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Study Design Systematic Review Introduction 3D printed orthoses are emerging as a possible option in the field of hand therapy to fabricate conventional casts and orthoses. It is unknown how this technology is currently being used to treat upper extremity musculoskeletal conditions, and if 3D orthoses are comparable to custom- made low temperature thermoplastic orthoses fabricated by hand therapists. Purpose of the Study The primary aim of this review was to investigate the utilization, effectiveness and feasibility of 3D printed technology to manufacture custom orthoses for musculoskeletal conditions of the upper extremity. Methods Studies describing 3D printed orthoses or casts used in treatment with patients were included following a comprehensive literature search using CINAHL, PubMed, Medline, ProQuest, and EBSCO databases. The selected studies had to address musculoskeletal conditions of the elbow, wrist, hand and/or digits that would typically be immobilized with a cast or brace or orthotic or orthosis. Results Ten studies met the inclusion criteria. Study designs included case studies, case series, and 1 randomized clinical trial. 3D printed orthoses/casts appear to be comfortable, provide adequate immobilization, and have pleasing aesthetics. However, expensive equipment, lack of appropriate software and scanning tools and lack of highly skilled clinicians are all factors preventing the implementation of 3D printed orthoses into current clinical practice. Discussion 3D printed orthoses appear to be effective at immobilization of a limb, aesthetically pleasing, and utilize lightweight and well -ventilated materials. However, the feasibility of implementing 3D printing technology in hand therapy settings remains challenging in part due to the resources required. Conclusions While 3D printing shows promise, the high cost of equipment, lack of training and skill of clinicians and the long time required for production are all factors that need to be improved to make 3D printing a viable option in the hand therapy setting.

The disposition of a drug is driven by various processes, such as drug metabolism, drug transport, glomerular filtration and body composition. These processes are subject to developmental changes reflecting growth and maturation along the paediatric continuum. However, knowledge gaps exist on these changes and their clinical impact. Filling these gaps may aid better prediction of drug disposition and creation of age-appropriate dosing guidelines. We present innovative approaches to study these developmental changes in relation to drug metabolism and transport. First, analytical methods such as including liquid chromatography-mass spectrometry for proteomic analyses allow quantitation of the expressions of a wide variety of proteins, e.g. membrane transporters, in a small piece of organ tissue. The latter is specifically important for paediatric research, where tissues are scarcely available. Second, innovative study designs using radioactive labelled microtracers allowed study-without risk for the child-of the oral bioavailability of compounds used as markers for certain drug metabolism pathways. Third, the use of modelling and simulation to support dosing recommendations for children is supported by both the European Medicines Agency and the US Food and Drug Administration. This may even do away with the need for a paediatric trial. Physiologically based pharmacokinetics models, which include age-specific physiological information are, therefore, increasingly being used, not only to aid paediatric drug development but also to improve existing drug therapies. ispartof: BRITISH JOURNAL OF CLINICAL PHARMACOLOGY vol:88 issue:10 pages:4285-4296 ispartof: location:England status: published

Background There is an established relationship between the degree of mitral regurgitation (MR) and prognosis. Quantitation of MR severity guides therapeutic approaches. Inconsistent definitions and categorization of MR severity in clinical studies limit meaningful comparisons between trials and compromise development of an effective evidence base. The purpose of this study was to quantify heterogeneity in grading systems for MR severity in the contemporary literature. Methods We performed a systematic review of randomized (RCT) and propensity score (PS) adjusted clinical studies of MV interventions (surgical or percutaneous). A total of 35 articles from 2015-2020 were included (15 RCT, 20 PS). Results There were 22 studies that reported MR severity in numerical categories, either values from the historical “plus” system or numerical MR grades, while 9 studies reported MR severity using text-only descriptive categories. Among the studies that used numerical categories, 2+ MR was defined as moderate in 64% of studies, mild in 27%, and mild-moderate in 9% and 3+ MR was defined as moderate in 14%, moderate-severe in 52%, and severe in 14%. Conclusions There was substantial variability in MR severity definition and reporting in contemporary clinical studies of MV interventions. We recommend the historical “plus” numerical grading system be abandoned and that inclusion and outcome criteria in MR clinical trials be based on American and European guideline-recommended categories as none/trace, mild, moderate, and severe. Adoption of these simple recommendations will improve the consistency and quality of MR clinical trial design and reporting.

Objective Dementia prevalence in Latin America (LATAM) is rapidly increasing, contributing to significant family burden. As families are responsible for care, supportive interventions are critical. To understand the state-of-the-science, a scoping review was conducted of non-pharmacologic interventions for caregivers of people living with dementia (PLWD) in LATAM. Design Eight databases were searched (PubMed, Embase, PsycINFO, Scopus, Scielo, Lilacs, Redalyc, Google Scholar) for nonpharmacological intervention studies published up to July, 2021 in LATAM reporting at least 1 caregiver outcome. A qualitative synthesis examined study designs, participants, and outcomes characteristics. Results Forty-five studies were identified from 25.8% (n = 8/31) of LATAM countries (28 = Brazil, 4 = Chile, 4 = Cuba, 4 = Mexico, 2 = Colombia, 1 = Peru, 1 = Ecuador, 1 = Argentina): 29% (n = 17) were randomized clinical trials (RCT), 7% (n = 3) nonrandomized comparison trials, 42% (n = 19) pre-post trials, 9% (n = 4) postintervention analyses, and 4% (n = 2) single case studies, comprising a total of 1,171 caregivers and 817 PLWD. For 20 RCT and nonrandomized comparison trials, 31 interventions were tested of which 48.4% (n = 15) targeted caregivers and 32.3% (n = 10) dyads. Most studies involved daughters with less than 12 years of education and tested multicomponent interventions involving disease education (90%), and cognitive behavioral coping (45%). Half of interventions (51.6%; n = 16/31) tested were adapted from other countries, and reported benefits for caregiver depression, quality of life, and burden. Conclusion Studies were conducted in a limited number of LATAM countries and few were RCTs. Results of RCTs showed benefits for socially vulnerable caregivers on psychosocial outcomes. There is an urgent need to rigorously evaluate more country/culturally specific interventions addressing unmet familial needs beyond psychosocial support.

