). [ABSTRACT FROM AUTHOR]

Background Amphotericin B is the gold standard treatment for severe mycoses. A new orally delivered, less-toxic formulation of amphotericin has been developed. Methods In our randomized clinical trial, we tested oral lipid nanocrystal (LNC) amphotericin B (MAT2203, Matinas Biopharma) vs intravenous (IV) amphotericin for human immunodeficiency virus–associated cryptococcal meningitis in 4 sequential cohorts. Two pilot cohorts assessed safety and tolerability (n = 10 each), and 2 cohorts assessed efficacy with/without 2 IV loading doses (n = 40 each). The experimental arm received 1.8 g/d oral LNC amphotericin through 2 weeks with 100 mg/kg/d flucytosine, then 1.2 g/d LNC amphotericin through 6 weeks. The randomized control arm (n = 41) received 7 days of IV amphotericin with flucytosine, then 7 days of fluconazole 1200 mg/d. The primary end point was cerebrospinal fluid (CSF) early fungicidal activity (EFA). Results We randomized 80 participants to oral LNC amphotericin + flucytosine with (n = 40) and without (n = 40) 2 IV loading doses and 41 control participants to IV amphotericin + flucytosine. Mean EFA was 0.40 log10 colony-forming units (CFU)/mL/d for all-oral LNC amphotericin, 0.42 log10   Cryptococcus CFU/mL/d for oral LNC amphotericin with IV loading doses, and 0.46 log10 CFU/mL/d for IV amphotericin controls. LNC amphotericin groups achieved 2-week CSF sterility in 63% (44 of 70) vs 68% (23 of 34) of controls. The 18-week survival was 85% (34 of 40) with all-oral LNC amphotericin, 90% (36 of 40) with oral LNC amphotericin given IV loading doses, and 85% (35 of 41) with IV amphotericin. Grade 3–4 laboratory adverse events occurred less frequently in LNC amphotericin groups (41%) than the IV amphotericin group (61%, P =.05), particularly for anemia (21% vs 44%; P =.01) and potassium (5% vs 17%; P =.04). Conclusions This new oral amphotericin B LNC formulation appears promising for cryptococcal meningitis with antifungal activity, similar survival, and less toxicity than IV amphotericin. Clinical Trials Registration NCT04031833. [ABSTRACT FROM AUTHOR]

Background and Objectives Outdoor falls can negatively affect the independence and well-being of community-dwelling older adults. Although there is some overlap, there are also differences in risk factors for indoor and outdoor falls. There are no existing community-based fall prevention programs that specifically target outdoor fall prevention. To fill this gap, the Stroll Safe program was developed. Research Design and Methods A cluster-randomized controlled trial design was used with randomization at the site level. Participants (N = 86) were aged 60 and older, with a history of an outdoor fall or who had a fear of falling outdoors. Eight naturally occurring retirement community program sites were randomly assigned to the treatment or wait list control group. Outcome measures included the Outdoor Falls Questionnaire, the Falls Behavioral Scale for the Older Person, and the Falls Efficacy Scale-International to examine knowledge of risks, safe strategy use, protective behaviors, and fear of falling. An Analysis of Covariance (ANCOVA) was used to compare change scores between groups with covariates included for any initial differences between groups. A linear mixed model was also conducted to account for any clustering effects. Results Significant differences (p s <.05) were found between groups for knowledge of outdoor fall risks and safe strategy use. Effect sizes were large (Cohen's d = 1.2–1.9). Results were retained at 6-week follow-up. Discussion and Implications Stroll Safe is effective in improving knowledge of outdoor fall risks and increasing safe strategy use for community mobility. Stroll Safe fills a gap in outdoor fall prevention programs. Clinical Trials Registration Number: NCT03624777 [ABSTRACT FROM AUTHOR]

