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Background: Publication of clinical research findings in prominent journals influences health beliefs and medical practice, in part by engendering news coverage. Randomized controlled trials (RCTs) should be most influential in guiding clinical practice. We determined whether study design of clinical research published in high-impact journals influences media coverage. Methods and Findings: We compared the incidence and amount of media coverage of RCTs with that of observational studies published in the top 7 medical journals between 1 January 2013 and 31 March 2013. We specifically assessed media coverage of the most rigorous RCTs, those with >1000 participants that reported ‘hard’ outcomes. There was no difference between RCTs and observational studies in coverage by major newspapers or news agencies, or in total number of news stories generated (all P>0.63). Large RCTs reporting ‘hard’ outcomes did not generate more news coverage than small RCTs that reported surrogate outcomes and observational studies (all P>0.32). RCTs were more likely than observational studies to attract a journal editorial (70% vs 46%, P = 0.003), but less likely to be the subject of a journal press release (17% vs 50%, P<0.001). Large RCTs that reported ‘hard’ outcomes did not attract an editorial more frequently than other studies (61% vs 58%, P>0.99), nor were they more likely to be the subject of a journal press release (14% vs 38%, P = 0.14). Conclusions: The design of clinical studies whose results are published in high-impact medical journals is not associated with the likelihood or amount of ensuing news coverage. [ABSTRACT FROM AUTHOR]

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]

Background: Intravenous zoledronate 5 mg annually reduces fracture risk, and 5 mg every 2 years prevents bone loss, but the optimal dosing regimens for these indications are uncertain.Methods: We conducted a 3-year open-label extension of a 2-year randomized, placebo-controlled, double-blind study. Late postmenopausal women with osteopenia were assigned to receive a single baseline dose of 1 mg, 2.5 mg or 5 mg of zoledronate or placebo. The primary outcome was change in spine bone mineral density (BMD). Secondary outcomes were changes in hip BMD and serum markers of bone turnover.Results: The study involved 160 women. Zoledronate increased BMD and reduced markers of bone turnover in a dose-dependent manner. After 2 years, the 1-mg, 2.5-mg and 5-mg zoledronate doses increased spine BMD over placebo by 5.0% (95% confidence interval [CI] 3.0% to 7.0%), 5.7% (95% CI 3.7% to 7.7%) and 5.7% (95% CI 3.7% to 7.6%), respectively; after 5 years, the respective increases were 2.0% (95% CI -1.1% to 5.0%), 2.2% (95% CI -1.0% to 5.4%) and 5.1% (95% CI 2.2% to 8.1%). After 2 years, the 1-mg, 2.5-mg and 5-mg zoledronate doses increased total hip BMD over placebo by 2.6% (95% CI 1.3% to 3.9%), 4.1% (95% CI 2.9% to 5.4%) and 4.7% (95% CI 3.4% to 5.9%), respectively; after 5 years, the respective increases were 1.8% (95% CI -0.1% to 3.8%), 2.8% (95% CI 0.8% to 4.8%) and 5.4% (95% CI 3.5% to 7.3%). BMD remained above baseline values for 2-3 years in the 1-mg group, 3-4 years in the 2.5-mg group and at least 5 years in the 5-mg group.Interpretation: The antiresorptive activity of single zoledronate doses of 1-5 mg persist for at least 3 years in postmenopausal women with osteopenia. Clinical trials would be justified to evaluate the effects on fracture risk of less frequent or lower doses of zoledronate than are currently recommended.Trial Registration: www.anzctr.org.au, no. ACTRN12607000576426. [ABSTRACT FROM AUTHOR]

