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.

Loss of the placental iron exporter ferroportin 1 causes embryonic demise in late-gestation mouse pregnancy.

Fetal development relies on adequate iron supply by the placenta. The placental syncytiotrophoblasts (SCTB) express high levels of iron transporters, including ferroportin1 (Fpn1). Whether they are essential in the placenta has not been tested directly, mainly due to the lack of gene manipulation tools in SCTB. Here, we aimed to generate a SCTB-specific Cre mouse and use it to determine the role of placental Fpn1. Using CRISPR/Cas9 technology, we created a syncytin b (Synb) Cre line (SynbCre) targeting the fetal-facing SCTB layer in mouse placental labyrinth. SynbCre deleted Fpn1 in late gestation mouse placentas reliably with high efficiency. Embryos without placental Fpn1 were pale and runted, and died before birth. Fpn1 null placentas had reduced transferrin receptor expression, increased oxidative stress and detoxification responses, and accumulated ferritin in the SCTB instead of the fetal endothelium. In summary, we demonstrate that SynbCre is an effective and specific tool to investigate placental gene function in vivo. The loss of Fpn1 in late gestation mouse placenta is embryonically lethal, providing direct evidence for an essential role of Fpn1 in placental iron transport.

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.

Diagnostic Performance and Safety of 18F-rhPSMA-7.3 Positron Emission Tomography in Men With Suspected Prostate Cancer Recurrence: Results From a Phase 3, Prospective, Multicenter Study (SPOTLIGHT).

PURPOSE: SPOTLIGHT (NCT04186845) evaluated diagnostic performance and safety of radiohybrid 18F-rhPSMA-7.3, a novel high-affinity positron emission tomography radiopharmaceutical. MATERIALS AND METHODS: Men with prostate cancer recurrence underwent positron emission tomography/CT 50-70 minutes after intravenous administration of 296±20% MBq 18F-rhPSMA-7.3. To assess the coprimary end points (verified detection rate and combined region-level positive predictive value), 3 blinded, independent central readers evaluated the scans. Verified detection rate is equivalent to the overall detection rate × positive predictive value. Standard of truth was established for each patient using histopathology or confirmatory imaging. Statistical thresholds (lower bounds of the confidence intervals) of 36.5% and 62.5% were prespecified for verified detection rate and combined region-level positive predictive value, respectively. Additional end points included detection rate, verified detection rate, and combined region-level positive predictive value in patients with histopathology standard of truth, and safety. RESULTS: The overall 18F-rhPSMA-7.3 detection rate among all 389 patients with an evaluable scan was 83% (majority read). Among the 366 patients (median prostate-specific antigen 1.27 ng/mL) for whom a standard of truth (histopathology [n=69]/confirmatory imaging only [n=297]) was available, verified detection rate ranged from 51% (95% CI 46.1-56.6) to 54% (95% CI 48.8-59.3), exceeding the prespecified statistical threshold. Combined region-level positive predictive value ranged from 46% (95% CI 42.0-50.3) to 60% (95% CI 55.1-65.5) across the readers, not meeting the threshold. In the subset of patients with histopathology standard of truth, the verified detection rate and combined region-level positive predictive value were both above the prespecified thresholds (majority read, 81% [95% CI 69.9-89.6] and 72% [95% CI 62.5-80.7], respectively). No significant safety concerns were identified. CONCLUSIONS: 18F-rhPSMA-7.3 offers a clinically meaningful verified detection rate for localization of recurrent prostate cancer. Despite missing the coprimary end point of combined region-level positive predictive value, the totality of the data support the potential clinical utility of 18F-rhPSMA-7.3.

Associations of Race, Ethnicity, and Social Determinants of Health With Colorectal Cancer Screening.

