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Background: Observational studies (OS) and randomized controlled trials (RCTs) often report discordant results. In the Women’s Health Initiative Calcium and Vitamin D (WHI CaD) RCT, women were randomly assigned to CaD or placebo, but were permitted to use personal calcium and vitamin D supplements, creating a unique opportunity to compare results from randomized and observational analyses within the same study. Methods: WHI CaD was a 7-year RCT of 1g calcium/400IU vitamin D daily in 36,282 post-menopausal women. We assessed the effects of CaD on cardiovascular events, death, cancer and fracture in a randomized design- comparing CaD with placebo in 43% of women not using personal calcium or vitamin D supplements- and in a observational design- comparing women in the placebo group (44%) using personal calcium and vitamin D supplements with non-users. Incidence was assessed using Cox proportional hazards models, and results from the two study designs deemed concordant if the absolute difference in hazard ratios was ≤0.15. We also compared results from WHI CaD to those from the WHI Observational Study(WHI OS), which used similar methodology for analyses and recruited from the same population. Results: In WHI CaD, for myocardial infarction and stroke, results of unadjusted and 6/8 covariate-controlled observational analyses (age-adjusted, multivariate-adjusted, propensity-adjusted, propensity-matched) were not concordant with the randomized design results. For death, hip and total fracture, colorectal and total cancer, unadjusted and covariate-controlled observational results were concordant with randomized results. For breast cancer, unadjusted and age-adjusted observational results were concordant with randomized results, but only 1/3 other covariate-controlled observational results were concordant with randomized results. Multivariate-adjusted results from WHI OS were concordant with randomized WHI CaD results for only 4/8 endpoints. Conclusions: Results of randomized analyses in WHI CaD were concordant with observational analyses for 5/8 endpoints in WHI CaD and 4/8 endpoints in WHI OS. [ABSTRACT FROM AUTHOR]

Objective: To determine whether a therapeutic approach of intensive serum urate lowering results in improved bone erosion scores in patients with erosive gout. Methods: We undertook a 2‐year, double‐blind randomized controlled trial of 104 participants with erosive gout who were receiving serum urate–lowering therapy orally and who had serum urate levels of ≥0.30 mmoles/liter at baseline. Participants were randomly assigned to either an intensive serum urate target of <0.20 mmoles/liter or a standard target of <0.30 mmoles/liter (considered the standard according to rheumatology guidelines). Oral serum urate–lowering therapy was titrated to target using a standardized protocol (with the maximum approved doses of allopurinol, probenecid, febuxostat, and benzbromarone). The primary end point was the total computed tomography (CT) bone erosion score. Outcome Measures in Rheumatology (OMERACT) gout core outcome domains were secondary end points. Results: Although the serum urate levels were significantly lower in the intensive target group compared to the standard target group over the study period (P = 0.002), fewer participants in the intensive target group achieved the randomized serum urate target level by year 2 (62% versus 83% of patients in the standard target group; P < 0.05). The intensive target group required higher doses of allopurinol (mean ± SD 746 ± 210 mg/day versus 497 ± 186 mg/day; P < 0.001) and received more combination therapy (P = 0.0004) compared to the standard target group. We observed small increases in CT bone erosion scores in both serum urate target groups over 2 years, with no between‐group difference (P = 0.20). OMERACT core outcome domains (gout flares, tophi, pain, patient's global assessment of disease activity, health‐related quality of life, and activity limitation) improved in both groups over 2 years, with no between‐group differences. Adverse event and serious adverse event rates were similar between the groups. Conclusion: Compared to a serum urate target of <0.30 mmoles/liter, more intensive serum urate lowering is difficult to achieve with an oral urate‐lowering therapy. Intensive serum urate lowering leads to a high medication burden and does not improve bone erosion scores in patients with erosive gout. [ABSTRACT FROM AUTHOR]

