Murine models of erythroid 5ALA synthesis disorders and their conditional synthetic lethal dependency on pyridoxine.

X-linked sideroblastic anemia (XLSA) and X-linked protoporphyria (XLPP) are uncommon diseases caused by loss-of-function and gain-of-function mutations, respectively, in the erythroid form of 5-aminolevulinic acid synthetase, ALAS2, which encodes the first enzyme in heme biosynthesis. A related sideroblastic anemia is due to mutations in SLC25A38, which supplies mitochondrial glycine for ALAS2 (SLC25A38-CSA). The lack of viable animal models has limited studies on the pathophysiology and development of therapies for these conditions. Here, using CRISPR-CAS9 gene editing technology, we have generated knock-in mouse models that recapitulate the main features of XLSA and XLPP, and, using conventional conditional gene targeting in embryonic stem cells, we also developed a faithful model of the SLC25A38-CSA. In addition to examining the phenotypes and natural history of each disease, we determine the effect of restriction or supplementation of dietary pyridoxine (vitamin B6), the essential cofactor of ALAS2, on the anemia and porphyria. In addition to the well-documented response of XLSA mutations to pyridoxine supplementation, we also demonstrate the relative insensitivity of the XLPP porphyria, severe sensitivity of the XLSA models, and an extreme hypersensitivity of the SLC25A38-CSA model to pyridoxine deficiency, a phenotype that is not shared with another mouse hereditary anemia model, Hbbth3/+ -thalassemia intermedia. Thus, in addition to generating animal models useful for examining the pathophysiology and treatment of these diseases, we have uncovered an unsuspected conditional synthetic lethality between the heme synthesis-related CSAs and pyridoxine deficiency. These findings have the potential to inform novel therapeutic paradigms for the treatment of these diseases.

Prostate Cancer Foundation Screening Guidelines for Black Men in the United States.

BACKGROUND: In the United States, Black men are at highest risk for being diagnosed with and dying from prostate cancer. Given this disparity, we examined relevant data to establish clinical prostate-specific antigen (PSA) screening guidelines for Black men in the United States. METHODS: A comprehensive literature search identified 1848 unique publications for screening. Of those screened, 287 studies were selected for full-text review, and 264 were considered relevant and form the basis for these guidelines. The numbers were reported according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. RESULTS: Three randomized controlled trials provided Level 1 evidence that regular PSA screening of men 50 to 74 years of age of average risk reduced metastasis and prostate cancer death at 16 to 22 years of follow-up. The best available evidence specifically for Black men comes from observational and modeling studies that consider age to obtain a baseline PSA, frequency of testing, and age when screening should end. Cohort studies suggest that discussions about baseline PSA testing between Black men and their clinicians should begin in the early 40s, and data from modeling studies indicate prostate cancer develops 3 to 9 years earlier in Black men compared with non-Black men. Lowering the age for baseline PSA testing to 40 to 45 years of age from 50 to 55 years of age, followed by regular screening until 70 years of age (informed by PSA values and health factors), could reduce prostate cancer mortality in Black men (approximately 30% relative risk reduction) without substantially increasing overdiagnosis. CONCLUSIONS: These guidelines recommend that Black men should obtain information about PSA screening for prostate cancer. Among Black men who elect screening, baseline PSA testing should occur between ages 40 and 45. Depending on PSA value and health status, annual screening should be strongly considered. (Supported by the Prostate Cancer Foundation.).

True-Positive 18F-Flotufolastat Lesions in Patients with Prostate Cancer Recurrence with Baseline-Negative Conventional Imaging: Results from the Prospective, Phase 3, Multicenter SPOTLIGHT Study.