Purpose The purpose of the study was to appraise the methodological quality of the highest impact blepharoplasty research and to describe prevalent research themes. Methods The 100 most highly cited research papers relevant to blepharoplasty were obtained from Web of Science, with no journal or date limitations applied. Data extraction included the study design, main research topic and specialty, outcome measures, and citation count. Each paper's level of evidence was independently evaluated by 2 authors according to the Oxford Centre for Evidence-Based Medicine system. Results Overall, the 100 most cited blepharoplasty research papers were cited by 4,194 papers. The mean number of citations for each paper was 73 (range: 42-239). Most of the papers presented level 4 (n = 51) or level 5 (n = 35) evidence, which is consistent with the predominance of case series (n = 47) and expert opinions (n = 18) amongst study designs. No papers achieved level 1 (highest) evidence. Six papers presented level 2 evidence and 8 papers presented level 3. Significant research foci included innovative surgical techniques (n = 65) and anatomical considerations (n = 10), with reconstructive and cosmetic implications. Senior authors were mainly affiliated with centers of plastic (n = 53) or ophthalmic/oculoplastic (n = 34) surgery. Only 3 papers used validated subjective or objective cosmetic outcome measures. Conclusions Despite a significant impact on current practice, the level of evidence of the highly cited blepharoplasty research was predominantly low. Robust research methodology, through well-designed studies and standardized outcome measures, is necessary to facilitate evidence synthesis and guide clinical practice.

The concept of ‘one size fits all’ - one treatment for patients with a particular disease, seems to be outdated. The advent of precision medicine has prompted profound changes in clinical research and it allows researchers to predict more accurately, the prevention and treatment strategies for a specific disease population. Novel study designs are, therefore, essential to establish safe and effective personalized medicine. Basket, umbrella and platform trial designs (collectively referred to as master protocols) are biomarker enrichment designs that allow for testing more than one hypotheses within a protocol, thus accelerating drug development. These trial designs tailor intervention strategies based on patient’s risk factor(s) that can help predict whether they will respond to a specific treatment. Basket trials evaluate therapy for various diseases that share a common molecular alteration, while umbrella trials evaluate multiple targeted therapies for a single disease that is stratified into subgroups based on different molecular alterations/ risk factors. These designs are complex and their major limitations stem from the fact that it would be inappropriate to completely replace histological typing with molecular profiling alone. However, in the upcoming decades, these trial designs are likely to gain popularity and improve the efficiency of clinical research. This article briefly overviews the characteristics of master protocol designs with examples of completed and ongoing clinical trials utilizing these study designs.

The purpose of this systematic review was to critically analyze the recent literature to present the state of the art in customized reconstruction of orbital fractures. Three electronic databases and manual search approaches were used to identify relevant articles. Only studies with a controlled clinical study design were included. Primary outcome was defined as the status of recovery (complete/partial functional and esthetic disturbances). The benefit of intra-surgical navigation should be described. Secondary outcome was defined as the time of surgery, post-surgical events and hospitalization. A total of eight studies out of 552 records identified met the inclusion criteria. Post-surgical results in sense of recovery were shown to be superior in the customized group, and comparable to the control group in five studies. Time of surgery was shorter in the customized groups, as well as liquid infusion and time of hospitalization were reduced. Four studies documented a higher degree of accuracy in reconstruction by using navigation. All the studies presented at least one bias. A considerable heterogeneity of the studies was evaluated. This review documented, that in combination with navigated surgery, a higher accuracy in reconstruction could be obtained by using customized meshes. A significant reduction of surgery time was revealed.

Poor communication within healthcare teams occurs commonly, contributing to inefficiency, medical errors, conflict, and other adverse outcomes. Interprofessional bedside rounds (IBR) are a promising model that brings two or more health professions together with patients and families as part of a consistent, team-based routine to share information and collaboratively arrive at a daily plan of care. The purpose of this systematic scoping review was to investigate the breadth and quality of IBR literature to identify and describe gaps and opportunities for future research. We followed an adapted Arksey and O'Malley Framework and PRISMA scoping review guidelines. PubMed, CINAHL, PsycINFO, and Embase were systematically searched for key IBR words and concepts through June 2020. Seventy-nine articles met inclusion criteria and underwent data abstraction. Study quality was assessed using the Mixed Methods Assessment Tool. Publications in this field have increased since 2014, and the majority of studies reported positive impacts of IBR implementation across an array of team, patient, and care quality/delivery outcomes. Despite the preponderance of positive findings, great heterogeneity, and a reliance on quantitative non-randomized study designs remain in the extant research. A growing number of interventions to improve safety, quality, and care experiences in hospital settings focus on redesigning daily inpatient rounds. Limited information on IBR characteristics and implementation strategies coupled with widespread variation in terminology, study quality, and design create challenges in assessing the effectiveness of models of rounds and optimal implementation strategies. This scoping review highlights the need for additional studies of rounding models, implementation strategies, and outcomes that facilitate comparative research.

