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The article presents reporting the results of a clinical trial across multiple papers. Topics discussed include the trial was prospectively registered on the clinicaltrials.gov registry and the protocol published in BMC public health; and according to the trial registry entry, the primary outcome was ‘Mediterranean diet compliance' which is discrepant with the protocol where the authors state the ‘first objective of the study is increase physical activity.

Journal Activities and Accomplishments In order to make comparisons to prior editorial terms, I summarize data concerning the submissions and papers published during my editorial term, and when possible, have included comparison data from the last editor ([9]). Journal of Pediatric Psychology (JPP), 2008-2012: Editor's Vale Dictum. Journal of Pediatric Psychology (JPP), 1998-2002: Editor's Vale Dictum. Journal of Pediatric Psychology (JPP), 2003-2007: Editor's Vale Dictum. [Extracted from the article]

Background Few studies have assessed participant safety in human challenge trials (HCTs). Key questions regarding HCTs include how risky such trials have been, how often adverse events (AEs) and serious adverse events (SAEs) occur, and whether risk mitigation measures have been effective. Methods A systematic search of PubMed and PubMed Central for articles reporting on results of HCTs published between 1980 and 2021 was performed and completed by 7 October 2021. Results Of 2838 articles screened, 276 were reviewed in full. A total of 15 046 challenged participants were described in 308 studies that met inclusion criteria; 286 (92.9%) of these studies reported mitigation measures used to minimize risk to the challenge population. Among 187 studies that reported on SAEs, 0.2% of participants experienced at least 1 challenge-related SAE. Among 94 studies that graded AEs by severity, challenge-related AEs graded "severe" were reported by between 5.6% and 15.8% of participants. AE data were provided as a range to account for unclear reporting. Eighty percent of studies published after 2010 were registered in a trials database. Conclusions HCTs are increasingly common and used for an expanding list of diseases. Although AEs occur, severe AEs and SAEs are rare. Reporting has improved over time, though not all papers provide a comprehensive report of relevant health impacts. We found very few severe symptoms or SAEs in studies that reported them, but many HCTs did not report relevant safety data. This study was preregistered on PROSPERO as CRD42021247218. [ABSTRACT FROM AUTHOR]

We read with interest the paper by Koda I et al i .[1] entitled 'Randomized trial of granulocyte colony-stimulating factor for spinal cord injury'. However, the manner in which the results are presented - and I post hoc i subgroup analyses performed - would suggest that the mixed-effect model described in the protocol was not used. Study participants, who were in the acute phase of their spinal cord injury, enrolled in the trial in the hope that, in the future, others who sustain a spinal cord injury would have improved outcomes. [Extracted from the article]

Summary: Background: The Harmonising Outcome Measures for Eczema (HOME) initiative has established a core outcome set of domains for atopic eczema (AE) clinical trials. Previous consensus meetings have agreed on preferred instruments for clinician‐reported signs (Eczema Area and Severity Index, EASI) and patient‐reported symptoms (Patient‐Oriented Eczema Measure, POEM). This paper reports consensus decisions from the HOME VII meeting. Objectives: To complete the core outcome set for AE by agreeing on core outcome instruments for the domains of quality of life (QoL), long‐term control and itch intensity. Methods: A face‐to‐face consensus meeting was held in Tokyo, Japan (8–10 April 2019) including 75 participants (49 healthcare professionals/methodologists, 14 patients, 12 industry representatives) from 16 countries. Consensus decisions were made by presentations of evidence, followed by whole and small group discussions and anonymous voting using predefined consensus rules. Results: It was agreed by consensus that QoL should be measured using the Dermatology Life Quality Index (DLQI) for adults, the Children's Dermatology Life Quality Index (CDLQI) for children and the Infant's Dermatology Quality of Life Index (IDQoL) for infants. For long‐term control, the Recap of Atopic Eczema (RECAP) instrument or the Atopic Dermatitis Control Test (ADCT) should be used. Consensus was not reached over the frequency of data collection for long‐term control. The peak itch numerical rating scale (NRS)‐11 past 24 h was recommended as an additional instrument for the symptom domain in trials of older children and adults. Agreement was reached that all core outcome instruments should be captured at baseline and at the time of primary outcome assessment as a minimum. Conclusions: For now, the core outcome set for clinical trials in AE is complete. The specified domains and instruments should be used in all new clinical trials and systematic reviews of eczema treatments. What is already known about this topic? Core outcomes sets improve the design and reporting of clinical trials, reduce selective outcome reporting bias and facilitate meta‐analysis of results in systematic reviews.The HOME core outcome set for eczema recommends the inclusion of four core domains in all atopic eczema trials: clinician‐reported signs, patient‐reported symptoms, health‐related quality of life (HrQoL) and long‐term control.Clinician‐reported signs should be captured using the Eczema Area and Severity Index (EASI) and patient‐reported symptoms using the Patient‐Oriented Eczema Measure (POEM). What does this study add? The HOME core outcome set is now complete and recommended core outcome instruments have been agreed on for all four domains.Core outcome instruments for HrQoL: Dermatology Life Quality Index (DLQI) for adults, Children's Dermatology Life Quality Index (CDLQI) for children and Infant's Dermatology Quality of Life Index (IDQoL) for infants.Core outcome instruments for long‐term control: either the Recap of Atopic Eczema (RECAP) or the Atopic Dermatitis Control Test (ADCT).In addition, itch intensity should be measured using the peak NRS‐11 past 24 h for trials including older children and adults. What are the clinical implications of this work? If all future trials of eczema treatments include the HOME core outcome instruments, then trial results will be more readily incorporated into meta‐analyses in systematic reviews and clinical care will be informed by the best available evidence. Linked Comment: D.F. Murrell and C.F. Paul. Br J Dermatol 2021; 185:13–14. [ABSTRACT FROM AUTHOR]

Background: Surgical interventions, such as paraoesophageal hernia (POH) repair, are complex with multiple components that require consideration in the reporting of clinical trials. Many aspects of POH repair, including mesh hiatal reinforcement and fundoplication type, are contentious. This review summarizes the reporting of components and outcomes in RCTs of POH repair. Methods: Systematic searches identified RCTs of POH repair published from 1995 to 2020. The patient selection criteria for RCT involvement were noted. The components of the surgical interventions in these RCTs were recorded using the CONSORT guidelines for non-pharmacological treatments, Template for Intervention Description and Replication (TIDieR) and Blencowe frameworks. The outcomes were summarized and definitions sought for critical variables, including recurrence. Results: Of 1918 abstracts and 21 screened full-text articles, 12 full papers reporting on six RCTs were included in the review. The patient selection criteria and definitions of POH between trials varied considerably. Although some description of trial interventions was provided in all RCTs, this varied in depth and detail. Four RCTs described efforts to standardize the trial intervention. Outcomes were reported inconsistently, were rarely defined fully, and overall trial conclusions varied during follow-up. Conclusion: This lack of detail on the surgical intervention in POH repair RCTs prevents full understanding of what exact procedure was evaluated and how it should be delivered in clinical practice to gain the desired treatment effects. Improved focus on the definitions, descriptions and reporting of surgical interventions in POH repair is required for better future RCTs. [ABSTRACT FROM AUTHOR]

