The incidence of fractures in children under two years of age: a systematic review.

BACKGROUND: Epidemiological research on fractures in children under the age of two is of great importance to help understand differences between accidental and abusive trauma. OBJECTIVE: This systematic review aimed to evaluate studies reporting on the incidence of fractures in children under two years of age, excluding birth injuries. Secondary outcome measures included fracture location, mechanisms of injury and fracture characteristics. METHODS: A systematic literature review (1946 to February 7th 2024), including prospective and retrospective cohort studies and cross-sectional cohort studies, was performed. Studies including children from other age groups were included if the actual measures for those aged 0-2 years could be extracted. We also included studies restricted to infants. Annual incidence rates of fractures were extracted and reported as the main result. Critical appraisal of was performed using the Appraisal tool for Cross-Sectional Studies. RESULTS: Twelve moderate to good quality studies met eligibility criteria, of which seven were based on data from medical records and five were registry studies. Studies investigated different aspects of fractures, making comprehensive synthesis challenging. There was an overall annual fracture incidence rate of 5.3 to 9.5 per 1,000 children from 0-2 years of age; with commonest sites being the radius/ulna (25.2-40.0%), followed by tibia/fibula (17.3-27.6%) and the clavicle (14.6-14.8%) (location based on 3 studies with a total of 407 patients). In infants, the reported incidence ranged between 0.7 to 4.6 per 1,000 (based on 3 studies), with involvement of the clavicle in 22.2% and the distal humerus in 22.2% of cases (based on 1 study). Only a single metaphyseal lesion was reported (proximal humerus of an 11-month-old infant). Fracture mechanisms were detailed in four studies, with fall from chair, bed, table, own height or fall following indoor activities causing 50-60% of fractures. CONCLUSIONS: There is a paucity of good quality data on fracture incidence in children under the age of two. Larger, prospective and unbiased studies would be helpful in determining normal pattern of injuries, so that differences from abusive trauma may be better understood.

Inequalities in access to neuro-oncology supportive care and rehabilitation: A survey of healthcare professionals' perspectives.

Background: Neuro-oncology patients and caregivers should have equitable access to rehabilitation, supportive-, and palliative care. To investigate existing issues and potential solutions, we surveyed neuro-oncology professionals to explore current barriers and facilitators to screening patients' needs and referral to services. Methods: Members of the European Association of Neuro-Oncology and the European Organisation for Research and Treatment of Cancer Brain Tumor Group (EORTC-BTG) were invited to complete a 39-item online questionnaire covering the availability of services, screening, and referral practice. Responses were analyzed descriptively; associations between sociodemographic/clinical variables and screening/referral practice were explored. Results: In total, 103 participants completed the survey (67% women and 57% medical doctors). Fifteen professions from 23 countries were represented. Various rehabilitation, supportive-, and palliative care services were available yet rated "inadequate" by 21-37% of participants. Most respondents with a clinical role (n = 94) declare to screen (78%) and to refer (83%) their patients routinely for physical/cognitive/emotional issues. Survey completers (n = 103) indicated the main reasons for not screening/referring were (1) lack of suitable referral options (50%); (2) shortage of healthcare professionals (48%); and (3) long waiting lists (42%). To improve service provision, respondents suggested there is a need for education about neuro-oncology-specific issues (75%), improving the availability of services (65%) and staff (64%), developing international guidelines (64%), and strengthening the existing evidence-base for rehabilitation (60%). Conclusions: Detecting and managing neuro-oncology patients' and caregivers' rehabilitation, supportive,- and palliative care needs can be improved. Better international collaboration can help address healthcare disparities.

Timing of Palliative Care Consultation Impacts End of Life Care Outcomes in Metastatic Non-Small Cell Lung Cancer.