Background Benzodiazepines and sedative-hypnotic drugs (BZD/SHD) are commonly utilized in the acute care setting for insomnia and anxiety and are associated with cognitive impairment, falls, and fractures. Interventions to reduce use of BZD/SHD in hospitals are not well characterized. Objective The objective was to conduct a scoping review to identify and characterize interventions to reduce the use of BZD/SHD by adults in the acute care setting. Methods English language studies and abstracts that described an intervention to reduce BZD/SHD in adult hospital patients were included. Six databases (PubMed, EMBASE, CINAHL, PsycINFO, Scopus, and Web of Science) were searched up to July 2018 and updated to February 3, 2021. The grey literature (Opengrey, Grey Matters, Google Advanced) was searched up to July 2018. Titles and abstracts were screened and full-text articles were reviewed and charted by three independent reviewers. Stakeholders were consulted to inform the scoping review and collect perspectives on the findings. Results There were 13,046 records identified and 43 studies included. The most common study designs were uncontrolled before and after (23/43, 53.5%) and randomized controlled trials (7/43, 16.3%). The majority of studies tested a single intervention (32/43, 74.4%) such as education, deprescribing, relaxation training and sleep protocols. Patients were frequently the target of relaxation training and behavior change interventions; while sleep protocols, multifaceted interventions, education and deprescribing were usually directed at healthcare providers, either alone or in combination with patients. Most studies reported positive results in decreasing BZD/SHD use (27/43, 62.8%). Conclusions The scoping review found a variety of interventions to decrease the utilization of BZD/SHD in hospitals. Multifaceted interventions aimed at patients and healthcare providers that include a combination of education, sleep protocols, and deprescribing may support reductions in BZD/SHD use. Stakeholders also recommended policy and system changes such as computer alerts due to feasibility and workload.

An individual's pain experiences vary substantially over time. Though variability in pain may be an important metric which usually predicts health consequences, research on the measurement of pain variability estimates is lacking among older adults. We aimed to examine the reliabilities of both intra-individual mean (IIM) and intra-individual variability (IIV) of pain assessed using ecological momentary assessments (EMA) among racially diverse, systematically recruited community dwelling cohort of older adults. Participants (N = 311, age = 70-91) completed a 14-day EMA protocol which included self-reports of pain intensity, pain interference with activities, and pain interference with concentration multiple times a day. Over a 2-week period, we found excellent reliabilities for both pain IIM (.99), and pain IIV (≥.90). We also found that we need 5 to 6 days to achieve good reliability (.8) for pain IIV, suggesting that a shorter protocol may be used to reduce participants' burden among the current sample, although caution is required when using this result to determine EMA study designs among different samples. Future studies are required to examine the associations of various EMA pain metrics with different health outcomes among older adults to facilitate the detection of underlying mechanisms linking pain to health as a prelude to interventions. PERSPECTIVE: Mean levels and variability in pain intensity, pain interference with activities, and pain interference with concentration can be reliably measured to be linked with various health outcomes in older adults. Future studies including these pain metrics will assess the natural history, the consequences, and effects of intervention of pain.

Blocking the complement system as a therapeutic strategy has been proposed for numerous glomerular diseases but presents a myriad of questions and challenges, not the least of which is demonstrating efficacy and safety. In light of these potential issues and because there are an increasing number of anti-complement therapy trials either planned or underway, the National Kidney Foundation (NKF) facilitated an all-virtual format scientific workshop entitled, "Improving Clinical Trials for Anti-complement Therapies in Complement-mediated Glomerulopathies." Attended by patient representatives and experts in glomerular diseases, complement physiology, and clinical trial design, the aim of this workshop was to develop standards applicable for designing and conducting clinical trials for anti-complement therapies across a wide spectrum of complement-mediated glomerulopathies. Discussions focused on study design, subject risk assessment and mitigation, laboratory measurements and biomarkers to support these studies, and identification of optimal outcome measures to detect benefit, specifically for trials in complement-mediated diseases. This report summarizes the discussions from this workshop and outlines consensus recommendations.

Background Microneedling as an adjuvant to topical medications has shown promising but variable results in the treatment of melasma. Objective To conduct a systematic review and meta-analysis on the efficacy of microneedling as an adjuvant to topical therapies for the treatment of melasma. Methods This study followed PRISMA guidelines. All comparative, prospective studies on the use of topical interventions with microneedling for the treatment of melasma were included. Studies involving radiofrequency microneedling were excluded. Results Twelve eligible studies comprising 459 patients from 7 different countries were included. Topical therapies included topical tranexamic acid, vitamin C, platelet-rich plasma, non-hydroquinone-based depigmentation serums, and hydroquinone-based depigmenting agents. Topical therapy with microneedling improved melasma severity with a large effect (standardized mean difference >0.8) beyond 8 weeks, with best results seen at 12 weeks. Compared to topical therapy alone, topical therapy with microneedling resulted in an additional improvement in melasma severity with a moderate effect at 8 weeks and a large effect at 12-16 weeks. Microneedling was well tolerated across studies, with no serious adverse events reported. Limitations Heterogeneity in study designs did not allow for a comparison of the efficacy of various topical therapies with microneedling. Conclusion Microneedling is useful adjuvant to topical therapies for the treatment of melasma.

