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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.

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.

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.

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.

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.

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.

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.

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.

Mobile dietary record apps have been increasingly validated by studies with various study designs. This review aims to evaluate the overall accuracy of dietary record apps in measuring the intake of energy, macro- and micronutrients, and food groups in real-life settings and the designs of validation studies. We systematically searched mobile dietary record validation studies published during the period from 2013 to 2019. We identified 14 studies for the systematic review, of which 11 studies were suitable for meta-analyses on energy intake and 8 studies on macronutrient intake. Mean differences and SDs of nutrient estimations between the app and the reference method from studies were pooled using a random-effects model. All apps underestimated energy intake when compared with their reference methods, with a pooled effect of −202 kcal/d (95% CI: −319, −85 kcal/d); the heterogeneity of studies was 72%. After stratification, studies that used the same food-composition table for both the app and the reference method had a lower level of heterogeneity (0%) and a pooled effect of −57 kcal/d (95% CI: −116, 2 kcal/d). The heterogeneity of studies in the differences in carbohydrate, fat, and protein intake was 54%, 73%, and 80%, with the pooled effect of −18.8 g/d, −12.7 g/d, and −12.2 g/d, respectively, after excluding outliers. The intakes of micronutrients and food groups were statistically nonsignificantly underestimated by the apps in most cases. In conclusion, dietary record apps underestimated food consumption compared with traditional dietary assessment methods. Moreover, varying study designs have been found across studies. Recommended practices for conducting validation studies were formulated including considering biomarkers as the reference, testing in a larger and more representative study population for a longer period, avoiding the learning effect of each method, and comparing food group or food item consumption in addition to comparing energy and nutrient intakes.

People report substituting cannabis for pain medications, but whether cannabidiol (CBD) is used similarly remains unknown. CBD products can be CBD alone (isolate), hemp extract (containing0.3% Δ-9-tetrahydrocannabinol [THC], other cannabinoids, and terpenes), or CBD-cannabis (containing0.3% THC). In a secondary analysis from a cross-sectional survey, we examined substitution patterns among n = 878 individuals with fibromyalgia who currently used CBD. We sub-grouped participants by most commonly used CBD product (CBD isolate, hemp, CBD-cannabis, no preference) and whether they substituted CBD for medications. We investigated rationale for substituting, substitution-driven medication changes, CBD use patterns, and changes in pain-related symptoms (eg, sleep, anxiety). The study population was 93.6% female and 91.5% Caucasian, with an average age of 55.5 years. The majority (n = 632, 72.0%) reported substituting CBD products for medications, most commonly NSAIDs (59.0%), opioids (53.3%), gabapentanoids (35.0%), and benzodiazepines (23.1%). Most substituting participants reported decreasing or stopping use of these pain medications. The most common reasons for substitution were fewer side effects and better symptom management. Age, hemp products, past-year use of marijuana, and higher somatic burden were all associated with substituting (P's ≤ .05). Those who substituted reported larger improvements in health and pain than those who did not. Participants using CBD-cannabis reported significantly more substitutions than any other group (P's ≤ .001) and larger improvements in health, pain, memory, and sleep than other subgroups. This widespread naturalistic substitution for pain medications suggests the need for more rigorous study designs to examine this effect. PERSPECTIVE: This article shows that people with fibromyalgia are deliberately substituting CBD products for conventional pain medications despite the dearth of evidence suggesting CBD products may be helpful for fibromyalgia. CBD's medication-sparing and therapeutic potential should be examined in more rigorous study designs.

Objective:The fragility index is a clinically interpretable metric increasingly used to interpret the robustness of clinical trials results that is generally not incorporated in sample size calculation and applied post-hoc. In this manuscript, we propose to base the sample size calculation on the fragility index in a way that supplements the classical prefixed alpha and power cutoffs and we provide a dedicated R software package for the design and analysis tools. Study design and setting:This approach follows from a novel hypothesis testing framework that is based on the fragility index and builds on the classical testing approach. As case studies, we re-analyse the design of two important trials in cardiovascular medicine, the FAME and FAMOUS-NSTEMI trials. Results:The analyses show that approach returns sample sizes which results in a higher power for the P value based test and most importantly a lower and context dependent Type I error rate for the fragility index based test compared to standard tests. Conclusion:Our method allows clinicians to control for the fragility index during clinical trial design.

