The purpose of a first-in-human (FIH) clinical trial is to gather information about how the drug or device affects and interacts with the human body: its safety, side effects, and (potential) dosage. As such, the primary goal of a FIH trial is not participant benefit but to gain knowledge of drug or device efficacy, i.e., baseline human safety knowledge. Some FIH clinical trials carry significant foreseeable risk to participants with little to no foreseeable participant benefit. Participation in such trials would be a bad deal for participants, and the research is considered justifiable because of the promise of significant potential social benefit. I argue that there is an ethical tension inherent in risky FIH research and that researchers should fairly compensate risky FIH trial participants. This does not make the risk-benefit outcome more favorable for participants; rather, it amounts to a collective reckoning with the ethical tension inherent in the research.

UNASSIGNED: For adult patients with grade 1-3 gliomas, identifying patients with an indication for proton therapy (PT) can be challenging due to sparse evidence supporting its benefits. In this study, we aimed to ensure national consensus and develop a decision support tool to aid clinicians in identifying patients with grade 1-3 gliomas eligible for PT.
UNASSIGNED: Sixty-one historic patients referred for postoperative radiotherapy for glioma grade 1-3 were included in this study and had new photon therapy and PT plans calculated. These plans along with clinical parameters were presented to neurooncologists with experience in treating brain tumours. The patients were presented at three workshops (WSs), where each neurooncologist individually had to choose between photon and proton therapy. Important parameters were selected using cross validation. Multivariable logistic regression was used to predict the neurooncologists\' treatment modality choice.
UNASSIGNED: At the three WSs 23, 24 and 19 randomly selected patients were presented. Seventy-five percent of the neurooncologists agreed for 14 patients (61%), 16 patients (67%) and 15 patients (79%) at WS1, WS2 and WS3. Age at radiotherapy and difference in mean dose (ΔDmean) to the residual brain were significant predictors of the choice of treatment modality, p < 0.001. Model coefficients were: βage = 0.07 per year (95% confidence interval [CI] = 0.05-0.09), and βΔdose = -0.27 per Gy (95% CI=-0.36--0.18).
UNASSIGNED: Higher degree of agreement was reached. Age and ΔDmean to the residual brain significantly predicted the choice of radiation modality. We have developed a decision support model which may aid in the selection of patients with glioma grade 1-3 to PT.

BACKGROUND: This study aimed to explore the clinical utility of targeted MECP2 testing in a large cohort of females with neurodevelopmental delays. Our aim was to identify suitable candidates for testing based on prevailing diagnostic criteria.
METHODS: Eligible participants with global developmental delay/arrest or regression before age 36 months underwent MECP2 testing. MECP2-positive patients were further categorized based on Rett syndrome (RTT) diagnostic criteria, including typical, atypical, possible, and unclassified, to assess disease typicality and progression with respect to age.
RESULTS: Of the 683 patients, 162 (23.7%) were diagnosed with MECP2-related RTT. Global developmental delay was the predominant initial symptom in approximately 75% of the cohort with developmental arrest/regression at testing. Symptoms emerged before age six months in 14 patients (8.6%). The average age at the time of MECP2 testing was 3.7 years, with 31.5% of the patients tested under two years. Of those under two years, 15 were initially categorized into the unclassified group; however, 12 were later reclassified into the typical/atypical RTT groups based on follow-up evaluation. Among the 119 patients monitored beyond age five years, 80% displayed typical RTT symptoms, 10 remained unclassified, and 9.8% had exonic deletions, posing challenges for detection using next-generation sequencing.
CONCLUSIONS: Targeted MECP2 testing has emerged as a clinically valuable tool with a high diagnostic yield, including the identification of small deletions. Given that younger patients may not always meet the classic RTT criteria, this study recommends targeted MECP2 testing in younger patients without typical RTT features.