BACKGROUND: Racial and ethnic disparities in receipt of recommended colorectal cancer screening exist; however, the impact of social determinants of health on such disparities has not been recently studied in a national cohort. OBJECTIVE: This study aimed to determine whether social determinants of health attenuate racial disparities in receipt of colorectal cancer screening. DESIGN: This was a cross-sectional telephone survey of self-reported race and ethnicity and up-to-date colorectal cancer screening. Associations between race/ethnicity and colorectal cancer screening were tested before and after adjustment for demographics, behavioral factors, and social determinants of health. SETTING: This was a nationally representative telephone survey of US residents in 2018. PATIENTS: The patients included were US residents aged 50 to 75 years. MAIN OUTCOME MEASURES: The primary outcome was up-to-date colorectal cancer screening status, according to 2008 US Preventive Services Task Force recommendations. RESULTS: This study included 226,106 respondents aged 50 to 75 years. Before adjustment, all minority racial and ethnic groups demonstrated a significantly lower odds of screening than those of non-Hispanic white respondents. After adjustment for demographics, behavioral factors, and social determinants of health, compared to non-Hispanic white respondents, odds of screening were found to be increased among non-Hispanic black respondents (OR, 1.10; p = 0.02); lower but attenuated among Hispanic respondents (OR, 0.73; p < 0.001), non-Hispanic American Indian/Alaskan Native respondents (OR, 0.85; p = 0.048), and non-Hispanic respondents of other races (OR, 0.82; p = 0.01); and lower but not attenuated among non-Hispanic Asian respondents (OR, 0.68; p < 0.001). LIMITATIONS: Recall bias, participant bias, and residual confounding. CONCLUSIONS: Adjustment for social determinants of health reduced racial and ethnic disparities in colorectal cancer screening among all minority racial and ethnic groups except non-Hispanic Asian individuals; however, other unmeasured confounders likely exist. See Video Abstract at http://links.lww.com/DCR/B977 . ASOCIACIN DE RAZA, ETNICIDAD Y DETERMINANTES SOCIALES DE LA SALUD CON LA DETECCIN DEL CNCER COLORRECTAL: ANTECEDENTES: Existen disparidades raciales y étnicas en la recepción de las pruebas recomendadas de detección de cáncer colorrectal; sin embargo, el impacto de los determinantes sociales de la salud en dichas disparidades no se ha estudiado recientemente en una cohorte nacional.OBJETIVO: El objetivo de este estudio fue determinar si los determinantes sociales de la salud atenúan las disparidades raciales en la recepción de pruebas de detección del cáncer colorrectal.DISEÑO: Encuesta telefónica transversal de raza y etnia autoinformada y detección actualizada de cáncer colorrectal. Las asociaciones entre la raza/etnicidad y la detección del cáncer colorrectal se probaron antes y después del ajuste por demografía, factores conductuales y determinantes sociales de la salud.ESCENARIO: Esta fue una encuesta telefónica representativa a nivel nacional de los residentes de EE. UU. en 2018.PACIENTES: Los pacientes eran residentes de EE. UU. de 50 a 75 años.PRINCIPALES MEDIDAS DE RESULTADO: Estado actualizado de detección de cáncer colorrectal, según las recomendaciones del Grupo de Trabajo de Servicios Preventivos de EE. UU. de 2008.RESULTADOS: Este estudio incluyó a 226.106 encuestados de 50 a 75 años. Antes del ajuste, todos los grupos étnicos y raciales minoritarios demostraron probabilidades significativamente más bajas de detección en comparación con los encuestados blancos no hispanos. Después del ajuste por demografía, factores conductuales y determinantes sociales de la salud, en comparación con los encuestados blancos no hispanos, las probabilidades de detección aumentaron entre los encuestados negros no hispanos (OR 1,10, p = 0,02); más bajo pero atenuado entre los encuestados hispanos (OR 0,73, p < 0,001), los encuestados indios americanos/nativos de Alaska no hispanos (OR 0,85, p = 0,048) y los encuestados no hispanos de otras razas (OR 0,82, p = 0,01); y menor pero no atenuado entre los encuestados asiáticos no hispanos (OR 0,68, p < 0,001).LIMITACIONES: Sesgo de recuerdo y sesgo de participante, así como confusión residual.CONCLUSIONES: El ajuste para los determinantes sociales de la salud redujo las disparidades raciales y étnicas en la detección del cáncer colorrectal entre todos los grupos étnicos y raciales minoritarios, excepto las personas asiáticas no hispanas; sin embargo, es probable que existan otros factores de confusión no medidos. Consulte Video Resumen en http://links.lww.com/DCR/B977 . (Traducción-Dr. Felipe Bellolio ).

