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Background The increasing incidence of chronic kidney disease (CKD) is straining the capacity of outpatient clinics. Remote healthcare delivery might improve CKD follow-up compared with conventional face-to-face follow-up. Patient-reported outcomes (PROs) are used to empower remote follow-up and patient engagement. The consequences of shifting from face-to-face follow-up to remote outpatient follow-up on kidney function, health resource utilisation and quality of life remain unknown. Methods We conducted a multicentre pragmatic non-inferiority trial at three outpatient clinics in the Central Denmark Region. A total of 152 incident outpatients with CKD were randomised (1:1:1) to either PRO-based, PRO-telephone follow-up or standard of care (SoC). The primary outcome was the annual change in kidney function measured by the slope of the estimated glomerular filtration rate (eGFR). The non-inferiority margin was an eGFR of 2.85 ml/min/1.73 m2/year. Mean differences were estimated using intention-to-treat (ITT), per protocol and random coefficient models. Results Mean eGFR slope differences between PRO-based and SoC were −0.97 ml/min/1.73 m2/year [95% confidence interval (CI) −3.00–1.07] and −1.06 ml/min/1.73 m2/year (95% CI −3.02–0.89) between PRO-telephone and SoC. Non-inferiority was only established in the per-protocol analysis due to CIs exceeding the margin in the ITT group. Both intervention groups had fewer outpatient visits: −4.95 (95% CI −5.82 to −4.08) for the PRO-based group and −5.21 (95% CI −5.95 to −4.46) for the PRO-telephone group. We found no significant differences in quality of life, illness perception or satisfaction. Conclusion Differences in the eGFR slope between groups were non-significant and results on non-inferiority were inconclusive. Thus, transitioning to remote PRO-based follow-up requires close monitoring of kidney function. Reducing patients' attendance in the outpatient clinic was possible without decreasing either quality of life or illness perception. ClinicalTrials.gov identifier: NCT03847766 [ABSTRACT FROM AUTHOR]

Objective This study examined the influence of a pregnancy and postnatal multicomponent lifestyle intervention for women with gestational diabetes mellitus (GDM) and overweight/obesity from 6 weeks to 12 months postnatal. The primary outcome was weight at 12 months. Secondary outcomes included change in body mass index (BMI), waist circumference (WC) and fasting plasma glucose (FPG). Methods The study involved 235 pregnant women with GDM and BMI ≥ 25 kg/m2 during pregnancy. Intervention components included an educational session, activity tracker (Fitbit), monthly phone calls, weekly motivational text messages, 12-week voucher for a commercial weight management organization and anthropometric, biochemical, and clinical measurements taken at 6 weeks, 6 months, and 12 months postnatal. The control group received routine local maternity care. Results A mean weight change of −2.0 (SD 7.1) kg was observed in the intervention group compared with −0.6 (SD 8.0) kg in the control group, difference −1.4 (95% CI −4.4, 1.5) kg from 6 weeks to 12 months postnatal, but this was not statistically significant (P =.34). Neither were significant differences obtained for any secondary outcomes: BMI −0.6 (−1.6, 0.5) kg/m2, WC −1.0 (−5.1, 3.2) cm and FPG 0.07 (−0.15, 0.29) mmol/L. Conclusion This lifestyle intervention among women with overweight/obesity and GDM resulted in a statistically nonsignificant 1.4 kg greater weight loss compared with routine care at 12 months postnatal. Further research is needed to understand how the different components of this lifestyle intervention might be better applied to elicit more successful results. [ABSTRACT FROM AUTHOR]

Background After antiretroviral therapy (ART) initiation, people with HIV (PWH) treated for tuberculosis (TB) may develop TB-associated immune reconstitution inflammatory syndrome (TB-IRIS). Integrase inhibitors, by providing a faster HIV-RNA decline than efavirenz, might increase the risk for this complication. We sought to assess incidence and determinants of TB-IRIS in PWH with TB on raltegravir- or efavirenz-based ART. Methods We conducted a secondary analysis of the Reflate TB 2 trial, which randomized ART-naive PWH on standard TB treatment, to receive raltegravir- or efavirenz-based ART. The primary objective was to evaluate the incidence of TB-IRIS. Incidence rate ratio comparing TB-IRIS incidence in each arm was calculated. Kaplan-Meier curves were used to compare TB-IRIS–free survival probabilities by ART arm. Cox regression models were fitted to analyze baseline characteristics associated with TB-IRIS. Results Of 460 trial participants, 453 from Brazil, Côte d'Ivoire, Mozambique, and Vietnam were included in this analysis. Baseline characteristics were median age 35 years (interquartile range [IQR], 29–43), 40% female, 69% pulmonary TB only, median CD4, 102 (IQR, 38–239) cells/mm³, and median HIV RNA, 5.5 (IQR, 5.0–5.8) log copies/mL. Forty-eight participants developed TB-IRIS (incidence rate, 24.7/100 PY), 19 cases in the raltegravir arm and 29 in the efavirenz arm (incidence rate ratio 0.62, 95% confidence interval.35–1.10). Factors associated with TB-IRIS were: CD4 ≤ 100 cells/μL, HIV RNA ≥500 000 copies/mL, and extrapulmonary/disseminated TB. Conclusions We did not demonstrate that raltegravir-based ART increased the incidence of TB-IRIS compared with efavirenz-based ART. Low CD4 counts, high HIV RNA, and extrapulmonary/disseminated TB at ART initiation were associated with TB-IRIS. [ABSTRACT FROM AUTHOR]

Background Emotional symptoms are recognized as a key feature in individuals with major depressive disorder. Previously, emotional blunting has been described both as a side effect of antidepressant treatment and as a symptom of depression. Little is known about the change of emotional blunting during antidepressant treatment. Methods The PREDDICT trial is a randomized, placebo-controlled, 6-week trial on the augmentation of vortioxetine with the anti-inflammatory agent celecoxib or placebo. Presently we report on exploratory secondary outcomes of changes in emotional blunting in depression assessed with the Oxford Depression Questionnaire (ODQ) total score and subscores from baseline to 8-week, 3-month, and 6-month follow-up assessments. Results In the whole group, there was a significant improvement in the ODQ total score and all subscores after 8 weeks. After stratification of participants into the treatment groups, the ODQ total score as well as subscores related to emotional blunting as a symptom of depression (reduction in positive emotions, not caring) improved between baseline and all follow-up time points in both treatment groups. Changes in subscores considered as a side effect of antidepressants (general reduction in emotions, emotional detachment) were inconclusive in both treatment groups. Overall, the placebo-augmented group showed slightly better results in changes of emotional blunting scores than the celecoxib group as did those with elevated inflammation at screening, regardless of treatment group. Conclusions This analysis suggests favorable effects of vortioxetine on emotional blunting in both short- and long-term course. The beneficial impact of vortioxetine on emotional blunting was weaker in celecoxib-augmented patients compared with placebo, possibly due to pharmacokinetic interactions. Clinical Trials Registration: Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12617000527369p. Registered on 11 April 2017, http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12617000527369p. [ABSTRACT FROM AUTHOR]

Aims When it occurs, pulmonary vein (PV) stenosis after atrial fibrillation (AF) ablation is associated with significant morbidity. Even mild-to-moderate PV narrowing may have long-term implications. Unlike thermal ablation energies, such as radiofrequency (RF) or cryothermy, pulsed field ablation (PFA) is a non-thermal modality associated with less fibrotic proliferation. Herein, we compared the effects of PFA vs. thermal ablation on PV narrowing after AF ablation. Methods and results ADVENT was a multi-centre, randomized, single-blind study comparing PFA (pentaspline catheter) with thermal ablation—force-sensing RF or cryoballoon (CB)—to treat drug-refractory paroxysmal AF. Pulmonary vein diameter and aggregate cross-sectional area were obtained by baseline and 3-month imaging. The pre-specified, formally tested, secondary safety endpoint compared a measure of PV narrowing between PFA vs. thermal groups, with superiority defined by posterior probability > 0.975. Among subjects randomized to PFA (n = 305) or thermal ablation (n = 302), 259 PFA and 255 thermal ablation (137 RF and 118 CB) subjects had complete baseline and 3-month PV imaging. No subject had significant (≥70%) PV stenosis. Change in aggregate PV cross-sectional area was less with PFA (−0.9%) than thermal ablation (−12%, posterior probability > 0.999)—primarily driven by the RF sub-cohort (−19.5%) vs. CB sub-cohort (−3.3%). Almost half of all PFA PV diameters did not decrease, but the majority (80%) of RF PVs decreased, regardless of PV anatomic location. Conclusion In this first randomized comparison of PFA vs. thermal ablation, PFA resulted in less PV narrowing—thereby underscoring the qualitatively differential and favourable impact of PFA on PV tissue. [ABSTRACT FROM AUTHOR]

Background Recent studies suggest that early tumor shrinkage (ETS) and depth of response (DpR) reflect outcomes of chemotherapy in various cancers. This study evaluated the association of ETS and DpR with clinical outcomes using data from JCOG1113, which demonstrated the non-inferiority of gemcitabine plus S-1 (GS) to gemcitabine plus cisplatin (GC) for chemotherapy-naïve advanced biliary tract cancer. Material and Methods In total, 354 (289 with measurable target lesions) patients enrolled in JCOG1113 were divided into ETS-unachieved and ETS-achieved groups (≥20% tumor reduction at week 6) and DpR-low and DpR-high groups (≥40% maximum shrinkage) until 12 weeks after enrollment. The impact of ETS and DpR on survival outcome was evaluated using the multivariable Cox proportional hazard model. Results The proportions of patients in the ETS-achieved and DpR-high groups were similar between the 2 treatment arms. The hazard ratios (HRs) of progression-free survival (PFS) and overall survival (OS) for the ETS-achieved group were 0.70 (95% confidence interval (CI), 0.52-0.93) and 0.60 (95%CI, 0.44-0.81), respectively. The HRs of PFS and OS for the DpR-high group were 0.67 (95%CI, 0.48-0.94) and 0.64 (95%CI, 0.46-0.90), respectively. In the subpopulation treatment effect pattern plot analysis, most patients in the ETS-achieved group in the GC arm did not experience disease progression after 12 weeks from the landmark. Conclusion As on-treatment markers, ETS and DpR were effective tools. ETS was clinically useful, because it can be used to evaluate the outcomes of treatment early at a specific time. [ABSTRACT FROM AUTHOR]