CONTEXT: Early specialist palliative care (PC) involvement in metastatic non-small cell lung cancer (mNSCLC) is associated with improved quality of life, less aggressive end of life (EoL) care, and longer survival. As treatment paradigms for NSCLC have evolved, PC utilization remains low. OBJECTIVES: This work examines how the timing and extent of PC involvement impacts outcomes and the patient experience in mNSCLC in the era of immunotherapy. METHODS: This retrospective review analyzed patients with mNSCLC who initiated first-line treatment with chemotherapy, immunotherapy, or combined chemoimmunotherapy at Duke University between March 2015 and July 2019. PC consultation and outcomes data were abstracted through November 2022. EoL care variables were analyzed using descriptive statistics. RESULTS: 152 patients were stratified based on whether PC was consulted during their disease course. 80 patients (53%) never saw PC, while the 72 patients (47%) who saw PC were further stratified by time to first PC encounter and total number of PC visits. 31% were seen within 2 months of diagnosis (early), 33% between 2-6 months (intermediate), and 36% after 6 months (late). Patients who received early PC had longer median time on hospice (35 days), had lower rates of aggressive EoL care (43%), and experienced less frequent in-hospital death (14%) compared to other groups. CONCLUSION: This real-world study reveals that referrals to PC still occur late or not at all in mNSCLC despite demonstrated benefits of early PC integration. Early outpatient PC referrals resulted in longer time on hospice, lower frequency of aggressive EoL care, and lower rates of in-hospital death.

Neutralizing Antibody Sample Testing and Report Harmonization.

Immunogenicity testing and characterization is an important part of understanding the immune response to administration of a protein therapeutic. Neutralizing antibody (NAb) assays are used to characterize a positive anti-drug antibody (ADA) response. Harmonization of reporting of NAb assay performance and results enables efficient communication and expedient review by industry and health authorities. Herein, a cross-industry group of NAb assay experts have harmonized NAb assay reporting recommendations and provided a bioanalytical report (BAR) submission editable template developed to facilitate agency filings. This document addresses key bioanalytical reporting gaps and provides a report structure for documenting clinical NAb assay performance and results. This publication focuses on the content and presentation of the NAb sample analysis report including essential elements such as the method, critical reagents and equipment, data analysis, study samples, and results. The interpretation of immunogenicity data, including the evaluation of the impact of NAb on safety, exposure, and efficacy, is out of scope of this publication.

First-line Osimertinib for Lung Cancer With Uncommon EGFR Exon 19 Mutations and EGFR Compound Mutations.

Introduction: Up to 20% of EGFR-mutated NSCLC cases harbor uncommon EGFR mutations, including atypical exon 19 and compound mutations. Relatively little is known about the efficacy of osimertinib in these cases. Methods: Patients treated with first-line osimertinib for NSCLC with rare EGFR exon 19 (non E746_A750del) or compound mutations were included. Response assessment and time to progression were determined using Response Evaluation Criteria in Solid Tumors version 1.1 criteria. Kaplan-Meier analyses were used to estimate progression-free survival (PFS), time to treatment discontinuation (TTD), and overall survival (OS). Results: Thirty-seven patients with NSCLC harboring an atypical EGFR exon 19 mutation or compound mutation were treated with first-line osimertinib at Johns Hopkins from 2016 to 2021. Overall response rate (ORR) was 76% and median PFS, TTD, and OS were 13 months (95% confidence interval [CI]: 10-15), 22 months (95% CI: 17-32) and 36 months (95% CI, 29-48), respectively. Among atypical exon 19 mutations (n = 25), ORR was 80%, median PFS was 12 months (95% CI: 10-15), median TTD was 19 months (95% CI: 17-38), and median OS was 48 months (95% CI: 25-not reached). Compound mutations (n = 12) had an ORR of 67%, median PFS of 14 months (95% CI: 5-22), median TTD of 26 months (95% CI: 5-36), and median OS of 36 months (95% CI: 20-46). Twelve patients (32%) continued first-line osimertinib after local therapy for oligoprogression. Conclusions: Osimertinib exhibited favorable outcomes for rare EGFR exon 19 and compound mutations. The heterogeneity in outcomes among these groups of tumors with similar mutations underscores the need for continued reporting and further study of outcomes among rare variants to optimize management for each patient.

"Sickness has no time": Awareness and perceptions of health care workers on universal health coverage in Uganda.