Barrett's esophagus (BE) is the main pathological precursor of esophageal adenocarcinoma (EAC). Progression to high-grade dysplasia (HGD) or EAC from nondysplastic BE (NDBE), low-grade dysplasia (LGD) and indefinite for dysplasia (IND) varies widely between population-based studies and specialized centers for many reasons, principally the rigor of the biopsy protocol and the accuracy of pathologic definition. In the Republic of Ireland, a multicenter prospective registry and bioresource (RIBBON) was established in 2011 involving six academic medical centers, and this paper represents the first report from this network. A detailed clinical, endoscopic and pathologic database registered 3,557 patients. BE was defined strictly by both endoscopic evidence of Barrett's epithelium and the presence of specialized intestinal metaplasia (SIM). A prospective web-based database was used to gather information with initial and follow-up data abstracted by a data manager at each site. A total of 2,244 patients, 1,925 with no dysplasia, were included with complete follow-up. The median age at diagnosis was 60.5 with a 2.1:1 male to female ratio and a median follow-up time of 2.7 years (IQR 1.19–4.04), and 6609.25 person years. In this time period, 125 (5.57%) progressed to HGD/EAC, with 74 (3.3%) after 1 year of follow-up and 38 (1.69%) developed EAC, with 20 (0.89%) beyond 1 year. The overall incidence of HGD/EAC was 1.89% per year; 1.16% if the first year is excluded. The risk of progression to EAC alone overall was 0.57% per year, 0.31% excluding the first year, and 0.21% in the 1,925 patients who had SIM alone at diagnosis. Low-grade dysplasia (LGD) progressed to HGD/EAC in 31% of patients, a progression rate of 12.96% per year, 6.71% with the first year excluded. In a national collaboration of academic centers in Ireland, the progression rate for NDBE was similar to recent population studies. Almost one in two who progressed was evident within 1 year. Crucially, LGD diagnosed and confirmed by specialist gastrointestinal pathologists represents truly high-risk disease, highlighting the importance of expertise in diagnosis and management, and providing indirect support for ablative therapies in this context. [ABSTRACT FROM AUTHOR]

In this paper, we propose a Bayesian design framework for a biosimilars clinical program that entails conducting concurrent trials in multiple therapeutic indications to establish equivalent efficacy for a proposed biologic compared to a reference biologic in each indication to support approval of the proposed biologic as a biosimilar. Our method facilitates information borrowing across indications through the use of a multivariate normal correlated parameter prior (CPP), which is constructed from easily interpretable hyperparameters that represent direct statements about the equivalence hypotheses to be tested. The CPP accommodates different endpoints and data types across indications (eg, binary and continuous) and can, therefore, be used in a wide context of models without having to modify the data (eg, rescaling) to provide reasonable information‐borrowing properties. We illustrate how one can evaluate the design using Bayesian versions of the type I error rate and power with the objective of determining the sample size required for each indication such that the design has high power to demonstrate equivalent efficacy in each indication, reasonably high power to demonstrate equivalent efficacy simultaneously in all indications (ie, globally), and reasonable type I error control from a Bayesian perspective. We illustrate the method with several examples, including designing biosimilars trials for follicular lymphoma and rheumatoid arthritis using binary and continuous endpoints, respectively. [ABSTRACT FROM AUTHOR]

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Objective: to assess the proportion of registered randomised controlled trials in five core clinical geriatric journals and to analyse whether registered study outcomes correspond with published outcomes.Design: survey of original papers published 2008 to 2012.Methods: two independent reviewers retrieved the sample through search in the web-based archives of Age and Ageing, the Journal of the American Geriatric Society, the American Journal of Geriatric Psychiatry, the Journal of the American Medical Directors Association and International Psychogeriatrics. Data extraction was performed by two independent reviewers using a pre-tested 13-item checklist. Registration status was checked and information provided in registers compared with information presented in the original publication. A third reviewer was consulted if no consensus could be reached.Results: the sample comprised 220 original publications on randomised controlled trials. A total of 140 (63.6%) were registered. Registration was in accordance with the ICMJE requirements in 54 out of 140 registered trials (38.6%). Less than one-third of registered papers (n = 40) reported on all study outcomes listed in the study register. In 74 out of the 80 non-registered trials, the missing registration was not declared in the publication. There was no consistent upward trend towards higher registration compliance throughout journals and years.Conclusion: our survey shows that prospective trial registration and compliance between outcomes declared in the registry and reported in the publication is poor. Concerted action of authors, editors and peer-reviewers is overdue aimed to irreversibly implement the imperative of registration of randomised controlled trials and complete outcome reporting. [ABSTRACT FROM AUTHOR]

Background Coronary microvascular dysfunction (CMD) could be a potential underlying mechanism for myocardial disease in HIV. Methods Comparisons of coronary flow reserve corrected for heart rate-blood pressure product (CFRCOR) were made among people with HIV (PWH) with no known history of cardiovascular disease (CVD) or diabetes mellitus, persons without HIV (PWOH), and persons with diabetes (PWDM) and no known history of CVD or HIV. Results PWH (n = 39, 74% male, age 55 [7] years, body mass index [BMI] 32.3 (26.8-34.9) kg/m2, duration of antiretroviral therapy 13 [5] years, CD4+ count 754 [598-961] cells/μL) were similar to PWOH (n = 69, 74% male, age 55 [8] years, BMI 32.2[25.6-36.5] kg/m2) and PWDM (n = 63, 63% male, age 55 [8] years, BMI 31.5 [28.6-35.6] kg/m2). CFRCOR was different among groups: PWOH 2.76 (2.37-3.36), PWH 2.47 (1.92-2.93), and PWDM 2.31 (1.98-2.84); overall P =.003. CFRCOR was reduced comparing PWH to PWOH (P =.04) and PWDM to PWOH (P =.007) but did not differ when comparing PWH to PWDM (P =.98). A total 31% of PWH had CFRCOR < 2.0, a critical cutoff for CMD, compared to 14% of PWOH and 27% with PWDM. A total 40% of women with HIV had a CFRCOR < 2.0 compared to 6% of women without HIV (P =.02). Conclusions Subclinical CMD is present among chronically infected and well-treated, asymptomatic PWH who are immunologically controlled. This study demonstrates CFR is reduced in PWH compared to PWOH and comparable to PWDM, further highlighting that well-treated HIV infection is a CVD-risk enhancing factor for CMD similar to diabetes. Clinical Trials Registration: NCT02740179 [ABSTRACT FROM AUTHOR]

Background More than half of childhood tuberculosis cases remain undiagnosed yearly. The World Health Organization recommends the Xpert-Ultra assay as a first pediatric diagnosis test, but microbiological confirmation remains low. We aimed to determine the diagnostic performance of Xpert-Ultra with stool and urine samples in presumptive pediatric tuberculosis cases in 2 high-tuberculosis-burden settings. Methods This Médecins Sans Frontières cross-sectional multicentric study took place at Simão Mendes Hospital, Guinea-Bissau (July 2019 to April 2020) and in Malakal Hospital, South Sudan (April 2021 to June 2023). Children aged 6 months to 15 years with presumptive tuberculosis underwent clinical and laboratory assessment, with 1 respiratory and/or extrapulmonary sample (reference standard [RS]), 1 stool, and 1 urine specimen analyzed with Xpert-Ultra. Results A total of 563 children were enrolled in the study, 133 from Bissau and 400 from Malakal; 30 were excluded. Confirmation of tuberculosis was achieved in 75 (14.1%), while 248 (46.5%) had unconfirmed tuberculosis. Of 553 with an RS specimen, the overall diagnostic yield was 12.4% (66 of 533). A total of 493 stool and 524 urine samples were used to evaluate the performance of Xpert-Ultra with these samples. Compared with the RS, the sensitivity and specificity of Xpert-Ultra were 62.5% (95% confidence interval, 49.4%–74%) and 98.3% (96.7%–99.2%), respectively, with stool samples, and 13.9% (7.5%–24.3%) and 99.4% (98.1%–99.8%) with urine samples. Nine patients were positive with stool and/or urine samples but negative with the RS. Conclusions Xpert-Ultra in stool samples showed moderate to high sensitivity and high specificity compared with the RS and an added diagnostic yield when RS results were negative. Xpert-Ultra in stool samples was useful in extrapulmonary cases. Xpert-Ultra in urine samples showed low test performance. Clinical Trials Registration NCT06239337 [ABSTRACT FROM AUTHOR]