Aims Modern clinical management of patients with an implantable cardioverter defibrillator (ICD) largely consists of remote device monitoring, although a subset is at risk of mental health issues post-implantation. We compared a 12-month web-based intervention consisting of goal setting, monitoring of patients' mental health—with a psychological intervention if needed—psychoeducational support from a nurse, and an online patient forum, with usual care on participants' device acceptance 12 months after implantation. Methods and results This national, multi-site, two-arm, non-blinded, randomized, controlled, superiority trial enrolled 478 first-time ICD recipients from all 6 implantation centres in Denmark. The primary endpoint was patient device acceptance measured by the Florida Patient Acceptance Survey (FPAS; general score range = 0–100, with higher scores indicating higher device acceptance) 12 months after implantation. Secondary endpoints included symptoms of depression and anxiety. The primary endpoint of device acceptance was not different between groups at 12 months [ B = −2.67, 95% confidence interval (CI) (−5.62, 0.29), P = 0.08]. Furthermore, the secondary endpoint analyses showed no significant treatment effect on either depressive [ B = −0.49, 95% CI (−1.19; 0.21), P = 0.17] or anxiety symptoms [ B = −0.39, 95% CI (−0.96; 0.18), P = 0.18]. Conclusion The web-based intervention as supplement to usual care did not improve patient device acceptance nor symptoms of anxiety and depression compared with usual care. This specific web-based intervention thus cannot be recommended as a standardized intervention in ICD patients. [ABSTRACT FROM AUTHOR]

Background: This phase III, randomized, double-blind, placebo-controlled, parallel-group study assessed the efficacy and safety of tanezumab in subjects with cancer pain predominantly due to bone metastasis receiving background opioid therapy. Methods: Subjects were randomized (stratified by (1) tumor aggressiveness and (2) presence/absence of concomitant anticancer treatment) to placebo or tanezumab 20 mg. Treatment was administered by subcutaneous injection every 8 weeks for 24 weeks (3 doses) followed by a 24-week safety follow-up period. The primary outcome was change in daily average pain in the index bone metastasis cancer pain site (from 0 = no pain to 10 = worst possible pain) from baseline to week 8. Results: LS mean (SE) change in pain at week 8 was −1.25 (0.35) for placebo (n = 73) and –2.03 (0.35) for tanezumab 20 mg (n = 72). LS mean (SE) [95% CI] difference from placebo was –0.78 (0.37) [–1.52, –0.04]; P =.0381 with α = 0.0478. The number of subjects with a treatment-emergent adverse event during the treatment period was 50 (68.5%) for placebo and 53 (73.6%) for tanezumab 20 mg. The number of subjects with a prespecified joint safety event was 0 for placebo and 2 (2.8%) for tanezumab 20 mg (pathologic fracture; n = 2). Conclusion: Tanezumab 20 mg met the primary efficacy endpoint at week 8. Conclusions on longer-term efficacy are limited since the study was not designed to evaluate the durability of the effect beyond 8 weeks. Safety findings were consistent with adverse events expected in subjects with cancer pain due to bone metastasis and the known safety profile of tanezumab. Clinicaltrials.gov identifier: NCT02609828. Bone metastasis is a common cause of cancer-related pain. This article reports on the potential of anti-nerve growth factor therapies, such as tanezumab, to reduce pain caused by bone metastases. [ABSTRACT FROM AUTHOR]

STUDY QUESTION What is the effect of a blended preconception lifestyle programme on reproductive and lifestyle outcomes of couples going through their first 12 months of IVF as compared to an attention control condition? SUMMARY ANSWER This randomized controlled trial (RCT) was stopped prematurely because of the coronavirus disease 2019 (Covid-19) pandemic but the available data did not suggest that a blended preconception lifestyle programme could meaningfully affect time to ongoing pregnancy or other reproductive and lifestyle outcomes. WHAT IS KNOWN ALREADY Increasing evidence shows associations between a healthy lifestyle and IVF success rates. Lifestyle programmes provided through a mobile phone application have yet to be evaluated by RCTs in couples undergoing IVF. STUDY DESIGN, SIZE, DURATION A multicentre RCT (1:1) was carried out. The RCT started in January 2019 and was prematurely stopped because of the Covid-19 pandemic, leading to a reduced sample size (211 couples initiating IVF) and change in primary outcome (cumulative ongoing pregnancy to time to ongoing pregnancy). PARTICIPANTS/MATERIALS, SETTING, METHODS Heterosexual couples initiating IVF in five fertility clinics were randomized between an attention control arm and an intervention arm for 12 months. The attention control arm received treatment information by mobile phone in addition to standard care. The intervention arm received the blended preconception lifestyle (PreLiFe)-programme in addition to standard care. The PreLiFe-programme included a mobile application, offering tailored advice and skills training on diet, physical activity and mindfulness, in combination with motivational interviewing over the telephone. The primary outcome was 'time to ongoing pregnancy'. Secondary reproductive outcomes included the Core Outcome Measures for Infertility Trials and IVF discontinuation. Changes in the following secondary lifestyle outcomes over 3 and 6 months were studied in both partners: diet quality, fruit intake, vegetable intake, total moderate to vigorous physical activity, sedentary behaviour, emotional distress, quality of life, BMI, and waist circumference. Finally, in the intervention arm, acceptability of the programme was evaluated and actual use of the mobile application part of the programme was tracked. Analysis was according to intention to treat. MAIN RESULTS AND THE ROLE OF CHANCE A total of 211 couples were randomized (105 control arm, 106 intervention arm). The hazard ratio of the intervention for time to ongoing pregnancy was 0.94 (95% CI 0.63 to 1.4). Little to no effect on other reproductive or lifestyle outcomes was identified. Although acceptability of the programme was good (6/10), considerable proportions of men (38%) and 9% of women did not actively use all the modules of the mobile application (diet, physical activity, or mindfulness). LIMITATIONS, REASONS FOR CAUTION The findings of this RCT should be considered exploratory, as the Covid-19 pandemic limited its power and the actual use of the mobile application was low. WIDER IMPLICATIONS OF THE FINDINGS This is the first multicentre RCT evaluating the effect of a blended preconception lifestyle programme for women and their partners undergoing IVF on both reproductive and lifestyle outcomes. This exploratory RCT highlights the need for further studies into optimal intervention characteristics and actual use of preconception lifestyle programmes, as well as RCTs evaluating effectiveness. STUDY FUNDING/COMPETING INTEREST(S) Supported by the Research foundation Flanders (Belgium) (FWO-TBM; reference: T005417N). No competing interests to declare. TRIAL REGISTRATION NUMBER ClinicalTrials.gov Identifier: NCT03790449 TRIAL REGISTRATION DATE 31 December 2018 DATE OF FIRST PATIENT'S ENROLMENT 2 January 2019 [ABSTRACT FROM AUTHOR]

Background: Low-intensity shockwave therapy for erectile dysfunction is emerging as a promising treatment option. Aim: This randomized sham-controlled crossover trial assessed the efficacy of low-intensity shockwave therapy in the treatment of erectile dysfunction. Methods: Thirty-three participants with organic erectile dysfunction were enrolled and randomized to shockwave therapy (n = 17) or sham (n = 16). The sham group was allowed to cross over to receive shockwave therapy after 1 month. Outcomes: Primary outcomes were the changes in Sexual Health Inventory for Men (SHIM) score and Erection Hardness Score at 1 month following shockwave therapy vs sham, and secondary outcomes were erectile function measurements at 1, 3, and 6 months following shockwave therapy. Results: At 1 month, mean SHIM scores were significantly increased in the shockwave therapy arm as compared with the sham arm (+3.0 vs −0.7, P = .024). Participants at 6 months posttreatment (n = 33) showed a mean increase of 5.5 points vs baseline (P < .001), with 20 (54.6%) having an increase ≥5. Of the 25 men with an initial Erection Hardness Score <3, 68% improved to a score ≥3 at 6 months. When compared with baseline, the entire cohort demonstrated significant increases in erectile function outcomes at 1, 3, and 6 months after treatment. Clinical Implications: In this randomized sham-controlled crossover trial, we showed that 54.6% of participants with organic erectile dysfunction met the minimal clinically important difference in SHIM scores after treatment with low-intensity shockwave therapy. Strengths and Limitations: Strengths of this study include a sham-controlled group that crossed over to treatment. Limitations include a modest sample size at a single institution. Conclusions: Low-intensity shockwave therapy improves erectile function in men with erectile dysfunction as compared with sham treatment, which persists even 6 months after treatment. Clinical Trial Registration: ClinicalTrials.gov NCT04434352. [ABSTRACT FROM AUTHOR]

Objectives Although the painful and disabling features of early diffuse cutaneous SSc (dcSSc) have an inflammatory basis and could respond to corticosteroids, corticosteroids are a risk factor for scleroderma renal crisis. Whether or not they should be prescribed is therefore highly contentious. Our aim was to examine safety and efficacy of moderate-dose prednisolone in early dcSSc. Methods PRedSS set out as a Phase II, multicentre, double-blind randomized controlled trial, converted to open-label during the Covid-19 pandemic. Patients were randomized to receive either prednisolone (∼0.3 mg/kg) or matching placebo (or no treatment during open-label) for 6 months. Co-primary endpoints were the HAQ Disability Index (HAQ-DI) and modified Rodnan skin score (mRSS) at 3 months. Over 20 secondary endpoints included patient reported outcome measures reflecting pain, itch, fatigue, anxiety and depression, and helplessness. Target recruitment was 72 patients. Results Thirty-five patients were randomized (17 prednisolone, 18 placebo/control). The adjusted mean difference between treatment groups at 3 months in HAQ-DI score was −0.10 (97.5% CI: −0.29, 0.10), P  = 0.254, and in mRSS −3.90 (97.5% CI: −8.83, 1.03), P  = 0.070, both favouring prednisolone but not significantly. Patients in the prednisolone group experienced significantly less pain (P  = 0.027), anxiety (P  = 0.018) and helplessness (P  = 0.040) than control patients at 3 months. There were no renal crises, but sample size was small. Conclusion PRedSS was terminated early primarily due to the Covid-19 pandemic, and so was underpowered. Therefore, interpretation must be cautious and results considered inconclusive, indicating the need for a further randomized trial. Trial registration ClinicalTrials.gov , https://clinicaltrials.gov , NCT03708718. [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 Kidney transplant has become the preferred therapy for end-stage renal disease. However, kidney transplant recipients (KTRs) still face several challenges, such as physical inactivity. The purpose of this study was to explore the effects of a nurse-led physical exercise program in Chinese KTRs. Methods A total of 106 participants were enrolled from the Third Xiangya Hospital of Central South University between July 2021 and June 2022 and randomly assigned to the control or intervention groups. Participants in the control group were provided with routine nursing care and participants in the intervention group received a nurse-led rigorous physical exercise program that was divided into two stages: the pre-discharge stage and the post-discharge stage. The pre-discharge stage included the non-ambulatory and ambulatory stages. The Chinese traditional exercise Baduanjin was incorporated into the physical exercise during the ambulatory stage. The post-discharge stage continued the same exercise as the ambulatory stage at home. After 3 months of intervention, both groups received the same follow-up for 3 months. The primary and secondary outcomes of all participants were collected. The data were analysed with repeated measures analysis of variance to examine the effectiveness of the intervention. Results Compared with the control group, the intervention group had less fatigue and more motivation to be active in primary outcomes. Moreover, patients in the intervention group had a higher phase angle, a longer 6-minute walk distance, more 30-second chair stand times and decreased anxiety and depression levels in secondary outcomes. No adverse events were observed during the intervention. There were no significant differences in all dimensions of the quality-of-life questionnaire between the intervention and the control group. Conclusion Chinese KTRs could benefit from the nurse-led physical exercise program post-operatively. Trial registration ChiCTR2100048755 [ABSTRACT FROM AUTHOR]