Since 2012, HIV pre-exposure prophylaxis (PrEP) has been available to prevent HIV transmission; yet, uptake, adherence, and persistence to PrEP have been suboptimal. This narrative review examines the latest interventions and programs to improve all 3 stages of PrEP adherence and reviews ongoing studies to promote effective PrEP use. From 2017 to 2020, a total of 20 studies analyzed different individual- and structural-level approaches to increase PrEP adherence, including behavior change interventions, technology-based interventions (e.g., short message service messages and mobile applications), and alternate delivery strategies (e.g., pharmacy-based PrEP, integration with other services, and home delivery). Most published interventions involved men who have sex with men, although 3 assessed women (2 transgender, 1 cisgender). Randomized, controlled data support 3 behavioral change interventions and 1 technology-based intervention. Alternate delivery strategies seem promising, although more robust study designs are generally needed. In addition, data on the alignment of ongoing HIV risk and PrEP persistence (i.e., prevention-effective adherence) were limited. The authors also identified 20 ongoing studies that are promoting PrEP adherence. Future work should be inclusive of all at-risk groups in the U.S., including African American and Latinx heterosexual populations and people who inject drugs. Proven and promising approaches may work well in combination and may also need to be adapted with the introduction of long-acting pre-exposure prophylaxis formulations. Collectively, this body of work indicates considerable progress toward understanding the role PrEP adherence will play in Ending the HIV Epidemic in the U.S. that will be bolstered by the outcomes of ongoing trials.

Vaccines are vital to control the Coronavirus disease 2019 (COVID-19) pandemic, but the pressure to quickly move from research to implementation in the context of a pandemic crisis raises concerns about benefits and harms, vaccine acceptance and fair access. Here we present a strategy for the COVID-19 vaccination rollout which can be rapidly embedded and would offer direct real-world evidence of vaccines on a large scale to generate otherwise unobtainable knowledge on the safety and perhaps efficacy of COVID-19 vaccines. Such strategic rollouts leveraging randomization can provide important evidence, for COVID-19 and in future occasions, for vaccines and beyond.

Background Coronary artery disease (CAD) is a concerning late outcome for cancer survivors. However, uniform surveillance guidelines are lacking. Aim To harmonise international recommendations for CAD surveillance for survivors of childhood, adolescent and young adult (CAYA) cancers. Methods A systematic literature review was performed and evidence graded using the Grading of Recommendations, Assessment, Development and Evaluation criteria. Eligibility included English language studies, a minimum of 20 off-therapy cancer survivors assessed for CAD, and 75% diagnosed prior to age 35 years. All study designs were included, and a multidisciplinary guideline panel formulated and graded recommendations. Results 32 of 522 identified articles met eligibility criteria. The prevalence of CAD ranged from 0 to 72% and was significantly increased compared to control populations. The risk of CAD was increased among survivors who received radiotherapy exposing the heart, especially at doses ≥15 Gy (moderate-quality evidence). The guideline panel agreed that healthcare providers and CAYA cancer survivors treated with radiotherapy exposing the heart should be counselled about the increased risk for premature CAD. While the evidence is insufficient to support primary screening, monitoring and early management of modifiable cardiovascular risk factors are recommended. Initiation and frequency of surveillance should be based on the intensity of treatment exposures, family history, and presence of co-morbidities but at least by age 40 years and at a minimum of every 5 years. All were strong recommendations. Conclusion These systematically assessed and harmonised recommendations for CAD surveillance will inform care and guide research concerning this critical outcome for CAYA cancer survivors.