18F-rhPSMA-7.3 (18F-flotufolastat) is a high-affinity prostate-specific membrane antigen-targeted diagnostic radiopharmaceutical for PET imaging in patients with prostate cancer. Here, we report findings from the SPOTLIGHT study (NCT04186845), assessing the performance of 18F-flotufolastat PET/CT for identifying prostate-specific membrane antigen-positive lesions confirmed by standard of truth (SoT) in men with biochemical recurrence of prostate cancer and negative conventional imaging at baseline. Methods: Men with biochemical recurrence received 296 MBq of 18F-flotufolastat intravenously and then underwent PET/CT 50-70 min later. 18F-flotufolastat PET/CT findings were evaluated by 3 masked central readers and verified using histopathology or follow-up confirmatory imaging (CT, MRI, bone scan, or 18F-fluciclovine PET/CT) as the SoT. The present analysis evaluated all patients who had negative conventional imaging at baseline, underwent 18F-flotufolastat PET/CT, and had SoT verification by histopathology or follow-up confirmatory imaging to report detection rate (DR), which is the number of patients with at least 1 PET-positive lesion, divided by the number of evaluable patients, and verified DR (VDR), which is the proportion of patients with at least 1 true-positive lesion as verified by SoT, of all patients scanned (PET-positive and PET-negative scans). DR and VDR were calculated and stratified according to prior therapy. Majority read data (agreement between ≥2 readers) are reported. Results: In total, 171 patients with negative baseline conventional imaging and SoT by histopathology or post-PET confirmatory imaging were evaluated. By majority read, the overall 18F-flotufolastat DR among these patients was 95% (163/171; 95% CI, 91.0%-98.0%), and 110 of 171 of these patients had at least 1 true-positive lesion identified (VDR, 64%; 95% CI, 56.7%-71.5%). In the postprostatectomy group (133/171), 8.3% of patients had at least 1 true-positive lesion in the prostate bed, 28% in pelvic lymph nodes, and 35% in other sites. Among those who had received radiotherapy (36/171), 50% of patients had true-positive detections in the prostate, 8.3% in pelvic lymph nodes, and 36% in other sites. Conclusion: 18F-flotufolastat frequently identified true-positive prostate cancer lesions in patients with negative conventional imaging. 18F-flotufolastat may help to better define sites of disease recurrence and inform salvage therapy decisions than does conventional imaging, potentially leading to improved outcomes.

Heterotopic Ossification Is Associated with Painful Neuromas in Transtibial Amputees Undergoing Surgical Treatment of Symptomatic Neuromas.

BACKGROUND: A relationship between nerve and osseous regeneration has been described. During the surgical treatment of symptomatic neuroma in transtibial amputees, we have noticed that heterotopic ossification (HO) depicted on preoperative radiographs appears to be associated with the location of symptomatic neuromas in both the peroneal and tibial nerve distributions. METHODS: Data were collected for transtibial amputees who underwent surgical management of symptomatic neuroma and were prospectively enrolled from 2018 through 2023. Preoperative radiographs were assessed for the presence of HO located at the distal fibula and tibia. The presence of a peroneal and/or tibial neuroma was based on findings contained within the operative reports. Pain levels were measured on a numeric rating scale (0-10). RESULTS: Sixty-five limbs of 62 amputees were include. Peroneal neuroma and presence of fibular HO (P=0.001), and tibial neuroma and presence of tibial HO (P=0.038) demonstrated an association. The odds of having a symptomatic peroneal neuroma with fibular HO present are greater than the odds of a symptomatic peroneal neuroma when fibular HO is absent (OR 9.3; 95%CI [1.9-45.6], P=0.006). Pre-operative pain scores were significantly higher for all patients with HO (P<0.001), those with fibular HO (P<0.001), and those with tibial HO (P<0.001), compared to patients without HO. CONCLUSIONS: In patients with symptomatic neuromas, preoperative pain was worse when HO was present in the transtibial amputee's residual limb. Further research on the neuroma-HO-complex in symptomatic amputees is required. LEVEL OF EVIDENCE: Therapeutic Level IV.

Comprehensive Genomic Analysis Identifies a Diverse Landscape of Sideroblastic and Nonsideroblastic Iron-Related Anemias with Novel and Pathogenic Variants in an Iron-Deficient Endemic Setting.