Background Health care professionals seek information about effectiveness of treatments in patients who would be offered them in routine clinical practice. Electronic medical records (EMRs) and randomized controlled trials (RCTs) can both provide data on treatment effects; however, each data source has limitations when considered in isolation. Methods A novel modelling methodology which incorporates RCT estimates in the analysis of EMR data via informative prior distributions is proposed. A Bayesian mixed modelling approach is used to model outcome trajectories among patients in the EMR dataset receiving the treatment of interest. This model incorporates an estimate of treatment effect based on a meta-analysis of RCTs as an informative prior distribution. This provides a combined estimate of treatment effect based on both data sources. Results The superior performance of the novel combined estimator is demonstrated via a simulation study. The new approach is applied to estimate the effectiveness at 12 months after treatment initiation of acetylcholinesterase inhibitors in the management of the cognitive symptoms of dementia in terms of Mini-Mental State Examination scores. This demonstrated that estimates based on either trials data only (1.10, SE = 0.316) or cohort data only (1.56, SE = 0.240) overestimated this compared with the estimate using data from both sources (0.86, SE = 0.327). Conclusions It is possible to combine data from EMRs and RCTs in order to provide better estimates of treatment effectiveness. [ABSTRACT FROM AUTHOR]

To date, the VIT amin D and Omeg A -3 Tria L (VITAL) is the only large-scale randomized trial of marine omega-3 fatty acid (n −3 FA) supplementation for cardiovascular disease (CVD) prevention in a general population unselected for elevated cardiovascular risk. We review the findings of VITAL, as well as results from recent secondary prevention trials and updated meta-analyses of n −3 FA trials in the primary and secondary prevention of CVD. In VITAL, a nationwide sample of 25 871 US adults aged 50 and older, including 5106 African Americans, were randomized in a 2 × 2 factorial design to n −3 FAs (1 g/day; 1.2:1 ratio of eicosapentaenoic to docosahexaenoic acid) and vitamin D3 (2000 IU/day) for a median of 5.3 years. Compared with an olive oil placebo, the n −3 FA intervention did not significantly reduce the primary endpoint of major CVD events [composite of myocardial infarction (MI), stroke, and CVD mortality; hazard ratio (HR) = 0.92 (95% confidence interval 0.80–1.06)] but did significantly reduce total MI [HR = 0.72 (0.59–0.90)], percutaneous coronary intervention [HR = 0.78 (0.63–0.95)], fatal MI [HR = 0.50 (0.26–0.97)], and recurrent (but not first) hospitalization for heart failure [HR = 0.86 (0.74–0.998)]. The intervention neither decreased nor increased risk of atrial fibrillation. African Americans derived the greatest treatment benefit for MI and for recurrent hospitalization for heart failure (P interaction < 0.05 for both outcomes). Meta-analyses that include VITAL and high-risk or secondary prevention n −3 FA trials show coronary, but generally not stroke, risk reduction. More research is needed to determine which individuals may be most likely to derive net benefit. (VITAL clinicaltrials.gov identifier: NCT01169259). [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 To develop a computable representation for medical evidence and to contribute a gold standard dataset of annotated randomized controlled trial (RCT) abstracts, along with a natural language processing (NLP) pipeline for transforming free-text RCT evidence in PubMed into the structured representation. Materials and methods Our representation, EvidenceMap , consists of 3 levels of abstraction: Medical Evidence Entity, Proposition and Map, to represent the hierarchical structure of medical evidence composition. Randomly selected RCT abstracts were annotated following EvidenceMap based on the consensus of 2 independent annotators to train an NLP pipeline. Via a user study, we measured how the EvidenceMap improved evidence comprehension and analyzed its representative capacity by comparing the evidence annotation with EvidenceMap representation and without following any specific guidelines. Results Two corpora including 229 disease-agnostic and 80 COVID-19 RCT abstracts were annotated, yielding 12 725 entities and 1602 propositions. EvidenceMap saves users 51.9% of the time compared to reading raw-text abstracts. Most evidence elements identified during the freeform annotation were successfully represented by EvidenceMap , and users gave the enrollment, study design, and study Results sections mean 5-scale Likert ratings of 4.85, 4.70, and 4.20, respectively. The end-to-end evaluations of the pipeline show that the evidence proposition formulation achieves F1 scores of 0.84 and 0.86 in the adjusted random index score. Conclusions EvidenceMap extends the participant, intervention, comparator, and outcome framework into 3 levels of abstraction for transforming free-text evidence from the clinical literature into a computable structure. It can be used as an interoperable format for better evidence retrieval and synthesis and an interpretable representation to efficiently comprehend RCT findings. [ABSTRACT FROM AUTHOR]

Context: The 2021 consensus report on the definition and interpretation of remission of type 2 diabetes (T2D) has been released. Although intermittent fasting diets (IF) are becoming very popular, no studies have investigated their benefit in diabetes remission. Objective: The present study examined the effectiveness of IF in diabetes remission and potential remission durability. Methods: Participants between ages 38 and 72 years with a duration of T2D of 1 to 11 years, a body mass index (BMI) of 19.1 to 30.4, 66.7% male, and antidiabetic agent use and/or insulin injection were randomly allocated at a ratio of 1:1 to the Chinese Medical Nutrition Therapy (CMNT) or control group. The primary outcome was diabetes remission, defined as a stable glycated hemoglobin A1c (HbA1c) level of less than 48 mmol/mol (< 6.5%) for at least 3 months after discontinuing all antidiabetic medications. The secondary outcomes included HbA1c level, fasting blood glucose level, blood pressure, weight, quality of life, and medication costs. We conducted a 12-month follow-up to assess the continuation of remission. Results: On completing the 3-month intervention plus 3-month follow-up, 47.2% (17/36) of participants achieved diabetes remission in the CMNT group, whereas only 2.8% (1/36) of individuals achieved remission in the control group (odds ratio 31.32; 95% CI, 2.39-121.07; P<0.0001). The mean body weight of participants in the CMNT group was reduced by 5.93 kg (SD 2.47) compared to 0.27 kg (1.43) in the control group. After the 12-month follow-up, 44.4% (16/36) of the participants achieved sustained remission, with an HbA1c level of 6.33% (SD 0.87). The medication costs of the CMNT group were 77.22% lower than those of the control group (60.4/month vs 265.1/month). Conclusion: This study demonstrated the clinical efficacy of CMNT in achieving diabetes remission for at least 1 year. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Does a short interval (i.e. ≤90 min), compared to a long interval (i.e. ≥180 min), between semen collection and intrauterine insemination (IUI) increase the cumulative chance of an ongoing pregnancy after six IUI cycles? SUMMARY ANSWER A long interval between semen collection and IUI resulted in a borderline significant improvement in cumulative ongoing pregnancies and a statistically significant shorter time to pregnancy. WHAT IS KNOWN ALREADY Retrospective studies assessing the effect of the time interval between semen collection and IUI on pregnancy outcomes have shown inconclusive results. Some studies have indicated a beneficial effect of a short interval between semen collection and IUI on IUI outcomes, while others have not found any differences. To date, no prospective trials have been published on this subject. STUDY DESIGN, SIZE, DURATION The study was performed as a non-blinded, single-center RCT with 297 couples undergoing IUI treatment in a natural or stimulated cycle. The study was conducted between February 2012 and December 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS Couples with unexplained or mild male subfertility and an indication for IUI were randomly assigned for up to six IUI cycles into either the control group (long interval, i.e. 180 min or more between semen collection and insemination) or the study group (short interval, i.e. insemination as soon as possible after semen processing and within 90 min of semen collection). The study was carried out in an academic hospital-based IVF center in the Netherlands. The primary endpoint of the study was ongoing pregnancy rate per couple, defined as a viable intrauterine pregnancy at 10 weeks after insemination. MAIN RESULTS AND THE ROLE OF CHANCE In the short interval group, 142 couples were analyzed versus 138 couples in the long interval group. In the intention-to-treat (ITT) analysis, the cumulative ongoing pregnancy rate was significantly higher in the long interval group (71/138; 51.4%) compared to that in the short interval group (56/142; 39.4%; relative risks 0.77; 95% CI 0.59–0.99; P  = 0.044). The time to pregnancy was significantly shorter in the long interval group (log-rank test, P  = 0.012). A Cox regression analysis showed similar results (adjusted hazard ratio 1.528, 95% CI 1.074–2.174, P  = 0.019). LIMITATIONS, REASONS FOR CAUTION Limitations of our study are the non-blinded design, the long inclusion and follow-up period of nearly seven years and the large number of protocol violations, especially because they predominantly occurred in the short interval group. The non-significant results in the per-protocol (PP) analyses and the weaknesses of the study should be taken into account in the assessment of the borderline significance of the results in the ITT analyses. WIDER IMPLICATIONS OF THE FINDINGS Because it is not necessary to perform the IUI immediately after semen processing, there can be more time available to choose the optimum work-flow and clinic occupancy. Clinics and laboratories should find their optimal timing of insemination, considering the time between human chorionic gonadotropin injection and insemination in relation to the sperm preparation techniques used as well as the storage time and conditions until insemination. STUDY FUNDING/COMPETING INTEREST(S) There were no external funding and no competing interests to declare. TRIAL REGISTRATION NUMBER Dutch trial registry, trial registration number NTR3144. TRIAL REGISTRATION DATE 14 November 2011. DATE OF FIRST PATIENT'S ENROLLMENT 5 February 2012. [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]