Context Globally, people most often die within hospitals. As such, healthcare providers in hospitals are frequently confronted with dying persons and their bereaved relatives. Objectives To provide an overview of the current role hospitals take in providing bereavement care. Furthermore, we want to present an operational definition of bereavement care, the way it is currently implemented, relatives’ satisfaction of receiving these services, and finally barriers and facilitators regarding the provision of bereavement care. Methods An integrative review was conducted by searching four electronic databases, from January 2011 to December 2020, resulting in 47 studies. Different study designs were included and results were reported in accordance with the theoretical framework of Whittemore and Knafl (2005). Results Only four articles defined bereavement care: two as services offered solely post loss and the other two as services offered pre and post loss. Although different bereavement services were delivered the time surrounding the death, the follow-up of bereaved relatives was less routinely offered. Relatives appreciated all bereavement services, which were rather informally and ad-hoc provided to them. Healthcare providers perceived bereavement care as important, but the provision was challenged by numerous factors (such as insufficient education and time). Conclusion Current in-hospital bereavement care can be seen as an act of care that is provided ad-hoc, resulting from the good-will of individual staff members. A tiered or stepped approach based on needs is preferred, as it allocates funds towards individuals-at-risk. Effective partnerships between hospitals and the community can be a useful, sustainable and cost-effective strategy.

The design of clinical trials, formalized in the immediate post-war period, has undergone major changes due to therapeutic innovations, particularly the arrival of targeted therapies in onco-hematology. The traditional phase I-II-III regimen is regularly questioned and multiple adaptations are proposed. This article proposes to expose some of these modifications and the issues they lead to.

Purpose/Objective(s) To develop a comprehensive framework to simulate the response to immune checkpoint inhibitors (ICIs) in combination with radiotherapy (RT) and to apply the framework for investigating ICI-RT combination regimen in hepatocellular carcinoma (HCC) patients. Materials/Methods The mechanistic mathematical model is based on dynamic biological interactions between the immune system and the tumor using input data from patient blood samples and outcomes of clinical trials. The cell compartments are described by ordinary differential equations and represent irradiated and non-irradiated tumor cells and lymphocytes. The effect of ICI is modeled using an immune activation term that is based on tumor size changes observed in a phase 1/2 clinical trial for HCC. Simulated combination regimen are based on ongoing ICI-RT trials. Results The proposed framework successfully describes tumor volume trajectories observed in early-stage clinical trials of durvalumab monotherapy in HCC patients. For ICI-RT treatment regimen the irradiated tumor fraction is the most important parameter for the efficacy. For 90% of the tumor cells being irradiated, adding RT to ICI yields an increase in clinical benefit from 33% to 71% in non-irradiated tumor sites. The model agrees with clinical data showing an association of outcome with initial tumor volume and lymphocyte counts. We demonstrate model application in clinical trial design to predict progression-free survival curves, showing that the cohort size to show significant improvement heavily depends on the irradiated tumor fraction. Conclusion We present a framework extending radiation cell kill models to include circulating lymphocytes and the effect of ICIs and enable simulation of combination strategies. The simulations predict that a significant amount of the benefit from RT in combination with ICI stems from the reduction in irradiated tumor burden and associated immune suppression. This aspect needs to be included in the interpretation of outcomes and the design of novel combination trials.

Introduction Nurses in neonatal intensive care units (NICUs) provide more direct care at the end-of-life than other health care providers, yet report feeling inadequately prepared for neonatal palliative care. The purpose of this review was to identify studies testing educational interventions for palliative care to NICU nurses. Methods Rapid Review Results Four studies reported education interventions lasting 6–21 h with 30–142 participants. All used convenience samples and pre/posttest designs. A variety of outcome measures were used, including objective knowledge tests and structured clinical observations. The studies showed statistically significant improvements in at least one outcome, although these results should be viewed cautiously because of less rigorous study designs. Discussion The small number of studies identified indicates a need to implement and evaluate further educational interventions. While the evidence from these studies suggested positive outcomes, additional studies using more rigorous research methods are needed.

Introduction The U.S. Preventive Services Task Force (USPSTF) issues “Insufficient Evidence” (I) statements when scientific evidence is inadequate for making recommendations about clinical preventive services. Insufficient Evidence statements may be changed to definitive recommendations if new research closes evidence gaps. This study examines the characteristics of evidence that informed changes from I statements to definitive recommendations, including NIH's role as a funder. Methods A total of 11 USPSTF Insufficient Evidence statements that were changed between 2010 and 2019 were assessed. Study designs, bibliometric influence, and funding sources for scientific articles cited in USPSTF evidence reviews were characterized for each I statement. Data were analyzed in 2019–2020. Results Most I statements (82%) changed to a B grade; an average of 8.4 years elapsed between issuing the I statement and releasing the definitive recommendation. An average of 63 (range=19−253) articles were included in each USPSTF evidence review. NIH support was cited in 28.8% of articles, on average. The proportion of NIH-funded articles reporting RCT designs was similar to that of non–NIH-funded articles (64.5% vs 59.5%). A higher proportion of NIH-funded articles were rated good quality for study design (39.0%) than the proportion of non–NIH-funded articles (24.4%). Bibliometric influence measured by relative citation ratios was higher for NIH-funded (mean=14.78) than for non–NIH-funded (mean=5.07) articles. Conclusions Study designs and funding supports varied widely across topics, but overall, NIH was the largest single funder of evidence informing 11 changed USPSTF I statements. Enhanced efforts by NIH and other stakeholders to address I statement evidence gaps are needed.