Inherited iron metabolism defects are possibly missed or underdiagnosed in iron-deficient endemic settings because of a lack of awareness or a methodical screening approach. Hence, we systematically evaluated anemia cases (2019 to 2021) based on clinical phenotype, normal screening tests (high-performance liquid chromatography, α gene sequencing, erythrocyte sedimentation rate, C-reactive protein, and tissue transglutaminase), and abnormal iron profile by targeted next-generation sequencing (26-gene panel) supplemented with whole-exome sequencing, multiplex ligation probe amplification/mitochondrial DNA sequencing, and chromosomal microarray. Novel variants in ALAS2, STEAP3, and HSPA9 genes were functionally validated. A total of 290 anemia cases were screened, and 41 (14%) enrolled for genomic testing as per inclusion criteria. Comprehensive genomic testing revealed pathogenic variants in 23 of 41 cases (56%). Congenital sideroblastic anemia was the most common diagnosis (14/23; 61%), with pathogenic variations in ALAS2 (n = 6), SLC25A38 (n = 3), HSPA9 (n = 2) and HSCB, SLC19A2, and mitochondrial DNA deletion (n = 1 each). Nonsideroblastic iron defects included STEAP3-related microcytic anemia (2/23; 8.7%) and hypotransferrenemia (1/23; 4.3%). A total of 6 of 22 cases (27%) revealed a non-iron metabolism gene defect on whole-exome sequencing. Eleven novel variants (including variants of uncertain significance) were noted in 13 cases. Genotype-phenotype correlation revealed a significant association of frameshift/nonsense/splice variants with lower presentation age (0.8 months versus 9 years; P < 0.01) compared with missense variants. The systematic evaluation helped uncover an inherited iron defect in 41% (17/41) of cases, suggesting the need for active screening and awareness for these rare diseases in an iron-deficient endemic population.

Folate depletion induces erythroid differentiation through perturbation of de novo purine synthesis.

Folate, an essential vitamin, is a one-carbon acceptor and donor in key metabolic reactions. Erythroid cells harbor a unique sensitivity to folate deprivation, as revealed by the primary pathological manifestation of nutritional folate deprivation: megaloblastic anemia. To study this metabolic sensitivity, we applied mild folate depletion to human and mouse erythroid cell lines and primary murine erythroid progenitors. We show that folate depletion induces early blockade of purine synthesis and accumulation of the purine synthesis intermediate and signaling molecule, 5'-phosphoribosyl-5-aminoimidazole-4-carboxamide (AICAR), followed by enhanced heme metabolism, hemoglobin synthesis, and erythroid differentiation. This is phenocopied by inhibition of folate metabolism using the inhibitor SHIN1, and by AICAR supplementation. Mechanistically, the metabolically driven differentiation is independent of mechanistic target of rapamycin complex 1 (mTORC1) and adenosine 5'-monophosphate-activated protein kinase (AMPK) and is instead mediated by protein kinase C. Our findings suggest that folate deprivation-induced premature differentiation of erythroid progenitor cells is a molecular etiology to folate deficiency-induced anemia.

PROMISE Registry: A prostate cancer registry of outcomes and germline mutations for improved survival and treatment effectiveness.

BACKGROUND: Recently approved treatments and updates to genetic testing recommendations for prostate cancer have created a need for correlated analyses of patient outcomes data via germline genetic mutation status. Genetic registries address these gaps by identifying candidates for recently approved targeted treatments, expanding clinical trial data examining specific gene mutations, and understanding effects of targeted treatments in the real-world setting. METHODS: The PROMISE Registry is a 20-year (5-year recruitment, 15-year follow-up), US-wide, prospective genetic registry for prostate cancer patients. Five thousand patients will be screened through an online at-home germline testing to identify and enroll 500 patients with germline mutations, including: pathogenic or likely pathogenic variants and variants of uncertain significance in genes of interest. Patients will be followed for 15 years and clinical data with real time patient reported outcomes will be collected. Eligible patients will enter long-term follow-up (6-month PRO surveys and medical record retrieval). As a virtual study with patient self-enrollment, the PROMISE Registry may fill gaps in genetics services in underserved areas and for patients within sufficient insurance coverage. RESULTS: The PROMISE Registry opened in May 2021. 2114 patients have enrolled to date across 48 US states and 23 recruiting sites. 202 patients have met criteria for long-term follow-up. PROMISE is on target with the study's goal of 5000 patients screened and 500 patients eligible for long-term follow-up by 2026. CONCLUSIONS: The PROMISE Registry is a novel, prospective, germline registry that will collect long-term patient outcomes data to address current gaps in understanding resulting from recently FDA-approved treatments and updates to genetic testing recommendations for prostate cancer. Through inclusion of a broad nationwide sample, including underserved patients and those unaffiliated with major academic centers, the PROMISE Registry aims to provide access to germline genetic testing and to collect data to understand disease characteristics and treatment responses across the disease spectrum for prostate cancer with rare germline genetic variants.