BACKGROUND: Students constantly seek ways to improve productivity within academia. With the advancement of technology in the recent decade, virtual implementations may provide additional support for student productivity, particularly during the COVID-19 pandemic with online learning. One of the virtual realms for motivation include gamification, which has potential as an effective tool to further bolster an individual's source of intrinsic motivation. METHODS: Qualitative and quantitative studies were extracted from APA PsycInfo, ProQuest, and IEEE for relevance to virtual gamification and intrinsic motivation. Studies were reviewed based on a pre-determined and piloted screening tool. Included studies were published between 1990 and 2020 in English within Asia, North America, or Europe. Only systematic reviews, randomized control trials (RCTs), meta-analysis, and grey literature were included. Study screening, extraction, and quality appraisals using the Mixed Methods Appraisal Tool (MMAT) were performed independently among two authors. Disagreements following reconciliation between two authors were settled by a third author. Heterogeneity in study designs, outcomes, and measurements precluded meta and statistical analyses; thus, a qualitative analysis of studies was provided. RESULTS: Based on the appraised articles, gamification improves intrinsic motivation through badges, social interactions, points, and leaderboards. Experimental studies also displayed a correlation between learning behaviour. CONCLUSION: The data exhibited an increase in intrinsic motivation due to gamification features, which can be integrated within a virtual context to enhance motivation with potential for application towards online learning settings.

Summary During the past decade, health technology assessment bodies have faced new challenges in establishing the benefits of new drugs for individuals and health-care systems. A topic of increasing importance to the field of oncology is the so-called agnostic regulatory approval of targeted therapies for cancer (independent of tumour location and histology) granted on the basis of basket trials. Basket trials in oncology offer the advantage of simultaneously evaluating treatments for multiple tumours, even rare cancers, in a single clinical trial. To address the novel challenges introduced by these trials, an interdisciplinary panel was convened on behalf of the Transparency Committee of the French National Authority for Health to clarify an approach designed to guarantee a transparent, reproducible, and fair assessment of histology-agnostic treatments for reimbursement by the French National Health Insurance Fund. The requirements of this approach include the need for randomisation, clinically relevant endpoints, appropriate correction for multiple significance testing, characterisation of subgroup heterogeneity, and validation of underlying biomarker assays. A prospectively designated external control is encouraged when the implementation of a direct comparison is deemed infeasible. We also underline the importance of recording outcomes from basket trials in a registry for use as future external controls.

Summary Background Parkinson's disease is heterogeneous in symptom presentation and progression. Increased understanding of both aspects can enable better patient management and improve clinical trial design. Previous approaches to modelling Parkinson's disease progression assumed static progression trajectories within subgroups and have not adequately accounted for complex medication effects. Our objective was to develop a statistical progression model of Parkinson's disease that accounts for intra-individual and inter-individual variability and medication effects. Methods In this longitudinal data study, data were collected for up to 7-years on 423 patients with early Parkinson's disease and 196 healthy controls from the Parkinson's Progression Markers Initiative (PPMI) longitudinal observational study. A contrastive latent variable model was applied followed by a novel personalised input-output hidden Markov model to define disease states. Clinical significance of the states was assessed using statistical tests on seven key motor or cognitive outcomes (mild cognitive impairment, dementia, dyskinesia, presence of motor fluctuations, functional impairment from motor fluctuations, Hoehn and Yahr score, and death) not used in the learning phase. The results were validated in an independent sample of 610 patients with Parkinson's disease from the National Institute of Neurological Disorders and Stroke Parkinson's Disease Biomarker Program (PDBP). Findings PPMI data were download July 25, 2018, medication information was downloaded on Sept 24, 2018, and PDBP data were downloaded between June 15 and June 24, 2020. The model discovered eight disease states, which are primarily differentiated by functional impairment, tremor, bradykinesia, and neuropsychiatric measures. State 8, the terminal state, had the highest prevalence of key clinical outcomes including 18 (95%) of 19 recorded instances of dementia. At study outset 4 (1%) of 333 patients were in state 8 and 138 (41%) of 333 patients reached stage 8 by year 5. However, the ranking of the starting state did not match the ranking of reaching state 8 within 5 years. Overall, patients starting in state 5 had the shortest time to terminal state (median 2·75 [95% CI 1·75–4·25] years). Interpretation We developed a statistical progression model of early Parkinson's disease that accounts for intra-individual and inter-individual variability and medication effects. Our predictive model discovered non-sequential, overlapping disease progression trajectories, supporting the use of non-deterministic disease progression models, and suggesting static subtype assignment might be ineffective at capturing the full spectrum of Parkinson's disease progression. Funding Michael J Fox Foundation.