Keywords: Randomized controlled trial; Clinical trial; Trial design; Registry; Heart failure; Reduced ejection fraction; Mildly reduced ejection fraction; Preserved ejection fraction; Outcomes; Mortality; Heart failure hospitalization EN Randomized controlled trial Clinical trial Trial design Registry Heart failure Reduced ejection fraction Mildly reduced ejection fraction Preserved ejection fraction Outcomes Mortality Heart failure hospitalization 1526 1529 4 05/03/23 20230501 NES 230501 Randomized controlled trials (RCTs) form the basis for guidelines, regulatory approval, and reimbursement.[1] They are commonly industry-funded and apply selective eligibility criteria,[2] potentially limiting generalizability. Real-world heart failure management in 10,910 patients with chronic heart failure in the Netherlands: design and rationale of the chronic heart failure ESC guideline-based cardiology practice quality project (CHECK-HF) registry. [Extracted from the article]

Background We previously reported that modified-release nicotinamide (NAMR) was superior to placebo in reducing serum phosphate concentrations over 12 weeks in a large cohort of haemodialysis patients with hyperphosphataemia. Here we report outcomes after 52 weeks of treatment. Methods NOPHOS was a phase 3, international, randomized, controlled, double-blind trial with a parallel group design. NAMR (250–1500 mg/day) was investigated in comparison to placebo as an add-on therapy to an individual therapy with approved phosphate binders. Results In the intention-to-treat population (NAMR: n  = 539; placebo: n  = 183), serum phosphate was significantly lower in the NAMR group compared with the placebo group at week 24 (5.40 ± 1.55 versus 5.79 ± 1.37 mg/dl, P  < .001) with a mean difference of −0.39 mg/dl [95% confidence interval (CI) −0.66 to −0.13], but was comparable between the groups at week 52 [mean difference −0.08 (95% CI −0.36–0.20)]. In the completer population (n  = 358), statistical significance in favour of NAMR was reached at weeks 24 and 52. The treatment effect was reduced in patients with high baseline serum intact parathyroid hormone (iPTH) compared with patients with low baseline serum iPTH. Compliant patients in the NAMR group had a more pronounced and sustained reduction in serum phosphate than non-compliant patients. NAMR treatment was associated with a significantly increased risk of thrombocytopenia, pruritus, anaemia, and diarrhoea. Herpes zoster occurred exclusively in patients randomized to NAMR. Conclusions NAMR combined with phosphate binders significantly reduced serum phosphate over the first 24 weeks of treatment, but the treatment effect was not maintained up to week 52. Non-compliance may have contributed to reduced long-term efficacy. Several newly identified safety signals warrant further evaluation. [ABSTRACT FROM AUTHOR]

Background: Despite the frequent use of symptomatic therapies in cough, evidence of their benefits is lacking.Objective: We compared the effectiveness of 3 symptomatic therapies and usual care in acute bronchitis.Methods: Multicenter, pragmatic, multiarm parallel group, open randomized trial in primary care (ClinicalTrials.gov, Identifier: NCT03738917) was conducted in Catalonia. Patients ≥18 with uncomplicated acute bronchitis, with cough<3 weeks as the main symptom, scoring ≥4 in either daytime or nocturnal cough (7-point Likert scale), were randomized to usual care, dextromethorphan 15 mg t.i.d., ipratropium bromide inhaler 20 µg 2 puffs t.i.d, or 30 mg of honey t.i.d., all taken for up to 14 days. The main outcome measure was the number of days with moderate-to-severe cough. A symptom diary was given. A second visit was scheduled at days 2-3 for assessing evolution, with 2 more visits at days 15 and 29 for clinical assessment, evaluation of adverse effects, re-attendance, and complications.Results: We failed to achieve the sample size scheduled due to the COVID-19 pandemic. We finally recruited 194 patients. The median number of days with moderate-to-severe cough (score ≥ 3) in the usual care arm was 5 (interquartile range [IQR], 4, 8.75), 5 in the ipratropium bromide arm (IQR, 3, 8), 5 in the dextromethorphan arm (IQR, 4, 9.75), and 6 in the honey arm (IQR, 3.5, 7). The same results were obtained in the Kaplan-Meier survival analysis for the median survival time of each arm with the usual care as the reference group.Conclusion: The symptomatic treatment evaluated has shown to be ineffective against cough. [ABSTRACT FROM AUTHOR]

The provision of high-quality antenatal care (ANC) is important for preventing maternal and newborn mortality and morbidity, but only around half of pregnant women in Tanzania attended four or more ANC visits in 2019. Although there is emerging evidence on the benefit of community health worker (CHW) interventions on ANC uptake, few large-scale pragmatic trials have been conducted. This pragmatic cluster-randomized trial, implemented directly through the public sector health system, assessed the impact of an intervention that trained public sector CHWs to promote uptake of ANC. We randomized 60 administrative wards in Dar es Salaam to either a targeted CHW intervention or standard of care. The impact of the intervention was assessed using generalized estimating equations (GEE) with an independent working correlation matrix to account for clustering within wards. A total of 243,908 women were included in the analysis of our primary outcome of four or more ANC visits. The intervention significantly increased the likelihood of attending four or more ANC visits (RR 1.42; 95% CI: 1.05, 1.92), and had a modest beneficial effect on the total number of ANC visits (percent change: 7.7%; 95% CI: 0.2%, 15.5%). While slightly more women in the intervention arm attended ANC in their first trimester compared to the standard-of-care arm (19% vs 18.7%) the difference was not significant (RR:1.02; 95% CI: 0.84, 1.22). Our findings suggest that trained CHWs can increase attendance of ANC visits in Dar es Salaam and similar settings. However, additional interventions appear necessary to promote early initiation of ANC. This study demonstrates that routine health systems data can be leveraged for outcome assessment in trials and program evaluation, and that the results are likely superior, both in terms of bias and precision, to data that is collected specifically for science. [ABSTRACT FROM AUTHOR]

Objective The aim of this study was to examine the efficacy of the SMART (Self-Management After Recent Traumatic brain injury) program and potential moderators. Methods Parallel randomized controlled trial (ClinicalTrials.gov Identifier: NCT03498495) was conducted. Eligibility criteria included treatment for mild traumatic brain injury in the emergency department and age 11–18 years. Participants were assigned equally to SMART (n  = 35) or usual care (UC; n  = 36). SMART included symptom monitoring and online modules supporting the return to activities and symptom management. Coping and quality of life (QoL) (primary outcomes) and post-concussive symptoms (secondary outcome) were assessed at baseline and weekly for 4 weeks. Results Groups did not differ in coping, QoL, or return to pre-injury symptom levels at any time point. Problem-focused engagement (PFE) moderated group differences over time (p  = .02). At high PFE, UC participants reported lower QoL at time 1 (effect size [ES] = 0.60); SMART participants did not report a decline at any point. At low PFE, SMART participants reported declining QoL from pre-injury to time 1 (ES = 0.68), whereas UC participants reported an increase from time 1 to 3 (ES = 0.56). PFE also moderated group differences on the Health and Behavior Inventory (HBI) cognitive (p  = .02) and somatic symptom scales (p  = .05). At high PFE, SMART participants reported a more rapid return to pre-injury levels than UC participants (p  = .05). Resilience also moderated group differences in QoL and HBI cognitive recovery. Conclusion Effectiveness of the SMART app varied based on preinjury coping styles and resilience, underscoring the potential need to tailor treatments to individual characteristics. [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]

Objective To quantify the different types of health outcomes assessed as primary outcomes in randomized controlled trials (RCTs) in the primary care (PC) setting during the last 20 years and identify whether potential gaps exist in specific types of health care and types of intervention. Methods We systematically searched PubMed, Scopus, and Cochrane Central Register of Controlled Trials, from January 2000 to September 2020 for published RCTs in PC. We recorded characteristics of eligible studies and mapped evidence by health outcome category (patient health outcomes, health services outcomes); and for each outcome category, by types of health care (preventive, acute, chronic, palliative), and by types of intervention (drug, behavioural, on structure, and on process). For RCTs assessing patient health outcomes as primary outcomes, we further mapped using the quality-of-care dimensions, that is, effectiveness, safety, and patient-centredness. Results Of the 518 eligible RCTs in PC, 357 (68.9%) evaluated a patient health outcome as the primary outcome, and 161 (31.1%) evaluated only health services outcomes as primary outcomes. Many focused on population with chronic illness (224 trials; 43.2%) and evaluated interventions on processes of health care (239 trials; 46.1%). Research gaps identified include preventive and palliative care, behavioural interventions, and safety and patient-centredness outcomes as primary outcomes. Conclusion Our evidence map showed research gaps in certain types of health care and interventions. It also showed research gaps in assessing safety and measures to place patient at the centre of health care delivery as primary outcomes. [ABSTRACT FROM AUTHOR]

Study Question: Does an estradiol-based combined oral contraceptive (COC) have a milder effect on the serum proteome than an ethinylestradiol (EE)-based COC or dienogest (DNG) only?Summary Answer: The changes in serum proteome were multifold after the use of a synthetic EE-based COC compared to natural estrogen COC or progestin-only preparation.What Is Known Already: EE-based COCs widely affect metabolism, inflammation, hepatic protein synthesis and blood coagulation. Studies comparing serum proteomes after the use of COCs containing EE and natural estrogens are lacking.Study Design, Size, Duration: This was a spin-off from a randomized, controlled, two-center clinical trial. Women (n = 59) were randomized to use either EE + DNG, estradiol valerate (EV) + DNG or DNG only continuously for 9 weeks.Participants/materials, Setting, Methods: Participants were healthy, young, white volunteer women. Serum samples were collected before and after 9 weeks of hormonal exposure. Samples from 44 women were available for analysis (EE + DNG n = 14, EV + DNG n = 16 and DNG only n = 14). Serum proteins were analyzed by quantitative, discovery-type label-free proteomics.Main Results and the Role Of Chance: Altogether, 446 proteins/protein families with two or more unique peptides were detected and quantified. The number of proteins/families that altered over the 9-week period within the study groups was 121 for EE + DNG and 5 for EV + DNG, while no changes were detected for DNG only. When alterations were compared between the groups, significant differences were detected for 63 proteins/protein families, of which 58 were between the EE + DNG and EV + DNG groups. The most affected functions during the use of EE + DNG were the complement system, acute phase response signaling, metabolism and the coagulation system. The results were validated by fetuin-B and cortisol-binding globulin ELISA and sex hormone-binding globulin immunoassay.Large Scale Data: Data are available via ProteomeXchange with identifiers PXD033617 (low abundance fraction) and PXD033618 (high abundance fraction).Limitations, Reasons For Caution: The power analysis of the trial was not based on the proteomic analysis of this spin-off study. In the future, targeted proteomic analysis with samples from another trial should be carried out in order to confirm the results.Wider Implications Of the Findings: The EE-based COC exerted a broader effect on the serum proteome than the EV-based COC or the DNG-only preparation. These results demonstrate that the effects of EE in COCs go far beyond the established endpoint markers of estrogen action, while the EV combination is closer to the progestin-only preparation. The study indicates that EV could provide a preferable option to EE in COCs in the future and signals a need for further studies comparing the clinical health outcomes of COCs containing EE and natural estrogens.Study Funding/competing Interest(s): Funding for this researcher-initiated study was obtained from the Helsinki University Hospital research funds, the Hospital District of Helsinki and Uusimaa, the Sigrid Juselius Foundation, the Academy of Finland, the Finnish Medical Association, the University of Oulu Graduate School, the Emil Aaltonen Foundation, the Swedish Cultural Foundation in Finland, the Novo Nordisk Foundation, Orion Research Foundation and the Northern Ostrobothnia Regional Fund. The funders had no role in study design, data collection and analysis, publishing decisions or manuscript preparation. T.P. has received honoraria for lectures, consultations and research grants from Exeltis, Gedeon Richter, MSD, Merck, Pfizer, Roche, Stragen and Mithra Pharmaceuticals. O.H. occasionally serves on advisory boards for Bayer AG and Gedeon Richter and has designed and lectured at educational events for these companies. The other authors have nothing to disclose. O.H. occasionally serves on advisory boards for Bayer AG and Gedeon Richter and has designed and lectured at educational events for these companies. The other authors have nothing to disclose.Trial Registration Number: ClinicalTrials.gov NCT02352090.Trial Registration Date: 27 January 2015.Date Of First Patient’s Enrolment: 1 April 2015. [ABSTRACT FROM AUTHOR]