Post-operative Opioid Reduction Protocol Reduces Racial Disparity in Clinical Outcomes in Children.

INTRODUCTION: Racial disparities in health outcomes continue to exist for children requiring surgery. Previous investigations suggest that clinical protocols may reduce racial disparities. A post-operative opioid reduction protocol was implemented in children undergoing abdominal surgery who were less than 1 years old at a tertiary level hospital. The purpose of this investigation was to determine if the clinical protocol was associated with a reduction in racial disparity in post-operative opioid prescribing patterns and associated clinical outcomes. METHODS: A post-operative opioid reduction protocol based on standing intravenous acetaminophen, educational sessions with nursing staff, and standardized post-operative sign-out between the surgical and NICU teams was implemented in children under 1 year old in 2016. A time series and before and after analysis was conducted using a historical pre-intervention cohort (Jan 2011-Dec 2015) and prospectively collected post-intervention cohort (Jan 2016-Jan 2021). Primary outcomes included post-operative opioid use and post-operative pain scores stratified by race. Secondary outcomes included associated clinical outcomes also stratified by race. RESULTS: A total of 249 children were included in the investigation, 117 in the pre-intervention group and 132 in the post intervention group. The majority of patients in both cohorts were either White or Black. The two cohorts were equally matched in terms of pre-operative clinical variables. In the pre-intervention cohort, the median post-operative morphine equivalents in White children was 2.1 mg/kg (IQR 0.2, 11.1) while in Black children it was 13.1 mg/kg (IQR 2.4, 65.3), p-value = 0.0352. In the post-intervention cohort, the median value for White children and Black children was statistically identical (0.05 mg/kg (IQR 0, 0.5) and 0.0 mg/kg (IQR 0, 0.3), respectively, p-value = 0.237). This pattern was also demonstrated in clinical variables including length of stay, intubation length and total parenteral nutrition use. In the pre-intervention cohort, the total length of stay for white children was 16 days while for black children it was 45 days (p = 0.007). In the postintervention cohort the length of stay for both White and Black children were identical at 8 days (p = 0.748). CONCLUSION: The use of a clinical opioid reduction protocol implemented at a tertiary medical center was associated with a reduction in racial disparity in opioid prescribing habits in children. Prior to the protocol, there was a racial disparity in clinical variables associated with prolonged opioid use including length of stay, TPN use, and intubation length. The clinical protocol reduced variability in opioid prescribing patterns in all racial groups which was associated with a reduction in variability in associated clinical variables. LEVEL OF EVIDENCE: Level III.

Organizational and community resilience for COVID-19 and beyond: Leveraging a system for health and social services integration.

OBJECTIVE: To examine how a preexisting initiative to align health care, public health, and social services influenced COVID-19 pandemic response. DATA SOURCES AND STUDY SETTING: In-depth interviews with administrators and frontline staff in health care, public health, and social services in Contra Costa County, California from October, 2020, to May, 2021. STUDY DESIGN: Qualitative, semi-structured interviews examined how COVID-19 response used resources developed for system alignment prior to the pandemic. DATA COLLECTION: We interviewed 31 informants including 14 managers in public health, health care, or social services and 17 social needs case managers who coordinated services across these sectors on behalf of patients. An inductive-deductive qualitative coding approach was used to systematically identify recurrent themes. PRINCIPAL FINDINGS: We identified four distinct components of the county's system alignment capabilities that supported COVID-19 response, including (1) an organizational culture of adaptability fostered through earlier system alignment efforts, which included the ability and willingness to rapidly implement new organizational processes, (2) trusting relationships among organizations based on prior, positive experiences of cross-sector collaboration, (3) capacity to monitor population health of historically marginalized community members, including information infrastructures, data analytics, and population monitoring and outreach, and (4) frontline staff with flexible skills to support health and social care who had built relationships with the highest risk community members. CONCLUSIONS: Prior investments in aligning systems provided unanticipated benefits for organizational and community resilience during the COVID-19 pandemic. Our results illustrate a pathway for investment in system alignment efforts that build capacity within organizations and relationships between organizations to enhance resilience to crisis. Our findings suggest the usefulness of an integrated concept of organizational and community resilience that understands the resilience of systems of care as a vital resource for community resilience during crisis.