Background Observing medication ingestion through self-recorded videos (video directly observed therapy [VDOT]) has been shown to be a cost-effective alternative to in-person directly observed therapy (DOT) for monitoring adherence to treatment for tuberculosis disease. VDOT could be a useful tool to monitor short-course latent tuberculosis infection (LTBI) treatment. Methods We conducted a prospective randomized controlled trial comparing VDOT (intervention) and clinic-based DOT (control) among patients newly diagnosed with LTBI who agreed to a once-weekly 3-month treatment regimen of isoniazid and rifapentine. Study outcomes were treatment completion and patient satisfaction. We also assessed costs. Pre- and posttreatment interviews were conducted. Results Between March 2016 and December 2019, 130 participants were assigned to VDOT (n = 68) or DOT (n = 62). Treatment completion (73.5% vs 69.4%, P =.70) and satisfaction with treatment monitoring (92.1% vs 86.7%, P =.39) were slightly higher in the intervention group than the control group, but neither was statistically significant. VDOT cost less per patient (median, $230; range, $182−$393) vs DOT (median, $312; range, $246−$592) if participants used their own smartphone. Conclusions While both groups reported high treatment satisfaction, VDOT was not associated with higher LTBI treatment completion. However, VDOT cost less than DOT. Volunteer bias might have reduced the observed effect since patients opposed to any treatment monitoring could have opted for alternative unobserved regimens. Given similar outcomes and lower cost, VDOT may be useful for treatment monitoring when in-person observation is prohibited or unavailable (eg, during a respiratory disease outbreak). The trial was registered at the National Institutes of Health (ClinicalTrials.gov NTC02641106). Clinical Trials Registration ClinicalTrials.gov NTC02641106; registered 24 October 2016. [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]

Background Incidence data of respiratory syncytial virus–associated lower respiratory tract illness (RSV-LRTI) are sparse in low- and middle-income countries (LMICs). We estimated RSV-LRTI incidence rates (IRs) in infants in LMICs using World Health Organization case definitions. Methods This prospective cohort study, conducted in 10 LMICs from May 2019 to October 2021 (largely overlapping with the coronavirus disease 2019 [COVID-19] pandemic), followed infants born to women with low-risk pregnancies for 1 year from birth using active and passive surveillance to detect potential LRTIs, and quantitative reverse-transcription polymerase chain reaction on nasal swabs to detect RSV. Results Among 2094 infants, 32 (1.5%) experienced an RSV-LRTI (8 during their first 6 months of life, 24 thereafter). Seventeen (0.8%) infants had severe RSV-LRTI and 168 (8.0%) had all-cause LRTI. IRs (95% confidence intervals [CIs]) of first RSV-LRTI episode were 1.0 (.3–2.3), 0.8 (.3–1.5), and 1.6 (1.1–2.2) per 100 person-years for infants aged 0–2, 0–5, and 0–11 months, respectively. IRs (95% CIs) of the first all-cause LRTI episode were 10.7 (8.1–14.0), 11.7 (9.6–14.0), and 8.7 (7.5–10.2) per 100 person-years, respectively. IRs varied by country (RSV-LRTI: 0.0–8.3, all-cause LRTI: 0.0–49.6 per 100 person-years for 0- to 11-month-olds). Conclusions RSV-LRTI IRs in infants in this study were relatively low, likely due to reduced viral circulation caused by COVID-19–related nonpharmaceutical interventions. Clinical Trials Registration NCT03614676. [ABSTRACT FROM AUTHOR]

Publication bias is a major concern in conducting systematic reviews and meta‐analyses. Various sensitivity analysis or bias‐correction methods have been developed based on selection models, and they have some advantages over the widely used trim‐and‐fill bias‐correction method. However, likelihood methods based on selection models may have difficulty in obtaining precise estimates and reasonable confidence intervals, or require a rather complicated sensitivity analysis process. Herein, we develop a simple publication bias adjustment method by utilizing the information on conducted but still unpublished trials from clinical trial registries. We introduce an estimating equation for parameter estimation in the selection function by regarding the publication bias issue as a missing data problem under the missing not at random assumption. With the estimated selection function, we introduce the inverse probability weighting (IPW) method to estimate the overall mean across studies. Furthermore, the IPW versions of heterogeneity measures such as the between‐study variance and the I2 measure are proposed. We propose methods to construct confidence intervals based on asymptotic normal approximation as well as on parametric bootstrap. Through numerical experiments, we observed that the estimators successfully eliminated bias, and the confidence intervals had empirical coverage probabilities close to the nominal level. On the other hand, the confidence interval based on asymptotic normal approximation is much wider in some scenarios than the bootstrap confidence interval. Therefore, the latter is recommended for practical use. [ABSTRACT FROM AUTHOR]

Background Time to symptom resolution measures were used in outpatient coronavirus disease 2019 (COVID-19) treatment trials without prior validation. Methods ACTIV-2/A5401 trial participants completed a COVID-19 diary assessing 13 targeted symptoms and global experience (overall COVID-19 symptoms, return to pre–COVID-19 health) daily for 29 days. We evaluated concordance of time to sustained (2 days) resolution of all targeted symptoms (TSR) with resolution of overall symptoms and return to health in participants receiving placebo. Results The analysis included 77 high-risk and 81 standard-risk participants with overall median 6 days of symptoms at entry and median age 47 years, 50% female, 82% white, and 31% Hispanic/Latino. Correlation between TSR and resolution of overall symptoms was 0.80 and 0.68, and TSR and return to health, 0.66 and 0.57 for high- and standard-risk groups, respectively. Of the high- and standard-risk participants, 61% and 79%, respectively, achieved targeted symptom resolution, of which 47% and 43%, respectively, reported symptom recurrence. Requiring >2 days to define sustained resolution reduced the frequency of recurrences. Conclusions There was good internal consistency between TSR and COVID-19–specific global outcomes, supporting TSR as a trial end point. Requiring >2 days of symptom resolution better addresses natural symptom fluctuations but must be balanced against the potential influence of non-COVID-19 symptoms. Clinical Trials Registration NCT04518410. [ABSTRACT FROM AUTHOR]

Clinical Trials Registration ClinicalTrials.gov Identifier: NCT04518410. [ABSTRACT FROM AUTHOR]

Peripherally inserted central catheter (PICC) and umbilical venous catheter (UVC) in terms of success rate, complications, cost and time of insertion in neonatal intensive care were compared. Neonates requiring vascular access for minimum 7 days were included. Sample size of 72 per group was determined. Trial was registered at Clinical Trials Registry of India (CTRI/2015/02/005529). Success rates of the UVC and PICC were 68.1% and 65.3%, respectively (p = 0.724). Mean (SD) time needed for PICC and UVC insertion was 34.13 (34.69) and 28.31 (17.19) min, respectively (p = 0.205). Mean (SD) cost of PICC insertion vs. UVC insertion was 60.9 (8.6) vs. 11.9 (8.7) US dollars (p < 0.0001). Commonest cause for failure of UVC was displacement [6 (8.3%)] and that for PICC was blockage [9 (12.5%)].Conclusions: UVC is a cheaper alternative to PICC, with similar success rate, short-term complications and time needed for insertion. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Does exogenous estrogen use affect COVID-19-related mortality in women? SUMMARY ANSWER Menopausal hormone therapy (MHT) was associated with a lower likelihood of all-cause fatality related to COVID-19 in postmenopausal women (odds ratio (OR) 0.28, 95% CI 0.18, 0.44; 4 studies, 21 517 women) but the combined oral contraceptive pill in premenopausal women did not have a significant effect (OR 1.00, 95% CI 0.42–2.41; 2 studies, 5099 women). WHAT IS KNOWN ALREADY Men are much more likely to die from COVID-19 than women. STUDY DESIGN, SIZE, DURATION In this systematic meta-analysis, a literature search was conducted using the following search terms related toCOVID-19 and estrogen, sex hormones, hormonal replacement, menopause, or contraception. The PubMed, Scopus, Cochrane Library, and EMBASE databases were searched to identify relevant studies published between December 2019 and December 2021. We also searched MedRxiv as a preprint database and reviewed the reference lists of all included studies and clinical trial registries for ongoing clinical studies until December 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS All comparative studies that compared the rates mortality and morbidity (hospitalization, intensive care unit (ICU) admission, and ventilation support) due to COVID-19 in women using exogenous estrogen to a control group of women (nonusers) were included. A review of the studies for inclusion, extraction of data, and assessment of the risk of bias was performed independently by two reviewers. The ROBINS-I tool and the RoB 2 tool were used for bias assessment of the included studies. Pooled odds ratios (ORs) with 95% CIs were calculated using Review Manager V5.4.1. The I 2 statistic was used to quantify heterogeneity. The quality of the evidence was assessed using GRADE criteria. MAIN RESULTS AND THE ROLE OF CHANCE After searching the databases, we identified a total of 5310 studies. After removing duplicate records, ineligible studies, and ongoing studies, a total of four cohort studies and one randomized controlled trial comprising 177 809 participants were included in this review. There was a moderate certainty of evidence that MHT was associated with a lower likelihood of all-cause fatality related to COVID-19 (OR 0.28, 95% CI 0.18, 0.44; I 2 = 0%; 4 studies, 21 517 women). The review indicated a low certainty of evidence for other outcomes. The mortality rate of premenopausal women in the combined oral contraceptive pill group did not differ significantly from the control group (OR 1.00, 95% CI 0.42–2.41; 2 studies, 5099 women). MHT marginally increased the rate of hospitalization and ICU admission (OR 1.37, 95% CI 1.18–1.61; 3 studies, 151 485 women), but there was no significant difference in the need for respiratory support between MHT users and nonusers (OR 0.91, 95% CI 0.52–1.59; 3 studies, 151 485 women). Overall, the tendency and magnitude of the effects of MHT in postmenopausal women with COVID-19 were consistent across the included studies. LIMITATIONS, REASONS FOR CAUTION The certainty of the evidence for other outcomes of this review may be limited, as all included studies were cohort studies. In addition, the dosages and durations of exogenous estrogen used by postmenopausal women varied from study to study, and combined progestogen administration may have had some effect on the outcomes. WIDER IMPLICATIONS OF THE FINDINGS The findings of this study can aid in counseling postmenopausal women taking MHT when they are diagnosed with COVID, as they have a lower chance of death than those not taking MHT. STUDY FUNDING/COMPETING INTEREST(s) Khon Kaen University provided financial support for this review and had no involvement at any stage of the study. The authors have no conflicts of interest to declare. REGISTRATION NUMBER PROSPERO, CRD42021271882. [ABSTRACT FROM AUTHOR]