Meningiomas are largely indolent tumors with a benign clinical course, but a minority exhibit aggressive behavior characterized by rapid growth, neurologic deficits, and increased mortality. Identifying high-risk patients requiring intervention is challenging, but recent insights into meningioma biology provide a useful guide for decision making. Standard of care for recurrent or biologically aggressive tumors consists of surgery and radiation therapy. Systemic therapies targeting vascular endothelial growth factor signaling and somatostatin analogues are potential options for those with refractory disease but display only modest activity. New paradigms in meningioma clinical trial design provide hope for improved options in the future.

Objective To perform a systematic-review and meta-analysis of all population-based studies reporting on incidence of acute aortic dissections. Methods We searched MEDLINE, EMBASE, CENTRAL and Open Grey databases from inception to August 2020 for population-based studies reporting on the incidence of AAD. A systematic review was conducted following the PRISMA guidelines using a registered protocol (CRD42020204007). Data was pooled using a random-effects model of proportions using Freeman-Tukey double arcsine transformation. The main outcome was the incidence of AAD. Secondary outcomes were incidence type A aortic dissections (TAAD) and type B aortic dissections (TBAD); incidence of aortic dissection repair and medical management and incidence of in-hospital mortality. In addition, we estimated the proportion of aortic dissection repair and mortality (in hospital, overall and specific mortality according to sub-type) among patients with AAD. Results Thirty-three studies were included. The pooled incidence of AADs was 4.8 per 100 000 individuals/year (95%CI: 3.6; 6.1). Incidence of TAAD was 3.0 per 100 000/year (95%CI: 1.8; 4.4) and incidence of TBAD was 1.6 per 100 000/year (95%CI: 1.1; 2.2). The incidence of AAD needing repair was 1.4 per 100 000/year (95%CI: 1.0; 2.0) [1.4 (95%CI: 1.2; 1.7) for TAAD and 0.4 (95%CI: 0.2; 0.7) for TBAD]. Incidence of medically managed AAD was 3.4 per 100 000/year (95%CI: 2.4; 4.5). Incidence of in-hospital death due to AAD was 1.3 per 100 000 individuals/year (95%CI: 0.9; 1.9); 1.0 (95%CI: 0.6; 1.4; I297%) for TAAD and 0.3 for TBAD (95%CI: 0.2; 0.4; I296%). Conclusion A global estimate regarding the incidence rate of acute aortic dissections was achieved. Incidence of acute aortic dissection varied significantly between study designs and geographical regions. More accurate information on acute aortic dissection epidemiology is crucial for public-health decisions, clinical understanding, and healthcare management.

Background Isolation is effective in preventing transmission of infectious disease. However, it has been shown to have negative effects including increased anxiety and poor physical outcomes. Objectives To summarize the effects of interventions to improve safety and outcomes for patients in isolation Design Systematic review (PROSPERO protocol registration - CRD42020222779). Setting Acute hospital Participants Intervention studies including patients in preventative or protective isolation in a single room. Methods MEDLINE, Global Health, Cumulative Index to Nursing and Allied Health Literature, PsycINFO, and Excerpta Medica database were searched from 1996-October 2020. Two independent reviewers screened references and assessed risk of bias. One reviewer extracted data and was checked by another. Main outcomes were Quality of Life and mortality. Results We identified 16,698 references and included 6 studies with different study designs. Average age ranged from 4-71 years. Samples sizes were small (range 10-49 participants) apart from one non-randomized controlled trial including >600 participants. Interventions were music therapy (n = 3), psychological counseling (n = 2) and exercise training (n = 1). One study reporting on Quality of Life and found no change after exercise. None of the studies reported on mortality. Due to heterogeneous results no meta-analyses were performed. Conclusions There is a lack of high-quality evidence for effective comprehensive interventions to manage adverse effects associated with isolation. Future studies should investigate the effect of multi-component interventions using rigorous methods to improve outcomes for hospitalized isolated patients.

Objectives A recent paper by Doi et al. advocated completely replacing the relative risk (RR) with the odds ratio (OR) as the effect measure in clinical trials and meta-analyses with binary outcomes. Besides some practical advantages of RR over OR, Doi et al.’s key assumption that the OR is “portable” in the meta-analysis, that is, study-specific ORs are likely not correlated with baseline risks, was not well justified. Study designs and settings We summarized Spearman's rank correlation coefficient between study-specific ORs and baseline risks in 40,243 meta-analyses from the Cochrane Database of Systematic Reviews. Results Study-specific ORs tend to be higher in studies with lower baseline risks of disease for most meta-analyses in Cochrane Database of Systematic Reviews. Using an actual meta-analysis example, we demonstrate that there is a strong negative correlation between OR (RR or RD) with the baseline risk and the conditional effects notably vary with baseline risks. Conclusions Replacing RR or RD with OR is currently unadvisable in clinical trials and meta-analyses. It is possible that no effect measure is “portable” in a meta-analysis. In addition to the overall (or marginal) effect, we suggest presenting the conditional effect based on the baseline risk using a bivariate generalized linear mixed model.