BACKGROUND: Ensuring diversity in clinical trials can be a challenge, which may be exacerbated when recruiting vulnerable populations, such as participants with mental health illness. As recruitment continues to be the major cause of trial delays, researchers are turning to online recruitment strategies, e.g. social media, to reach a wider population and reduce recruitment time and costs. There is mixed evidence for the use of online recruitment strategies; therefore, the REcruitment in Mental health trials: broadening the \'net\', opportunities for INclusivity through online methoDs (RE-MIND) study aimed to identify evidence and provide guidance for use of online strategies in recruitment to mental health trials, with a focus on whether online strategies can enhance inclusivity. This commentary, as part of the RE-MIND study, focusses on providing recommendations for recruitment strategy selection in future research with the aim to improve trial efficiency. A mixed-methods approach was employed involving three work packages: (I) an evidence review of a cohort of 97 recently published randomised controlled trials/feasibility or pilot studies in mental health to assess the impact of online versus offline recruitment; (II) a qualitative study investigating the experiences of n = 23 key stakeholders on use of an online recruitment approach in mental health clinical trials; (III) combining the results of WP1 and WP2 to produce recommendations on the use of an online recruitment strategy in mental health clinical trials. The findings from WP1 and 2 have been published elsewhere; this commentary represents the results of the third work package.
CONCLUSIONS: For external validity, clinical trial participants should reflect the populations that will ultimately receive the interventions being tested, if proven effective. To guide researchers on their options for inclusive recruitment strategies, we have developed a list of considerations and practical recommendations on how to maximise the use of online recruitment methods.

BACKGROUND: While laparoscopic cholecystectomy has largely been performed in an outpatient setting in some countries for years, in Germany it is still generally performed on an inpatient basis; however, with the progressive ambitions for more outpatient treatment within the German healthcare system, laparoscopic cholecystectomy will (have to) increasingly be performed on an outpatient basis in the upcoming years.
OBJECTIVE: Presentation of the current framework conditions and the potential for outpatient performance of laparoscopic cholecystectomy in Germany. Presentation and discussion on the current state of knowledge regarding patient selection, treatment pathways and safety of outpatient laparoscopic cholecystectomy.
RESULTS: The potential for outpatient management of laparoscopic cholecystectomy in Germany is high. Based on the current literature, there are no safety concerns regarding outpatient performance of laparoscopic cholecystectomy in selected patients.
CONCLUSIONS: Outpatient management of laparoscopic cholecystectomy is inevitably heading our way in the next years. The key to successful change will be comprehensive patient information, patient selection and structured outpatient treatment pathways.
UNASSIGNED: HINTERGRUND: Während die laparoskopische Cholezystektomie in einigen Ländern bereits seit Jahren großteils im ambulanten Setting durchgeführt wird, erfolgt sie in Deutschland bis dato in aller Regel noch stationär. Mit der fortschreitenden Ambulantisierung im deutschen Gesundheitswesen wird jedoch auch in Deutschland die laparoskopische Cholezystektomie in den kommenden Jahren zunehmend ambulant durchgeführt werden (müssen).
UNASSIGNED: Darstellung der aktuellen Rahmenbedingungen und des Potenzials zur ambulanten Durchführung der laparoskopischen Cholezystektomie in Deutschland. Darstellung und Diskussion des aktuellen Wissensstandes bez. der Patientenauswahl, Behandlungspfade und Sicherheit der ambulanten laparoskopischen Cholezystektomie.
UNASSIGNED: Das Ambulantisierungspotenzial für die laparoskopische Cholezystektomie in Deutschland ist hoch. Anhand der aktuellen Studienlage bestehen keine Sicherheitsbedenken bez. der ambulanten Durchführung der laparoskopischen Cholezystektomie bei ausgewählten Patienten.
UNASSIGNED: Die Ambulantisierung der laparoskopischen Cholezystektomie wird in den nächsten Jahren unweigerlich auf uns zukommen. Der Schlüssel zum erfolgreichen Wandel werden eine umfassende Patienteninformation, Patientenselektion und strukturierte ambulante Behandlungspfade sein.