Importance: Prophylactic oral dextrose gel reduces neonatal hypoglycemia, but later benefits or harms remain unclear.Objective: To assess the effects on later development of prophylactic dextrose gel for infants born at risk of neonatal hypoglycemia.Design, Setting, and Participants: Prospective follow-up of a multicenter randomized clinical trial conducted in 18 Australian and New Zealand hospitals from January 2015 to May 2019. Participants were late preterm or term at-risk infants; those randomized in 9 New Zealand centers (n = 1359) were included and followed up between January 2017 and July 2021.Interventions: Infants were randomized to prophylactic 40% dextrose (n = 681) or placebo (n = 678) gel, 0.5 mL/kg, massaged into the buccal mucosa 1 hour after birth.Main Outcomes and Measures: The primary outcome of this follow-up study was neurosensory impairment at 2 years' corrected age. There were 44 secondary outcomes, including cognitive, language, and motor composite Bayley-III scores (mean [SD], 100 [15]; higher scores indicate better performance).Results: Of eligible infants, 1197 (91%) were assessed (581 females [49%]). Neurosensory impairment was not significantly different between the dextrose and placebo gel groups (20.8% vs 18.7%; unadjusted risk difference [RD], 2.09% [95% CI, -2.43% to 6.60%]; adjusted risk ratio [aRR], 1.13 [95% CI, 0.90 to 1.41]). The risk of cognitive and language delay was not significantly different between the dextrose and placebo groups (cognitive: 7.6% vs 5.3%; RD, 2.32% [95% CI, -0.46% to 5.11%]; aRR, 1.40 [95% CI, 0.91 to 2.17]; language: 17.0% vs 14.7%; RD, 2.35% [95% CI, -1.80% to 6.50%]; aRR, 1.19 [95% CI, 0.92 to 1.54]). However, the dextrose gel group had a significantly higher risk of motor delay (2.5% vs 0.7%; RD, 1.81% [95% CI, 0.40% to 3.23%]; aRR, 3.79 [95% CI, 1.27 to 11.32]) and significantly lower composite scores for cognitive (adjusted mean difference [aMD], -1.30 [95% CI, -2.55 to -0.05]), language (aMD, -2.16 [95% CI, -3.86 to -0.46]), and motor (aMD, -1.40 [95% CI, -2.60 to -0.20]) performance. There were no significant differences between groups in the other 27 secondary outcomes.Conclusions and Relevance: Among late preterm and term infants born at risk of neonatal hypoglycemia, prophylactic oral 40% dextrose gel at 1 hour of age, compared with placebo, resulted in no significant difference in the risk of neurosensory impairment at 2 years' corrected age. However, the study may have been underpowered to detect a small but potentially clinically important increase in risk, and further research including longer-term follow-up is required.Trial Registration: anzctr.org.au Identifier: ACTRN12614001263684. [ABSTRACT FROM AUTHOR]

Objective: We investigated whether responses about possible scientific misconduct from journals to journalists would differ in speed, usefulness, and tone from responses to academics. Twelve journals that published 23 clinical trials about which concerns had been previously raised were randomly assigned to enquiries by a journalist or academics. Emails were sent every 3 weeks to the journal editor. We recorded the time for the journal to respond, and two investigators independently assessed the usefulness and tone of the journal responses. Results: 10/12 journals responded: 3 after one email, 5 after two emails, and 2 after three emails (median time from first email to response: 21 days; no difference in response times to journalist or academics, P = 0.25). Of the 10 responses, 8 indicated the journal was investigating, 5 had a positive tone, 4 a neutral tone, and 1 a negative tone. Five of the enquiries by the academics produced information of limited use and 1 no useful information, whereas none of the 6 journalist enquiries produced useful information (P = 0.015). None of the 10 responses was considered very useful. In conclusion, journal responses to a journalist were less useful than those to academics in understanding the status or outcomes of journal investigations. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate whether patients who have undergone trabeculectomy with mitomycin C have a different intraocular pressure (IOP) response profile after the water drinking test (WDT) from that of patients who are medically managed with a similar baseline IOP and level of visual field (VF) damage. Design: Prospective observational study. Participants: Thirty glaucoma patients with IOP controlled by trabeculectomy and 30 with medically treated glaucoma matched for level of VF damage and IOP at baseline (7–14 mmHg). Methods: All patients underwent the WDT, which involved drinking 1000 ml of water in 15 minutes. Main Outcome Measures: The IOP was measured before the WDT and subsequently at 15-minute intervals for 1 hour. The peak IOP with the WDT was compared between both groups using Tukey post hoc multiple comparison and paired t tests. Results: Baseline IOPs were 10.4±2.3 mmHg in surgically treated and 11.1±1.8 mmHg (P = 0.07) in medically treated eyes. After the WDT, mean IOPs in the surgically and medically treated groups were 10.7±2.3 mmHg and 14.6±2.2 mmHg. Mean maximum IOPs were 11.7±2.6 mmHg and 17.3±2.7 mmHg in the surgically and medically treated groups, respectively (P<0.0001), increases of 12.5% and 56%. Ranges of IOP during the WDT were 2.2±1.3 mmHg and 5.6±1.9 mmHg in the surgically and medically treated patients (P<0.0001). Conclusions: Patients with advanced glaucoma who are medically controlled show greater IOP elevation and peak IOP after the WDT than eyes that have undergone trabeculectomy. Financial Disclosure(s): The authors have no proprietary or commercial interest in any materials discussed in this article. [Copyright &y& Elsevier]

The article discusses a study which investigated the effect of calcium supplements without coadministered vitamin D on the risk of cardiovascular events. The authors analysed randomised placebo controlled trials of calcium supplements published in Medline, Embase, and the Cochrane Central Register of Controlled trials. It was suggested by a previous randomised placebo controlled trial that there was an association between an increased risk of myocardial infarction and calcium supplements, which was confirmed by the current study.