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Systematic Review of Pharmacologic Treatment for Migraine Prevention in Adults: Report of the AAN Guidelines Subcommittee and the American Headache Society.

BACKGROUND AND OBJECTIVES: This systematic review (SR) provides updated evidence-based conclusions regarding the use of pharmacologic migraine prevention in adults to inform a new joint American Academy of Neurology (AAN) and American Headache Society practice guideline. METHODS: A multidisciplinary panel conducted an SR following the 2017 AAN Clinical Practice Guideline Process Manual. Randomized controlled trials evaluating pharmacologic preventive treatments for adults with episodic or chronic migraine were included. Searches encompassed MEDLINE, Embase, and ClinicalTrials.gov from database inception through June 6, 2024. Studies were screened in duplicate, with dual independent risk-of-bias assessment. Outcomes included change in monthly headache days, ≥50% responder rate, and validated patient-reported quality of life (QOL) measures. Raw mean differences, standardized mean differences, and risk ratios were calculated. A modified Grading of Recommendations Assessment, Development, and Evaluation process was used to classify certainty of evidence. RESULTS: A total of 217 studies met inclusion criteria. For episodic migraine, high-confidence evidence showed that galcanezumab and erenumab are more effective than placebo in reducing headache frequency. Moderate-confidence evidence supported benefit from atogepant, eptinezumab, fremanezumab, propranolol, topiramate, and valproate. Several additional oral agents including amitriptyline, bisoprolol, flunarizine, fluoxetine, levetiracetam, metoprolol, nifedipine, pizotifen, and telmisartan had low-confidence evidence suggesting possible benefit. For chronic migraine, high-confidence evidence supported reductions in headache frequency with fremanezumab, galcanezumab, and onabotulinumtoxinA. Moderate-confidence evidence supported benefit from atogepant, eptinezumab, erenumab, topiramate and valproate. Across both episodic and chronic migraine populations, erenumab, fremanezumab, galcanezumab, eptinezumab, rimegepant, atogepant, topiramate and onabotulinumtoxinA demonstrated improvements in patient-reported QOL outcomes on validated instruments. Evidence comparing active treatments was limited and generally of low or very low confidence, restricting conclusions about comparative effectiveness. DISCUSSION: This SR provides a comprehensive synthesis of evidence on pharmacologic migraine prevention in adults. High- and moderate-confidence findings confirm the efficacy of several established and newer preventive therapies and demonstrate improvements in patient-reported outcomes across multiple validated measures. These conclusions informed the development of evidence-based recommendations, presented in a companion publication, to guide clinicians in selecting preventive medications for adults with episodic and chronic migraine.

Humans

Simultaneous determination of imiquimod and terbinafine in skin permeation studies: Validation of a liquid chromatography method with fluorescence detection.

Chromoblastomycosis is a chronic, neglected subcutaneous mycosis posing significant therapeutic challenges. A topical strategy combining terbinafine (TBF), an antifungal, with imiquimod (IMQ), a TLR-7/8 agonist immunomodulator, has emerged a promising alternative. However, no validated analytical method is currently available to simultaneously quantify both drugs in skin, which is crucial for novel formulation development. This study reports the development and validation of a simple HPLC method with fluorescence detection (excitation 236 nm, emission 340 nm) for the simultaneous determination of TBF and IMQ extracted from porcine skin. Separation was achieved on a C8 reversed-phase column (125 × 4.0 mm, 5 μm) using a mobile phase of methanol and water (60,40, v/v), both containing 0.1% formic acid at a flow rate of 0.8 mL/min. The method showed excellent linearity (r > 0.999) over 0.01-1.0 μg/mL for IMQ and 0.1-2.0 μg/mL for TBF. Intra- and inter-day precision demonstrated coefficients of variation below 5%, and recovery rates from skin (79-105%) confirmed accuracy. Limits of detection were 0.001 μg/mL for IMQ and 0.004 μg/mL for TBF, with quantification limits of 0.02 μg/mL and 0.16 μg/mL, respectively. This selective, sensitive, and reproducible method represents a valuable analytical tool for supporting the development and quality control of topical formulations for chromoblastomycosis and other fungal skin diseases.

Animals

The role of adjunctive aqueous suppressants for anti-vascular endothelial growth factor therapy: A systematic review.