Objective Due to the increasing concerns about polypharmacy, there is a growing need for clinical recommendations for drug discontinuation. This requires studies investigating the process on several levels. This paper addresses the methodological problems of drug discontinuation trials (DDTs). To that end, we offer a new typology of research aims and corresponding methodological recommendations for trials evaluating drug discontinuation. Study Design and Setting Multi-stage development process, including literature search and expert panels. Results Clinical trials are only required in cases of scientific uncertainty. We identified three situations of uncertainty associated with drug discontinuation from which we derived three study types: 1) Uncertainty regarding the effectiveness and/or safety of a drug; 2) Uncertainty regarding the procedure of discontinuing a previously taken drug; 3) Uncertainty regarding the effectiveness of complex strategies used to discontinue one or more drugs. We developed specific methodological recommendations for each study type. Conclusion We offer a comprehensive definition of research aims, study designs, and methodological recommendations regarding DDTs. The typology we propose can help investigators clarify their research aims and study design. The type-specific methodological recommendation should improve the quality of future drug discontinuation trials.

>Goal-concordant care is a priority outcome for palliative care research, yet the field lacks consensus on optimal methods for measurement. We sought to 1) categorize methods used to measure goal-concordant care, and 2) discuss strengths and limitations of each method using empirical examples from palliative care research. We categorized measurement methods for goal-concordant care. We identified empirical examples of each method to illustrate the strengths, limitations, and applicability of each method to relevant study designs. We defined four methods used to measure goal-concordant care: 1) Patient- or Caregiver-Reported, 2) Caregiver-Reported After Death, 3) Concordance in Longitudinal Data, and 4) Population-Level Indicators. Patient or caregiver-reported goal-concordant care draws on strengths of patient-reported outcomes, and can be captured for multiple aspects of treatment; these methods are subject to recall bias or family-proxy bias. Concordance in longitudinal data is optimal when a treatment preference can be specifically and temporally linked to actual treatment; the method is limited to common life-sustaining treatment choices and validity may be affected by temporal variation between preference and treatment. Population-level indicators allow pragmatic research to include large populations; its primary limitation is the assumption that preferences held by a majority of persons should correspond to patterns of actual treatment in similar populations. Methods used to measure goal-concordant care have distinct strengths and limitations, and methods should be selected based on research question and study design. Existing methods could be improved, yet a future gold standard is unlikely to suit all research designs.

Summary Polycythaemia vera is a challenging disease to study given its low prevalence and prolonged time-to-event for important clinical endpoints such as thrombosis, progression, and mortality. Although researchers in this space often rise to meet these challenges, there is considerable room for improvement in the analysis of retrospective data, the development of risk-stratification tools, and the design of randomised controlled trials. In this Viewpoint, we review the evidence behind the contemporary approach to risk stratification and treatment of polycythaemia vera. Frameworks for using data more efficiently, constructing more nuanced prognostic models, and overcoming challenges in clinical trial design are discussed.

Objective: To inform a research plan for future studies by obtaining stakeholder input on the application of preference-based methods to clinical trial design. Methods: We conducted a virtual OMERACT session to encourage stakeholder engagement. We developed materials for the session to facilitate discussion based on identified case examples and feedback sessions. Results: Participants prioritized incorporating patient preferences in all aspects of trial design with an empha-sis on outcome selection. Participants highlighted the need for careful consideration around preference het-erogeneity and equity factors. Conclusion: Including patient preferences in trial design was considered a priority requiring further explora-tion to develop comprehensive guidance. (c) 2021 Elsevier Inc. All rights reserved.