INTRODUCTION: Each person having access to needed health services, of sufficient quality, and without suffering financial hardship, defined as universal health coverage (UHC) by the World Health Organization, is critical to improve population health, particularly for vulnerable populations. UHC requires multisectoral collaboration and good governance, and this will require buy-in of key stakeholders; but their views are under-documented. The aim of this stakeholder analysis was to explore the awareness and perceptions of UHC by health care workers (HCWs) in Uganda. METHODS: A mixed-methods study was conducted based on primary data from HCWs including an online QualtricsXM survey of 274 HCWs (from a database of persons who had received training at an academic institution), 23 key informant semi-structured interviews, and one eight-person focus group discussion. Data was collected from February to April 2022. Microsoft Excel and R Programme were used for quantitative analyses and NVivo version 12 for qualitative analyses. RESULTS: HCWs attributed a high level of importance to UHC in Uganda. Participants discussed national communication and management practices, organisational roles, health financing and power dynamics, health care demand and the impact of and learnings from COVID-19. Four main themes-each with related sub-themes-emerged from the interview data providing insights into: (1) communication, (2) organisation, (3) power, and (4) trust. CONCLUSION: There is a critical need for better communication of UHC targets by policymakers to improve understanding at a grassroots level. Results indicated that ensuring trust among the population through transparency in metrics and budgets, strong accountability measures, awareness of local cultural sensitivities, sensitisation of the UHC concept and community inclusion will be essential for a multisectoral roll out of UHC. Further provision of quality health services, a harmonisation of efforts, increased domestic health financing and investment of HCWs through fair remuneration will need to underpin the delivery of UHC.

Exploring determinants of flourishing: a comprehensive network analysis of retirees in Taiwan.

BACKGROUND: Human flourishing is an emerging concept, extending beyond the conventional boundaries of subjective well-being and evolving into a comprehensive capture of the diverse dimensions of human life within complex societal structures. Therefore, moving away from traditional approaches centered on the single latent construct, this study aims to explore the multiple aspects of human flourishing and the intricate interplay of their contributing factors. METHODS: Data were collected from the Health and Living Environments Survey of Taiwanese Retirees during 2023 (valid sample n = 1,111). Human flourishing was measured using the Secure Flourish Index developed by Harvard University, which includes 12 indicators: (1) life satisfaction, (2) happiness, (3) mental health, (4) physical health, (5) meaning in life, (6) sense of purpose, (7) promoting good, (8) delaying gratification, (9) content relationships, (10) satisfying relationships, (11) financial stability, and (12) material stability. A mixed graphical network analysis was employed to analyze the related determinants, divided into four groups: (a) sociodemographic factors, (b) physical functions and health status, (c) social and family engagement, and (d) community environmental characteristics as nodes. RESULTS: We analyzed 31 variables and identified 133 nonzero edges out of 465 potential connections in the comprehensive network. Results showed that happiness and promoting good were the two most critical indicators influencing retirees' overall flourishing. Different flourishing indicators were also associated with various influential factors. For instance, personal characteristics, especially gender and education, emerged as central factors. Family caregiving negatively affected happiness and financial stability, whereas social engagement was positively associated with life satisfaction and meaning in life. Employment status had mixed effects, negatively associated with life satisfaction but positively associated with mental health. Community environments, such as a sense of community and neighborhood safety, generally enhanced flourishing. However, the accessibility of neighborhood resources was paradoxically associated with material stability, pointing to the complexity of environmental factors in human flourishing. CONCLUSION: This study provides a comprehensive network analysis that reveals intricate connections between personal, behavioral, and environmental factors, offering profound insights for targeted interventions to foster human flourishing.

Male-mediated early maturation unlikely to evolve via adaptive evolution.

The Vandenbergh effect, or male-mediated maturation, occurs when females reach sexual maturation upon exposure to a novel male. Male-mediated maturation is found across mammals, including in geladas, Theropithecus gelada, where it may be an adaptive counterstrategy to infanticide that follows the immigration of a new male; maturing after male immigration maximizes a female's chances of weaning her first offspring before the next infanticidal male immigrates (the 'optimal timing hypothesis'). Alternatively, the nonadaptive 'Bruce effect by-product hypothesis' posits that male-mediated maturation in geladas (and possibly other mammals) is triggered by the same physiological changes that, in pregnant females, produce spontaneous abortion (the Bruce effect). We test both hypotheses using theory and observational data. We show that neither male-mediated maturation nor its associated hormonal changes occur in baboons (Papio cynocephalus × P. anubis), a primate without the Bruce effect. An individual-based model suggests that male-mediated maturation should not evolve via adaptive evolution in either geladas or baboons. Finally, we derive the selection coefficient for male-mediated maturation and show it is likely to be very small because male-mediated maturation yields only marginal potential benefits unless the system is extremely fine-tuned. We conclude that male-mediated maturation in geladas is a by-product of the Bruce effect and more broadly that the Vandenbergh effect may be nonadaptive.