Implementation of ultrasound and fast magnetic resonance imaging pathway reduces computed tomography utilization in children with suspected appendicitis.

PURPOSE: Computed tomography (CT) is still used in the imaging diagnosis of acute appendicitis in children at many hospitals. We implemented an ultrasound (US) and fast magnetic resonance imaging (MRI) pathway for suspected appendicitis at our institution with the goal of reducing radiation exposure in children. METHODS: All children (< 18 years old) who underwent appendectomy between January 2011 and July 2021 were reviewed. Data were collected on all imaging studies performed. In December 2015, we initiated an imaging pathway for suspected acute appendicitis. US was the initial imaging study, and a rapid protocol MRI was performed if US was equivocal. Those could not tolerate MRI underwent CT. We evaluated the difference in percentage of patients who underwent CT before and after pathway initiation. RESULTS: 554 patients who underwent appendectomy did not have prior imaging studies on presentation to our hospital and were included in analysis. After initiating the pathway, the use of abdominal US increased from 87% (220 of 254) to 97% (291 of 300, p < 0.0001) and the use of MRI increased by 100% (0 MRIs pre-protocol, 90 of 300 patients post-protocol, p < 0.0001). CT utilization decreased significantly from 32% (82 of 254) to 2% (6 of 300, p < 0.0001). CONCLUSION: Embracing a new US and rapid MRI pathway to evaluate pediatric patients with suspected acute appendicitis resulted in significant reduction in CT utilization and therefore radiation exposure.

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.

Exploring the well-being of community pharmacy professionals, turnover intention and patient safety: Time to include operational responsibility.

Background: The COVID-19 pandemic added significant occupational pressures on community pharmacists. The objective of this research project was to investigate the level of distress and burnout among community pharmacy professionals and its association with their retention within their occupation as well as patient safety outcomes. Method: We conducted a cross-sectional study on 722 community pharmacy professionals from all Canadian provinces using an online survey, including scientifically validated measures. The data were analyzed using multiple regression analysis. Results: In Canada, 85% of community pharmacy professionals reported their mental health had suffered since the COVID-19 pandemic. Younger pharmacy professionals and those paid hourly reported a worsening level of mental health and an increasing level of turnover intention. Pharmacists with more dynamic/disrupted work schedules and those working for a large pharmacy chain (more than 25 pharmacies in Canada) reported lower levels of mental health quality. Pharmacy professionals working in pharmacies that are open more than 70 hours a week reported a lower level of patient safety culture. Pharmacists' mental health was the significant predictor of their turnover intention, implying a heightened risk to professional effectiveness and retention. Compassion satisfaction was positively associated with patient safety culture and safety behaviour, while compassion fatigue and secondary traumatic stress were significantly associated with pharmacists' level of risk-taking behaviours. Conclusion: This study emphasized the importance of prioritizing the mental health and well-being of community pharmacy professionals and demonstrated individual and systemic factors predicting the well-being and turnover intention of community pharmacists, as well as patient safety culture within their pharmacy. This research makes a case to consider actions to shift the monitoring focus from community pharmacists (also known as "individual responsibility") to community pharmacies (also known as "operational responsibility") for managing patient safety. Additionally, community pharmacists should be provided with the professional autonomy to affect their working conditions and alleviate the stress that has the potential to negatively affect the delivery of care.

Efficacy and safety of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma: long-term follow-up of a phase 2 study.