BackgroundAcute respiratory tract infections (RTIs) are the most common reason to seek medical care, with many patients receiving inappropriate antibiotics. Novel testing approaches to identify aetiology at the point-of-care are required to accurately guide antibiotic treatment.ObjectiveTo assess the diagnostic accuracy of biomarker combinations to rapidly differentiate between acute bacterial or viral RTI aetiology.Data sourcesMEDLINE, Embase and Web of Science databases were searched to February 2021.Study eligibility criteriaDiagnostic accuracy studies comparing accuracy of point-of-care and rapid diagnostic tests in primary or secondary care, consisting of biomarker combinations, to identify bacterial or viral aetiology of RTI.MethodsRisk of bias was assessed using the QUADAS-2 tool. Sensitivity and specificity of tests reported by more than one study were meta-analysed using a random effects model.ResultsTwenty observational studies (3514 patients) were identified. Eighteen were judged at high risk of bias. For bacterial aetiologies, sensitivity ranged from 61% to 100% and specificity from 18% to 96%. For viral aetiologies, sensitivity ranged from 59% to 97% and specificity from 74% to 100%. Studies evaluating two commercial tests were meta-analysed. For ImmunoXpert, the summary sensitivity and specificity were 85% (95% CI 75%–91%, k = 4) and 86% (95% CI 73%–93%, k = 4) for bacterial infections, and 90% (95% CI 79%–96%, k = 3) and 92% (95% CI 83%–96%, k = 3) for viral infections, respectively. FebriDx had pooled sensitivity and specificity of 84% (95% CI 75%–90%, k = 4) and 93% (95% CI 90%–95%, k = 4) for bacterial infections, and 87% (95% CI 72%–95%; k = 4) and 82% (95% CI 66%–86%, k = 4) for viral infections, respectively.ConclusionCombinations of biomarkers show potential clinical utility in discriminating the aetiology of RTIs. However, the limitations in the evidence base, due to a high proportion of studies with high risk of bias, preclude firm conclusions. Future research should be in primary care and evaluate patient outcomes and cost-effectiveness with experimental study designs.Clinical trialPROSPERO registration number: CRD42020178973.

Objectives This article provides GRADE guidance on how authors of evidence syntheses and health decision makers, including guideline developers, can rate the certainty across a body of evidence for comparative test accuracy questions. Study design and setting This guidance extends the previously published GRADE guidance for assessing certainty of evidence for test accuracy to scenarios in which two or more index tests are compared. Through an iterative brainstorm-discussion-feedback process within the GRADE working group, we developed a guidance accompanied by practical examples. Results Rating the certainty of evidence for comparative test accuracy shares many concepts and ideas with the existing GRADE guidance for test accuracy. The rating in comparisons of test accuracy requires additional considerations, such as the selection of appropriate comparative study designs, additional criteria for judging risk of bias, and the consequences of using comparative measures of test accuracy. Distinct approaches to rating certainty are required for comparative test accuracy studies and between-study (indirect) comparisons. Conclusion This GRADE guidance will support transparent assessment of the certainty for a body of comparative test accuracy evidence.

Purpose To objectively identify the 50 most influential studies in knee arthroscopy and provide an analysis of their key characteristics. Methods The Clarivate Analytics Web of Knowledge database was used to gather data and metrics of knee arthroscopy research. The search list was sorted by the number of citations, and articles were included or excluded based on relevance to knee arthroscopy. The information extracted for each article included author name, publication year, country of origin, journal name, article type, and the level of evidence. Results For these 50 studies, the total number of citations was calculated to be 12,168, with an average of 243.4 citations per paper. The most-cited article was cited 1,220 times. The 50 studies included in this analysis were published between 1972 and 2013. All 50 articles were published in English and came from 10 different orthopaedic journals. The United States was responsible for the majority of articles (n = 26); however, many other countries were represented. The most prevalent study designs were case series (n = 20). Conclusions The 50 most influential articles in knee arthroscopy were cited a total of 12,168 times. The study designs most commonly used were case series and cohort studies. This article serves as a reference to direct orthopaedic practitioners to the 50 most influential studies in knee arthroscopy. We hope that these 50 studies and the analysis we provide help health care professionals efficiently assess consensus, trends, and needs within the field. Clinical Relevance This analysis of the 50 most influential studies in knee arthroscopy will provide medical students, residents, fellows, and attending physicians with a comprehensive inventory and citation analysis of the most impactful academic contributions to one of the most important fields within orthopaedic surgery.