Minimal Clinically Important Difference (MCID) for the Short Musculoskeletal Function Assessment (SMFA) in Severe Lower Extremity Trauma: Pooled Data from 7 Multicenter, Prospective Clinical Trials.

BACKGROUND: The Short Musculoskeletal Function Assessment (SMFA) is a well validated, widely used patient-reported outcome (PRO) measure for orthopaedic patients. Despite its widespread use and acceptance, this measure does not have an agreed upon minimal clinically important difference (MCID). The purpose of the present study was to create distributional MCIDs with use of a large cohort of research participants with severe lower extremity fractures. METHODS: Three distributional approaches were used to calculate MCIDs for the Dysfunction and Bother Indices of the SMFA as well as all its domains: (1) half of the standard deviation (one-half SD), (2) twice the standard error of measurement (2SEM), and (3) minimal detectable change (MDC). In addition to evaluating by patient characteristics and the timing of assessment, we reviewed these calculations across several injury groups likely to affect functional outcomes. RESULTS: A total of 4,298 SMFA assessments were collected from 3,185 patients who had undergone surgical treatment of traumatic injuries of the lower extremity at 60 Level-I trauma centers across 7 multicenter, prospective clinical studies. Depending on the statistical approach used, the MCID associated with the overall sample ranged from 7.7 to 10.7 for the SMFA Dysfunction Index and from 11.0 to 16.8 for the SMFA Bother Index. For the Dysfunction Index, the variability across the scores was small (<5%) within the sex and age subgroups but was modest (12% to 18%) across subgroups related to assessment timing. CONCLUSIONS: A defensible MCID can be found between 7 and 11 points for the Dysfunction Index and between 11 and 17 points for the Bother Index. The precise choice of MCID may depend on the preferred statistical approach and the population under study. While differences exist between MCID values based on the calculation method, values were consistent across the categories of the various subgroups presented. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Borderline Personality Disorder and Eating Disorders: Investigating the Role of Emotion Regulation.

Objective: Borderline personality disorder (BPD) and eating disorders (EDs) both cause significant distress and co-occur at rates higher than expected, signifying potential overlapping regulatory mechanisms between both disorders. More specifically, both disorders involve emotion regulation deficits, suggesting they may share specific maladaptive regulatory components. The present study sought to examine the predictive role of emotion dysregulation within the comorbidity between EDs and BPD.Methods: A sample of psychiatric outpatients (N = 872) collected from a longitudinal study spanning the mid-1990s to 2015 completed the Structured Clinical Interview for DSM-IV for Axis I Disorders as well as a measure of emotion regulation strategies, the Difficulties in Emotion Regulation Scale, in order to assess overall functioning.Results: In a regression analysis, BPD was significantly predicted by emotion regulation deficits and was strongly related to categories of emotion dysregulation. EDs were not significantly predicted by emotion regulation deficits but did predict BPD diagnoses (B = -0.14, P < .001). Overall, BPD demonstrated strong relationships to emotion regulation deficits.Conclusions: Results indicate that targeted treatment focusing on emotion regulation deficits may be particularly indicated with co-occurring BPD and ED diagnoses.

In vivo modeling recapitulates radiotherapy delivery and late-effect profile for childhood medulloblastoma.

Background: Medulloblastoma (MB) is the most common malignant pediatric brain tumor, with 5-year survival rates > 70%. Cranial radiotherapy (CRT) to the whole brain, with posterior fossa boost (PFB), underpins treatment for non-infants; however, radiotherapeutic insult to the normal brain has deleterious consequences to neurocognitive and physical functioning, and causes accelerated aging/frailty. Approaches to ameliorate radiotherapy-induced late-effects are lacking and a paucity of appropriate model systems hinders their development. Methods: We have developed a clinically relevant in vivo model system that recapitulates the radiotherapy dose, targeting, and developmental stage of childhood medulloblastoma. Consistent with human regimens, age-equivalent (postnatal days 35-37) male C57Bl/6J mice received computerized tomography image-guided CRT (human-equivalent 37.5 Gy EQD2, n = 12) ±â€…PFB (human-equivalent 48.7 Gy EQD2, n = 12), via the small animal radiation research platform and were longitudinally assessed for > 12 months. Results: CRT was well tolerated, independent of PFB receipt. Compared to a sham-irradiated group (n = 12), irradiated mice were significantly frailer following irradiation (frailty index; P = .0002) and had reduced physical functioning; time to fall from a rotating rod (rotarod; P = .026) and grip strength (P = .006) were significantly lower. Neurocognitive deficits were consistent with childhood MB survivors; irradiated mice displayed significantly worse working memory (Y-maze; P = .009) and exhibited spatial memory deficits (Barnes maze; P = .029). Receipt of PFB did not induce a more severe late-effect profile. Conclusions: Our in vivo model mirrored childhood MB radiotherapy and recapitulated features observed in the late-effect profile of MB survivors. Our clinically relevant model will facilitate both the elucidation of novel/target mechanisms underpinning MB late effects and the development of novel interventions for their amelioration.