Objective: Preclinical studies, observational studies, and clinical trials suggest that thiazolidinediones (TZDs) reduce bone mineral density (BMD) and increase fracture risk. Most of the evidence on the skeletal effects of TZDs is from studies of rosiglitazone. We set out to investigate the magnitude and etiology of the adverse skeletal effects of pioglitazone. Design: Double-blind, randomized controlled trial. Trial registration: Australia New Zealand Clinical Trials Registry, actr.org.au Identifier: ACTRN12607000610437, date of registration 28/11/07. Methods: A total of 86 people with type 2 diabetes mellitus (T2DM) or impaired glucose tolerance (IGT), median age 64 years, were randomized to receive either pioglitazone 30 mg/day or placebo for 1 year, in addition to their usual diabetes treatments. The primary outcome was change in lumbar spine BMD; secondary outcomes included changes in BMD at other sites and in biochemical markers of bone turnover. Results: Change in spine BMD was not altered by treatment with pioglitazone (Ptreatment × time = 0.5). After 1 year, the mean (95% CI) between-groups difference in lumbar spine BMD was --0.7% (--2.1, 0.7). Pioglitazone increased bone loss at the proximal femur (Ptreatment × time = 0.03). After 12 months, the between-groups difference in total hip BMD was --1.2% (--2.1, 0.2). Pioglitazone did not alter change in BMD at other skeletal sites, nor did it affect changes in the levels of either of the biochemical markers of bone turnover, procollagen type 1 N-terminal propeptide, or ß-C-terminal telopeptide of type 1 collagen. Conclusions: Over 1 year, treatment with pioglitazone 30 mg/day did not produce consistent effects on either BMD or bone turnover in people with T2DM or IGT. The mechanism(s) by which pioglitazone increases fracture risk in T2DM is unclear. [ABSTRACT FROM AUTHOR]

Aims To assess the efficacy of methylphenidate as a substitution therapy for amphetamine/methamphetamine dependence in Finland and New Zealand. Design Parallel-group, double-blind, randomized placebo-controlled trial. Setting Out-patient care. Participants Amphetamine-/methamphetamine-dependent, aged 16-65 years. Measurements The primary outcome measure was presence/absence of amphetamine/methamphetamine in urine samples collected twice weekly. Secondary measures included treatment adherence, alterations in craving scores and self-reported use. Primary analysis was by intention-to-treat ( ITT). The study drug, methylphenidate (as Concerta®), was up-titrated over 2 weeks to a maximum dose of 54 mg daily and continued for a further 20 weeks. Doses were given under daily supervision at the clinics. Findings Seventy-nine participants were randomized (40 methylphenidate; 39 placebo); 76 received allocated treatment and 27 completed the trial. ITT analysis ( n = 78) showed no statistically significant difference in the percentage of positive urines between the methylphenidate and placebo arms (odds ratio: 0.95, 95% confidence interval: 0.83-1.08). However, there was a significant difference ( P < 0.05) between the active and placebo arms in retention, the placebo arm displaying a significantly lower retention from 6 weeks that persisted until the end of the trial. Conclusions The trial failed to replicate earlier findings suggesting that methylphenidate was superior to placebo. The low retention rate confounded the ability to draw firm conclusions about efficacy. The higher retention rate was observed in the methylphenidate arm. Any replication of this work would need to consider alternatives to the rigid clinic attendance criteria, and consider an increased dose. [ABSTRACT FROM AUTHOR]

Abstract: Intravenous zoledronate 5mg, administered annually, prevents fractures in people with osteoporosis, but the optimal dosing schedule is not known. Previously, we reported that a single dose of 5mg zoledronate stably decreased bone turnover and increased bone mineral density (BMD) for 3years in a randomized controlled trial in 50 postmenopausal women with osteopenia. We have now completed a 2-year double-blind extension of this trial, during which no additional treatment was administered. The primary endpoint was change in the bone turnover markers procollagen type-I N-terminal propeptide (P1NP) and β-C-terminal telopeptide of type I collagen (β-CTX); the secondary endpoint was change in BMD at lumbar spine, total hip and total body. Mean levels of the each of the bone turnover markers were lower in the zoledronate group throughout the study (P<0.0001 for each marker). After 5years, mean (95% CI) levels of β-CTX and P1NP were 277ng/L (150, 404) and 28μg/L (16, 40) lower in the zoledronate group, corresponding to reductions of 48% and 45%, respectively. BMD was higher in the zoledronate group during the study (P<0.0001 for each site). After 5years, BMD in the zoledronate group was higher by 4.2% (1.1, 7.2) at the lumbar spine, by 5.3% (2.7, 7.9) at the total hip, and by 2.7% (1.1, 4.2) at the total body. These findings suggest that the anti-resorptive effects of a single 5mg dose of zoledronate persist for at least 5years in postmenopausal women. Trials assessing the anti-fracture efficacy of dosing intervals of zoledronate of up to 5years are justified. [Copyright &y& Elsevier]