Globalizing transit worker stress.

Health scientists have claimed that urban transit workers suffer from higher rates of stress-related disease than workers in most other occupations. This paper examines how a network of scientists and labor organizers constructed the problem of transit worker stress as a global phenomenon. According to study participants, transit workers worldwide are subject to a similar set of stress-related risks, which can serve as a basis for worker solidarity. This paper analyzes how the concept of stress has been used to identify pathogenic environments and considers anthropological claims that the concept often abstracts and depoliticizes harmful arrangements. The findings show that scientists and labor organizers use the stress concept to construct a figure of a universally at-risk transit worker that serves the ends of transnational labor organizing. At the same time, by focusing on the case of San Francisco's transit workers, this analysis shows that a persistent association between stress and 'hard work'-in both lay and scientific discourses-may block recognition of stress-related harms for transit workers who are accused of being lazy and overpaid.

Biomedicine and the treatment of difference in a Jerusalem emergency department.

Biomedicine has played a key role in the dissemination of modern social norms, such as the emphasis on individual autonomy and the distinction between science and religion. This study examines the way the mostly-Jewish members of the medical staff at an emergency department of a Jerusalem hospital perceive Jewish ultra-Orthodox and Arab patients' behaviors vis-à-vis the existing biomedical norms. We analyzed participants' perceptions in terms of the social constructs they reveal, their meanings, and their implications. Semi-structured in-depth interviews were conducted with 24 staff members and were analyzed using content analysis. The staff described challenges in treating Arab and ultra-Orthodox patients, which they related to both groups' embeddedness in traditional "cultures" and collective identities. According to the participants, in both cases, the patients' cultural affiliations constrained their sense of individual autonomy and rationality. However, in the comparative analysis, two differences emerged. First, while both groups were perceived to diverge from modern norms of individual autonomy, in the case of Arab patients, these characteristics were presented as disruptive and potentially threatening to the hospital staff. By contrast, in the case of ultra-Orthodox patients, adherence to traditional and collective values was more likely to be represented as a risk to the patient, rather than to the staff. Second, staff were more likely to provide accommodations for ultra-Orthodox patients than for Arab patients. These accommodations were often described in the frame of "cultural competency." We suggest that divergences in how staff understood and responded to perceived cultural differences of each group reflect unequal impacts of structural determinants of health, including of political conflict. We recommend moving beyond the conceptual framework of cultural competency to strengthen the staff's structural competency, cultural and structural humility, and critical consciousness.

Adaptation of the collaborative care model to integrate behavioral health care into a low-barrier HIV clinic.

Background: The collaborative care management (CoCM) model is an evidence-based intervention for integrating behavioral health care into nonpsychiatric settings. CoCM has been extensively studied in primary care clinics, but implementation in nonconventional clinics, such as those tailored to provide care for high-need, complex patients, has not been well described. Method: We adapted CoCM for a low-barrier HIV clinic that provides walk-in medical care for a patient population with high levels of mental illness, substance use, and housing instability. The Exploration, Preparation, Implementation, and Sustainment model guided implementation activities and support through the phases of implementing CoCM. The Framework for Reporting Adaptations and Modifications to Evidence-Based Interventions guided our documentation of adaptations to process-of-care elements and structural elements of CoCM. We used a multicomponent strategy to implement the adapted CoCM model. In this article, we describe our experience through the first 6 months of implementation. Results: The key contextual factors necessitating adaptation of the CoCM model were the clinic team structure, lack of scheduled appointments, high complexity of the patient population, and time constraints with competing priorities for patient care, all of which required substantial flexibility in the model. The process-of-care elements were adapted to improve the fit of the intervention with the context, but the core structural elements of CoCM were maintained. Conclusions: The CoCM model can be adapted for a setting that requires more flexibility than the usual primary care clinic while maintaining the core elements of the intervention.