The Psychoneurologic Symptom Cluster and Its Association With Breast Cancer Genomic Instability.

OBJECTIVES: To phenotype the psychoneurologic (PN) symptom cluster in individuals with metastatic breast cancer and associate those phenotypes with individual characteristics and cancer genomic variables from circulating tumor DNA. SAMPLE & SETTING: This study included 201 individuals with metastatic breast cancer recruited in western Pennsylvania. METHODS & VARIABLES: A descriptive, cross-sectional design was used. Symptom data were collected via the MD Anderson Symptom Inventory, and cancer genomic data were collected via ultra-low-pass whole-genome sequencing of circulating tumor DNA from participant blood. RESULTS: Three distinct PN symptom phenotypes were described in a population with metastatic breast cancer: mild symptoms, moderate symptoms, and severe mood-related symptoms. Breast cancer TP53 deletion was significantly associated with membership in a moderate to severe symptoms phenotype (p = 0.013). IMPLICATIONS FOR NURSING: Specific cancer genomic changes associated with increased genomic instability may be predictive of PN symptoms. This finding may enable proactive treatment or reveal new therapeutic targets for symptom management.

Preferences for Management of Pediatric Pneumonia: A Clinician Survey of Artificially Generated Patient Cases.

BACKGROUND: It is unknown which factors are associated with chest radiograph (CXR) and antibiotic use for suspected community-acquired pneumonia (CAP) in children. We evaluated factors associated with CXR and antibiotic preferences among clinicians for children with suspected CAP using case scenarios generated through artificial intelligence (AI). METHODS: We performed a survey of general pediatric, pediatric emergency medicine, and emergency medicine attending physicians employed by a private physician contractor. Respondents were given 5 unique, AI-generated case scenarios. We used generalized estimating equations to identify factors associated with CXR and antibiotic use. We evaluated the cluster-weighted correlation between clinician suspicion and clinical prediction model risk estimates for CAP using 2 predictive models. RESULTS: A total of 172 respondents provided responses to 839 scenarios. Factors associated with CXR acquisition (OR, [95% CI]) included presence of crackles (4.17 [2.19, 7.95]), prior pneumonia (2.38 [1.32, 4.20]), chest pain (1.90 [1.18, 3.05]) and fever (1.82 [1.32, 2.52]). The decision to use antibiotics before knowledge of CXR results included past hospitalization for pneumonia (4.24 [1.88, 9.57]), focal decreased breath sounds (3.86 [1.98, 7.52]), and crackles (3.45 [2.15, 5.53]). After revealing CXR results to clinicians, these results were the sole predictor associated with antibiotic decision-making. Suspicion for CAP correlated with one of 2 prediction models for CAP (Spearman's rho = 0.25). Factors associated with a greater suspicion of pneumonia included prior pneumonia, duration of illness, worsening course of illness, shortness of breath, vomiting, decreased oral intake or urinary output, respiratory distress, head nodding, focal decreased breath sounds, focal rhonchi, fever, and crackles, and lower pulse oximetry. CONCLUSIONS: Ordering preferences for CXRs demonstrated similarities and differences with evidence-based risk models for CAP. Clinicians relied heavily on CXR findings to guide antibiotic ordering. These findings can be used within decision support systems to promote evidence-based management practices for pediatric CAP.

Bridging the Gap: A Qualitative Assessment of General Surgery Resident Confidence and Knowledge Deficits in Managing Surgical Endocrinopathy.