Our goal is to determine whether adjunctive aqueous suppressants (topical β-blockers, carbonic anhydrase inhibitors, or oral acetazolamide) enhance outcomes of anti-vascular endothelial growth factor (anti-VEGF) therapy for diabetic macular edema (DME), retinal vein occlusion (RVO), and neovascular age-related macular degeneration (nAMD), focusing on retinal thickness, visual acuity, injection burden, intraocular pressure (IOP), and safety. DME, RVO, and nAMD are leading causes of vision loss treated with repeated intravitreal injections, yet many eyes show persistent fluid. Aqueous suppressants are inexpensive and widely available, with potential to prolong intravitreal drug residence and improve outcomes, but their clinical value remains uncertain. Following a registered protocol, we searched 4 databases (January, 2000 toMay, 2025) for randomized and comparative studies evaluating adjunct aqueous suppressants with anti-VEGF therapy. Primary outcome was change in retinal thickness; secondary outcomes included visual acuity, injection burden, IOP, and adverse events. Risk of bias was assessed and findings synthesized narratively. Twelve studies (7 randomized trials; 495 eyes) met inclusion criteria. In DME, 3 of 4 trials showed greater thickness reduction with adjunctive dorzolamide (±timolol), although visual gains were inconsistent. In RVO, 1 trial suggested transient anatomical benefit, whereas oral acetazolamide showed no added effect. In nAMD, adjunctive dorzolamide-timolol reduced residual fluid in refractory cases without visual or treatment-sparing benefit. Topical therapy produced modest IOP reductions without serious adverse events. Adjunct aqueous suppressants may provide limited short-term anatomical benefit, particularly in DME and refractory nAMD, but consistent functional or durability effects are not found in this study. Larger, longer-term randomized studies are needed.

Humans

Cardiovascular risks in psychiatric disorders and psychiatric risks in cardiovascular disorders: implications for prevention and clinical management - a large-scale umbrella review encompassing 76 meta-analyses.

OBJECTIVE: Psychiatric and cardiovascular disorders often co-occur, complicating their assessment and management. No umbrella review(UR) has summarized the meta-analytic evidence on the co-occurrence of psychiatric and cardiovascular disorders and assessed its credibility. METHODS: Meta-analytic systematic reviews of observational studies documenting the prevalence, risk factors, and outcomes associated with the co-occurrence of cardiovascular and psychiatric disorders, indexed from inception through March.16.2026, and meeting established diagnostic criteria, were included. Meta-analytic association and prevalence estimates were recalculated and graded based on established or adapted criteria. The AMSTAR-2 assessed the quality of the meta-analyses, while several subgroup analyses and meta-regressions aimed to explain the heterogeneity. RESULTS: We included 76 meta-analyses yielding 131 meta-analytic estimates. Based on pre-existing meta-analytic evidence, 22/24 prevalence estimates (91.7%) met moderate/strong credibility criteria. Strong credibility emerged for: orthostatic hypotension in Lewy body(58%;95%C.I. = 50-66%) and Alzheimer's dementias(28.0% = 95%C.I. = 17.0-40.0%); pericardial effusion in anorexia nervosa(25.0%;95%C.I. = 17.0-34.0%); in heart failure(HF): major depressive disorder(MDD)(41.9%;95%C.I. = 36.7-47.1%), mild cognitive impairment(MCI)(41.4%;95%C.I. = 38.3-45.6%), anxiety(32.0%;95%C.I. = 26.5-37.6%), MDD + anxiety(24.7%;95%C.I. = 17.9-34.3%), and dementia(19.8%;95%C.I. = 12.9-27.8%); in atrial fibrillation(AF): MCI(26.0%;95%C.I. = 21.0-30.0%), anxiety in patients undergoing pulmonary vein isolation(PVI)(25.0%;95%C.I. = 12.0-46.0%), MDD in PVI patients (20.0%;95%C.I. = 13.0-29.0%); in coronary artery disease: MDD + anxiety(19.8%;95%C.I. = 16.0-24.6%): in schizophrenia spectrum disorders: clozapine-associated-cardiomyopathy(0.6%;95%C.I. = 0.2-2.3%); clozapine-associated-cardiomyopathy absolute death rates (0.0003;95%C.I. = 0.0001-0.0012); clozapine-associated-cardiomyopathy case fatality rate (0.078;95%C.I. = 0.018-0.285). Several additional disorders were multimorbid in>5% of people, yet with a lower credibility rating. No re-pooled risk factors/outcomes reached strong credibility criteria. CONCLUSIONS: The present study provides an atlas of cardiovascular and psychiatric multimorbidity across varying levels of credibility, reinforcing the need for an integrated, multidisciplinary approach to patient care and for more research on actionable risk/protective factors and outcomes.