BackgroundThe number of new noncommercial clinical studies conducted in Japan declined within the first year of the implementation of the Clinical Trials Act (CTA) on April 1, 2018. This study aimed to examine the impact of the CTA’s enforcement on the number of new noncommercial clinical studies registered in the Japanese Clinical Trial Registry.MethodsAn interrupted time-series design was used in the analysis, which was conducted for the period of April 2015 to March 2019. We collected data for trials registered in the Clinical Trial Registry, managed by the University Hospital Medical Information Network.ResultsIn total, 35,811 studies were registered in the registry; of these, 16,455 fulfilled the eligibility criteria. The difference in the trend of monthly number of new trials after CTA enforcement decreased significantly by 15.0 trials (95% CI, −18.7 to −11.3), and the level decreased by 40.8 (95% CI, −68.2 to −13.3) from the pre-enforcement to the post-enforcement period. Multigroup analyses indicated that the act exerted a significant effect on the trend of new clinical trials, particularly those with smaller sample sizes, interventional study designs, and nonprofit funding sponsors.ConclusionsThe number of Japanese noncommercial clinical studies declined significantly following implementation of the CTA. It is necessary to establish a system to promote clinical studies in Japan while ensuring transparency and safety.

Background Nursing Doctor of Philosophy (PhD) enrollments are languishing, and little is known about PhD enrollment strategies that may lessen nursing's PhD shortage. Purpose This study examined strategies for bolstering PhD enrollments or enrollment intentions among college students and graduates. Methods An integrative review was undertaken using Whittemore and Knafl's methodology and Garrard's Matrix Method. Nine databases were searched, and a hand search was conducted. Findings Strategies were predominantly situated in science, technology, engineering, and mathematics (STEM) disciplines. Features of successful strategies contained core components of faculty mentoring, hands-on research, funding and compensation, undergraduate participation, summer timeframe, informational sessions, and social support. Discussion Less rigorous study designs and mostly STEM samples inhibit the transferability of these strategies to nursing. Qualitative research is needed to better understand nursing students’ perspectives about the PhD. Additionally, current PhD enrollment strategies within nursing schools need to be systematically evaluated and the findings disseminated.

Alpha-1 antitrypsin deficiency (AATD) predisposes to emphysema, liver disease, and panniculitis. This emphysema risk naturally invites a comparison between “regular” chronic obstructive pulmonary disease (COPD) (i.e., unrelated to AATD) and AATD-associated emphysema. Several features characterize both conditions. Both can be life-limiting and highly debilitating. Both are highly under-recognized. An important corollary of this comparison between “regular” COPD and AATD-associated COPD is whether both should be treated similarly and whether clinical trials to assess new therapies can be conducted similarly in both. Here, the distinctions between “regular” COPD and AATD-associated COPD are quite pronounced. Therapeutically, sparse available data suggest that lung volume reduction surgery confers less improvement in forced expiratory volume in 1 second (FEV(1)) in AATD and that such benefits are shorter-lived. Perhaps the most striking contrast between the 2 conditions is that clinical trial designs and conduct are necessarily very different. The relative scarcity of diagnosed individuals with AATD hampers recruitment to trials. Furthermore, primary outcome measures in trials of “regular” COPD must differ markedly from those of AATD-associated emphysema. Specifically, power calculations show that FEV(1) and exacerbation frequency, which are amply represented as endpoints in large COPD trials, are infeasible in studies of AATD-associated emphysema. Rather, in the 3 available randomized controlled trials of intravenous augmentation therapy, the rate of emphysema progression based on serial computed tomography densitometry measurements has been the only feasible primary outcome measure. These considerations underscore the distinctive challenges and needs of conducting treatment trials in AATD-associated emphysema and emphasize that, with regard to clinical study design, the 2 conditions are “more unalike than alike.”

Item does not contain fulltext Spinocerebellar ataxias (SCA) comprise a rare, genetic subgroup within the degenerative ataxias and are dominantly inherited, with up to 48 recognized genetic subtypes. While an updated review on the management of degenerative ataxia is published recently, an evidence-based review focussed on the management of SCA is lacking. Here, we reviewed the pharmacological and non-pharmacological management of SCA by conducting a systematic review on Medline Ovid and Scopus. Of 29,284 studies identified, 47 studies (pharmacological: n = 25; non-pharmacological: n = 22) that predominantly involved SCA patients were included. Twenty studies had a high risk of bias based on the Cochrane's Collaboration risk of bias tool. As per the European Federation of Neurological Societies 2004 guideline for therapeutic intervention, the remaining 27 studies were of Class I (n = 4) and Class II (n = 23) evidence. Only two therapies had Level A recommendations for the management of ataxia symptoms: riluzole and immediate in-patient neurorehabilitation. Ten therapies had Level B recommendations for managing ataxia symptoms and require further investigations with better study design. These include high dose valproate acid, branched-chain amino acid, intravenous trehalose; restorative rehabilitation using cycling regimen and videogame; and cerebellar stimulations using transcranial direct current stimulation and transcranial magnetic stimulation. Lithium and coaching on psychological adjustment received Level B recommendation for depressive symptoms and quality of life, respectively. Heterogeneous study designs, different genotypes, and non-standardized clinical measures alongside short duration and small sample sizes may hamper meaningful clinical translation. Therefore, rating of recommendations only serve as points of reference. 23 p.

Purpose: Current practice recommendations support the widespread implementation of reproductive genetic carrier screening (RGCS). These consensus-based recommendations highlight a research gap, with findings from current studies being insufficient to meet the standard required for more rigorous evidence-based recommendations. This systematic review assessed methodological aspects of studies on RGCS to inform the need for a core outcome set. Methods: We conducted a systematic search to identify peer-reviewed published studies offering population-based RGCS. Study designs, outcomes, and measurement methods were extracted. A narrative synthesis was conducting using an existing outcome taxonomy and criteria used in the evaluation of genetic screening programs as frameworks. Results: Sixty-five publications were included. We extracted 120 outcomes representing 24 outcome domains. Heterogeneity in outcome selection, measurement methods and time points of assessment was extensive. Quality appraisal raised concerns for bias. We found that reported outcomes had limited applicability to criteria used to evaluate genetic screening programs. Conclusions: Despite a large body of literature, diverse approaches to research have limited the conclusions that can be cumulatively drawn from this body of evidence. Consensus regarding meaningful outcomes for evaluation of RGCS would be valuable first step in working towards evidence-based practice recommendations, supporting the development of a core outcome set. Funding: This study is supported by the University of Technology Sydney and Graduate School of Health in the form of the Australian Research Training Program Fee Waiver Scholarship and Research Excellence Scholarship. Declaration of Interest: The authors declare no conflicts of interest.