What is already known about this topic? Collaborative care management is an evidence-based intervention to integrate behavioral health care into primary medical care. The model uses a task-sharing approach in which a behavioral health care manager who is supervised by a remote psychiatrist works with the primary medical team. What does this paper add? We describe adaptation of the collaborative care management model for a low-barrier HIV care clinic. Adaptation was necessary because the clinic provides all care on a walk-in basis, the team structure differs from usual primary care, and the patient population has complex medical and social needs. What are the implications for practice, research or policy? Our experience can inform implementation of collaborative care management into other medical settings that are designed to provide care for high-need, complex patient populations.

Greater Covid-19 vaccine uptake among enrollees offered health and social needs case management: Results from a randomized trial.

OBJECTIVE: To investigate Covid-19 vaccination as a potential secondary public health benefit of case management for Medicaid beneficiaries with health and social needs. DATA SOURCES AND STUDY SETTING: The CommunityConnect case management program for Medicaid beneficiaries is run by Contra Costa Health, a county safety net health system in California. Program enrollment data were merged with comprehensive county vaccination records. STUDY DESIGN: Individuals with elevated risk of hospital and emergency department use were randomized each month to a case management intervention or usual care. Interdisciplinary case managers offered coaching, community referrals, healthcare connections, and other support based on enrollee interest and need. Using survival analysis with intent-to-treat assignment, we assessed rates of first-dose Covid-19 vaccination from December 2020 to September 2021. In exploratory sub-analyses we also examined effect heterogeneity by gender, race/ethnicity, age, and primary language. DATA COLLECTION AND EXTRACTION METHODS: Data were extracted from county and program records as of September 2021, totaling 12,866 interventions and 25,761 control enrollments. PRINCIPAL FINDINGS: Approximately 58% of enrollees were female and 41% were under age 35. Enrollees were 23% White, 12% Asian/Pacific Islander, 20% Black/African American, and 36% Hispanic/Latino, and 10% other/unknown. Approximately 35% of the intervention group engaged with their case manager. Approximately 56% of all intervention and control enrollees were vaccinated after 9 months of analysis time. Intervention enrollees had a higher vaccination rate compared to control enrollees (adjusted hazard ratio [aHR]: 1.06; 95% confidence interval [CI]: 1.02-1.10). In sub-analyses, the intervention was associated with stronger likelihood of vaccination among males and individuals under age 35. CONCLUSIONS: Case management infrastructure modestly improved Covid-19 vaccine uptake in a population of Medicaid beneficiaries that over-represents social groups with barriers to early Covid-19 vaccination. Amidst mixed evidence on vaccination-specific incentives, leveraging trusted case managers and existing case management programs may be a valuable prevention strategy.

Metabolic Syndrome Increases Risk of Readmission and Complications in Operative Fixation of Pilon Fractures.

Background Studies demonstrate that metabolic syndrome (MetS) negatively impacts surgical outcomes. This study sought to identify how metabolic syndrome affects outcomes after open reduction and internal fixation (ORIF) of traumatic pilon fractures. Methods Patients who underwent ORIF for pilon fractures from 2012 to 2019 were identified in the American College of Surgeons National Surgical Quality Improvement Program database. Patients with MetS were compared to non-MetS patients for rates of adverse events, prolonged stay, readmission, discharge location, and operative time in the 30-day postoperative period. All statistical analyses were conducted using SPSS version 26.0 (IBM Corp., Armonk, NY, USA). Paired student t-tests were used to assess continuous variables. Pearson's Chi-square and odds ratios were used for categorical variables. Results A total of 1,915 patients met this study's inclusion criteria, and 127 MetS patients were identified in the cohort. The MetS cohort was older (62.7 vs 49.5 years old, p-value <0.01), with a greater proportion of female patients (59.1% vs 50.2%, p=0.054). MetS patients experienced significantly higher rates of infectious complications (7.9% vs 3.9% OR 2.75 (CI 1.36-5.53), p=0.008), major adverse events (11% vs 4.3%, OR 2.79 (CI 1.53-5.09) p=0.002), and readmissions. MetS patients also had longer lengths of stay (7 days vs 3.8 days, p-value<0.001), and were more likely to be discharged to a non-home location (51.2% vs 19.5%, p-value<0.01, OR 4.32 (CI=3.0-6.24) p<0.001). Conclusion Patients with MetS have an increased risk of 30-day major complications, infection, readmissions, discharge to a non-home location, and prolonged operative time, and therefore warrant additional consideration for perioperative monitoring.