Objective To examine as secondary analyses the effect the FAMily-Oriented Support (FAMOS) family therapy program on reducing parent-reported medical traumatic stress in the sub-sample of pediatric cancer survivors, age 2–5 years. Methods The FAMOS study was a national multicenter randomized controlled trial with all four pediatric oncology departments in Denmark (Clinicaltrials.gov [NCT02200731]). Families were randomized in parallel design (1:1) to intervention or usual care. The FAMOS program includes seven home-based psychotherapeutic sessions and is based on family systems therapy to address the individuals in the family system using cognitive behavioral, problem-solving and goal-setting techniques. Questionnaires were completed by parents at baseline, 6, and 12 months. In linear mixed-effects models, the effect of FAMOS on reducing children's trauma-related behavior after 6 and 12 months was examined in 62 children (31 in the intervention and 29 in the control group, respectively). It was also examined if a trauma-related behavior effect was mediated through reduced symptoms of depression in mothers and fathers, respectively. Results On average, children in the intervention group experienced significantly larger decreases in trauma-related behaviors at 6 and 12 months than the control group (predicted mean difference –3.89, p  = .02 and –6.24, p  = .003, respectively). The effect on trauma-related behavior was partly mediated through reduced symptoms of depression in mothers, but not fathers. Conclusions Adding to previously reported positive effects of the FAMOS intervention on parents' symptoms of post-traumatic stress and depression, significant improvements were found in young children's trauma related-behavior. Further research is needed to develop therapy for children with cancer. [ABSTRACT FROM AUTHOR]

Objectives: This study examined the effectiveness of a newly developed work–family life support program on the work–family interface and mental health indicators among Japanese dual‐earner couples with a preschool child(/ren) using a randomized controlled trial with a waitlist. Methods: Participants who met the inclusion criteria were randomly allocated to the intervention or the control groups (n = 79 and n = 85, respectively). The program comprised two 3‐h sessions with a 1‐month interval between them and provided comprehensive skills by including self‐management, couple management, and parenting management components. The program sessions were conducted on weekends in a community center room with 3–10 participants. Outcomes were assessed at baseline, 1‐month, and 3‐month follow‐ups. Primary outcomes were work–family balance self‐efficacy (WFBSE), four types of work–family spillovers (i.e., work‐to‐family conflict, family‐to‐work conflict, work‐to‐family facilitation, and family‐to‐work facilitation), psychological distress, and work engagement reported by the participants. Results: The program had significantly pooled intervention effects on WFBSE (P =.031) and psychological distress (P =.014). The effect sizes (Cohen's d) were small, with values of 0.22 at the 1‐month follow‐up and 0.24 at the 3‐month follow‐up for WFBSE, and −0.36 at the 3‐month follow‐up for psychological distress. However, the program had nonsignificant pooled effects on four types of work–family spillovers and work engagement. Conclusions: The program effectively increased WFBSE and decreased psychological distress among Japanese dual‐earner couples with a preschool child(/ren). [ABSTRACT FROM AUTHOR]

Transcranial direct current stimulation (tDCS) has been proposed as a potential intervention for subjective tinnitus, but supporting evidence remains limited. We aimed to investigate the effect of anodal high-definition tDCS of the left temporal area and right dorsolateral prefrontal cortex on tinnitus severity. This double-blind randomized controlled trial included 77 patients (age range 18-79, 43 male) with chronic subjective tinnitus as their primary complaint. Thirty-eight subjects received six consecutive sessions of dual-site sequential high-definition-tDCS with electrodes positioned over the left temporal area and right dorsolateral prefrontal cortex. Both areas were stimulated for 15 min per session, with total stimulation time amounting to 30 min. Thirty-nine subjects received sham stimulation. The primary outcome measure was the change in tinnitus severity, as evaluated by the Tinnitus Functional Index, from baseline to a follow-up visit at 8 ± 2 weeks after treatment completion. Secondary outcomes included changes in perceived tinnitus loudness, as measured with a visual analogue scale and a tinnitus matching procedure, as well as scores on the Hospital Anxiety and Depression Scale, and the Hyperacusis Questionnaire. No differences in Tinnitus Functional Index change scores were identified between the active treatment and sham control groups (linear regression: P = 0.86). The Tinnitus Functional Index scores decreased significantly over time in both groups (P = 0.0012), indicating the presence of a considerable placebo effect. These change scores were significantly influenced by sex (linear regression: P = 0.037) and baseline symptoms of anxiety (linear regression: P = 0.049) in both groups. In general, Tinnitus Functional Index scores decreased more profoundly in males and in subjects with a higher degree of anxiety at baseline. None of the included secondary measures differed significantly between experimental arms. Our results suggest that dual-site sequential high-definition-tDCS of the left temporal area and right dorsolateral prefrontal cortex does not alleviate tinnitus severity. Interestingly, in our study population, fluctuations in tinnitus severity were influenced by gender and concurrent mental condition. It is therefore important to take these factors into account when conducting or planning randomized controlled trials in tinnitus populations. [ABSTRACT FROM AUTHOR]

Study Question: For couples with unexplained subfertility and a poor prognosis for natural conception, is 6 months expectant management (EM) inferior to IUI with ovarian stimulation (IUI-OS), in terms of live births?Summary Answer: In couples with unexplained subfertility and a poor prognosis for natural conception, 6 months of EM is inferior compared to IUI-OS in terms of live births.What Is Known Already: Couples with unexplained subfertility and a poor prognosis are often treated with IUI-OS. In couples with unexplained subfertility and a relatively good prognosis for natural conception (>30% in 12 months), IUI-OS does not increase the live birth rate as compared to 6 months of EM. However, in couples with a poor prognosis for natural conception (<30% in 12 months), the effectiveness of IUI-OS is uncertain.Study Design, Size, Duration: We performed a non-inferiority multicentre randomized controlled trial within the infrastructure of the Dutch Consortium for Healthcare Evaluation and Research in Obstetrics and Gynaecology. We intended to include 1091 couples within 3 years. The couples were allocated in a 1:1 ratio to 6 months EM or 6 months IUI-OS with either clomiphene citrate or gonadotrophins.Participants/materials, Setting, Methods: We studied heterosexual couples with unexplained subfertility and a poor prognosis for natural conception (<30% in 12 months). The primary outcome was ongoing pregnancy leading to a live birth. Non-inferiority would be shown if the lower limit of the one-sided 90% risk difference (RD) CI was less than minus 7% compared to an expected live birth rate of 30% following IUI-OS. We calculated RD, relative risks (RRs) with 90% CI and a corresponding hazard rate for live birth over time based on intention-to-treat and per-protocol (PP) analysis.Main Results and the Role Of Chance: Between October 2016 and September 2020, we allocated 92 couples to EM and 86 to IUI-OS. The trial was halted pre-maturely owing to slow inclusion. Mean female age was 34 years, median duration of subfertility was 21 months. Couples allocated to EM had a lower live birth rate than couples allocated to IUI-OS (12/92 (13%) in the EM group versus 28/86 (33%) in the IUI-OS group; RR 0.40 90% CI 0.24 to 0.67). This corresponds to an absolute RD of minus 20%; 90% CI: -30% to -9%. The hazard ratio for live birth over time was 0.36 (95% CI 0.18 to 0.70). In the PP analysis, live births rates were 8 of 70 women (11%) in the EM group versus 26 of 73 women (36%) in the IUI-OS group (RR 0.32, 90% CI 0.18 to 0.59; RD -24%, 90% CI -36% to -13%) in line with inferiority of EM.Limitations, Reasons For Caution: Our trial did not reach the planned sample size, therefore the results are limited by the number of participants.Wider Implications Of the Findings: This study confirms the results of a previous trial that in couples with unexplained subfertility and a poor prognosis for natural conception, EM is inferior to IUI-OS.Study Funding/competing Interest(s): The trial was supported by a grant of the SEENEZ healthcare initiative. The subsidizing parties were The Dutch Organisation for Health Research and Development (ZonMW 837004023, www.zonmw.nl) and the umbrella organization of 10 health insurers in The Netherlands. E.R.G. receives personal fees from Titus Health care outside the submitted work. M.G. declares unrestricted research and educational grants from Guerbet, Merck and Ferring not related to the presented work, paid to their institution VU medical centre. A.B.H. reports receiving travel and speakers fees from Nordic Pharma and Merck and he is member of the Nordic Pharma ANGEL group and of the Safety Monitoring Board of Womed. C.B.L. reports speakers fee from Inmed and Yingming, and his department receives research grants from Ferring, Merck and Guerbet paid to VU medical centre. B.W.J.M. is supported by a NHMRC Investigator grant (GNT1176437) and reports consultancy for ObsEva and Merck. M.v.W. received a grant from the Netherlands Organisation for Health Research and Development ZonMW (80-8520098-91072). F.M. received two grants from the Netherlands Organisation for Health Research and Development ZonMW (NTR 5599 and NTR 6590). The other authors report no competing interest.Trial Registration Number: Dutch Trial register NL5455 (NTR5599).Trial Registration Date: 18 December 2015.Date Of First Patient’s Enrolment: 26 January 2017. [ABSTRACT FROM AUTHOR]