Ordinal endpoints are common in clinical studies. For example, many clinical trials for evaluating COVID-19 infection therapies have adopted an ordinal scale as recommended by the World Health Organization. Despite their importance in clinical studies, design methods for ordinal endpoints are limited; in practice, a dichotomized approach is often used for simplicity. Here, we introduce a Bayesian group sequential scheme to assess ordinal endpoints, which considers a proportional-odds (PO) model, a nonproportional-odds (NPO) model, and a PO/NPO-switch model to handle various scenarios. Extensive simulations are conducted to demonstrate desirable performance, and the R package BayesOrdDesign has been made publicly available. [ABSTRACT FROM AUTHOR]

Background Evidence suggests an association between atopic eczema (AE) or psoriasis and mental illness; however, the factors associated with mental illness are unclear. Objectives To synthesize and evaluate all available evidence on factors associated with depression, anxiety and severe mental illness (SMI) among adults with AE or psoriasis. Methods We searched electronic databases, grey literature databases and clinical trial registries from inception to February 2022 for studies of adults with AE or psoriasis. Eligible studies included randomized controlled trials (RCTs), cohort, cross-sectional or case–control studies where effect estimates of factors associated with depression, anxiety or SMI were reported. We did not apply language or geographical restrictions. We assessed risk of bias using the Quality in Prognosis Studies tool. We synthesized results narratively, and if at least two studies were sufficiently homogeneous, we pooled effect estimates in a random effects meta-analysis. Results We included 21 studies (11 observational, 10 RCTs). No observational studies in AE fulfilled our eligibility criteria. Observational studies in people with psoriasis mostly investigated factors associated with depression or anxiety – one cross-sectional study investigated factors associated with schizophrenia. Pooled effect estimates suggest that female sex and psoriatic arthritis were associated with depression [female sex: odds ratio (OR) 1.62, 95% confidence interval (CI) 1.09–2.40, 95% prediction intervals (PIs) 0.62–4.23, I 2 = 24.90%, τ 2 = 0.05; psoriatic arthritis: OR 2.26, 95% CI 1.56–3.25, 95% PI 0.21–24.23, I 2 = 0.00%, τ 2 = 0.00] and anxiety (female sex: OR 2.59, 95% CI 1.32–5.07, 95% PI 0.00–3956.27, I 2 = 61.90%, τ 2 = 0.22; psoriatic arthritis: OR 1.98, 95% CI 1.33–2.94, I 2 = 0.00%, τ 2 = 0.00). Moderate/severe psoriasis was associated with anxiety (OR 1.14, 95% CI 1.05–1.25, I 2 0.00%, τ 2 = 0.00), but not depression. Evidence from RCTs suggested that adults with AE or psoriasis given placebo had higher depression and anxiety scores compared with comparators given targeted treatment (e.g. biologic agents). Conclusions Our review highlights limited existing research on factors associated with depression, anxiety and SMI in adults with AE or psoriasis. Observational evidence on factors associated with depression or anxiety in people with psoriasis was conflicting or from single studies, but some identified factors were consistent with those in the general population. Evidence on factors associated with SMIs in people with AE or psoriasis was particularly limited. Evidence from RCTs suggested that AE and psoriasis treated with placebo was associated with higher depression and anxiety scores compared with skin disease treated with targeted therapy; however, follow-up was limited. Therefore, long-term effects on mental health are unclear. [ABSTRACT FROM AUTHOR]

Background: Few data exist on early-life metabolic perturbations in newborns with perinatal HIV and antiretroviral (ARV) exposure but uninfected (HEU) compared to those perinatally HIV unexposed and uninfected (HUU).Methods: We enrolled pregnant persons with HIV (PWH) receiving tenofovir (TDF)/emtricitabine or lamivudine (XTC) plus dolutegravir (DTG) or efavirenz (EFV), and pregnant individuals without HIV, as well as their liveborn infants. Newborns were randomized to receive either zidovudine (AZT) or nevirapine (NVP) postnatal prophylaxis. Preprandial homeostasis model assessment for insulin resistance (HOMA-IR) was assessed at birth and 1 month. Linear mixed models were fit to assess the association between in utero HIV/ARV exposure and average HOMA-IR from birth to 1 month, adjusting for confounders.Results: Of 450 newborns, 306 were HEU. HOMA-IR was higher in newborns HEU versus HUU after adjusting for confounders (mean difference of 0.068 in log HOMA-IR, P = .037). Among newborns HEU, HOMA-IR was not significantly different between TDF/XTC/DTG versus TDF/XTC/EFV in utero ARV exposure and between AZT versus NVP newborn postnatal prophylaxis arms.Conclusions: Newborns HEU versus HUU had lower insulin sensitivity at birth and at 1 month of life, raising potential concern for obesity and other metabolic perturbations later in life for newborns HEU.Clinical Trials Registration: NCT03088410. [ABSTRACT FROM AUTHOR]

Background: Genogroup II noroviruses are the most common cause of acute infectious gastroenteritis. We evaluated the use of a new GII.2 inoculum in a human challenge.Methods: Forty-four healthy adults (36 secretor-positive and 8 secretor-negative for histo-blood group antigens) were challenged with ascending doses of a new safety-tested Snow Mountain virus (SMV) GII.2 norovirus inoculum (1.2 × 104 to 1.2 × 107 genome equivalent copies [GEC]; n = 38) or placebo (n = 6). Illness was defined as diarrhea and/or vomiting postchallenge in subjects with evidence of infection (defined as GII.2 norovirus RNA detection in stool and/or anti-SMV immunoglobulin G [IgG] seroconversion).Results: The highest dose was associated with SMV infection in 90%, and illness in 70% of subjects with 10 of 12 secretor-positive (83%) and 4 of 8 secretor-negative (50%) becoming ill. There was no association between prechallenge anti-SMV serum IgG concentration, carbohydrate-binding blockade antibody, or salivary immunoglobulin A and infection. The median infectious dose (ID50) was 5.1 × 105 GEC.Conclusions: High rates of infection and illness were observed in both secretor-positive and secretor-negative subjects in this challenge study. However, a high dose will be required to achieve the target of 75% illness to make this an efficient model for evaluating potential norovirus vaccines and therapeutics.Clinical Trials Registration: NCT02473224. [ABSTRACT FROM AUTHOR]