Baclofen may reduce the symptoms of alcohol withdrawal, as an alternative or as an adjuvant for benzodiazepines, but the available data are insufficient to support baclofen-assisted alcohol withdrawal. This study investigated the need for diazepam during acute alcohol withdrawal in patients receiving baclofen. In a single-blind, dose-dependent randomized controlled trial with three study arms, 63 patients with alcohol use disorder, starting in-patient benzodiazepine-assisted alcohol detoxification, were randomly assigned to receive placebo (n  = 18), baclofen 30 mg/day (N  = 20), or baclofen 60 mg/day (N  = 25) for 7 days. Diazepam was provided as needed based on the withdrawal symptoms stated by Clinical Institute Withdrawal Assessment for Alcohol-revised. The primary outcome measure was the number of patients in need of diazepam during alcohol detoxification. Secondary outcome measure included the between-group difference in the amount of diazepam needed during alcohol detoxification. Using baclofen 60 mg/day, 32% of patients needed additional diazepam compared to 35% on baclofen 30 mg/day and compared to 72% on placebo (P  = .013). The median total amount of diazepam needed was significantly lower in patients receiving baclofen 60 mg/day (0 ± 10 mg diazepam) and baclofen 30 mg/day (0 ± 10 mg diazepam) compared to placebo (10 ± 43 mg diazepam; P  = .017). Adverse events were comparable between patients on baclofen and placebo. Baclofen can reduce the withdrawal symptoms during alcohol detoxification. Baclofen was well tolerated and may be considered for the management of alcohol withdrawal syndrome, especially useful in situations where benzodiazepines should be withheld, such as patients with liver impairment. [ABSTRACT FROM AUTHOR]

Background Few studies have focused on the immune response to more recent influenza vaccine formulations such as cell-cultured inactivated influenza vaccine (ccIIV4) or live-attenuated influenza vaccine (LAIV4) in older children and young adults, or differences in immunoglobulin response using newer antibody landscape technology. Methods Participants ages 4–21 were randomized to receive ccIIV4 (n = 112) or LAIV4 (n = 118). A novel high-throughput multiplex influenza antibody detection assay was used to provide detailed IgG, IgA, and IgM antibody isotypes, along with hemagglutination inhibition levels (HAI), measured pre- and 28 days post-vaccination. Results The HAI and immunoglobulin isotype response to ccIIV4 was greater than LAIV4, with significant increases in IgG but not IgA or IgM. The youngest participants had the highest LAIV4 response. Prior LAIV4 vaccination was associated with a higher response to current season ccIIV4. Cross-reactive A/Delaware/55/2019(H1N1)pdm09 antibodies were present pre-vaccination and increased in response to ccIIV4, but not LAIV4. Immunoglobulin assays strongly correlated with and confirmed the findings of HAI titers to measure immune response. Conclusions Age and prior season vaccination may play a role in the immune response in children and young adults to ccIIV4 and LAIV4. While immunoglobulin isotypes provide high-level antigen-specific information, HAI titers alone can provide a meaningful representation of day 28 post-vaccination response. Clinical Trials No NCT03982069 [ABSTRACT FROM AUTHOR]

Objective Alcohol withdrawal syndrome (AWS) is a frequent and potentially life-threatening condition experienced in alcohol use disorder. Since hypomagnesemia is involved in AWS's severity, we conducted a multicenter double-blind randomized placebo-controlled trial to examine the efficacy of oral magnesium supplementation as an adjuvant therapy of AWS. Material and Methods Inpatients were recruited in six different centers if they had a baseline score higher than eight on the Revised Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar). The experimental treatment was magnesium lactate dehydrate, administrated three times per day providing a total of 426.6 mg per day and up to 15 days. The primary endpoint was the significant between-group difference of the CIWA-Ar total score change from baseline to 3 days later. The treatment group and baseline score were introduced as covariables in an analysis of covariance. Results A total of 98 inpatients were included {71.4% of men; mean age of 49.1 years [standard deviation (SD): 10.3]}. In the intention-to-treat population, the mean reduction of the CIWA-Ar score in the experimental group between baseline and 3 days later was 10.1 (SD: 5.2), whereas it was 9.2 (SD: 3.9) in the control group. The absolute difference of the adjusted mean in the experimental group compared with the control group was −0.69 (SD: 0.72), which did not correspond to a significant between-group difference (P  = 0.34). Per-protocol analysis and sensitivity analyses also supported this result. Supplementary analyses found no significant difference regarding benzodiazepine consumption, magnesium blood concentration, and satisfaction to care. Conclusions The present study does not support the rationale of systematic oral magnesium supplementation in patients with AWS. [ABSTRACT FROM AUTHOR]