BACKGROUND: Erdafitinib, a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, was shown to be clinically active and tolerable in patients with advanced urothelial carcinoma and prespecified FGFR alterations in the primary analysis of the BLC2001 study at median 11 months of follow-up. We aimed to assess the long-term efficacy and safety of the selected regimen of erdafitinib determined in the initial part of the study. METHODS: The open-label, non-comparator, phase 2, BLC2001 study was done at 126 medical centres in 14 countries across Asia, Europe, and North America. Eligible patients were aged 18 years or older with locally advanced and unresectable or metastatic urothelial carcinoma, at least one prespecified FGFR alteration, an Eastern Cooperative Oncology Group performance status of 0-2, and progressive disease after receiving at least one systemic chemotherapy or within 12 months of neoadjuvant or adjuvant chemotherapy or were ineligible for cisplatin. The selected regimen determined in the initial part of the study was continuous once daily 8 mg/day oral erdafitinib in 28-day cycles, with provision for pharmacodynamically guided uptitration to 9 mg/day (8 mg/day UpT). The primary endpoint was investigator-assessed confirmed objective response rate according to Response Evaluation Criteria In Solid Tumors version 1.1. Efficacy and safety were analysed in all treated patients who received at least one dose of erdafitinib. This is the final analysis of this study. This study is registered with ClinicalTrials.gov, NCT02365597. FINDINGS: Between May 25, 2015, and Aug 9, 2018, 2328 patients were screened, of whom 212 were enrolled and 101 were treated with the selected erdafitinib 8 mg/day UpT regimen. The data cutoff date for this analysis was Aug 9, 2019. Median efficacy follow-up was 24·0 months (IQR 22·7-26·6). The investigator-assessed objective response rate for patients treated with the selected erdafitinib regimen was 40 (40%; 95% CI 30-49) of 101 patients. The safety profile remained similar to that in the primary analysis, with no new safety signals reported with longer follow-up. Grade 3-4 treatment-emergent adverse events of any causality occurred in 72 (71%) of 101 patients. The most common grade 3-4 treatment-emergent adverse events of any cause were stomatitis (in 14 [14%] of 101 patients) and hyponatraemia (in 11 [11%]). There were no treatment-related deaths. INTERPRETATION: With longer follow-up, treatment with the selected regimen of erdafitinib showed consistent activity and a manageable safety profile in patients with locally advanced or metastatic urothelial carcinoma and prespecified FGFR alterations. FUNDING: Janssen Research & Development.

The Human-Specific BOLA2 Duplication Modifies Iron Homeostasis and Anemia Predisposition in Chromosome 16p11.2 Autism Individuals.

Human-specific duplications at chromosome 16p11.2 mediate recurrent pathogenic 600 kbp BP4-BP5 copy-number variations, which are among the most common genetic causes of autism. These copy-number polymorphic duplications are under positive selection and include three to eight copies of BOLA2, a gene involved in the maturation of cytosolic iron-sulfur proteins. To investigate the potential advantage provided by the rapid expansion of BOLA2, we assessed hematological traits and anemia prevalence in 379,385 controls and individuals who have lost or gained copies of BOLA2: 89 chromosome 16p11.2 BP4-BP5 deletion carriers and 56 reciprocal duplication carriers in the UK Biobank. We found that the 16p11.2 deletion is associated with anemia (18/89 carriers, 20%, p = 4e-7, OR = 5), particularly iron-deficiency anemia. We observed similar enrichments in two clinical 16p11.2 deletion cohorts, which included 6/63 (10%) and 7/20 (35%) unrelated individuals with anemia, microcytosis, low serum iron, or low blood hemoglobin. Upon stratification by BOLA2 copy number, our data showed an association between low BOLA2 dosage and the above phenotypes (8/15 individuals with three copies, 53%, p = 1e-4). In parallel, we analyzed hematological traits in mice carrying the 16p11.2 orthologous deletion or duplication, as well as Bola2+/- and Bola2-/- animals. The Bola2-deficient mice and the mice carrying the deletion showed early evidence of iron deficiency, including a mild decrease in hemoglobin, lower plasma iron, microcytosis, and an increased red blood cell zinc-protoporphyrin-to-heme ratio. Our results indicate that BOLA2 participates in iron homeostasis in vivo, and its expansion has a potential adaptive role in protecting against iron deficiency.

Phase II Clinical and Translational Study of Everolimus ± Paclitaxel as First-Line Therapy in Cisplatin-Ineligible Advanced Urothelial Carcinoma.