Study background Back injuries are common among nurses worldwide with lifetime prevalence of lower back pain ranging from 35% to 80%, making nursing a profession at great risk for back injuries. Purpose This systematic scoping review explored and mapped existing evidence regarding the prevention of low back injury and pain among nurses and nursing students. Methods Using a scoping review methodology, six databases were searched initially in September 2017 and updated June 2020. Studies investigating interventions designed to reduce back injuries and pain among regulated nurses and student nurses, published in peer-review journals and written in English, were eligible for inclusion in this review. Quantitative, qualitative, and mixed methods studies of regulated nurses, nursing students, and nursing aides were included. Two independent reviewers screened, critically analysed studies using a quality appraisal tool, extracted data, and performed quality appraisals. Results Two searches yielded 3,079 abstracts and after title, abstract and screening, our final synthesis was based on 48 research studies. Conclusions Forty years of research has demonstrated improvements in quality over time, the efficacy of interventions to prevent back injury and pain remains unclear, given the lack of high-quality studies. Further research, using multi-dimensional approaches and rigorous study designs, are needed.

Despite numerous promising therapeutic targets, there are no proven medical treatments for calcific aortic stenosis (AS). Multiple stakeholders need to come together and several scientific, operational, and trial design challenges must be addressed to capitalize on the recent and emerging mechanistic insights into this prevalent heart valve disease. This review briefly discusses the pathobiology and most promising pharmacologic targets, screening, diagnosis and progression of AS, identification of subgroups that should be targeted in clinical trials, and the need to elicit the patient voice earlier rather than later in clinical trial design and implementation. Potential trial end points and tools for assessment and approaches to implementation and design of clinical trials are reviewed. The efficiencies and advantages offered by a clinical trial network and platform trial approach are highlighted. The objective is to provide practical guidance that will facilitate a series of trials to identify effective medical therapies for AS resulting in expansion of therapeutic options to complement mechanical solutions for late-stage disease.

Purpose Evidenced-based decision-making is rooted in comparative clinical studies; however, a small number of outcome event reversals have the potential to change study significance. The purpose of this study was to determine the utility of applying fragility analysis to comparative studies in the published orthopaedic shoulder literature. Methods Comparative clinical shoulder research studies reporting 1:1 dichotomous categorical data were analyzed in 6 leading orthopaedic journals between 2006 and 2016. Statistical significance was defined as a P value of less than .05. The fragility index (FI) for each study outcome was determined by the number of event reversals required to change the P value to either greater or less than 0.05, thus changing the study conclusions. The associated fragility quotient (FQ) was determined by dividing the FI by the total population comprising a particular outcome. Results Of the 23,897 studies screened, 3,591 met search criteria, with 198 comparative studies ultimately included for analysis, 67 of which were randomized controlled trials. There were 357 total outcome events with 74 reported as significant and 283 as not significant. The FI was 4 (IQR 2-6) with an associated FQ of 0.066 (interquartile range [IQR] 0.038-0.102). There was no difference in statistical fragility between randomized and nonrandomized trials with both revealing a FI of 4 and FQ of 0.068 (IQR 0.044-0.107) and 0.065 (IQR 0.031-0.101), respectively. Conclusions This current analysis reveals that comparative shoulder studies published in six leading orthopaedic journals are at risk of statistical fragility. As such, contemporary clinical shoulder literature may not be as robust as traditionally perceived with the reversal of only a few outcome events required to change study significance. Therefore, we advocate the reporting of both FI and FQ in addition to the P value as statistical complements to all comparative investigations to provide a more comprehensive understanding of trial stability and significance in the published shoulder literature. Clinical Relevance Comparative study designs are commonly employed in shoulder research. Several studies in both the general medical and orthopaedic literature have identified a lack of statistical robustness through comprehensive fragility analysis. Our findings demonstrate the P value may be an inadequate independent statistical metric requiring the complement of a FI and FQ to aid in the interpretation and understanding of study significance for clinical decision-making.

The relaxin-3/RXFP3 system is one of several neuropeptidergic systems putatively implicated in regulating the behavioural alterations that characterise clinical depression and anxiety, making it a potential target for clinical translation. Accordingly, this systematic review identified published reports on the role of relaxin-3/RXFP3 signalling in these neuropsychiatric disorders and their behavioural endophenotypes, evaluating evidence from animal and human studies to ascertain any relationship. We searched PubMed, EMBASE, PsycINFO and Google Scholar databases up to February 2021, finding 609 relevant records. After stringent screening, 51 of these studies were included in the final synthesis. There was considerable heterogeneity in study designs and some inconsistency across study outcomes. However, experimental evidence is consistent with an ability of relaxin-3/RXFP3 signalling to promote arousal and suppress depressive- and anxiety-like behaviour. Moreover, meta-analyses of six to eight articles investigating food intake revealed that acute RXFP3 activation had strong orexigenic effects in rats. This appraisal also identified the lack of high-quality clinical studies pertinent to the relaxin-3/RXFP3 system, a gap that future research should attempt to bridge.