BACKGROUND Apparent treatment–resistant hypertension (aTRH) is defined as failure to achieve adequate blood pressure (BP) control despite taking ≥3 antihypertensive medications from different categories or when taking ≥4 antihypertensives regardless of BP levels. METHODS In this cross-sectional study, we estimated the prevalence of aTRH in 140 patients receiving long-term peritoneal dialysis (PD) in four centers of Northern Greece, using the "gold-standard" method of ambulatory BP monitoring for the assessment of BP control status. The presence of subclinical overhydration was evaluated with the method of bioimpedance spectroscopy (BIS). RESULTS Incorporating the diagnostic threshold of 130/80 mmHg for 24-hour ambulatory BP, the prevalence of aTRH in the overall study population was 30%. Compared to patients without aTRH, those with aTRH tended to be older in age, had higher PD vintage, had higher dialysate-to-plasma creatinine ratio, had more commonly history of diabetes mellitus, and were more commonly current smokers. With respect to the volume status, the overhydration index in BIS was higher in those with versus without aTRH (2.0 ± 1.9 L vs. 1.1 ± 2.0 L, P  < 0.05). The prevalence of volume overload, defined as an overhydration index in BIS > 2.5 L, was also higher in the subgroup of patients with aTRH (38.1% vs. 18.4, P  = 0.01). CONCLUSION The present study showed that among patients on PD, the prevalence of aTRH was 30%. However, 38% of PD patients with aTRH had subclinical overhydration in BIS, suggesting that the achievement of adequate volume control may be a therapeutic opportunity to improve the management of hypertension in this high-risk patient population. The present study showed that among patients on PD, the prevalence of aTRH was 30%. However, 38% of PD patients with aTRH had subclinical overhydration in BIS, suggesting that the achievement of adequate volume control may be a therapeutic opportunity to improve the management of hypertension in this high-risk patient population. CLINICAL TRIALS REGISTRATION Trial Number NCT03607747 [ABSTRACT FROM AUTHOR]

Background Deaths following Staphylococcus aureus bacteremia (SAB) may be related or unrelated to the infection. In SAB therapeutics research, the length of follow-up should be optimized to capture most attributable deaths and minimize nonattributable deaths. We performed a secondary analysis of a systematic review to describe attributable mortality in SAB over time. Methods We systematically searched Medline, Embase, and Cochrane Database of Systematic Reviews from 1 January 1991 to 7 May 2021 for human observational studies of SAB. To be included in this secondary analysis, the study must have reported attributable mortality. Two reviewers extracted study data and assessed risk of bias independently. Pooling of study estimates was not performed due to heterogeneity in the definition of attributable deaths. Results Twenty-four observational cohort studies were included. The median proportion of all-cause deaths that were attributable to SAB was 77% (interquartile range [IQR], 72%–89%) at 1 month and 62% (IQR, 58%–75%) at 3 months. At 1 year, this proportion was 57% in 1 study. In 2 studies that described the rate of increase in mortality over time, 2-week follow-up captured 68 of 79 (86%) and 48 of 57 (84%) attributable deaths that occurred by 3 months. By comparison, 1-month follow-up captured 54 of 57 (95%) and 56 of 60 (93%) attributable deaths that occurred by 3 months in 2 studies. Conclusions The proportion of deaths that are attributable to SAB decreases as follow-up lengthens. Follow-up duration between 1 and 3 months seems optimal if evaluating processes of care that impact SAB mortality. Clinical Trials Registration PROSPERO CRD42021253891. [ABSTRACT FROM AUTHOR]

Background: We report long-term safety and immunogenicity of Takeda's tetravalent dengue vaccine candidate (TAK-003) in healthy children and adults living in dengue-endemic areas in Puerto Rico, Columbia, Singapore, and Thailand.Methods: In part 1 of this phase 2, randomized, placebo-controlled trial we sequentially enrolled 1.5-45 year olds (n = 148) into 4 age-descending groups, randomized 2:1 to receive 2 doses of TAK-003 or placebo 90 days apart. In part 2, 1-11 year olds (n = 212) were enrolled and randomized 3:1 to TAK-003 or placebo groups. We assessed neutralizing antibody titers for the 4 dengue serotypes (DENV) up to month 36 in part 1, and symptomatic dengue and serious adverse events (SAEs) up to month 36 in both parts.Results: At month 36, seropositivity rates were 97.3%, 98.7%, 88.0% and 56.0% for DENV-1, -2, -3 and -4, respectively. Seropositivity rates varied significantly for DENV-4 according to serostatus at baseline (89.5% in seropositives versus 21.6% in seronegatives). No vaccine-related SAEs were reported.Conclusions: The trial demonstrated persistence of neutralizing antibody titers against TAK-003 over 3 years in children and adults living in dengue-endemic countries, with limited contribution from natural infection. TAK-003 was well tolerated.Clinical Trials Registration: NCT01511250. [ABSTRACT FROM AUTHOR]

Background: Takeda's dengue vaccine is under evaluation in an ongoing phase 3 efficacy study; we present a 2-year update.Methods: Children (20 099, 4-16 years old) were randomized to receive 2 doses of TAK-003 or placebo 3 months apart and are under surveillance to detect dengue by serotype-specific RT-PCR.Results: Cumulative efficacy against dengue approximately 27 months since first dose was 72.7% (95% confidence interval [CI], 67.1%-77.3%), including 67.0% (95% CI, 53.6%-76.5%) in dengue-naive and 89.2% (95% CI, 82.4%-93.3%) against hospitalized dengue. In the second year, decline in efficacy was observed (56.2%; 95% CI, 42.3%-66.8%) with the largest decline in 4-5 year olds (24.5%; 95% CI, -34.2% to 57.5%); efficacy was 60.6% (95% CI, 43.8%-72.4%) in 6-11 year and 71.2% (95% CI, 41.0%-85.9%) in 12-16 year age groups. As TAK-003 efficacy varies by serotype, changes in serotype dominance partially contributed to efficacy differences in year-by-year analysis. No related serious adverse events occurred during the second year.Conclusions: TAK-003 demonstrated continued benefit independent of baseline serostatus in reducing dengue with some decline in efficacy during the second year. Three-year data will be important to see if efficacy stabilizes or declines further.Clinical Trials Registration. NCT02747927.Takeda's tetravalent dengue vaccine (TAK-003) continued to demonstrate benefit in reducing dengue independent of baseline serostatus up to 2 years after completing vaccination with some decline in efficacy during the second year in 4-16 year olds in dengue-endemic countries. [ABSTRACT FROM AUTHOR]

Background: Universal varicella vaccination might reduce opportunities for varicella-zoster virus (VZV) exposure and protective immunological boosting, thus increasing herpes zoster incidence in latently infected adults. We assessed humoral and cell-mediated immunity (CMI), as markers of VZV exposure, in adults aged ≥50 years.Methods: We repurposed data from placebo recipients in a large multinational clinical trial (ZOE-50). Countries were clustered based on their varicella vaccination program characteristics, as having high, moderate, or low VZV circulation. Anti-VZV antibody geometric mean concentrations, median frequencies of VZV-specific CD4 T cells, and percentages of individuals with increases in VZV-specific CD4 T-cell frequencies were compared across countries and clusters. Sensitivity analyses using a variable number of time points and different thresholds were performed for CMI data.Results: VZV-specific humoral immunity from 17 countries (12 high, 2 moderate, 3 low circulation) varied significantly between countries (P < .0001) but not by VZV circulation. No significant differences were identified in VZV-specific CMI between participants from 2 high versus 1 low circulation country. In 3/5 sensitivity analyses, increases in CMI were more frequent in high VZV circulation countries (.03 ≤ P < .05).Conclusions: We found no consistent evidence of reduced VZV exposure among older adults in countries with universal varicella vaccination.Clinical Trials Registration: NCT01165177. [ABSTRACT FROM AUTHOR]