Objective: This single-blind parallel design randomized controlled trial evaluated the feasibility and effectiveness of a modified version of the Mother-Infant Transaction Program (MITP) in enhancing Chinese mothers' sensitivity towards their premature infants' physiological and social cues.Methods: Sixty mothers of hospitalized premature infants (mean gestational age = 32.1 weeks; SD = 2.8) were randomly assigned to either the MITP group or the treatment-as-usual control group. The intervention group (n = 30) received four sessions of parental sensitivity training adapted from the MITP, delivered by clinical psychologists before the infants were discharged. The control group (n = 30) received standard care provided by the hospitals. Each dyad was assessed at baseline (Time 1), immediately after intervention (Time 2), and when the infants were at the gestation-corrected ages of 3, 6, 9, and 12 months (Times 3-6). Maternal sensitivity, mother-infant interaction quality, parenting stress, postpartum depression, and mother's perception of infant's temperament were measured at Times 1-4, whereas infants' weight gain and developmental performance were assessed at Times 3-6.Results: The MITP group showed significantly higher maternal sensitivity and better mother-infant interaction quality after completing the training. They also reported less parenting stress and postnatal depression than the control group at Time 2 and subsequent follow-ups. The intervention significantly predicted better weight gain and developmental outcomes in infants across Times 3-6, mediated by maternal wellbeing and interaction quality.Conclusion:  Our results demonstrated the feasibility and effectiveness of this adapted sensitivity training among Chinese mothers with premature infants. [ClinicalTrials.gov NCT04383340]. [ABSTRACT FROM AUTHOR]

Objective: To assess the efficacy of interruptive electronic alerts in improving adherence to the American Board of Internal Medicine's Choosing Wisely recommendations to reduce unnecessary laboratory testing.Materials and Methods: We administered 5 cluster randomized controlled trials simultaneously, using electronic medical record alerts regarding prostate-specific antigen (PSA) testing, acute sinusitis treatment, vitamin D testing, carotid artery ultrasound screening, and human papillomavirus testing. For each alert, we assigned 5 outpatient clinics to an interruptive alert and 5 were observed as a control. Primary and secondary outcomes were the number of postalert orders per 100 patients at each clinic and number of triggered alerts divided by orders, respectively. Post hoc analysis evaluated whether physicians experiencing interruptive alerts reduced their alert-triggering behaviors.Results: Median postalert orders per 100 patients did not differ significantly between treatment and control groups; absolute median differences ranging from 0.04 to 0.40 for PSA testing. Median alerts per 100 orders did not differ significantly between treatment and control groups; absolute median differences ranged from 0.004 to 0.03. In post hoc analysis, providers receiving alerts regarding PSA testing in men were significantly less likely to trigger additional PSA alerts than those in the control sites (Incidence Rate Ratio 0.12, 95% CI [0.03-0.52]).Discussion: Interruptive point-of-care alerts did not yield detectable changes in the overall rate of undesired orders or the order-to-alert ratio between active and silent sites. Complementary behavioral or educational interventions are likely needed to improve efforts to curb medical overuse.Conclusion: Implementation of interruptive alerts at the time of ordering was not associated with improved adherence to 5 Choosing Wisely guidelines.Trial Registration: NCT02709772. [ABSTRACT FROM AUTHOR]

Aims To investigate the effectiveness of a 3-year worksite lifestyle intervention on cardiovascular metrics and to study whether outcomes are influenced by baseline subclinical atherosclerosis (SA) by non-invasive imaging. Methods and results A randomized controlled trial was performed to compare a lifestyle intervention with standard of care in asymptomatic middle-aged subjects, stratified by SA. The intervention consisted of nine motivational interviews during the first year, followed by three further sessions between Years 1 and 3. The primary outcome was the change in a pre-specified adaptation of the Fuster-BEWAT score (B lood pressure, E xercise, W eight, A limentation, and T obacco) between baseline and follow-up Years 1–3. A total of 1020 participants (mean age 50 ± 4 years) were enrolled, of whom 510 were randomly assigned to the intervention and 510 to the control group. The baseline adapted Fuster-BEWAT score was 16.2 ± 3.7 points in the intervention group and 16.5 ± 3.5 points in the control group. At Year 1, the score improved significantly in intervention participants compared with controls [estimate 0.83 (95% CI 0.52–1.15) points]. However, intervention effectiveness decreased to non-significant levels at Year 3 [0.24 (95% CI –0.10 to 0.59) points]. Over the 3-year period, the intervention was effective in participants having low baseline SA [0.61 (95% CI 0.30–0.93) points] but not in those with high baseline SA [0.19 (95% CI –0.26 to 0.64) points]. Conclusion In middle-aged asymptomatic adults, a lifestyle intervention was associated with a significant improvement in cardiovascular health and behavioural metrics. The effect attenuated after 1 year as the intensity of the intervention was reduced. Trial registration ClinicalTrials.gov (NCT02561065). [ABSTRACT FROM AUTHOR]

Aims The presence of pulmonary hypertension (PH) severely aggravates the clinical course of heart failure with preserved ejection fraction (HFpEF). To date, neither established heart failure therapies nor pulmonary vasodilators proved beneficial. This study investigated the efficacy of chronic treatment with the oral soluble guanylate cyclase stimulator riociguat in patients with PH-HFpEF. Methods and Results The phase IIb, randomized, double-blind, placebo-controlled, parallel-group, multicentre DYNAMIC trial assessed riociguat in PH-HFpEF. Patients were recruited at five hospitals across Austria and Germany. Key eligibility criteria were mean pulmonary artery pressure ≥25 mmHg, pulmonary arterial wedge pressure >15 mmHg, and left ventricular ejection fraction ≥50%. Patients were randomized to oral treatment with riociguat or placebo (1:1). Patients started at 0.5 mg three times daily (TID) and were up-titrated to 1.5 mg TID. The primary efficacy endpoint was change from baseline to week 26 in cardiac output (CO) at rest, measured by right heart catheterization. Primary efficacy analyses were performed on the full analysis set. Fifty-eight patients received riociguat and 56 patients placebo. After 26 weeks, CO increased by 0.37 ± 1.263 L/min in the riociguat group and decreased by −0.11 ± 0.921 L/min in the placebo group (least-squares mean difference: 0.54 L/min, 95% confidence interval 0.112, 0.971; P  = 0.0142). Five patients dropped out due to riociguat-related adverse events but no riociguat-related serious adverse event or death occurred. Conclusion The vasodilator riociguat improved haemodynamics in PH-HFpEF. Riociguat was safe in most patients but led to more dropouts as compared to placebo and did not change clinical symptoms within the study period. [ABSTRACT FROM AUTHOR]

Current standards for methodological rigor and trial reporting underscore the critical issue of statistical power. Still, the chance of detecting most effects reported in randomized controlled trials in medicine and other disciplines is currently lower than winning a toss of a fair coin. Here we propose that investigators who retain a practical understanding of how statistical power works can proactively avoid the potentially devastating consequences of underpowered trials. We first offer a vivid, carefully constructed analogy that illuminates the underlying relationships among 3 of the 5 essential parameters—namely, statistical power, effect size, and sample size—while holding the remaining 2 parameters constant (type of statistical test and significance level). Second, we extend the analogy to a set of critical scenarios in which investigators commonly miss detecting intervention effects due to insufficient statistical power. Third, we highlight effective pragmatic strategies for the design and conduct of sufficiently powered trials, without increasing sample size. [ABSTRACT FROM AUTHOR]

Objective: Health care expenditures for children with functional constipation (FC) are high, while conservative management is successful in only 50% of the children. The aim is to evaluate whether adding physiotherapy to conventional treatment (CT) is a cost-effective strategy in the management of children with FC aged 4-18 years in primary care.Methods: A cost-effectiveness analysis was performed alongside a randomized controlled trial (RCT) with 8-month follow-up. Costs were assessed from a societal perspective, effectiveness included both the primary outcome (treatment success defined as the absence of FC and no laxative use) and the secondary outcome (absence of FC irrespective of laxative use). Uncertainty was assessed by bootstrapping and cost-effectiveness acceptability curves (CEACs) were displayed.Results: One hundred and thirty-four children were randomized. The incremental cost-effectiveness ratio (ICER) for one additional successfully treated child in the physiotherapy group compared with the CT group was €24,060 (95% confidence interval [CI] €-16,275 to €31,390) and for the secondary outcome €1,221 (95% CI €-12,905 to €10,956). Subgroup analyses showed that for children with chronic laxative use the ICER was €2,134 (95% CI -24,975 to 17,192) and €571 (95% CI 11 to 3,566), respectively. At a value of €1,000, the CEAC showed a probability of 0.53 of cost-effectiveness for the primary outcome, and 0.90 for the secondary outcome.Conclusions: Physiotherapy added to CT as first-line treatment for all children with FC is not cost-effective compared with CT alone. Future studies should consider the cost-effectiveness of physiotherapy added to CT in children with chronic laxative use.Trial Registration: The RCT is registered in the Netherlands Trial Register (NTR4797), on the 8th of September 2014. The first child was enrolled on the 2nd of December 2014. https://www.trialregister.nl/trial/4654. [ABSTRACT FROM AUTHOR]

Objective: We developed a comprehensive, medication-related clinical decision support (CDS) software prototype for use in the operating room. The purpose of this study was to compare the usability of the CDS software to the current standard electronic health record (EHR) medication administration and documentation workflow.Materials and Methods: The primary outcome was the time taken to complete all simulation tasks. Secondary outcomes were the total number of mouse clicks and the total distance traveled on the screen in pixels. Forty participants were randomized and assigned to complete 7 simulation tasks in 1 of 2 groups: (1) the CDS group (n = 20), who completed tasks using the CDS and (2) the Control group (n = 20), who completed tasks using the standard medication workflow with retrospective manual documentation in our anesthesia information management system. Blinding was not possible. We video- and audio-recorded the participants to capture quantitative data (time on task, mouse clicks, and pixels traveled on the screen) and qualitative data (think-aloud verbalization).Results: The CDS group mean total task time (402.2 ± 85.9 s) was less than the Control group (509.8 ± 103.6 s), with a mean difference of 107.6 s (95% confidence interval [CI], 60.5-179.5 s, P < .001). The CDS group used fewer mouse clicks (26.4 ± 4.5 clicks) than the Control group (56.0 ± 15.0 clicks) with a mean difference of 29.6 clicks (95% CI, 23.2-37.6, P < .001). The CDS group had fewer pixels traveled on the computer monitor (59.5 ± 20.0 thousand pixels) than the Control group (109.3 ± 40.8 thousand pixels) with a mean difference of 49.8 thousand pixels (95% CI, 33.0-73.7, P < .001).Conclusions: The perioperative medication-related CDS software prototype substantially outperformed standard EHR workflow by decreasing task time and improving efficiency and quality of care in a simulation setting. [ABSTRACT FROM AUTHOR]