Improving access to kidney transplants remains a priority for the transplant community. However, many medical, psychosocial, geographic, and socioeconomic barriers exist that prevent or delay transplantation for candidates with certain conditions. There is a lack of consensus regarding how to best approach many of these issues and barriers, leading to heterogeneity in transplant centers\' management and acceptance practices for a variety of pretransplant candidate issues. In this review, we address several of the more common contemporary patient medical and psychosocial barriers frequently encountered by transplant programs. The barriers discussed here include kidney transplant candidates with obesity, older age, prior malignancy, cardiovascular disease, history of nonadherence, and cannabis use. Improving understanding of how to best address these specific issues can empower referring providers, transplant programs, and patients to address these issues as necessary to progress toward eventual successful transplantation.

BACKGROUND: Sepsis is a heterogeneous syndrome, and enrollment of more homogeneous patients is essential to improve the efficiency of clinical trials. Artificial intelligence (AI) has facilitated the identification of homogeneous subgroups, but how to estimate the uncertainty of the model outputs when applying AI to clinical decision-making remains unknown.
OBJECTIVE: We aimed to design an AI-based model for purposeful patient enrollment, ensuring that a patient with sepsis recruited into a trial would still be persistently ill by the time the proposed therapy could impact patient outcome. We also expected that the model could provide interpretable factors and estimate the uncertainty of the model outputs at a customized confidence level.
METHODS: In this retrospective study, 9135 patients with sepsis requiring vasopressor treatment within 24 hours after sepsis onset were enrolled from Beth Israel Deaconess Medical Center. This cohort was used for model development, and 10-fold cross-validation with 50 repeats was used for internal validation. In total, 3743 patients with sepsis from the eICU Collaborative Research Database were used as the external validation cohort. All included patients with sepsis were stratified based on disease progression trajectories: rapid death, recovery, and persistent ill. A total of 148 variables were selected for predicting the 3 trajectories. Four machine learning algorithms with 3 different setups were used. We estimated the uncertainty of the model outputs using conformal prediction (CP). The Shapley Additive Explanations method was used to explain the model.
RESULTS: The multiclass gradient boosting machine was identified as the best-performing model with good discrimination and calibration performance in both validation cohorts. The mean area under the receiver operating characteristic curve with SD was 0.906 (0.018) for rapid death, 0.843 (0.008) for recovery, and 0.807 (0.010) for persistent ill in the internal validation cohort. In the external validation cohort, the mean area under the receiver operating characteristic curve (SD) was 0.878 (0.003) for rapid death, 0.764 (0.008) for recovery, and 0.696 (0.007) for persistent ill. The maximum norepinephrine equivalence, total urine output, Acute Physiology Score III, mean systolic blood pressure, and the coefficient of variation of oxygen saturation contributed the most. Compared to the model without CP, using the model with CP at a mixed confidence approach reduced overall prediction errors by 27.6% (n=62) and 30.7% (n=412) in the internal and external validation cohorts, respectively, as well as enabled the identification of more potentially persistent ill patients.
CONCLUSIONS: The implementation of our model has the potential to reduce heterogeneity and enroll more homogeneous patients in sepsis clinical trials. The use of CP for estimating the uncertainty of the model outputs allows for a more comprehensive understanding of the model\'s reliability and assists in making informed decisions based on the predicted outcomes.

Treatment assignment for patients with personality disorders (PDs) involves a complex process consisting of diagnostic assessment and deciding on the most appropriate psychotherapeutic treatment. This article describes the development of a checklist for systematic analysis of life stories to support reflective and transparent assignment of patients to either dialectical behavioral therapy (DBT) or schema-focused therapy (SFT). In a first study, an email survey, focus group, and member check were conducted among eight clinical experts to identify relevant dimensions in life stories in patients with PDs. In a second study, a checklist based on these dimensions was developed in three rounds of testing with nine clinical experts and nine psychology students. Checklist results were compared to actual assigned treatment for 20 patients. Systematic evaluation of life stories, is promising in supporting the allocation of patients with PDs to a suitable treatment approach by focusing on specific and consensual dimensions in patients\' life stories.