Background: Intermittent preventive treatment of malaria during pregnancy (IPTp) with dihydroartemisinin-piperaquine (DP) provides greater protection from placental malaria than sulfadoxine-pyrimethamine (SP). Some studies suggest placental malaria alters risk of malaria infection in infants, but few have quantified the effect of IPTp on infant susceptibility to malaria.Methods: Infants born to women enrolled in a randomized clinical trial comparing IPTp-SP and IPTp-DP in Malawi were followed from birth to 24 months to assess effect of IPTp and placental malaria on time to first malaria episode and Plasmodium falciparum incidence.Results: In total, 192 infants born to mothers randomized to IPTp-SP and 195 randomized to IPTp-DP were enrolled. Infants in IPTp exposure groups did not differ significantly regarding incidence of clinical malaria (incidence rate ratio [IRR], 1.03; 95% confidence interval [CI], .58-1.86) or incidence of infection (IRR, 1.18; 95% CI, .92-1.55). Placental malaria exposure was not associated with incidence of clinical malaria (IRR, 1.03; 95% CI, .66-1.59) or infection (IRR, 1.15; 95% CI, .88-1.50). Infant sex, season of birth, and maternal gravidity did not confound results.Conclusions: We did not find evidence that IPTp regimen or placental malaria exposure influenced risk of malaria during infancy in this population. Clinical Trials Registration. NCT03009526. [ABSTRACT FROM AUTHOR]

Background: The Ambient Intelligent Geriatric Management (AmbIGeM) system augments best practice and involves a novel wearable sensor (accelerometer and gyroscope) worn by patients where the data captured by the sensor are interpreted by algorithms to trigger alerts on clinician handheld mobile devices when risk movements are detected.Methods: A 3-cluster stepped-wedge pragmatic trial investigating the effect on the primary outcome of falls rate and secondary outcome of injurious fall and proportion of fallers. Three wards across 2 states were included. Patients aged ≥65 years were eligible. Patients requiring palliative care were excluded. The trial was registered with the Australia and New Zealand Clinical Trials registry, number 12617000981325.Results: A total of 4924 older patients were admitted to the study wards with 1076 excluded and 3240 (1995 control, 1245 intervention) enrolled. The median proportion of study duration with valid readings per patient was 49% ((interquartile range [IQR] 25%-67%)). There was no significant difference between intervention and control relating to the falls rate (adjusted rate ratio = 1.41, 95% confidence interval [0.85, 2.34]; p = .192), proportion of fallers (odds ratio = 1.54, 95% confidence interval [0.91, 2.61]; p = .105), and injurious falls rate (adjusted rate ratio = 0.90, 95% confidence interval [0.38, 2.14]; p = .807). In a post hoc analysis, falls and injurious falls rate were reduced in the Geriatric Evaluation and Management Unit wards when the intervention period was compared to the control period.Conclusions: The AmbIGeM system did not reduce the rate of falls, rate of injurious falls, or proportion of fallers. There remains a case for further exploration and refinement of this technology given the post hoc analysis findings with the Geriatric Evaluation and Management Unit wards. Clinical Trials Registration Number: 12617000981325. [ABSTRACT FROM AUTHOR]

Phase IIb trials of tuberculosis therapy rely on early biomarkers of treatment effect. Despite limited predictive ability for clinical outcomes, culture conversion, the event in which an individual previously culture positive for Mycobacterium tuberculosis yields a negative culture after initiating treatment, is a commonly used endpoint. Lack of consensus on how to define the outcome and corresponding measure of treatment effect complicates interpretation and limits between-trial comparisons. We review common analytic approaches to measuring treatment effect and introduce difference in restricted mean survival times as an alternative to identify faster times to culture conversion and express magnitude of effect on the time scale. Findings from the PanACEA MAMS-TB trial are reanalyzed as an illustrative example. In a systematic review we demonstrate variability in analytic approaches, sampling strategies, and outcome definitions in phase IIb tuberculosis trials. Harmonization would allow for larger meta-analyses and may help expedite advancement of new tuberculosis therapeutics. [ABSTRACT FROM AUTHOR]

Background: Mechanisms underlying the associations of high levels of physical activity (PA) and adherence to the Mediterranean diet (MedDiet) with a better inflammatory profile remain unclear. Our objective was to assess the mediating role of changes in body mass index (BMI) and waist circumference (WC), as markers of body fat in the association of changes in PA and adherence to the MedDiet, with changes in the inflammatory profile.Method: This study included 489 adults, aged 55-75 years, from the PREDIMED-Plus multicenter lifestyle intervention trial. An inflammatory score was calculated, based on 8 blood biomarkers: high-sensitivity C-reactive protein, interleukin 6, interleukin 8, interleukin 18, monocyte chemo-attractant protein-1, C-peptide, leptin, and regulated on activation, normal T-cell-expressed and secreted chemokine. Biomarkers, levels of PA, score of MedDiet adherence, BMI, and WC were measured at baseline and at 1-year follow-up. Linear regression models were fitted according to the Baron and Kenny framework for mediation analysis.Results: Changes in BMI and WC mediated the association of both changes in PA and changes in the MedDiet adherence with the inflammatory score. Body mass index mediated 26% of the association of changes in total PA with the inflammatory profile, and 27% of the association of changes in the MedDiet, while WC mediated 13% and 12% of these associations, respectively.Conclusion: In older adults at high cardiovascular risk, increasing PA levels and adherence to a MedDiet during 1 year were associated with a lower inflammatory score, which was partly mediated by a reduction in body fat.Clinical Trials Registration Number: International Standard Randomized Controlled Trial Number: ISRCTN89898870; registration date July 24, 2014, retrospectively registered. [ABSTRACT FROM AUTHOR]

Background Inadequate treatment of hypertension is a widespread problem, especially in South Asian countries where cardiovascular disease mortality rates are high. We aimed to explore the effect of a multicomponent intervention (MCI) on antihypertensive medication intensification among rural South Asians with hypertension. Methods A post hoc analysis of a 2-year cluster-randomized controlled trial including 2,645 hypertensives aged ≥40 years from 30 rural communities, 10 each, in Bangladesh, Pakistan, and Sri Lanka. Independent assessors collected information on participants' self-reports and physical inspection of medications. The main outcomes were the changes from baseline to 24 months in the following: (i) the therapeutic intensity score (TIS) for all (and class-specific) antihypertensive medications; (ii) the number of antihypertensive medications in all trial participants. Results At 24 months, the mean increase in the TIS score of all antihypertensive medications was 0.11 in the MCI group and 0.03 in the control group, with a between-group difference in the increase of 0.08 (95% confidence interval (CI, 0.03, 0.12); P = 0.002). In MCI compared with controls, a greater increase in the TIS of renin–angiotensin–aldosterone system blockers (0.05; 95% CI (0.02, 0.07); P < 0.001) and calcium channel blockers (0.03; 95% CI (0.00, 0.05); P = 0.031), and in the number of antihypertensive medications (0.11, 95% CI (0.02, 0.19); P = 0.016) was observed. Conclusions In rural communities in Bangladesh, Pakistan, and Sri Lanka, MCI led to a greater increase in antihypertensive medication intensification compared with the usual care among adults with hypertension. Clinical trials registration Trial Number NCT02657746. [ABSTRACT FROM AUTHOR]

Aims Two complementary studies were used to assess the real-life use of nalmefene in alcohol-dependent patients and its impact on alcohol use health status. Methods USE-PACT was a prospective cohort study designed to evaluate the real-life effectiveness of nalmefene in the management of alcohol dependence, as assessed by total alcohol consumption (TAC) and number of heavy drinking days (HDD) at 1 year. USE-AM was a cohort study using data from the French nationwide claims database and was used to evaluate the external validity of the population in the prospective study. Results Overall, 256 of 700 new nalmefene users enrolled in the USE-PACT study had valid data at 1 year. After 1 year, patients treated with nalmefene showed a mean ± SD reduction from baseline in TAC (−41.5 ± 57.4 g/day) and number of HDD (−10.7 ± 11.7 days/4 weeks). Patients took a mean ± SD of 20.0 ± 12.0 tablets/4 weeks (median of 1 tablet/day) for the first 3 months and then reduced the dose. The proportion of patients who no longer took nalmefene gradually increased from 5% at 1 month to 52% at 1 year. The USE-AM study identified 486 patients with a first reimbursement for nalmefene in 2016; baseline characteristics confirmed external validity of the USE-PACT study. Overall, 46.3% of initial USE-AM prescriptions were made by GPs; most (91.8%) patients stopped treatment during follow-up. However, 15.2% of patients resumed treatment after stopping. Conclusions In this analysis of French routine practice, patients with alcohol dependence treated with nalmefene showed reduced alcohol consumption, and nalmefene was generally well tolerated. [ABSTRACT FROM AUTHOR]