Humans

Patient-reported outcomes in pediatric regional anesthesia trials: current use and limitations.

PURPOSE OF REVIEW: This review examines the current use and limitations of patient-reported outcome measures (PROMs) in pediatric regional anesthesia research. Despite the increasing emphasis on patient-centered outcomes, existing pediatric outcome assessment frameworks may inadequately capture the pain experience and interference with daily living. RECENT FINDINGS: Across 17 identified randomized controlled trials and 15 ongoing studies, PROM use remains highly variable, with consistent reliance on observational pain scales such as the Face, Legs, Activity, Cry, and Consolability scale and limited incorporation of standardized, longitudinal health-related quality-of-life measures. SUMMARY: Current pediatric PROM frameworks remain fragmented, limiting comprehensive evaluation of recovery. Greater standardization and incorporation of developmentally appropriate, longitudinal outcome measures are needed to better align clinical research with meaningful patient-centered endpoints and to improve assessment of functional and psychosocial recovery.

Humans

Voluntary Knowledge Brokering to Promote Evidence-Based Nursing Practice: A Qualitative Study.

Knowledge brokering is a process of connecting knowledge producers with users to facilitate evidence-based practice through relationship building and information sharing. This descriptive qualitative study aimed to clarify knowledge brokering by nurses in Japanese hospitals. Twelve registered nurses in Japanese hospitals participated. They had over 5 years' clinical experience, including experience in conducting research, particularly staff research, and education. Data were collected through semi-structured individual interviews and analyzed using qualitative content analysis. The analysis revealed a central theme: continuous efforts to foster empathy among colleagues and spontaneously promote evidence-based practice: multifaceted brokering activities by clinical nurses. Findings identified 10 categories categorized into four interconnected gears: establishing the foundational ground, assessing clinical needs and staff readiness, tailoring and diffusing evidence, and sustaining and evolving evidence-based practice. Even nurses without formal titles voluntarily bridged the research-practice gap, providing new insights into informal brokering. Brokers communicated considerately, balanced evidence with clinical context, negotiated practical compromises, and fostered staff research competency.

Humans

Family-Wise Error Rate Control in Clinical Trials With Overlapping Populations.

We consider clinical trials with multiple, overlapping patient populations that test multiple treatment policies specifically tailored to these populations. Such designs may lead to multiplicity issues, as false statements will affect several populations. For type I error control, often the family-wise error rate (FWER) is controlled, which is the probability to reject at least one true null hypothesis. If the joint distribution of the test statistics is known, the FWER level can be exhausted by determining critical values or adjusted-levels. The adjustment is typically done under the common ANOVA assumptions. However, the performed tests are then only valid under the rather strong assumption of homogeneous null effects, that is, when the null hypothesis applies to all subpopulations and their intersections. We show that under cancelling null effects, when heterogeneous effects cancel out in some or all subpopulations, this procedure does not provide FWER control. We also suggest different alternatives and compare them in terms of FWER control and their power.

Humans

Effects of exercise on aerobic capacity in people with prehypertension or hypertension: a systematic review and meta-analysis of randomized controlled trials.

This study aimed to quantify the effects of exercise on aerobic capacity in people with prehypertension or hypertension and to identify exercise prescription parameters that optimize improvements. A comprehensive search was conducted in PubMed, Web of Science, Embase, Cochrane Library, and Scopus from inception to 24 October 2025. Data were pooled using standardized mean differences (SMDs) with 95% confidence intervals (CI). Fifteen studies met the inclusion criteria. Exercise significantly improved aerobic capacity in people with prehypertension or hypertension (SMD&#x200a;=&#x200a;0.88; 95% CI: 0.61-1.15; P &#x200a;<&#x200a;0.00001), with multicomponent training demonstrating superior efficacy. Exploratory subgroup analyses suggest that longer programs (&#x2265;12&#x200a;weeks), lower frequency (<3&#x200a;sessions/week), 60-min sessions or longer, total weekly exercise less than 180&#x200a;min, and professional supervision may be associated with better outcomes.