BACKGROUND: Treatment options have been historically limited for cisplatin-ineligible patients with advanced urothelial carcinoma (UC). Given the need for alternatives to platinum-based chemotherapy, including non-chemotherapy regimens for patients with both impaired renal function and borderline functional status, in 2010 (prior to the immune checkpoint blockade era in metastatic UC), we initiated a phase II trial to test the activity of everolimus or everolimus plus paclitaxel in the cisplatin-ineligible setting. METHODS: This was an open-label phase II trial conducted within the US-based Hoosier Cancer Research Network (ClinicalTrials.gov number: NCT01215136). Patients who were cisplatin-ineligible with previously untreated advanced UC were enrolled. Patients with both impaired renal function and poor performance status were enrolled into cohort 1; patients with either were enrolled into cohort 2. Patients received everolimus 10 mg daily alone (cohort 1) or with paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 28-day cycle (cohort 2). The primary outcome was clinical benefit at 4 months. Secondary outcomes were adverse events, progression-free survival (PFS), and 1-year overall survival (OS). Exploratory endpoints included genomic correlates of outcomes. The trial was not designed for comparison between cohorts. RESULTS: A total of 36 patients were enrolled from 2010 to 2018 (cohort 1, N = 7; cohort 2, N = 29); the trial was terminated due to slow accrual. Clinical benefit at 4 months was attained by 0 (0%, 95% confidence interval [CI] 0-41.0%) patients in cohort 1 and 11 patients (37.9%, 95% CI 20.7-57.7%) in cohort 2. Median PFS was 2.33 (95% CI 1.81-Inf) months in cohort 1 and 5.85 (95% CI 2.99-8.61) months in cohort 2. Treatment was discontinued due to adverse events for 2 patients (29%) in cohort 1 and 11 patients (38%) in cohort 2. Molecular alterations in microtubule associated genes may be associated with treatment benefit but this requires further testing. CONCLUSION: Everolimus plus paclitaxel demonstrates clinical activity in cisplatin-ineligible patients with metastatic UC, although the specific contribution of everolimus cannot be delineated. Patients with both impaired renal function and borderline functional status may be difficult to enroll to prospective trials. (ClinicalTrials.gov Identifier NCT01215136).

Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma.

BACKGROUND: Alterations in the gene encoding fibroblast growth factor receptor (FGFR) are common in urothelial carcinoma and may be associated with lower sensitivity to immune interventions. Erdafitinib, a tyrosine kinase inhibitor of FGFR1-4, has shown antitumor activity in preclinical models and in a phase 1 study involving patients with FGFR alterations. METHODS: In this open-label, phase 2 study, we enrolled patients who had locally advanced and unresectable or metastatic urothelial carcinoma with prespecified FGFR alterations. All the patients had a history of disease progression during or after at least one course of chemotherapy or within 12 months after neoadjuvant or adjuvant chemotherapy. Prior immunotherapy was allowed. We initially randomly assigned the patients to receive erdafitinib in either an intermittent or a continuous regimen in the dose-selection phase of the study. On the basis of an interim analysis, the starting dose was set at 8 mg per day in a continuous regimen (selected-regimen group), with provision for a pharmacodynamically guided dose escalation to 9 mg. The primary end point was the objective response rate. Key secondary end points included progression-free survival, duration of response, and overall survival. RESULTS: A total of 99 patients in the selected-regimen group received a median of five cycles of erdafitinib. Of these patients, 43% had received at least two previous courses of treatment, 79% had visceral metastases, and 53% had a creatinine clearance of less than 60 ml per minute. The rate of confirmed response to erdafitinib therapy was 40% (3% with a complete response and 37% with a partial response). Among the 22 patients who had undergone previous immunotherapy, the confirmed response rate was 59%. The median duration of progression-free survival was 5.5 months, and the median duration of overall survival was 13.8 months. Treatment-related adverse events of grade 3 or higher, which were managed mainly by dose adjustments, were reported in 46% of the patients; 13% of the patients discontinued treatment because of adverse events. There were no treatment-related deaths. CONCLUSIONS: The use of erdafitinib was associated with an objective tumor response in 40% of previously treated patients who had locally advanced and unresectable or metastatic urothelial carcinoma with FGFR alterations. Treatment-related grade 3 or higher adverse events were reported in nearly half the patients. (Funded by Janssen Research and Development; BLC2001 ClinicalTrials.gov number, NCT02365597.).

Hereditary myopathies associated with hematological abnormalities.