Objective Our main aim was to investigate the effect of a single oral dose of C21, a selective angiotensin II type 2 receptor agonist, on cold-induced vasoconstriction in SSc-related RP. Methods This was a phase IIa, randomized, double-blind, cross-over, single-dose, placebo-controlled, single-centre study. Twelve female patients with SSc (median age 58.5 years, median duration of RP 19.0 years) attended on four occasions: screening, treatment visits 1 and 2 (separated by 3–7 days) and follow-up. At the first treatment visit, patients were randomized to receive either a single oral dose of C21 (200 mg) or placebo, then the opposite treatment on the second visit. Forty min after each treatment, each patient underwent a standard hand cold challenge. The primary end point was the area under the curve (AUC) for rewarming for each finger (eight fingers) over 15 min. Secondary end points included the maximum finger temperature after rewarming (MAX). Statistical analyses were performed by multiplicative ANCOVA models. Results For all eight fingers combined, mean AUC for rewarming was higher after treatment with C21 than after placebo (geometric mean 20 046°C*s vs 19 558°C*s), but not significantly (P  = 0.380) and MAX (at 15 min) was also higher (geometric mean 23.5°C vs 22.5°C; P  = 0.036). C21 was well tolerated. Conclusion Despite the small trial size, a signal emerged suggesting that even in patients with established SSc, C21 may confer benefit for RP and deserves further investigation. Trial registration ClinicalTrials.gov, https://clinicaltrials.gov , NCT04388176. [ABSTRACT FROM AUTHOR]

Background Point-of-care (POC) viral load (VL) tests provide results within hours, enabling same-day treatment interventions. We assessed treatment outcomes with POC vs standard-of-care (SOC) VL monitoring. Methods We implemented a randomized controlled trial at an urban and rural hospital in Nigeria. Participants initiating antiretroviral therapy (ART) were randomized 1:1 for monitoring via the POC Cepheid Xpert or SOC Roche COBAS (v2.0) HIV-1 VL assays. Viral suppression (VS) and retention in care at 12 months were compared via intention-to-treat (ITT) and per-protocol (PP) analyses. Post-trial surveys for POC patients and healthcare workers (HCWs) evaluated acceptability. Results During April 2018–October 2019, 268 SOC and 273 POC patients enrolled in the trial. Viral suppression at <1000 copies/mL at 12 months was 59.3% (162/273) for POC and 52.2% (140/268) for SOC (P =.096) in ITT analysis and 77.1% (158/205) for POC and 65.9% (137/208) for SOC (P =.012) in PP analysis. Retention was not significantly different in ITT analysis but was 85.9% for POC and 76.9% for SOC (P =.02) in PP analysis. The increased VS in the POC arm was attributable to improved retention and documentation of VL results. POC monitoring was preferred over SOC by 90.2% (147/163) of patients and 100% (15/15) of HCWs thought it facilitated patient care. Conclusions POC VL monitoring did not improve 12-month VS among those with results but did improve retention and VS documentation and was preferred by most patients and HCWs. Further research can inform best POC implementation conditions and approaches to optimize patient care. Clinical Trials Registration NCT03533868. [ABSTRACT FROM AUTHOR]

Aims Tai Chi is a promising exercise option in cardiac rehabilitation to manage coronary heart disease (CHD). Increasing attention was paid on home-based cardiac rehabilitation to improve participation rate, but no study has yet emphasized the effect of home-based Tai Chi. A single-blinded randomized controlled trial is used to examine the effects of a group- plus home-based Tai Chi program on functional health. Methods and results Ninety-eight community-dwelling patients with CHD were randomly assigned to the Tai Chi and control groups. Participants in the Tai Chi group attended 6-week group- plus 6-week home-based Tai Chi program. Outcome measures included physical functions, cardiovascular risk factors, and exercise self-efficacy. Data were collected at baseline, 6-week, 12-week, and 24-week. Intervention effects were analysed using the generalized estimating equation model. Compared with changes in the control group, the intervention group achieved significant improvements in aerobic endurance, lower-body strength, agility and dynamic balance, diastolic blood pressure, and exercise self-efficacy over the 24-week study period (all Ps < 0.05). Intervention adherence was high (79.6% of participants attending >75% of all Tai Chi sessions). Conclusions This Tai Chi program significantly improved the functional health of patients with CHD, indicating that Tai Chi could be taught in group sessions and then continued independently as a home exercise routine for health promotion. [ABSTRACT FROM AUTHOR]