Objective: To determine the effect of pioglitazone on bone marrow fat in humans. Design: Twenty participants in a double-blind, randomized, placebo-controlled trial of the skeletal effects of pioglitazone 30 mg daily in type 2 diabetes mellitus (T2DM) entered a 6-month substudy evaluating bone marrow fat. Main outcome measures were bone marrow fat in lumbar spine (L4) and proximal femur (intertrochanteric region), measured using magnetic resonance (MR) imaging, and bone mineral density (BMD), measured using dual-energy X-ray absorptiometry. Results: After 6 months, change in the fourth lumbar vertebra (L4) bone marrow lipid fraction, assessed using two different methods, was greater in the pioglitazone group than in the placebo group (Dixon method: mean (95% CI) change from baseline pioglitazone 1.3% (K0.3, 2.9), placebo K0.2% (-0.8, 0.4), P=0.06; MR spectroscopy: pioglitazone 2.5% (0.4, 4.7), placebo -1.1% (-3.7, 1.4), P=0.02). Similarly, the change in lipid fraction in the intertrochanteric region was greater in the pioglitazone group (Dixon method: mean (95% CI) change from baseline pioglitazone 1.3% (0.6, 1.9), placebo K0.8% (-1.8, 0.2), P=0.001). Within the pioglitazone group, there was no evidence of a significant relationship between change in marrow lipid fraction and BMD. Conclusions: Short-term treatment with pioglitazone increases bone marrow fat in patients with T2DM. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To further develop and trial a brief in-hospital illness perception intervention for myocardial infarction (MI) patients. Methods: One hundred and three patients admitted with acute MI were randomized to receive either standard care or standard care plus an illness perception intervention, which consisted of three half-hour patient sessions and one half-hour patient-and-spouse session delivered in hospital. Patients were followed up to 6 months. The main outcome was the difference between groups in rate of return to work. Results: The intervention group had a faster rate of return to work than the control group, and more patients in the intervention group had returned to full time work by 3 months than in the control group. At discharge, patients in the intervention group demonstrated changes in causal attributions regarding their MI and higher perceived understanding of their condition, which remained at the 6-month follow-up. They also reported a better understanding of the information given in hospital, higher intentions to attend cardiac rehabilitation classes, lower anxiety about returning to work, greater increases in exercise, and made fewer phone calls to their general practitioner about their heart condition at follow-up. Conclusion: This study replicates the findings of an earlier trial that a brief in-hospital illness perception intervention can change perceptions and improve rates of return to work in MI patients. It increases the generalizability of the intervention to the current broader definition of MI and to patients who have had previous infarcts. [Copyright &y& Elsevier]

Abstract: Objective: To investigate whether a brief in-hospital illness perception intervention for myocardial infarction (MI) patients and their spouses could change spouses'' illness perceptions and reduce spouses'' anxiety about the illness. Methods: Fifty-seven spouses participated in a randomized controlled trial of an illness perception intervention for MI patients. Spouses of patients randomized to the intervention attended one half-hour patient-and-spouse session with a psychologist in addition to standard care. Spouses completed measures of illness perceptions, expectations, and illness anxiety at admission and at 1 week following discharge, and spouses'' illness worry was rated by the patients at 3 months. The main outcome for spouses was differences in anxiety between intervention and control groups. Results: One week following discharge, spouses in the intervention group had higher illness understanding, lower concern, stronger causal attributions to hereditary factors, and fewer questions about their partner''s heart condition compared to the control group. Intervention group spouses reported more positive expectations about the ability of the patient''s heart to recover, and lower perceived likelihood of another MI. They had lower anxiety about the patient doing physical activity and about the patient''s medications, and lower distress about the patient''s symptoms. Spouses in the intervention group were rated as less worried about the illness at 3 months. Conclusion: Spouses of patients represent a new target for illness perception interventions and these results demonstrate that a brief illness perception intervention can change illness perceptions and reduce anxiety about the illness in spouses of MI patients. [Copyright &y& Elsevier]

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.