Study Question: Does processing of spermatozoa for IVF with ICSI by a microfluidic sperm separation device improve embryo quality compared with density-gradient centrifugation?Summary Answer: Patients randomized to microfluidic sperm preparation had similar cleavage- and blastocyst-stage embryo quality and clinical and ongoing pregnancy rates to those who underwent standard sperm processing for IVF with ICSI.What Is Known Already: Microfluidic sperm preparation can isolate spermatozoa for clinical use with minimal DNA fragmentation but with unclear impact on clinical outcomes.Study Design, Size, Duration: A prospective randomized controlled trial of 386 patients planning IVF from June 2017 through September 2021 was carried out.Participants/materials, Setting, Methods: One hundred and ninety-two patients were allocated to sperm processing with a microfluidic sperm separation device for ICSI, while 194 patients were allocated to clinical standard density-gradient centrifugation (control) at an academic medical centre.Main Results and the Role Of Chance: In an intention to treat analysis, there were no differences in high-quality cleavage-stage embryo fraction [66.0 (25.8)% control versus 68.0 (30.3) microfluidic sperm preparation, P = 0.541, absolute difference -2.0, 95% CI (-8.5, 4.5)], or high-quality blastocyst fraction [37.4 (25.4) control versus 37.4 (26.2) microfluidic sperm preparation, P = 0.985, absolute difference -0.6 95% CI (-6, 5.9)] between groups. There were no differences in the clinical pregnancy or ongoing pregnancy rates between groups.Limitations, Reasons For Caution: The population studied was inclusive and did not attempt to isolate male factor infertility cases or patients with a history of elevated sperm DNA fragmentation.Wider Implications Of the Findings: Microfluidic sperm separation performs similarly to density-gradient centrifugation in sperm preparation for IVF in an unselected population.Study Funding/competing Interest(s): No external funding to declare. M.P.R. is a member of the Clinical Advisory Board for ZyMōt® Fertility, Inc.Trial Registration Number: NCT03085433.Trial Registration Date: 21 March 2017.Date Of First Patient’s Enrollment: 16 June 2017. [ABSTRACT FROM AUTHOR]

Background Randomized controlled trials (RCTs) have been conducted, stratifying idiopathic immunoglobulin A nephropathy (IgAN) patients based on the laboratory findings [serum creatinine, estimated glomerular filtration rate (eGFR) and daily proteinuria]. In contrast, data from kidney biopsy have been used only for clinical diagnosis. Therefore, IgAN patients with active or chronic renal lesions have been receiving the same therapy in experimental and control arms of randomized clinical trials (RCTs). Methods Our clinical study of IgAN (CLIgAN) is a multicentre, prospective, controlled and open-label RCT based on patients' stratification at the time of their kidney biopsy. We will consider, first, the type of renal lesions, followed by serum creatinine values, eGFR and proteinuria. Primary and secondary endpoints will be monitored. Then, we will determine whether personalized therapy can slow the decline of renal function and delay end-stage kidney disease. Results We will enrol 132 IgAN patients with active renal lesions (66 patients per arm) in the first RCT (ACIgAN). They will receive corticosteroids combined with renin–angiotensin system blockers (RASBs) or only RASBs. A total of 294 IgAN patients with chronic or moderate renal lesions at high or very high risk of chronic kidney disease (147 patients per arm) will be enrolled in the second RCT (CHRONIgAN), in which they will receive dapagliflozin, a sodium–glucose cotransporter 2 inhibitor, combined with RASBs, or RASBs alone. Conclusion Using this approach, we hypothesize that patients could receive personalized therapy based on renal lesions to ensure that the right drug gets to the right patient at the right time. [ABSTRACT FROM AUTHOR]

Purpose: Little is known about the relations between changes in circulating microRNA-122 (miR-122) and liver fat in response to weight-loss interventions. We aimed to investigate the association between miR-122 and changes of hepatic fat content during 18-month diet and physical activity interventions. Methods: The CENTRAL trial is an 18-month randomized, controlled trial among adults with abdominal obesity or dyslipidemia. Subjects were randomly assigned to a low-fat diet or a Mediterranean/low-carbohydrate diet. After 6 months of dietary intervention, each diet group was further randomized into added physical activity groups or no added physical activity groups for the following 12 months of intervention. The current study included 220 participants at baseline and 134 participants with repeated measurements on serum miR-122 and hepatic fat content over 18 months. Results: Serum miR-122 significantly increased from baseline to 18 months, while no difference was observed across the 4 intervention groups. We found a significant association between miR-122 and hepatic fat content at baseline, as per unit increment in log-transformed miR122 was associated with 3.79 higher hepatic fat content (P < 0.001). Furthermore, we found that higher elevations in miR-122 were associated with less reductions in hepatic fat percentage during 18-month interventions (β = 1.56, P = 0.002). We also found a significant interaction between changes in miR-122 and baseline fasting plasma glucose with hepatic fat content changes in 18 months (P interaction = 0.02). Conclusions: Our data indicate that participants with higher elevation in serum miR-122 may benefit less in reduction of hepatic fat content in response to diet and physical activity interventions. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Is oral Vitamin D supplementation able to modify the intrauterine milieu in terms of cytokine/chemokine pattern? SUMMARY ANSWER No significant differences were detected in cytokine and chemokine levels in endometrial secretions between patients undergoing ART with or without Vitamin D supplementation. WHAT IS KNOWN ALREADY Cytokines and chemokines secreted into the intrauterine environment are fundamental for the molecular crosstalk between the endometrium and the preimplantation embryo. Whether Vitamin D can regulate these mediators in the endometrial environment is still unclear. STUDY DESIGN, SIZE, DURATION This study was an analysis of a secondary outcome from the Supplementation of Vitamin D and Reproductive Outcomes—SUNDRO—clinical trial, a multicenter randomized double-blinded trial designed to explore the effects of Vitamin D replacement in women with Vitamin D levels below 30 ng/ml undergoing autologous ART cycles. Uterine fluid samples were collected from both patients supplemented with Vitamin D (n   =   17) and from the placebo group (n = 32). PARTICIPANTS/MATERIALS, SETTING, METHODS Based on cutoff points for Vitamin D insufficiency (20–29.9 ng/ml) or deficiency (<20 ng/ml), 67% of patients in the study were insufficient, and 33% deficient, in Vitamin D, although they were considered together for the analysis. Women received a single dose of 600 000 IU 25-hydroxyvitamin D or placebo from 2 to 12 weeks before oocyte retrieval. Inclusion criteria were female age 18–39 years, with a BMI between 18 and 25 kg/m2. Serum 25-hydroxyvitamin D was assessed at the time of hCG administration. Uterine fluid samples were collected during the secretory phase of the menstrual cycle preceding oocyte retrieval. The quantitative determination of 27 cytokines in endometrial secretion samples was performed by using a multiplex immunoassay. MAIN RESULTS AND THE ROLE OF CHANCE Uterine fluid samples were collected after a median (range) of 21 (12–41) days after the oral Vitamin D supplementation. Both the supplemented and placebo groups had Vitamin D serum levels below 30 ng/ml at baseline/time of randomization ((median 23.4 ng/ml (interquartile range 19.5–28.4) and 23.4 ng/ml (17.8–25.9), respectively). At the time of hCG administration, serum Vitamin D in supplemented subjects was significantly raised compared to the placebo group ((median 52.9 ng/ml (interquartile range 40.7–64.1) and 24.6 ng/ml (19.3–29.2), respectively, P  < 0.001). Our data revealed no significant differences in uterine fluid cytokine/chemokine composition of Vitamin D-supplemented women compared with the placebo group. This finding remained when the concentrations of all mediators studied were normalized to total protein. In a further analysis, no significant differences were found in the content of cytokines/chemokines in uterine fluid from women who conceived (n   =   19) compared with the nonpregnant group (n   =   30). LIMITATIONS, REASONS FOR CAUTION Using a randomized study design (a single dose of 600 000 IU 25-hydroxyvitamin D versus placebo), we found no significant differences between groups. However, we cannot exclude that any benefit of Vitamin D supplementation may be specific for some subgroups of patients, such as those with an imbalance of T-helper 1 and T-helper 2 cell populations. The uterine secretions were collected during the menstrual cycle that preceded oocyte retrieval; therefore, it is possible the uterine fluid collection and analysis in the same cycle of the embryo transfer might have resulted in different conclusions. Moreover, the small sample size could limit the power of the study. WIDER IMPLICATIONS OF THE FINDINGS Our analysis of the uterine secretome profiling failed to show any significant difference in endometrial cytokine/chemokine patterns between women with oral Vitamin D supplementation and the placebo group. Vitamin D may act on the uterine environment through a different mechanism. STUDY FUNDING/COMPETING INTEREST(S) The study was funded by the Italian Ministry of Health following peer review in the competitive 'Bando di Ricerca Finalizzata e Giovani Ricercatori 2013' with reference code RF-2013-02358757. The authors declare that they have no conflict of interest. TRIAL REGISTRATION NUMBER EudraCT registration number: 2015-004233-27. [ABSTRACT FROM AUTHOR]