Objectives The aim of this study was to examine the effects of visual art therapy (VAT) on cognition, psychological and functional ability of people with mild cognitive impairment (MCI), and low education. Methods A single-blinded randomized controlled trial was conducted among 127 older adults with MCI, mean age 73.6 years, and level of education in years, median (range) = 0 (0–9). The intervention group received 12 VAT sessions over 6 weeks. The control group received 6 health education sessions. The outcomes measures at baseline, immediately postintervention, at 3-month, and 6-month follow-up included global cognitive functions, depression, mental well-being, and instrumental activities of daily living functions. Results The intervention group demonstrated greater improvement than the control group in global cognition (β = 2.56, 95% confidence interval [CI] = 1.16, 3.97, p <.001, standardized mean difference [SMD] = 0.75) and depression (β = −2.01, 95% CI = −3.09, −0.93, p <.001, SMD = −0.93) immediately postintervention. The effects on cognitive functions were sustained at 3 and 6 months follow-up. The differential effect of VAT on mental well-being and functional ability compared to health education were undetectable. Discussion VAT can improve cognitive functions and mood status of older adults with MCI who have no or low education. Clinical Trials Registration Number: PACTR201901731800445. This trial was registered with Pan African Clinical Trial Registry: www.pactr.org. [ABSTRACT FROM AUTHOR]

Aims Infective endocarditis is a complex and highly mortal disease requiring lengthy treatment. Physical and mental deconditioning is common. Nonetheless, rehabilitation is virtually unexplored in this population. The aim of this trial was therefore to investigate the effects of cardiac rehabilitation in patients following endocarditis. Methods and results In a randomized trial, adults with left-sided or cardiac device endocarditis were randomized 1:1 to 12 weeks of physical exercise training and five psycho-educational consultations (cardiac rehabilitation) vs. usual care without rehabilitation (control). Primary outcome was mental health measured by SF-36 Mental Component Summary (MCS) at 6 months. Secondary outcome was physical capacity measured by peak oxygen uptake (VO2) at 4 months. Exploratory outcomes were investigated. Low inclusion rate resulted in trial termination before reaching the target sample size. A total of 117 participants (mean age: 60 years, 81% male) were randomized to cardiac rehabilitation (n  = 58) or to control (n  = 59). Mental health and physical capacity at baseline were generally poor (MCS: 38.9–42.2 points, VO2 peak: 16.1–16.6 mL/kg/min). Cardiac rehabilitation compared with control showed no effect on mental health (MCS: 44.6 points vs. 48.8 points, P  = 0.41) or physical capacity (VO2 peak: 19.9 mL/kg/min vs. 18.0 mL/kg/min, P  = 0.09). Effects favouring the intervention were identified in exploratory outcomes including general fatigue (P  = 0.005), and physical capacity as maximal power (W) (P  = 0.005). Adherence to the intervention was 28%. Conclusions Results indicate no effect of cardiac rehabilitation in patients following endocarditis; however, lack of statistical power and poor adherence render findings inconclusive. Valuable insight into patients' capabilities and safety was gained, and further investigations into rehabilitation needs and modes of delivery in this high-need population should be a future priority. Registration The trial is registered at ClinicalTrials.gov, NCT01512615 [ABSTRACT FROM AUTHOR]