Humans

Histoplasmosis in children: emerging insights and evolving guidelines.

PURPOSE OF REVIEW: This review provides an update on the epidemiology, risk factors, clinical presentation, diagnosis, and management recommendations incorporating recommendations from recent publications including the Infectious Disease Society of America guidelines for the management of pulmonary and disseminated histoplasmosis. RECENT FINDINGS: Updates to the epidemiology of histoplasmosis indicate a broader geographic range than historically defined. Updated guidelines do not recommend routine treatment for asymptomatic, mild and moderate pulmonary histoplasmosis although itraconazole can be offered for immunocompromised children or for prolonged or worsening symptoms. Liposomal amphotericin B is recommended as initial treatment for severe histoplasmosis syndromes (severe pulmonary and disseminated histoplasmosis). Fibrosing mediastinitis, a late complication of histoplasmosis is treated with stenting of vessels and bronchi. Recent studies demonstrate that rituximab (anti-CD20 monoclonal antibody) may stop progression or lead to regression of progressive fibrosis. SUMMARY: Histoplasmosis has manifold manifestations, many of which are self-limited and do not require treatment. Severe histoplasmosis and its complications should be treated with liposomal amphotericin B followed by itraconazole. Clinical trials are needed to assess the efficacy of rituximab for the treatment of fibrosing mediastinitis.

Humans

Walking Together: A Cross-Cultural Study of the Relationship Between Religiosity and Substance Use Disorder.

The literature suggests that religiosity is a protective factor for substance use. However, individuals with substance use disorder (SUD) may actively cultivate their religiosity during substance use. This qualitative study analyzed the perceptions and meanings homeless people attribute to their substance use trajectories and religiosity, as well as the potential connections between these two themes. The analysis was conducted based on the content analysis technique proposed by Bardin. A total of 40 semi-structured interviews were conducted with 20 Brazilian and 20 Portuguese participants. The present study found that religiosity can play a role in the substance use trajectory and the development of SUD by offering a subjective sense of protection, serving as a marker for the need for change, or providing relief from the suffering associated with SUD. We discuss how homeless people with SUD experience religiosity and how religious aspects traditionally seen as protective in the literature, such as church attendance, may paradoxically become risk factors for these socially vulnerable populations.

Humans

Determinants of Nonspecific Response to Treatment in Randomized Controlled Trials of Major Depressive Disorder: A Narrative Review.

The design, conduct, and interpretation of double-blind randomized placebo-controlled clinical trials in major depressive disorder (MDD) are complicated by determinants of nonspecific response to treatment (NSRT). This narrative review provides a comprehensive overview of the determinants of NSRT in randomized controlled trials (RCTs) for MDD, including the placebo effect, factors related to measurement of the primary endpoint, the inclusion of misdiagnosed patients, the relapsing-remitting course of MDD, and factors related to functional unblinding. Potential strategies to reduce the impact of the determinants of NSRT and to improve the interpretation of RCT outcomes in MDD are also summarized. These strategies include use of centralized rating and standardized rater training, independent diagnostic confirmation, optimized site selection, minimizing financial incentives, exclusion of subjects participating in multiple clinical trials, exclusion of patients with unstable major depressive episode trajectories, and use of active placebo and alternative trial designs. Uniformity among experts in the definitions of determinants of NSRT and related concepts, as well as in strategies to address them, may facilitate progress in the development of novel treatments for MDD.

Humans

Virtual Reality Education for Hospitalized Pediatric Patients Improves Intrinsic Motivation: A Prospective, Randomized Crossover Study.

Hospitalized children experience educational disruption and reduced motivation during prolonged admissions. Despite the availability of in-hospital schools, many cannot participate due to illness severity or isolation precautions. This pragmatic, randomized crossover trial evaluated whether bedside virtual reality (VR) lessons improve intrinsic motivation among inpatients aged 5 to 25 years unable to attend the hospital school. Participants completed both VR-based educational sessions and standard of care (SOC) conditions on consecutive days. The primary outcome was intrinsic motivation, with secondary outcomes including educational self-efficacy, well-being, self-esteem, and parental experience. Of 156 enrolled patients, 100 were analyzed (mean age 11.5 [SD = 4.1 years]; 43.9% female). Intrinsic motivation scores were higher in the VR condition than SOC (P = .0048), and parental satisfaction was also greater (P = .0008). Bedside VR education represents a feasible, acceptable, and scalable adjunct to inpatient learning, supporting intrinsic motivation and caregiver satisfaction during hospitalization.Trial Registration: ClinicalTrials.gov NCT05725395, date first registered November 22, 2022.