In comparative effectiveness research (CER) for rare types of cancer, it is appealing to combine primary cohort data containing detailed tumor profiles together with aggregate information derived from cancer registry databases. Such integration of data may improve statistical efficiency in CER. A major challenge in combining information from different resources, however, is that the aggregate information from the cancer registry databases could be incomparable with the primary cohort data, which are often collected from a single cancer center or a clinical trial. We develop an adaptive estimation procedure, which uses the combined information to determine the degree of information borrowing from the aggregate data of the external resource. We establish the asymptotic properties of the estimators and evaluate the finite sample performance via simulation studies. The proposed method yields a substantial gain in statistical efficiency over the conventional method using the primary cohort only, and avoids undesirable biases when the given external information is incomparable to the primary cohort. We apply the proposed method to evaluate the long‐term effect of trimodality treatment to inflammatory breast cancer (IBC) by tumor subtypes, while combining the IBC patient cohort at The University of Texas MD Anderson Cancer Center and the external aggregate information from the National Cancer Data Base. [ABSTRACT FROM AUTHOR]

BACKGROUND In China, hypertension prevalence is high and increasing while the control rate is low, especially in rural areas. Traditionally, village doctors play an important role in infectious disease control and delivering essential health services to rural residents. We aim to test the effectiveness of a village doctor-led multifaceted intervention compared with usual care on blood pressure (BP) control and cardiovascular disease (CVD) among rural residents with hypertension in China. METHODS In the China Rural Hypertension Control Project (CRHCP), a cluster randomized trial, 163 villages were randomly assigned to the village doctor-led intervention and 163 villages to control. A total of 33,995 individuals aged ≥40 years with an untreated BP ≥140/90 mm Hg or treated BP ≥130/80 mm Hg or with an untreated BP ≥130/80 mm Hg and a history of clinical CVD were recruited into the study. The village doctor-led multifaceted intervention is designed to overcome barriers at the healthcare system, provider, patient, and community levels. Village doctors receive training on standard BP measurement, protocol-based hypertension treatment, and health coaching. They also receive technical support and supervision from hypertension specialists/primary care physicians and performance-based financial incentives. Study participants receive health coaching on home BP monitoring, lifestyle changes, and adherence to medications. The primary outcome is BP control (<130/80 mm Hg) at 18 months in phase 1 and CVD events over 36 months in phase 2. CONCLUSIONS The CRHCP will provide critically important data on the effectiveness, implementation, and sustainability of a hypertension control strategy in rural China for reducing the BP-related CVD burden. CLINICAL TRIALS REGISTRATION Trial Number NCT03527719. [ABSTRACT FROM AUTHOR]

Background: During the period of hospitalization, patients can develop functional decline. The main aim of our study was to assess the natural trajectory of each activity of daily living (ADL) and to assess how in-hospital exercise could influence short-term trajectory of ADLs.Method: Acutely hospitalized patients (n = 297, 56.5% women) were randomly assigned to the intervention or control (usual care) group within the first 48 hours of admission. An exercise training program was prescribed in 2 daily sessions (morning and evening) of 20 minutes duration during 5-7 consecutive days for the intervention group. The primary endpoint was the change in every ADL (assessed with the Barthel Index) from 2 weeks before admission to hospital discharge.Results: Acute hospitalization per se led to significant in-patient's functional ability impairment in ADLs during hospitalization, whereas the exercise intervention reversed this trend (3.7 points; 95% CI: 0.5-6.8 points). After analyzing the trajectory of each one of the ADLs, patients in the control group significantly worsened all activities, but with a different degree of loss. For the between-group analysis, significant differences were obtained in many ADLs including bathing, dressing, grooming, bladder control, toilet use, transfers, mobility, and climbing stairs (p < .05). The control group had the greatest impairment in all domains analyzed (ie, feeding, bathing, dressing, grooming, bowel control, bladder control, toilet use, transfers, mobility, and climbing stairs; p < .05).Conclusions: An individualized multicomponent exercise training program in older adults is effective to reverse the loss of specific ADLs that frequently occurs during hospitalization. Each patient profile should receive an individualized prescription of exercise during hospitalizations.Clinical Trials Registration Number: NCT02300896. [ABSTRACT FROM AUTHOR]

Background Sepsis is a leading cause of morbidity, mortality, and health care costs worldwide. Methods We conducted a multicenter, prospective cohort study evaluating the yield of blood cultures drawn before and after empiric antimicrobial administration among adults presenting to the emergency department with severe manifestations of sepsis. Enrolled patients who had the requisite blood cultures drawn were followed for 90 days. We explored the independent association between blood culture positivity and its time to positivity in relation to 90-day mortality. Results Three hundred twenty-five participants were enrolled; 90-day mortality among the 315 subjects followed up was 25.4% (80/315). Mortality was associated with age (mean age [standard deviation] in those who died was 72.5 [15.8] compared with 62.9 [17.7] years among survivors; P <.0001), greater Charlson Comorbidity Index (2 [interquartile range {IQR}, 1–3] vs 1 [IQR, 0–3]; P =.008), dementia (13/80 [16.2%] vs 18/235 [7.7%]; P =.03), cancer (27/80 [33.8%] vs 47/235 [20.0%]; P =.015), positive quick Sequential Organ Failure Assessment score (57/80 [71.2%] vs 129/235 [54.9%]; P =.009), and normal white blood cell count (25/80 [31.2%] vs 42/235 [17.9%]; P =.02). The presence of bacteremia, persistent bacteremia after antimicrobial infusion, and shorter time to blood culture positivity were not associated with mortality. Neither the source of infection nor pathogen affected mortality. Conclusions Although severe sepsis is an inflammatory condition triggered by infection, its 90-day survival is not influenced by blood culture positivity nor its time to positivity. Clinical Trials Registration NCT01867905. [ABSTRACT FROM AUTHOR]

Summary: In order to overcome inconsistencies in the reporting of outcomes in clinical trials, core outcome sets (COSs) have been developed in many clinical areas and the awareness of this concept is growing steadily. The Outcomes for Pressure Ulcer Trials (OUTPUTs) project aims to improve the quality of evidence from pressure ulcer prevention trials by developing a COS. As an initial step in the COS process we aimed to identify and classify both outcomes and concepts that represent potential outcomes for future trials that have been reported in pressure ulcer prevention research. A review was conducted in 12 major databases covering the literature indexed until 2016. Outcomes and relevant concepts reported in primary studies and/or reviews on pressure ulcer prevention in adult patients were extracted as presented in the articles, and afterwards inductively grouped into outcome domains. The domains were then categorized according to the outcome domain taxonomy recently proposed by the COMET group. In total 332 studies were included and 68 outcome domains were identified, covering multiple aspects of pressure ulcer prevention. Pressure ulcer occurrence was reported in 71% of all included studies, representing the most frequent outcome, followed by costs (22% of all studies) and acceptability of intervention and comfort (18% of all studies). A plethora of different outcomes are applied in pressure ulcer prevention research and substantial variations in definitions and reporting of similar outcomes were observed. A COS for pressure ulcer prevention trials is needed to overcome the noncomparability of outcomes. Linked Comment: Lechner. Br J Dermatol 2021; 184:587. [ABSTRACT FROM AUTHOR]

Background Increased blood pressure variability (BPV) is associated with increased cardiovascular and all-cause mortality in patients with type-2 diabetes mellitus (T2DM). Sodium-glucose co-transporter 2 (SGLT-2) inhibitors decrease the incidence of cardiovascular events, renal events, and death in this population. This study aimed to evaluate the effect of dapagliflozin on short-term BPV in patients with T2DM. Methods This is a secondary analysis of a double-blind, randomized, placebo-controlled trial in 85 patients with T2DM. Subjects were randomized to dapagliflozin 10 mg/day or placebo for 12 weeks. All participants underwent 24-hour ambulatory blood pressure (BP) monitoring with Mobil-O-Graph-NG device at baseline and study-end. SD, weighted SD (wSD), coefficient of variation, average real variability (ARV), and variation independent of mean were calculated for the 24-hour, daytime and nighttime periods. Results Dapagliflozin reduced 24-hour brachial BP compared with placebo. From baseline to study-end 24-hour brachial BPV indexes did not change with dapagliflozin (SBP-ARV: 11.51 ± 3.45 vs. 11.05 ± 3.35; P = 0.326, SBP-wSD: 13.59 ± 3.60 vs. 13.48 ± 3.33; P = 0.811) or placebo (SBP-ARV: 11.47 ± 3.63 vs. 11.05 ± 3.00; P = 0.388, SBP-wSD: 13.85 ± 4.38 vs. 13.97 ± 3.87; P = 0.308). Similarly, no significant changes in BPV indexes for daytime and nighttime were observed in any group. At study-end, no between-group differences were observed for any BPV index. Deltas (Δ) of all indexes during follow-up were minimal and not different between groups (SBP-wSD: dapagliflozin: −0.11 ± 3.05 vs. placebo: 0.12 ± 4.20; P = 0.227). Conclusions This study is the first to evaluate the effects of an SGLT-2 inhibitor on short-term BPV in T2DM, showing no effect of dapagliflozin on all BPV indexes studied. Clinical trials registration Trial Number NCT02887677. [ABSTRACT FROM AUTHOR]