Background With a steady rise in the number of urgent care centers in the United States and the establishment of urgent care medicine as a specialty, research in the field is likely to emerge. Objectives To perform a bibliometric analysis of published studies in the field of urgent care medicine over the past two decades. Methods A comprehensive literature review was conducted, including original and review articles pertaining to urgent care medicine published 2000–2020. Data abstracted from each article included publication year, journal, research study design, study population, clinical relevance (clinical or non-clinical), and study topics. Results A total of 144 publications from 94 peer-reviewed journals were analyzed. There has been a steady increase in the annual number of publications from 2010 to 2019. The most common study designs were retrospective (55.5%), study specific (24.3%), prospective (15.3%), and quality improvement (4.9%). Adults were the most frequently identified study population (33.3%), followed by pediatrics (18%), and both adults and pediatrics (16.7%). Publications were categorized as clinical (48.6%) and non-clinical (51.4%). The most common research topics were urgent care utilization [n = 34, 23.6%; especially effectiveness (n = 9) and disease based (n = 7)], diagnostic testing [(n = 20, 13.9%; especially HIV (n = 7) and sexually transmitted infections (n = 6)], and antibiotic stewardship (n = 17, 11.8%). Conclusion Based on our sample, published research in the field of urgent care medicine has evolved. By describing current trends, we hope that clinicians and researchers continue to advance the field by developing high quality research, including prospective, multi-institutional/center studies involving both clinical and non-clinical topics.

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that has gained relevance in recent years as an alternative treatment for neuropsychiatric conditions. The aim of this study is to conduct a systematic review of the use of tDCS in Autism Spectrum Disorder (ASD). Both electronic and manual searches were conducted to identify studies published in peer-reviewed scientific journals addressing the use of tDCS in ASD population. A total of 16 studies fulfilled the criteria to be included in the review. Studies were conducted both in child and adult population. Anodal stimulation on the left dorsolateral prefrontal cortex was the most commonly chosen methodology. Outcomes addressed ASD symptoms and neuropsychological functions. Meta-analytic synthesis identified improvements in social, health, and behavioral problem domains of the Autism Treatment Evaluation Checklist. Limitations included high heterogeneity in the methodology and low-efficacy study designs (pre-post and single-case studies). Recent controlled trials shed promising results for the use of tDCS in ASD. A standardized stimulation protocol and a consensus in the measures used in the evaluation of the efficacy are imperative.

The development of interventions to slow or halt the progression of Parkinson's disease remains a priority for patients and researchers alike. To date, no agents have been shown to have unequivocal evidence of disease-modifying effects in Parkinson's disease. The absence of disease-modifying treatments might relate not only to inadequate approaches for the selection of therapeutic candidates but also to insufficient attention to detail in clinical trial design. Better understanding of Parkinson's disease pathogenesis associated with advances in laboratory models, the use of objective biomarkers of disease progression and target engagement, and a focus on agents known to be safe for human use, alongside the use of precision medicine approaches, should together greatly increase the likelihood for successful identification of disease-modifying treatments for Parkinson's disease.