The diagnostic evaluation of a patient with suspected hereditary muscle disease can be challenging. Clinicians rely largely on clinical history and examination features, with additional serological, electrodiagnostic, radiologic, histopathologic, and genetic investigations assisting in definitive diagnosis. Hematological testing is inexpensive and widely available, but frequently overlooked in the hereditary myopathy evaluation. Hematological abnormalities are infrequently encountered in this setting; however, their presence provides a valuable clue, helps refine the differential diagnosis, tailors further investigation, and assists interpretation of variants of uncertain significance. A diverse spectrum of hematological abnormalities is associated with hereditary myopathies, including anemias, leukocyte abnormalities, and thrombocytopenia. Recurrent rhabdomyolysis in certain glycolytic enzymopathies co-occurs with hemolytic anemia, often chronic and mild in phosphofructokinase and phosphoglycerate kinase deficiencies, or acute and fever-associated in aldolase-A and triosephosphate isomerase deficiency. Sideroblastic anemia, commonly severe, accompanies congenital-to-childhood onset mitochondrial myopathies including Pearson marrow-pancreas syndrome and mitochondrial myopathy, lactic acidosis, and sideroblastic anemia phenotypes. Congenital megaloblastic macrocytic anemia and mitochondrial dysfunction characterize SFXN4-related myopathy. Neutropenia, chronic or cyclical, with recurrent infections, infantile-to-childhood onset skeletal myopathy and cardiomyopathy are typical of Barth syndrome, while chronic neutropenia without infection occurs rarely in DNM2-centronuclear myopathy. Peripheral eosinophilia may accompany eosinophilic inflammation in recessive calpainopathy. Lipid accumulation in leukocytes on peripheral blood smear (Jordans' anomaly) is pathognomonic for neutral lipid storage diseases. Mild thrombocytopenia occurs in autosomal dominant, childhood-onset STIM1 tubular aggregate myopathy, STIM1 and ORAI1 deficiency syndromes, and GNE myopathy. Herein, we review these hereditary myopathies in which hematological features play a prominent role.

Congenital X-linked neutropenia with myelodysplasia and somatic tetraploidy due to a germline mutation in SEPT6.

Septins play key roles in mammalian cell division and cytokinesis but have not previously been implicated in a germline human disorder. A male infant with severe neutropenia and progressive dysmyelopoiesis with tetraploid myeloid precursors was identified. No known genetic etiologies for neutropenia or bone marrow failure were found. However, next-generation sequencing of germline samples from the patient revealed a novel, de novo germline stop-loss mutation in the X-linked gene SEPT6 that resulted in reduced SEPT6 staining in bone marrow granulocyte precursors and megakaryocytes. Patient skin fibroblast-derived induced pluripotent stem cells (iPSCs) produced reduced myeloid colonies, particularly of the granulocyte lineage. CRISPR/Cas9 knock-in of the patient's mutation or complete knock-out of SEPT6 was not tolerated in non-patient-derived iPSCs or human myeloid cell lines, but SEPT6 knock-out was successful in an erythroid cell line and resulting clones revealed a propensity to multinucleation. In silico analysis predicts that the mutated protein hinders the dimerization of SEPT6 coiled-coils in both parallel and antiparallel arrangements, which could in turn impair filament formation. These data demonstrate a critical role for SEPT6 in chromosomal segregation in myeloid progenitors that can account for the unusual predisposition to aneuploidy and dysmyelopoiesis.

Neutrality, conflict, and structural determinants of health in a Jerusalem emergency department.

BACKGROUND: Medical neutrality is a normative arrangement that differentiates a zone of medical treatment disconnected from the field of politics. While medical neutrality aims to ensure impartial healthcare for all and to shield the healthcare personnel from political demands, it can also divert attention away from conflicts and their effects on health inequity. This article analyzes how healthcare professionals understand and negotiate the depoliticized space of the emergency department (ED) through their views on neutrality. It also examines how medical staff use depoliticized concepts of culture to account for differences in the health status of patients from disadvantaged groups. These questions are examined in the context of the Israeli-Palestinian conflict. METHODS: Twenty-four in-depth, semi-structured interviews were conducted with healthcare personnel in a Jerusalem hospital's ED. All but one of the participants were Jewish. The interviews were analyzed using qualitative content analysis and Grounded Theory. RESULTS: The ED staff endorsed the perspective of medical neutrality as a nondiscriminatory approach to care. At the same time, some medical staff recognized the limits of medical neutrality in the context of the Israeli-Palestinian conflict and negotiated and challenged this concept. While participants identified unique health risks for Arab patients, they usually did not associate these risks with the effects of conflict and instead explained them in depoliticized terms of cultural and behavioral differences. Culture served as a non-controversial way of acknowledging and managing problems that have their roots in politics. CONCLUSIONS: The normative demand for neutrality works to exclude discussion of the conflict from clinical spaces. The normative exclusion of politics is a vital but under-appreciated aspect of how political conflict operates as a structural determinant of health. Healthcare personnel, especially in the ED, should be trained in structural competency. This training may challenge the neglect of issues that need to be solved at the political level and enhance health equity, social justice, and solidarity.