BACKGROUND: Most thyroid and parathyroid surgeries are performed by nonfellowship trained, low-volume surgeons with associated higher complication rates. Furthermore, the average number of endocrine procedures performed by general surgery residents is decreasing. While previous studies have documented a lack of general surgery resident confidence in performing these procedures, the specific knowledge gaps in endocrine surgery remain unexplored. METHODS: We conducted semi-structured interviews with surgical residents (clinical PGY3-PGY5) at a high-volume academic center with an endocrine surgery fellowship to discuss their experience, knowledge, and deficits managing patients with surgical thyroid and parathyroid disease. Interviews were audio-recorded, de-identified, and transcribed verbatim. Content analysis was used to identify areas of confidence and knowledge deficits in all phases of care. RESULTS: Overall, 14 trainees participated in the study (50% women, mean PGY: 3.8). Preoperatively, residents were confident with thyroid nodule and primary hyperparathyroidism work-up, but less comfortable with rare conditions. Residents were uncomfortable using ultrasound to identify suspicious lymph nodes or abnormal parathyroid glands. Residents perceived knowledge deficits in the multidisciplinary care and work-up of patients with advanced thyroid cancer. Intraoperatively, most residents were confident performing thyroidectomy and focused parathyroidectomy, but less comfortable performing 4-gland explorations or neck dissections. Several had concern with independently identifying and protecting the recurrent laryngeal nerve or locating parathyroid glands in the setting of negative localization. Residents noted a lack of autonomy in both thyroidectomy and parathyroidectomy. Postoperatively, residents felt confident in the acute management of patients, but identified deficits in long-term management of patients with thyroid cancer or chronic complications. CONCLUSIONS: Despite confidence in managing "bread and butter" cervical endocrine surgery in all phases of care, residents perceive a lack of meaningful autonomy intraoperatively. Further educational endeavors may be required to ensure graduating residents are "practice ready" for straightforward cases they may encounter in practice as a general surgeon. A lack of exposure to complex endocrinopathy even at a high-volume center suggests that comprehensive endocrine surgery fellowship remains critical.

Exploring the care coordination experiences of professionals and caregivers of youth with acquired brain injuries in rural areas.

PURPOSE: Acquired brain injuries (ABIs) can have devastating effects on children and their families. Families living in rural communities experience unique barriers to receiving and coordinating care for complex medical needs, but little research has examined those barriers for rural youth with ABIs. MATERIALS AND METHODS: This qualitative study explored the experiences of rural adults caring for children with ABIs through interviews with six caregivers, three school staff members, and three medical professionals who had treated at least one child with an ABI. RESULTS: Themes in their accounts include difficulty navigating complex situations, support from small communities, isolation and loneliness, the need for more professional education about ABI, and feelings of hope. Barriers to quality care coordination include navigating complex situations, access to transportation, and a lack of communication and education from healthcare agencies. Facilitators of rural care coordination include support from small communities and interagency communication. CONCLUSIONS: The results support the need for more comprehensive coordination among rural agencies involved in ABI care. Suggestions for care improvement include providing flexibility due to transportation barriers, capitalizing on the benefits of a small and caring community, and providing healthcare and education professionals with more education about ABI interventions.

Practitioners should implement tailored support systems that include initiatives to facilitate direct communication between rural medical agencies and schools.Expanding the role of care coordinators to bridge gaps across healthcare, education, and community services could enhance care coordination for children with acquired brain injuries in rural areas.Schools in rural areas should develop formal reintegration programs tailored to the needs of children with mild acquired brain injuries, leveraging existing sports protocols for non-sports-related injuries.Collaborative efforts between schools, medical teams, and community agencies can provide comprehensive education programs tailored to the rural context.The development of online options for follow-up appointments would be particularly beneficial in rural areas, where transportation barriers are more pronounced.

A molecular glue degrader of the WIZ transcription factor for fetal hemoglobin induction.

Sickle cell disease (SCD) is a prevalent, life-threatening condition attributable to a heritable mutation in ß-hemoglobin. Therapeutic induction of fetal hemoglobin (HbF) can ameliorate disease complications and has been intently pursued. However, safe and effective small-molecule inducers of HbF remain elusive. We report the discovery of dWIZ-1 and dWIZ-2, molecular glue degraders of the WIZ transcription factor that robustly induce HbF in erythroblasts. Phenotypic screening of a cereblon (CRBN)-biased chemical library revealed WIZ as a previously unknown repressor of HbF. WIZ degradation is mediated by recruitment of WIZ(ZF7) to CRBN by dWIZ-1, as resolved by crystallography of the ternary complex. Pharmacological degradation of WIZ was well tolerated and induced HbF in humanized mice and cynomolgus monkeys. These findings establish WIZ degradation as a globally accessible therapeutic strategy for SCD.