Humans

Transcutaneous vagus nerve stimulation influences sleep quality and insomnia: A systematic review and meta-analysis.

Impairments in sleep quality, timing, or duration disrupt normal sleep patterns. This systematic review and meta-analysis investigated the effects of transcutaneous vagus nerve stimulation (tVNS) protocols on sleep outcomes. Thirteen randomized controlled trials with parallel or crossover designs that applied tVNS intervention and assessed sleep quality (Pittsburgh Sleep Quality Index) and insomnia severity (Athens Insomnia Scale and Insomnia Severity Index) were included. Effect sizes were calculated by comparing changes between the active tVNS and control groups. Moderator analyses examined whether stimulation of different targeted regions influences sleep outcomes. Meta-regression analyses examined potential relationships between the effects of tVNS protocols on sleep quality and demographic characteristics and multiple tVNS parameters, respectively. The random-effects meta-analysis indicated that tVNS protocols influenced better sleep quality and lower insomnia severity. Moderator variable analysis revealed that tVNS targeting the concha region induced better sleep quality. Meta-regression analysis revealed that better sleep quality was associated with lower ages of participants. These findings suggest that tVNS protocols, particularly those targeting the concha, were associated with favorable changes in sleep quality and insomnia severity, with age potentially moderating the treatment response.

Humans

Perioperative care for patients with opioid exposure and opioid use disorder: screening and treatment strategies.

PURPOSE OF REVIEW: The prevalence of opioid tolerance, dependence, and use disorder is increasing among patients presenting for surgical care, yet perioperative management strategies for these patients remain inconsistent. This review examines the impact of preoperative opioid exposure on surgical outcomes, the scope of untreated opioid use disorder (OUD) among surgical patients, and advances in clinical and systems-level approaches to perioperative care. RECENT FINDINGS: Preoperative opioid exposure independently predicts worse surgical outcomes, including higher opioid consumption, readmissions, complications, and mortality, in a dose-dependent manner. Perioperative opioid exposure predicts persistent opioid use after surgery, with the duration of exposure a stronger predictor of subsequent OUD than daily dose. Data-driven prescribing guidelines and structured opioid tapering reduce overprescribing without compromising pain control. Among surgical patients with diagnosed OUD, approximately two-thirds do not receive medications for opioid use disorder (MOUD), though treatment engagement and maintenance substantially improve outcomes. Evidence now clearly supports perioperative buprenorphine continuation over interruption. SUMMARY: Effective perioperative management of opioid-complex surgical patients requires systematic screening, evidence-based prescribing, MOUD continuation, and institutional infrastructure. The primary barrier is shifting from evidence generation to implementation.

Humans

School-based sexual violence prevention: A systematic review.

PURPOSE: Sexual violence profoundly affects the health and development of children, adolescents, and young adults, representing a persistent challenge to public policy. This systematic review examined the effectiveness of school-based interventions aimed at prevention. METHODS: Eighteen randomized controlled trials published between 2012 and 2024 were retrieved from four major databases. The programs were implemented in primary, secondary, and higher education settings and targeted children, adolescents, and young adults. RESULTS: The results revealed improvements in knowledge and attitude, particularly regarding consent and awareness, whereas evidence supporting behavioral changes was less frequent and often limited. Methodological limitations, such as short follow-up periods and participant attrition, restricted the assessment of long-term outcomes. CONCLUSIONS: This review highlights the importance of multicomponent, participatory, and culturally sensitive approaches, along with the integration of digital tools and continuous evaluation systems, to strengthen the role of schools as safe and transformative spaces in the prevention of sexual violence. IMPLICATIONS AND CONTRIBUTIONS: This systematic review suggests that school-based interventions hold significant potential for the prevention of sexual violence. It identifies promising strategies and reinforces the importance of culturally sensitive, sustained, evidence-based approaches to ensure learning environments that are safe, protective, and promotive of gender equity.