Targeting FGFR3 alterations with adjuvant infigratinib in invasive urothelial carcinoma: the phase III PROOF 302 trial.

PROOF 302 is an ongoing randomized, double-blind, placebo-controlled, adjuvant phase III trial (NCT04197986) in approximately 218 patients from 120 centers worldwide. Eligibility criteria include post-surgical high-risk muscle-invasive upper tract urothelial cancer (85% of patients) or urothelial bladder cancer (15%), susceptible FGFR3 alterations (activating mutations, gene fusions or rearrangements), ≤120 days following radical surgery and ineligible for/or refusing cisplatin-based (neo)adjuvant chemotherapy. Patients receive either oral infigratinib 125 mg or placebo daily on days 1-21 of a 28-day cycle for up to 52 weeks or until recurrence, unacceptable toxicity or death. Primary end point: centrally determined disease-free survival (DFS); secondary end points: investigator-assessed DFS, metastasis-free survival, overall survival and safety/tolerability; exploratory end points: correlative biomarker analysis, quality-of-life and infigratinib pharmacokinetics.

Cancers of the bladder and other parts in the urinary system, especially those that are invasive and grow into the muscle layer, may need extra treatment after surgical removal of the tumor, particularly if there is a high risk of the cancer coming back. Chemotherapy regimens that include cisplatin are often used postoperatively, although some patients are unable to tolerate this treatment or refuse it. FGFR3, a protein that is encoded by the FGFR3 gene, is often changed in these cancers. This helps the tumor grow. Infigratinib is an investigational drug that targets FGFR3 and inhibits the abnormal growth of the tumor. In the PROOF 302 study, patients are randomly assigned to treatment with infigratinib or a placebo pill for 1 year after surgery to see if the drug is effective. The aim is to see if patients who take infigratinib have a longer time free from the disease than those who receive a placebo. The study will also look at how long patients remain free from cancer spread and how long they live overall. The study will also investigate how safe the treatment is and how easy it is to live with it. PROOF 302 is an important study as it will define the role of infigratinib in patients with cancers of the bladder and urinary system who also have FGFR3 changes, for whom more treatment choices are needed. Clinical Trial Registration: NCT04197986 (ClinicalTrials.gov).

Conceptualizing the effective mechanisms of a social needs case management program shown to reduce hospital use: a qualitative study.

BACKGROUND: Social needs case management programs are a strategy to coordinate social and medical care for high-risk patients. Despite widespread interest in social needs case management, not all interventions have shown effectiveness. A lack of evidence about the mechanisms through which these complex interventions benefit patients inhibits effective translation to new settings. The CommunityConnect social needs case management program in Contra Costa County, California recently demonstrated an ability to reduce inpatient hospital admissions by 11% in a randomized study. We sought to characterize the mechanisms through which the Community Connect social needs case management program was effective in helping patients access needed medical and social services and avoid hospitalization. An in-depth understanding of how this intervention worked can support effective replication elsewhere. METHODS: Using a case study design, we conducted semi-structured, qualitative interviews with case managers (n = 30) and patients enrolled in social needs case management (n = 31), along with field observations of patient visits (n = 31). Two researchers coded all interview transcripts and observation fieldnotes. Analysis focused on program elements identified by patients and staff as important to effectiveness. RESULTS: Our analyses uncovered three primary mechanisms through which case management impacted patient access to needed medical and social services: [1] Psychosocial work, defined as interpersonal and emotional support provided through the case manager-patient relationship, [2] System mediation work to navigate systems, coordinate resources, and communicate information and [3] Addressing social needs, or working to directly mitigate the impact of social conditions on patient health. CONCLUSIONS: These findings highlight that the system mediation tasks which are the focus of many social needs assistance interventions offered by health care systems may be necessary but insufficient. Psychosocial support and direct assistance with social needs, enabled by a relationship-focused program, may also be necessary for effectiveness.