The continuous advances in the treatment landscape of multiple myeloma has led to the approval of several novel agents and their combinations that significantly improved patient outcomes. Despite their undoubtful effectiveness in the context of clinical trials, their impact on real-world (RW) clinical practice remains debatable. RW data on the role of novel agents and their combinations among patients with relapsed/refractory multiple myeloma have confirmed the efficacy of proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies. However, the magnitude of the benefit and the safety profile may differ among RW studies and between RW and pivotal clinical trials. Several variables may pertain to these observations and include patient selection, ethnicity, age, comorbidities, disease stage at diagnosis and at relapse, number of prior lines of therapy, disease subtype, presence of renal impairment, extramedullary disease, and cytogenetic abnormalities. All these contribute to a varying degree of disease and patient heterogeneity among the studies that may result in a differential treatment effect. The expertise of each medical center and the treatment setting in terms of availability and drug access are particularly important as well. Interestingly, RW observations may serve as proof of concept for designing novel clinical trials, as is the case with retreatment studies. In conclusion, clinical trial and RW data are complementary, and they should be considered to improve both clinical trial design and clinical practice.

Summary Hepatocellular carcinomas are not a homogenous group of tumors but have multiple layers of heterogeneity. This heterogeneity has been studied for many years with the goal to individualize care for patients and has led to the identification of numerous hepatocellular carcinoma subtypes, defined by morphology and or molecular methods. This article reviews both gross and histological levels of heterogeneity within hepatocellular carcinoma, with a focus on histological findings, reviewing how different levels of histological heterogeneity are used as building blocks to construct morphological hepatocellular carcinoma subtypes. The current best practice for defining a morphological subtype is outlined. Then, the definition for thirteen distinct hepatocellular carcinoma subtypes is reviewed. For each of these subtypes, unresolved issues regarding their definitions are highlighted, including recommendations for these problematic areas. Finally, three methods for improving the research on hepatocellular carcinoma subtypes are proposed: (1) Use a systemic, rigorous approach for defining hepatocellular carcinoma subtypes (four-point model); (2) Once definitions for a subtype are established, it should be followed in research studies, as this common denominator enhances the ability to compare results between studies; and (3) Studies of subtypes will be more effective when morphological and molecular results are used in synergistic and iterative study designs where the results of one approach are used to refine and sharpen the results of the other. These and related efforts to better understand heterogeneity within hepatocellular carcinoma are the most promising avenue for improving patient care by individualizing patient care.

Diagnostic test accuracy studies are performed in order to determine the value of a diagnostic test. Primary studies of diagnostic accuracy describe the accuracy of a test calculated using the number of true and false positive and negative cases of a given diagnosis of interest. Systematic reviews of diagnostic test accuracy are performed to identify accuracy of a test but also to investigate where the test might sit in a diagnostic pathway or determine how different tests compare against each other. This introductory discussion paper aims to give the reader an overview of the various features in primary and secondary diagnostic test accuracy study designs for medical imaging professionals.