Humans

Retention strategies and participant retention rates among prospective longitudinal pregnancy cohorts: a systematic mapping review.

Prospective longitudinal pregnancy cohorts can answer questions about fetal and early life exposures and later health outcomes; however, there are challenges to retaining participants in longitudinal studies, particularly over life transitions like the birth of a child. Optimal methods for retaining participants in longitudinal research are unclear. A systematic mapping review was conducted to identify prospective cohort studies and randomized controlled trials that enrolled pregnant participants and their infants. Data on retention rates and 17 retention strategies was extracted. A random effects meta-analysis generated pooled annual retention rates inversely weighted to the number of baseline participants. Spearman rank coefficients were used to assess correlation between strategy use and retention. A random-effects meta-regression was used to determine if select retention strategies were associated with participant retention. We identified 130 studies, involving 472 022 pregnancies. A downward trend in pooled mean retention rates were observed. Studies utilized an average of 6.8 (SD 3.9) retention strategies. Statistically significant associations were not observed between strategy use and retention rates at follow-up (p&#x202f;>&#x202f;0.05). Prospective studies of pregnant people and their infants used multiple retention strategies. Participant retention rates declined over time, suggesting that additional factors may influence study participation in the postpartum period.

Humans

A translational framework for early-phase inner-ear gene therapy: clinical trial design, regulatory strategy, and ethical considerations.

PURPOSE OF REVIEW: Hereditary hearing loss has historically been approached as a diagnostic category rather than a therapeutically modifiable disease. Recent advances in molecular genetics, cochlear gene delivery, and first-in-human clinical trials are changing that. This review summarizes contemporary progress in the genetics of hearing loss, with emphasis on emerging gene-based therapies, clinical trial design, regulatory and ethical considerations, and practical implications for otolaryngologists as biologic treatment enters clinical practice. RECENT FINDINGS: Early clinical trials targeting OTOF -related DFNB9 deafness have demonstrated satisfactory safety profiles and meaningful auditory recovery, establishing the first proof-of-concept for cochlear gene therapy in humans, culminating in the April 2026 FDA approval of Otarmeni. Genetic diagnoses are increasingly informing prognosis, cochlear implant counseling, and therapeutic candidacy. Preclinical research continues to expand toward recessive, dominant, and syndromic hearing loss using gene replacement, antisense, RNA interference, and genome-editing strategies. Substantial challenges remain, including heterogeneous outcome measures, uncertain long-term efficacy, regulatory complexity, and inequitable global access. SUMMARY: The genetics of hearing loss is transitioning from a diagnostic modality to an interventional one. Widespread clinical impact will require advances in vector engineering, equitable implementation, multidisciplinary counseling, and integration with established rehabilitation pathways. For otolaryngologists, genetic literacy is becoming essential to contemporary hearing care.

Humans

Closed-loop insulin delivery for glycaemic control in hospitalised and perioperative adults: A systematic review and meta-analysis of randomised controlled trials.

We evaluated whether closed-loop insulin delivery improves glycaemic control in hospitalised and perioperative adults. PubMed/MEDLINE, Embase, CENTRAL, and ClinicalTrials.gov were searched from inception to 29 June 2026 for randomised controlled trials comparing closed-loop or automated insulin delivery with usual care or conventional insulin therapy. Random-effects meta-analyses were conducted; risk of bias was assessed using RoB 2 and certainty of evidence using GRADE. Seven trials involving 375 analysed participants were included. Closed-loop insulin delivery increased time in target glucose range by 23.91 percentage points (95% CI 19.40 to 28.43; I2&#xa0;=&#xa0;0%) and reduced mean glucose by 1.79&#xa0;mmol/L (95% CI 1.06 to 2.53 lower; I2&#xa0;=&#xa0;36.3%); certainty was moderate for both outcomes. Two trials involving 69 participants reported compatible participant-level data for clinically significant hyperglycaemia, and both estimates favoured closed-loop insulin delivery, although the evidence was exploratory and imprecise. No severe hypoglycaemic events occurred in either group, precluding reliable estimation of comparative safety. Closed-loop insulin delivery may improve glycaemic process measures, but larger pragmatic trials are needed to establish clinical benefits, safety, and implementation feasibility.

Humans