Intravenous immunoglobulin treatment for chronic inflammatory demyelinating polyneuropathy usually starts with a 2.0 g/kg induction dose followed by 1.0 g/kg maintenance doses every 3 weeks. No dose-ranging studies with intravenous immunoglobulin maintenance therapy have been published. The Progress in Chronic Inflammatory Demyelinating polyneuropathy (ProCID) study was a prospective, double-blind, randomized, parallel-group, multicentre, phase III study investigating the efficacy and safety of 10% liquid intravenous immunoglobulin (Panzyga®) in patients with active chronic inflammatory demyelinating polyneuropathy. Patients were randomized 1:2:1 to receive the standard intravenous immunoglobulin induction dose and then either 0.5, 1.0 or 2.0 g/kg maintenance doses every 3 weeks. The primary end point was the response rate in the 1.0 g/kg group, defined as an improvement ≥1 point in adjusted Inflammatory Neuropathy Cause and Treatment score at Week 6 versus baseline and maintained at Week 24. Secondary end points included dose response and safety. This trial was registered with EudraCT (Number 2015-005443-14) and clinicaltrials.gov (NCT02638207). Between August 2017 and September 2019, the study enrolled 142 patients. All 142 were included in the safety analyses. As no post-infusion data were available for three patients, 139 were included in the efficacy analyses, of whom 121 were previously on corticosteroids. The response rate was 80% (55/69 patients) [95% confidence interval (CI): 69-88%] in the 1.0 g/kg group, 65% (22/34; CI: 48-79%) in the 0.5 g/kg group, and 92% (33/36; CI: 78-97%) in the 2.0 g/kg group. While the proportion of responders was higher with higher maintenance doses, logistic regression analysis showed that the effect on response rate was driven by a significant difference between the 0.5 and 2.0 g/kg groups, whereas the response rates in the 0.5 and 2.0 g/kg groups did not differ significantly from the 1.0 g/kg group. Fifty-six per cent of all patients had an adjusted Inflammatory Neuropathy Cause and Treatment score improvement 3 weeks after the induction dose alone. Treatment-related adverse events were reported in 16 (45.7%), 32 (46.4%) and 20 (52.6%) patients in the 0.5, 1.0 and 2.0 g/kg dose groups, respectively. The most common adverse reaction was headache. There were no treatment-related deaths. Intravenous immunoglobulin (1.0 g/kg) was efficacious and well tolerated as maintenance treatment for patients with chronic inflammatory demyelinating polyneuropathy. Further studies of different maintenance doses of intravenous immunoglobulin in chronic inflammatory demyelinating polyneuropathy are warranted. [ABSTRACT FROM AUTHOR]

Objective To estimate the extent of and the reasons for ineligibility in randomized controlled trials (RCTs) of SSc patients included in the EUSTAR database, and to determine the association between patient's features and generalizability of study results. Methods We searched Clinicaltrials.gov for all records on interventional SSc-RCTs registered from January 2013 to January 2018. Two reviewers selected studies, and information on the main trial features were retrieved. Data from 8046 patients having a visit in the EUSTAR database since 2013 were used to check patient's eligibility. The proportion of potentially eligible patients per trial, and the risk factors for ineligibility were analysed. Complete-, worst- and best-case analyses were performed. Results Of the 37 RCTs included, 43% were conducted in Europe, 35% were industry-funded, and 87% investigated pharmacological treatments. Ninety-one percent of 8046 patients included could have participated in at least one RCT. In complete-case analysis, the median [range] proportion of eligible patients having the main organ complication targeted by each study was 60% [10–100] in the overall sample of trials, ranging from 50% [32–79] for trials on skin fibrosis to 90% [34–77] for those targeting RP. Among the criteria checked, treatment- and safety-related but not demographic were the main barriers to patient's recruitment. Older age, absence of RP, and lower mRSS were independently associated with the failure to fulfill criteria for any of the included studies. Conclusions Patient's representativeness in SSc-RCTs is highly variable and is driven more by treatment- and safety-related rather than demographic criteria. [ABSTRACT FROM AUTHOR]

Background China has the biggest stroke burden in the world. Continued measures have been taken to enhance post-stroke rehabilitation management in the last two decades. The weak link is with home-based rehabilitation, with more attention and resources devoted to inpatient rehabilitation. Objective to address the service gap, this study tested a home-based transitional care model for stroke survivors. Methods a randomized controlled trial was conducted from February 2019 to May 2020 in Harbin, China, involving 116 patients with ischemic stroke. The intervention group participants (n  = 58, 50%) received a 12-week home-based care program with components of transitional care measures and the national guidelines for facilitating patients to perform home-based exercises with continued monitoring and gradual progression. Control group participants received standard care including medication advice, rehabilitation exercise and one nurse-initiated follow-up call. Data were collected at baseline and after a 90-day (post-intervention) and a 180-day (post-intervention) follow-up. The primary outcome was quality of life (QOL), measured using the EuroQol-Five Dimension 5-Level scale (EQ-5D-5L). Results both intervention and control groups showed improvement in EQ-5D-5L from baseline to post-intervention (0.66 versus 0.83, P  < 0.001) and (0.66 versus 0.77, P  < 0.001), respectively, and there was significant group-by-time interaction in EuroQol-Visual Analogue Scale from baseline to post-intervention at 90 days and follow-up at 180 days with the intervention group experiencing better improvement. Similarly, significant interaction effects were also found in the Stroke Impact Symptom scale, self-efficacy and modified Barthel Index. Conclusions home-based transitional care was effective in improving QOL, symptoms, self-efficacy and activities of daily living. [ABSTRACT FROM AUTHOR]

Study Question: Does in vitro maturation (IVM) result in non-inferior cumulative live birth rates compared to those after standard in vitro fertilization (IVF) in infertile women with polycystic ovary syndrome (PCOS)?Summary Answer: One cycle of IVM, without any stimulation, was inferior to one cycle of standard IVF in women with PCOS in terms of 6-month cumulative live birth rates, when choosing single vitrified-warmed blastocyst transfer.What Is Known Already: IVM is an emerging alternative treatment for women with PCOS who need assisted reproductive technology. Since a minimal or even zero dose of gonadotropins are required in the IVM procedure, the occurrence of ovarian hyperstimulation syndrome (OHSS) is eliminated. Only one clinical trial comparing the pregnancy outcome between IVM with FSH priming and IVF has been reported. However, it is still unknown whether IVM treatment without any stimulation can offer a similar live birth outcome in women with PCOS as compared to that in women receiving the standard IVF procedure with ovarian stimulation.Study Design, Size, Duration: This single-centre, open-label randomized controlled non-inferiority trial in an academic infertility centre in China was performed between March 2018 and July 2019.Participants/materials, Setting, Methods: Women aged 20-38 years with PCOS and infertility scheduled for their first IVF attempt were eligible. In total, 351 women were randomly allocated to receive one cycle of unstimulated IVM (n = 175) or one cycle of standard IVF with a flexible GnRH antagonist protocol and hCG as ovulatory trigger (n = 176). A freeze-all and single blastocyst transfer strategy was used in both groups. The primary outcome was ongoing pregnancy (leading to live birth) within 6 months after randomization. A non-inferiority margin of 15% was considered.Main Results and the Role Of Chance: The IVM procedure without additional gonadotropin resulted in a lower ongoing pregnancy (leading to live birth) within 6 months after randomization compared to standard IVF treatment (22.3% vs. 50.6%; rate difference -28.3%; 95% confidence interval [CI]: -37.9% to -18.7%). Moderate-severe OHSS did not occur in the IVM group, while in the IVF group, ten women (5.7%) had moderate OHSS and one woman (0.6%) had severe OHSS. There was no statistically significant difference in the occurrence of obstetric and perinatal complications.Limitations, Reasons For Caution: The trial was conducted using an IVM protocol without additional stimulation in a single centre, which may limit its generalizability. In addition, a GnRH agonist trigger rather than hCG for IVF stimulation in women with PCOS would be more consistent with current clinical practice.Wider Implications Of the Findings: Although IVM is considered to be a convenient, inexpensive and safe alternative to IVF for women with PCOS, our results indicated that one cycle of IVM without any stimulation was inferior to one cycle of standard IVF in terms of the cumulative live birth rate. The inferiority of IVM without ovarian stimulation could be mainly due to the limitations in the developmental potential of embryos. Further IVM development should be tested and validated in a freeze-only and blastocyst transfer setting. Further RCTs are needed to evaluate the effectiveness and safety of other IVM protocols or multiple cycles of IVM compared to IVF.Study Funding/competing Interest(s): This study was supported by the National Key Research and Development Program of China (2016YFC1000201 and 2018YFC1002104) and the National Science Foundation of China (81730038). B.W.M. is supported by a NHMRC Investigator grant (GNT1176437). All other authors declare no competing interests.Trial Registration Number: Clinicaltrials.gov NCT03463772.Trial Registration Date: 29 January 2018.Date Of First Patient’s Enrolment: 16 March 2018. [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]

Objectives: Multicomponent interventions reduce falls among community‐dwelling older adults. However, whether this strategy helps reduce occupational falls among older workers is unclear. This pilot trial tested the safety, adherence, and potential effectiveness of a multicomponent intervention for older workers. Methods: An assessor‐blind, parallel‐designed randomized controlled trial was conducted in five public employment agencies for seniors in Saitama, Japan. In total, 69 older adults who worked ≥4 days/month were randomly assigned to the intervention (n = 35) or control (n = 34) groups. The intervention group was provided a multicomponent intervention consisting of exercise, nutrition, and psychosocial programs once a week for 8 weeks. Safety was evaluated for all adverse events reported by participants. Adherence was assessed by rates for withdrawal/dropout, exercise practice, and nutritional diary completion. The primary outcome was a change in functional strength related to occupational falls. Secondary outcomes included changes in agility, balance, executive function, visuospatial ability, exercise self‐efficiency, dietary variety, social network, and functional capacity. Results: No adverse events were reported by participants. The median withdrawal/dropout, exercise practice, and nutritional diary completion rates were 0%, 80.4%–93.7%, and 100%, respectively. In the adjusted general linear model, the intervention group showed a non‐significant but clinically important improvement in functional strength (P value:.081, Cohen's d: 0.57) and significant improvements in agility, balance, and dietary variety compared to the control group. Conclusions: A multicomponent intervention for older workers would be a safe, acceptable, and effective strategy for improving risk factors for occupational falls. [ABSTRACT FROM AUTHOR]

Objectives: To assess the effectiveness of a web‐based brief intervention (BI) program to record daily drinking among people with problem drinking in workplace settings. Methods: A two‐armed, parallel‐group, randomized controlled trial were conducted at six workplaces in Japan. After obtaining written consent to participate in the study, workers with an Alcohol Use Disorders Identification Test (AUDIT) score of 8 or higher were randomly assigned into two groups. The participants allocated to the intervention group recorded their daily alcohol consumption for 4 weeks using the program, while those allocated to the control group received no intervention. Outcome measures included the amount of alcohol consumption in past 7 days using the Timeline Follow‐Back method in the program at baseline, 8th week, and 12th week and written AUDIT score at baseline and 12th week. Results: Hundred participants were assigned to either the intervention group (n = 50) or control group (n = 50). The results of two‐way repeated measures ANOVA showed a statistically significant interaction between the group and the week factors in the two primary outcomes (number of alcohol‐free days, total drinks) and secondary outcomes (AUDIT score) (p =.04,.02, and.03, respectively). The between‐group effect sizes (Hedges' g; 95% CI) of the outcomes at 12th week were 0.53; 0.13–0.93 (total drinks), 0.44; 0.04–0.84 (AUDIT score), 0.43; 0.03–0.83 (number of alcohol‐free days). Conclusions: The web‐based BI program for problem drinking was considered to be effective in reducing alcohol consumption and the AUDIT score in workplace settings. [ABSTRACT FROM AUTHOR]