Ecological momentary assessment (EMA) has increasingly been used to examine suicidality in naturalistic environments. Despite its potential to yield clinically relevant information, no EMA study has used an anonymous, fully online, design. This study reports on the feasibility and acceptability of real-time monitoring of suicide risk among 237 high-risk, anonymous, community-based adults (N = 237, 61.6% female, Mage = 27.12 years) who responded to six daily EMA prompts for 2 weeks. A subset (N = 69) completed a poststudy feedback survey to provide information on the acceptability of the study protocol. Response rates to EMA prompts (69.1%) demonstrated the feasibility of this design. Suicidal ideation was reported in 21.5% of prompts and by 86.1% of participants. Participants reported that their overall experience was positive, and that they would be willing to participate in a similar study again. Specific strengths and limitations of the study design were discussed in response to open-ended items. Finally, participants who created an alias email to ensure anonymity were less likely to report a suicide attempt (SA) history and more likely to complete the study. Overall, intensive EMA designs are feasible and acceptable when delivered online and to anonymous participants. Specific recommendations are provided for managing safety within these study designs, and for refinements in future work. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Background Cocaine abuse is a public health burden. Cocaine is known to cause vasospasm and acute myocardial infarction (AMI). The prevalence of AMI in patients presenting with chest pain and concurrent cocaine use (CPCC) varies among studies. We performed a systemic review and meta-analysis to assess the current literature for the prevalence of AMI in patients with CPCC. Methods We performed a literature search of PubMed, EMBASE, and Scopus from its beginning to May 18, 2020 and updated this search on February 18, 2021. Full-text studies that assessed the primary outcome (AMI) specifically among patients with CPCC who presented to the emergency department (ED) were included. We excluded studies that were not in English, did not take place in the ED, and case reports, which only reported positive cases and not incidence of AMI. Random effect meta-analysis was performed to assess the prevalence of primary outcome and to examine correlations between risk factors and AMI. Heterogeneity was assessed by I-square value. We also performed subgroup analysis to identify potential sources of heterogeneity. Results We identified 2178 studies and screened 102 full-text studies to include 16 studies (3269 patients) in our final analysis. The pooled prevalence of AMI was 4.7% (95% CI 0.8–23), I-square of 84%. However, rates among studies of low risk patients were lower (1.1% 95% CI 0.2–5) compared to studies of mixed risk patients (7.7%, 95% 5–11). A meta-regression was used to look at correlation between risk factors and AMI and found that AMI was positively correlated in patients with a history of CAD (correlation coefficient [Corr. Coeff.] 5.6, 96% CI 2.3–8.7), HTN (Corr. Coeff. 2.9, 95% CI 0.9–4.9), DM (Corr. Coeff. 8.0, 95% CI 2.4–14), HLD (Corr. Coeff. 5.9, 95% CI 2.4, 9). Sources of potential heterogeneity included patients' risk as defined by the authors, study designs, publication year, and study sample size. Conclusion The overall prevalence of AMI and death among patients with cocaine-associated chest pain was relatively low, although high risk patients were still associated with high prevalence of AMI. Clinicians should consider risk-stratify these patients and treat them accordingly.

Objectives To enhance the generalizability of the evidence it reviews, the US Food and Drug Administration (FDA) has encouraged manufacturers to expand the submission of real-world evidence (RWE). The extent to which this evidence, which is generated outside of research settings, can support decision making remains unclear. We described the current use of RWE for medical devices, assessed manufacturers’ challenges in generating and using it for regulatory and coverage decisions, and identified opportunities to expand its use. Methods We conducted 27 solo and group interviews with FDA officials and representatives of device manufacturers, payers, and health technology assessment organizations. All interviews used a semistructured protocol and were transcribed to allow thematic analysis. Results Accessing and linking real-world data sources, identifying unique devices, capturing longitudinal data, limited staff expertise, and uncertain return on investment have hampered efforts to use real-world data. Many companies in our sample were conducting research using real-world data, but none had submitted RWE as the primary evidence supporting a premarket approval. FDA guidance was helpful, but regulatory requirements remained ambiguous and examples of successful regulatory decisions based on RWE were limited. Payers mainly used RWE to supplement experimental evidence in coverage decisions, evaluated both types of evidence in similar ways, and had concerns about the rigor of RWE. Conclusions Technical challenges may slow efforts to generate and use RWE in the near term. Additional regulatory guidance and examples, greater use of rigorous study designs and analytic methods, and continued stakeholder engagement could accelerate the use of RWE.

Psychiatric genomics is providing insights into the nature of psychiatric conditions that in time should identify new drug targets and improve patient care. Less attention has been paid to psychiatric pharmacogenomics research, despite its potential to deliver more rapid change in clinical practice and patient outcomes. The pharmacogenomics of treatment response encapsulates both pharmacokinetic (“what the body does to a drug”) and pharmacodynamic (“what the drug does to the body”) effects. Despite early optimism and substantial research in both these areas, they have to date made little impact on clinical management in psychiatry. A number of bottlenecks have hampered progress, including a lack of large-scale replication studies, inconsistencies in defining valid treatment outcomes across experiments, a failure to routinely incorporate adverse drug reactions and serum metabolite monitoring in study designs, and inadequate investment in the longitudinal data collections required to demonstrate clinical utility. Nonetheless, advances in genomics and health informatics present distinct opportunities for psychiatric pharmacogenomics to enter a new and productive phase of research discovery and translation.