BACKGROUND: Research is needed to understand and address barriers to risk management for women at high (≥20% lifetime) risk for breast cancer, but recruiting this population for research studies is challenging.
OBJECTIVE: This paper compares a variety of recruitment strategies used for a cross-sectional, observational study of high-risk women.
METHODS: Eligible participants were assigned female at birth, aged 25-85 years, English-speaking, living in the United States, and at high risk for breast cancer as defined by the American College of Radiology. Individuals were excluded if they had a personal history of breast cancer, prior bilateral mastectomy, medical contraindications for magnetic resonance imaging, or were not up-to-date on screening mammography per American College of Radiology guidelines. Participants were recruited from August 2020 to January 2021 using the following mechanisms: targeted Facebook advertisements, Twitter posts, ResearchMatch (a web-based research recruitment database), community partner promotions, paper flyers, and community outreach events. Interested individuals were directed to a secure website with eligibility screening questions. Participants self-reported method of recruitment during the eligibility screening. For each recruitment strategy, we calculated the rate of eligible respondents and completed surveys, costs per eligible participant, and participant demographics.
RESULTS: We received 1566 unique responses to the eligibility screener. Participants most often reported recruitment via Facebook advertisements (724/1566, 46%) and ResearchMatch (646/1566, 41%). Community partner promotions resulted in the highest proportion of eligible respondents (24/46, 52%), while ResearchMatch had the lowest proportion of eligible respondents (73/646, 11%). Word of mouth was the most cost-effective recruitment strategy (US $4.66 per completed survey response) and paper flyers were the least cost-effective (US $1448.13 per completed survey response). The demographic characteristics of eligible respondents varied by recruitment strategy: Twitter posts and community outreach events resulted in the highest proportion of Hispanic or Latina women (1/4, 25% and 2/6, 33%, respectively), and community partner promotions resulted in the highest proportion of non-Hispanic Black women (4/24, 17%).
CONCLUSIONS: Although recruitment strategies varied in their yield of study participants, results overall support the feasibility of identifying and recruiting women at high risk for breast cancer outside of clinical settings. Researchers must balance the associated costs and participant yield of various recruitment strategies in planning future studies focused on high-risk women.

Introduction Complex distal humerus fractures pose significant challenges in orthopedic surgery, especially when traditional open reduction and internal fixation (ORIF) is not feasible. Primary elbow arthroplasty has emerged as an alternative treatment option for these fractures, but its application remains limited. This study aimed to evaluate the functional outcomes, patient selection criteria, and follow-up results of primary elbow arthroplasty in the management of complex distal humerus fractures. Methods A retrospective review was conducted on 15 patients who underwent primary elbow arthroplasty for Orthopaedic Trauma Association (OTA) type C distal humerus fractures between 2017 and 2023 at our institution. Inclusion criteria were patients aged 18 years or older who were offered either total elbow or hemiarthroplasty for acute complex distal humerus fracture. Data were collected from patient medical records, including demographic information, fracture classification, surgical details, and postoperative follow-up. Functional outcomes were assessed using the Oxford Elbow Score (OES) and Mayo Elbow Performance Score (MEPS). Complications were documented, and descriptive statistics were used to summarise the findings. Results The mean age of the patients was 71.8 years (IQR 17 years), with 12 females and three males. The mean time to surgery was 14.7 days post-injury (IQR: 12 days). The mean follow-up duration was 52 weeks (range: 8-234 weeks, IQR: 27 weeks) and variability was noted. The mean flexion-extension arc at the final follow-up was 93° (IQR: 32.5°). The mean OES was 46 (IQR: 22), and the mean MEPS was 75 (IQR: 37), indicating good to excellent functional outcomes. Scores for two patients were not available due to dementia. Reported complications included one case of ulnar sensory symptoms and one case requiring metalwork removal following olecranon osteotomy. Conclusion Primary elbow arthroplasty provides a viable treatment option for complex distal humerus fractures, demonstrating significant functional improvements and high patient satisfaction. However, the variability in follow-up and subjective decision-making underscores the need for standardized protocols. Future multicenter, prospective studies with larger cohorts and standardized follow-up protocols are recommended to confirm these findings and optimize patient care.