A dual-institutional study on first-year practice outcomes of pediatric surgeons who trained in the era of work hour restrictions.

BACKGROUND: In July 2003, an 80-h work week restriction for residencies was mandated. This was met with skepticism regarding its potential impact on operative training. We hypothesized no difference in outcomes for pediatric surgeons who trained under duty hour restrictions compared to historical complication rates. METHODS: Dual-institutional review of pediatric patients who underwent five of the most common operations (2013-2018) by first-year pediatric surgeons who trained under duty hour restrictions was performed. Tests of proportions were used to compare complication rates to published rates on data collected prior to 2003. RESULTS: Patient mean age was 10.1 years. No significant differences (p values > 0.05) were found in laparoscopic appendectomy rates of infection, bleeding or intra-abdominal abscess compared to previously published rates. Pyloromyotomy rates of infection or duodenal perforation were not different. No differences were detected in rates of infection, recurrence or testicular atrophy for inguinal hernia repair. Umbilical hernia rates of infection, bleeding, and recurrence were also not different. There was no difference in CVC rates of hemopneumothoraces; significantly more bleeding events were detected (1.2% vs. 0.1%; p value = 0.04). CONCLUSION: In this study, first-year complication rates of pediatric surgeons who trained under duty hour restrictions were not significantly different when compared to published rates.

"Housing Is Health Care": Treating Homelessness in Safety-net Hospitals.

As medicine integrates social and structural determinants into health care, some health workers redefine housing as medical treatment. This article discusses how health workers in two U.S. urban safety-net hospitals worked with patients without stable housing. We observed ethnographically how health workers helped patients seek housing in a sharply stratified housing economy. Analyzing in-depth interviews and observations, we show how health workers: (1) understood housing as health care and navigated limits of individual care in a structurally produced housing crisis; and (2) developed and enacted practices of biomedical and sociopolitical stabilization, including eligibilizing and data-tracking work. We discuss how health workers bridged individually focused techniques of clinical care with structural critiques of stratified housing economies despite contradictions in this approach. Finally, we analyze the implications of providers' extension of medical stabilization into social, economic, and political realms, even as they remained caught in the structural dynamics they sought to address.

Radiographic detection of lateral plateau involvement in medial tibial plateau fractures (AO/OTA 41-B1.2, 1.3, 3.2 and 3.3).

PURPOSE: To assess the accuracy of radiographs in detecting the lateral plateau involvement of medial tibial plateau fractures as well as describe the impact of CT on preoperative planning for this specific fracture morphology. METHODS: Radiograph and CT imaging of patients with a Schatzker type IV tibial plateau fractures (AO/OTA 41-B1.2, B1.3 h, B2.2. B3.2, and B3.3) between January 2013 and July 2017 were reviewed by three trauma fellowship-trained orthopedic surgeons to identify fractures of the medial condyle with an intact anterolateral articular surface. RESULTS: Lateral plateau involvement was identified in 16 (37%) radiographs and 26 (61%) CT images (p = 0.051). Radiographic detection of lateral plateau involvement demonstrated a sensitivity of 62% and specificity of 100%, and radiographs were able to predict the recommendation for surgical intervention for lateral plateau involvement with a positive predictive value (PPV) of 75% and a negative predictive value (NPV) of 60% compared to recommendations based on CT imaging. Radiographs predicted a need for a separate surgical approach with PPV of 63% and NPV of 70% when compared to recommendations based on CT images. CONCLUSIONS: Radiographs are reliable in ruling in lateral plateau involvement of medial plateau fractures, but occult lateral articular extension may only be identified in CT imaging for some cases. Surgical planning may be impacted by CT imaging for this fracture morphology, but further study is warranted to evaluate the correlation between preoperative planning and clinical outcomes. LEVEL OF EVIDENCE: III.