Evidence of comparative benefits of long-acting injectable antipsychotics (LAIs) versus oral antipsychotics for schizophrenia has been inconsistent across study designs. The aim of this study was to evaluate the comparative benefits of LAIs versus oral antipsychotics in three study designs to inform clinical decision making.We did a comprehensive systematic review and meta-analysis comparing LAIs versus oral antipsychotics for schizophrenia covering three study designs: randomised controlled trials (RCTs), cohort studies, and pre-post studies. Our literature search was without language restrictions, in MEDLINE and PubMed, the Cochrane Library, Scopus, and Embase, for studies published from database inception up to a last search on March 13, 2020. We also searched for unpublished studies and ClinicalTrials.gov. We included studies lasting at least 6 months that targeted adults with schizophrenia and related disorders (80% of participants). Studies on penfluridol (neither an LAI or daily oral antipsychotic), case reports, and case series with fewer than 20 patients were excluded. Two investigators independently extracted study-level data and resolved disagreement by consensus, or via a third investigator. Study authors were contacted to obtain additional information as needed. For our primary outcome we meta-analysed the risk ratio (RR) for hospitalisation or relapse with LAIs versus oral antipsychotics by a random-effects model, with hospitalisation used preferentially over relapse. As secondary analyses, we reversed the preferential order to relapse over hospitalisation, and assessed hospitalisation risk and relapse risk individually. Other secondary outcomes included all meta-analysable data, classed by relevance to effectiveness, efficacy, safety, quality of life, cognitive function, and other outcomes, and analysed by study design. Dichotomous outcomes were expressed as pooled RR and continuous outcomes as standardised mean difference (SMD). The protocol is registered with PROSPERO (CRD42019142094).We identified 14 687 records, of which 137 studies (397 319 patients) met the inclusion criteria (32 RCTs [23·4%; 8577 patients], 65 cohort studies [47·4%; 377 447 patients], and 40 pre-post studies [29·2%; 11 295 patients]) and were analysed. The quality of studies in terms of risk of bias varied across study designs and within each study design from low to high. LAIs were associated with a lower risk of hospitalisation or relapse than oral antipsychotics in each of the three study designs (RCTs: 29 studies, 7833 patients, RR 0·88 [95% CI 0·79-0·99], p=0·033; cohort studies: 44 studies, 106 136 patients, RR 0·92 [0·88-0·98], p=0·0044; pre-post studies: 28 studies, 17 876 patients, RR 0·44 [0·39-0·51], p0·0001). This association was maintained across the study designs when we reversed the preferential order to risk of relapse over hospitalisation, and in individual analysis of hospitalisation risk. The association was maintained only in pre-post studies for relapse risk alone. In all other outcomes related to effectiveness, efficacy, safety, quality of life, cognitive function, and other outcomes, LAIs were more beneficial than oral antipsychotics in 60 (18·3%) of 328 comparisons, not different in 252 (76·8%) comparisons, and less beneficial in 16 (4·9%) comparisons when analysed by study design. Significant heterogeneity was observed across all three study designs. Publication biases were apparent in cohort and pre-post studies, but effect sizes were similar after trim-and-fill analyses.Although study designs have strengths and weaknesses, including potential low quality of observational studies, we consistently identified significant benefit with LAIs versus oral antipsychotics in preventing hospitalisation or relapse, in settings ranging from restricted research (RCTs) to real-word application (cohort and pre-post studies). Our findings suggest that increased clinical use of LAIs could improve outcomes in schizophrenia.None.For the Chinese, French, German, Italian, Japanese, Portugese and Spanish translations of the abstract see Supplementary Materials section.

PURPOSE: Stereotactic body radiation therapy (SBRT) has emerged as a viable reirradiation strategy for locally recurrent previously-irradiated head and neck cancer. Doses in the literature have varied, which challenges clinical application of SBRT as well as clinical trial design. MATERIAL & METHODS: A working group was formed through the American Association of Physicists in Medicine to study tumor control probabilities for SBRT in head and neck cancer. We herein present a systematic review of the available literature addressing the dose/volume data for tumor control probability with SBRT in patients with locally recurrent previously-irradiated head and neck cancer. Dose-response models are generated that present tumor control probability as a function of dose. RESULTS: Data from more than 300 cases in 8 publications suggest that there is a dose-response relationship, with superior local control and possibly improved overall survival for doses of 35 to 45 Gy (in 5 fractions) compared with

Fluorescence-guided surgery is an intraoperative optical imaging method that provides surgeons with real-time guidance for the delineation of tumours. Currently, in phase 1 and 2 clinical trials, evaluation of fluorescence-guided surgery is primarily focused on its diagnostic performance, although the corresponding outcome variables do not inform about the added clinical benefit of fluorescence-guided surgery and are challenging to assess objectively. Nonetheless, the effect of fluorescence-guided surgery on intraoperative decision making is the most objective outcome measurement to assess the clinical value of this imaging method. In this Review, we explore the study designs of existing trials of fluorescence-guided surgery that allow us to extract information on potential changes in intraoperative decision making, such as additional or more conservative resections. On the basis of this analysis, we offer recommendations on how to report changes in intraoperative decision making that result from fluorescence imaging, which is of utmost importance for the widespread clinical implementation of fluorescence-guided surgery.