A Randomized Pilot Trial of the Donor Conception Tool to Empower Parental Telling and Talking (TELL Tool) with Their Children About Their Genetic Origins.

INTRODUCTION: Parents who use donated gametes or embryos to form their families struggle with telling their children about their genetic origins. We developed the Tool to Empower Parental Telling and Talking (TELL Tool) to support parents in disclosure to their children and an eBook attention control. METHOD: A randomized parallel, two-group, attention-controlled clinical pilot trial was conducted online during COVID-19. Feasibility, acceptability, and preliminary effects among parents with children aged 1-16 years were examined. RESULTS: Over 10 months, our target of 75 parents were enrolled (85% of eligible [95% confidence interval (CI), 76% to 91%]), and 68% (95% CI: 57% to 78%) were retained at 12 weeks. At 4 and 12 weeks, positive trends were found for parental disclosure, telling confidence, and anxiety compared with attention controls. DISCUSSION: The study protocol is feasible, and the TELL Tool is acceptable to parents and demonstrates a positive effect on parents' ability to tell their children. The results support the implementation of a large efficacy trial.

Contraceptive method usage pattern and percentage of new pregnancies among adolescent and young adult family planning patients: a mixed-methods retrospective study.

OBJECTIVES: Despite increased access to contraceptive methods (CM), the US still has the highest rate of adolescent pregnancy among industrialized nations, and adolescents from historically marginalized groups are disproportionately affected. In this study, we sought to (1) understand if differences in CM usage were associated with differential percentages of new pregnancies among adolescents and young adult patients attending a family planning (FP) clinic at an urban community practice and (2) identify areas of improvement in our FP counseling. METHODS: Mixed-methods study design consisting of (1) a 12-month retrospective chart review and (2) a self-answered cross-sectional survey of FP patients. Chi-square, Fisher's exact tests, and risk ratio were performed to analyze the percentage of new pregnancies according to CM usage. RESULTS: The percentage of new pregnancies was 11 among our FP patients (N=555) during this study period. As anticipated, pregnancy was associated with no CM use, CM discontinuation, and, interestingly, multiple CM changes (p<0.001). The probability of no-pregnancy significantly decreased among patients on no method, who discontinued their CM or made multiple CM changes compared to those with continuous CM use. There was no association between the percentage of new pregnancies and any particular CM type. CONCLUSION: Despite adequate access to FP patient services and high patient satisfaction levels, our findings indicate a need to adopt a more patient-centered approach in our FP counseling that addresses patient's reproductive life plans, preferences, and method side effects to increase CM uptake and satisfaction and decrease frequency of CM changes which is associated with increased risk of mistimed pregnancy during method switching.

The unseen impact - a deep dive into neurocognitive impairment among patients with intracranial meningiomas: a comprehensive systematic review of the literature.

Meningiomas are the most common intracranial tumors, predominantly affecting adults, with a higher incidence in female and elderly populations. Despite their prevalence, research on neurocognitive impairment in meningioma patients remains limited compared to intra-axial tumors such as gliomas. We conducted a comprehensive systematic review of the current literature on neurocognitive outcomes in meningioma patients pre- and post-surgery. Our review revealed significant disparities in reported neurocognitive outcomes, with prospective studies suggesting tumor-related factors as the primary contributors to postoperative deficits, while retrospective studies imply surgical intervention plays a significant role. Regardless of study design or specifics, most studies lack baseline preoperative neurocognitive assessments and standardized protocols for evaluating neurocognitive function. To address these gaps, we advocate for standardized neurocognitive assessment protocols, consensus on neurocognitive domains to be targeted in this population by tailored test batteries, and more prospective studies to elucidate correlations between tumor characteristics, patient attributes, surgical interventions, neurocognitive status, and planning for implementing tailored neurocognitive rehabilitation strategies early in the postoperative course which is crucial for achieving optimal long-term neurocognitive outcomes and enhancing patients' quality of life.