Background Hydration therapy is essential in the care of the older patient. Subcutaneous (SC) hydration is a relevant method for parenteral hydration, but clinical trials on the subject have methodological shortcomings compared to updated standards. Design Assessor-blinded, non-inferiority RCT to explore if SC is a safe alternative to intravenous (IV) hydration. Participants Eligible patients were: Admitted patients 65 years or older with a need for parenteral hydration. The targeted sample size was 67 patients in each group. Intervention Patients were randomised to parenteral hydration via an IV or SC catheter during a 24 hours observation period. The non-randomised catheter (inactive) was placed as a sham on the patient, thereby blinding the caregivers and outcome assessors. Measurement Our primary outcome was the proportion of patients reporting at least one adverse effect with a non-inferiority calculation using a 20% margin. Results We included 51 patients, with 24 randomised to SC and 27 to IV. We were unable to reach our target sample size due to challenges in recruitment, time limitation, and COVID-19. For the outcome of adverse effects, SC was non-inferior to IV (p = 0.012). Time spent on inserting the catheters was shorter with SC (p = 0.001). The groups did not differ by pain of insertion, discomfort during infusion, or the risk of developing delirium. Conclusion SC is a safe alternative to IV hydration, is faster to place and should be an available method for parenteral hydration wherever older adults are cared for. Trial registration ClinicalTrials.gov Identifier: NCT03710408 [ABSTRACT FROM AUTHOR]

Background No effective treatments for coronavirus disease 2019 (COVID-19) exist. We aimed to determine whether early treatment with hydroxychloroquine (HCQ) would be efficacious for outpatients with COVID-19. Methods Multicenter open-label, randomized, controlled trial conducted in Catalonia, Spain, between 17 March and 26 May 2020. Patients recently diagnosed with <5-day of symptom onset were assigned to receive HCQ (800 mg on day 1 followed by 400 mg once daily for 6 days) or usual care. Outcomes were reduction of viral load in nasopharyngeal swabs up to 7 days after treatment start, disease progression up to 28 days, and time to complete resolution of symptoms. Adverse events were assessed up to 28 days. Results A total of 293 patients were eligible for intention-to-treat analysis: 157 in the control arm and 136 in the intervention arm. The mean age was 41.6 years (SD, 12.6), mean viral load at baseline was 7.90 log10 copies/mL (SD, 1.82), and median time from symptom onset to randomization was 3 days. No differences were found in the mean reduction of viral load at day 3 (−1.41 vs −1.41 log10 copies/mL in the control and intervention arm, respectively) or at day 7 (−3.37 vs −3.44). Treatment did not reduce risk of hospitalization (7.1% control vs 5.9% intervention) nor shorten the time to complete resolution of symptoms (12 days, control vs 10 days, intervention). No relevant adverse events were reported. Conclusions In patients with mild COVID-19, no benefit was observed with HCQ beyond the usual care. [ABSTRACT FROM AUTHOR]

Background Antibiotic overprescribing in long-term care settings is driven by prescriber preferences and is associated with preventable harms for residents. We aimed to determine whether peer comparison audit and feedback reporting for physicians reduces antibiotic overprescribing among residents. Methods We employed a province wide, difference-in-differences study of antibiotic prescribing audit and feedback, with an embedded pragmatic randomized controlled trial (RCT) across all long-term care facilities in Ontario, Canada, in 2019. The study year included 1238 physicians caring for 96 185 residents. In total, 895 (72%) physicians received no feedback; 343 (28%) were enrolled to receive audit and feedback and randomized 1:1 to static or dynamic reports. The primary outcomes were proportion of residents initiated on an antibiotic and proportion of antibiotics prolonged beyond 7 days per quarter. Results Among all residents, between the first quarter of 2018 and last quarter of 2019, there were temporal declines in antibiotic initiation (28.4% to 21.3%) and prolonged duration (34.4% to 29.0%). Difference-in-differences analysis confirmed that feedback was associated with a greater decline in prolonged antibiotics (adjusted difference −2.65%, 95% confidence interval [CI]: −4.93 to −.28%, P =.026), but there was no significant difference in antibiotic initiation. The reduction in antibiotic durations was associated with 335 912 fewer days of treatment. The embedded RCT detected no differences in outcomes between the dynamic and static reports. Conclusions Peer comparison audit and feedback is a pragmatic intervention that can generate small relative reductions in the use of antibiotics for prolonged durations that translate to large reductions in antibiotic days of treatment across populations. Clinical Trials Registration. NCT03807466. [ABSTRACT FROM AUTHOR]