Background: The evidence to support effective fall prevention strategies in older people with cognitive impairment (CI) is limited. The aim of this randomized controlled trial (RCT) was to determine the efficacy of a fall prevention intervention in older people with CI.Method: RCT involving 309 community-dwelling older people with CI. The intervention group (n = 153) received an individually prescribed home hazard reduction and home-based exercise program during the 12-month study period. The control group (n = 156) received usual care. The primary outcome was rate of falls. Secondary outcomes included faller/multiple faller status, physical function, and quality of life.Results: Participants' average age was 82 years (95% CI 82-83) and 49% were female. There was no significant difference in the rate of falls (incidence rate ratio [IRR] 1.05; 95% confidence interval [95% CI] 0.73-1.51). A sensitivity analysis, controlling for baseline differences and capping the number of falls at 12 (4 participants), revealed a nonsignificant reduction in fall rate in the intervention group (IRR 0.78; 95% CI 0.57-1.07). Analyses of secondary outcomes indicated the intervention significantly reduced the number of multiple fallers by 26% (RR 0.74; 95% CI 0.54-0.99) when adjusting for baseline differences. There was a differential impact on falls in relation to physical function (interaction term p-value = .023) with a significant reduction in fall rate in intervention group participants with better baseline physical function (IRR 0.60; 95% CI 0.37-0.98). There were no significant between-group differences for other secondary outcomes.Conclusions: This intervention did not significantly reduce the fall rate in community-dwelling older people with CI. The intervention did reduce the fall rate in participants with better baseline physical function.Clinical Trials Registration Number: Australian and New Zealand Trials Registry ACTRN12614000603617. [ABSTRACT FROM AUTHOR]

Background: Strength and balance retraining exercises reduce the rate of subsequent falls in community-dwelling older adults who have previously fallen. Exercise can also improve cognitive function, including processing speed. Given processing speed predicts subsequent falls, we aimed to determine whether improved processing speed mediated the effects of the Otago Exercise Program on the rate of subsequent: (i) total falls, (ii) non-injurious falls, (iii) moderate injurious falls, and (iv) serious injurious falls.Method: A secondary complete case analysis of a 12-month, single-blind, randomized clinical trial among 256 of 344 adults aged at least 70 years who fell in the previous 12 months. Participants were randomized 1:1 to receive usual care plus the Otago Exercise Program (n = 123) or usual care (n = 133), consisting of fall prevention care provided by a geriatrician. The primary outcome was self-reported number of falls over 12 months (ie, rate of falls). Processing speed was assessed at baseline and at 12 months by the Digit Symbol Substitution Test (DSST). Causal mediation analyses were conducted using quasi-Bayesian estimates and 95% confidence intervals.Results: Exercise significantly reduced the rate of subsequent moderate injurious falls (IRR = 0.49; 95% CI: 0.31, 0.77; p = .002) and improved processing speed (estimated mean difference: 1.16 points; 95% CI: 0.11, 2.21). Improved DSST mediated the effect of exercise on the rate of subsequent moderate injurious falls (estimate: -0.06; 95% CI: -0.15, -0.001; p = .036).Conclusion: Improved processing speed may be a mechanism by which exercise reduces subsequent moderate injurious falls in older adults who fell previously.Clinical Trials Registration Number: ClinicalTrials.gov Protocol Registration System:NCT01029171: https://clinicaltrials.gov/ct2/show/NCT01029171NCT00323596: https://clinicaltrials.gov/ct2/show/NCT00323596. [ABSTRACT FROM AUTHOR]

Introduction: Tobacco heating products (THPs) generate lower machine yields of toxicants compared to those found in conventional cigarette smoke. During use, these products are likely to expose users to lower levels of particulate matter and harmful and potentially harmful compounds compared with smoking cigarettes.Aims and Methods: This randomized, controlled study is investigating whether biomarkers of exposure (BoE) to smoke toxicants are reduced when smokers switch from smoking cigarettes to using the glo THP in a naturalistic, ambulatory setting. Control groups include smokers who are abstaining from cigarette smoking and never-smokers. At a baseline study visit, 24-hour urine samples and spot blood samples were taken for BoE analysis, and exhaled carbon monoxide was also measured. N-(2-cyanoethyl) valine (CEVal) was used as a marker of compliance in subjects asked to refrain from combustible cigarette smoking. Subjects are being followed up at periodic intervals for 360 days; this article presents data following a planned interim analysis at day 90.Results: In continuing smokers, BoE remained stable between baseline (day 1) and day 90. In both per-protocol and CEVal-compliant analysis populations, reductions in BoE were observed in subjects switching to using glo or undergoing smoking cessation. These reductions were statistically significant for a number of BoE when switching to glo was compared with continued smoking. Furthermore, in both populations, reductions observed in subjects switching to using glo were comparable to those seen with smoking cessation and were also to levels similar to those seen in never-smokers.Conclusion: glo is a reduced-exposure tobacco product.Implications: This clinical study builds on a previous 5-day confinement study and demonstrates that when smokers switched from smoking combustible cigarettes to using the glo THP in a naturalistic, ambulatory setting, their exposure to tobacco smoke toxicants was significantly decreased. For most BoE examined, this was to the same extent as that seen when a control group of smokers ceased cigarette smoking, or even to levels seen in never-smoker controls. This indicates that glo is a reduced-exposure product with the potential to be a reduced-risk tobacco product, when used by smokers whose cigarette consumption is displaced completely.Clinical Trial Registration: ISRCTN81075760. [ABSTRACT FROM AUTHOR]

Background: Self-monitoring is a key component of behavioral weight loss (BWL) interventions. Past research suggests that individuals may avoid self-monitoring in certain contexts (e.g., skipping self-weighing after higher-than-usual calorie intake). However, no studies have attempted to quantify individuals' inclination to avoid information about their weight control ("weight-related information avoidance"; WIA) or prospectively examined its implications for treatment engagement and outcomes in BWL programs.Purpose: Characterize WIA using a validated questionnaire among adults enrolled in BWL treatment and examine whether WIA prospectively predicts self-monitoring adherence, session attendance, treatment discontinuation, or weight loss.Methods: Participants (N = 87; MBMI = 34.9 kg/m2, 83% female) completed a measure of WIA prior to starting a 12 week, group-based BWL intervention. Participants were given digital self-monitoring tools and instructed to self-monitor their food intake daily, physical activity daily, and body weight weekly (Weeks 1-10) and then daily (Weeks 11-12). Session attendance and treatment discontinuation were recorded. Weight was measured in-clinic pretreatment and posttreatment.Results: While mean WIA was low (M = 2.23, standard deviation [SD] = 0.95; potential scale range: 1-7), greater WIA predicted poorer attendance (r = -.23; p = .03) and poorer self-monitoring of physical activity (r = -.28; p = .009) and body weight (r = -.32; p = .003). WIA did not predict food monitoring (p = .08), treatment discontinuation (p = .09), or 12 week weight loss (p = .91).Conclusions: Greater WIA, as assessed via a brief questionnaire, may place individuals at risk for poorer self-monitoring and treatment engagement during BWL. Further research on the implications of WIA in the context of weight management is warranted, including evaluation of correlates, moderators, and mechanisms of action of WIA.Clinical Trial Registration: NCT03337139. [ABSTRACT FROM AUTHOR]