The sideroblastic anemias (SAs) are a group of inherited and acquired bone marrow disorders defined by pathological iron accumulation in the mitochondria of erythroid precursors. Like most ...hematological diseases, the molecular genetic basis of the SAs has ridden the wave of technology advancement. Within the last 30 years, with the advent of positional cloning, the human genome project, solid-state genotyping technologies, and next-generation sequencing have evolved to the point where more than two-thirds of congenital SA cases, and an even greater proportion of cases of acquired clonal disease, can be attributed to mutations in a specific gene or genes. This review focuses on an analysis of the genetics of these diseases and how understanding these defects may contribute to the design and implementation of rational therapies.
Health care systems throughout the United States are developing programmes to address patients' 'social determinants of health' - such as housing, food, income and transportation. I investigate the ...concepts, technologies and infrastructures through which health care systems are turning towards 'the social' as an object of clinical knowledge and intervention. Proponents of this movement suggest that developing the clinical capacity to prescribe social resources promises to improve the 'value' of care, defined as the amount of health achieved per dollar spent. I argue that initiatives to improve value through social intervention are reconstituting broader arrangements of welfare provisioning.
Optimal iron nutrition in utero is essential for development of the fetus and helps establish birth iron stores adequate to sustain growth in early infancy. In species with hemochorial placentas, ...such as humans and rodents, iron in the maternal circulation is transferred to the fetus by directly contacting placental syncytiotrophoblasts. Early kinetic studies provided valuable data on the initial uptake of maternal transferrin, an iron-binding protein, by the placenta. However, the remaining steps of iron trafficking across syncytiotrophoblasts and through the fetal endothelium into the fetal blood remain poorly characterized. Over the last 20 years, identification of transmembrane iron transporters and the iron regulatory hormone hepcidin has greatly expanded the knowledge of cellular iron transport and its regulation by systemic iron status. In addition, emerging human and animal data demonstrating comprised fetal iron stores in severe maternal iron deficiency challenge the classic dogma of exclusive fetal control over the transfer process and indicate that maternal and local signals may play a role in regulating this process. This review compiles current data on the kinetic, molecular, and regulatory aspects of placental iron transport and considers new questions and knowledge gaps raised by these advances.
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.
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.
Telemedicine has been rapidly adopted in the wake of the COVID-19 pandemic. There is limited work surrounding demographic and socioeconomic disparities that may exist in telemedicine utilization. ...This study aimed to examine demographic and socioeconomic differences in surgical patient telemedicine usage during the COVID-19 pandemic. Department of Surgery outpatients seen from July 1, 2019 to May 31, 2020 were stratified into three visit groups: pre-COVID-19 in-person, COVID-19 in-person, or COVID-19 telemedicine. Generalized linear models were used to examine associations of sex, race/ethnicity, Distressed Communities Index (DCI) scores, MyChart activation, and insurance status with telemedicine usage during the COVID-19 pandemic. 14,792 patients (median age 60, female 57.0%, non-Hispanic White 76.4%) contributed to 21,980 visits. Compared to visits before the pandemic, telemedicine visits during COVID-19 were more likely to be with patients from the least socioeconomically distressed communities (OR, 1.31; 95% CI, 1.08,1.58; P = 0.005), with an activated MyChart (OR, 1.38; 95% CI, 1.17-1.64; P < .001), and with non-government or commercial insurance (OR, 2.33; 95% CI, 1.84-2.94; P < .001). Adjusted comparison of telemedicine visits to in person visits during COVID-19 revealed telemedicine users were more likely to be female (OR, 1.38, 95% CI, 1.10-1.73; P = 0.005) and pay with non-government or commercial insurance (OR, 2.77; 95% CI, 1.85-4.16; P < .001). During the first three months of the COVID-19 pandemic, telemedicine was more likely utilized by female patients and those without government or commercial insurance compared to patients who used in-person visits. Interventions using telemedicine to improve health care access might consider such differences in utilization.
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.
This article explores the meaning, manifestations, and ramifications of medical neutrality in conflict zones. We analyse how Israeli healthcare institutions and leaders responded to the escalation of ...the Israeli-Palestinian conflict in May 2021 and how they represented the role of the healthcare system in society and during conflict. Based on content analysis of documents, we found that healthcare institutions and leaders called for cessation of violence between Jewish and Palestinian citizens of Israel, describing the Israeli healthcare system as a neutral space of coexistence. However, they largely overlooked the military campaign that was simultaneously taking place between Israel and Gaza, which was considered a controversial and 'political' issue. This depoliticised standpoint and boundary work enabled a limited acknowledgement of violence, while disregarding the larger causes of conflict. We suggest that a structurally competent medicine must explicitly recognise political conflict as a determinant of health. Healthcare professionals should be trained in structural competency to challenge the depoliticising effects of medical neutrality, with the aim of enhancing peace, health equity, and social justice. Concomitantly, the conceptual framework of structural competency should be broadened to include conflict-related issues and address the needs of the victims of severe structural violence in conflict areas.
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.
•Arab and ultra-Orthodox Jewish populations are prominent minorities in Israel.•In the Emergency Department, each group is seen as diverging from norms of modernity.•Cultural competency is a dominant framework for accommodating difference.•Qualitative investigation found that cultural competency was applied unequally.•Structural competency and critical consciousness are recommended as alternatives.
Poly(ADP-ribose) polymerase (PARP) inhibitors have antitumour activity against metastatic castration-resistant prostate cancers with DNA damage response (DDR) alterations in genes involved directly ...or indirectly in homologous recombination repair (HRR). In this study, we assessed the PARP inhibitor talazoparib in metastatic castration-resistant prostate cancers with DDR-HRR alterations.
In this open-label, phase 2 trial (TALAPRO-1), participants were recruited from 43 hospitals, cancer centres, and medical centres in Australia, Austria, Belgium, Brazil, France, Germany, Hungary, Italy, the Netherlands, Poland, Spain, South Korea, the UK, and the USA. Patients were eligible if they were men aged 18 years or older with progressive, metastatic, castration-resistant prostate cancers of adenocarcinoma histology, measurable soft-tissue disease (per Response Evaluation Criteria in Solid Tumors version 1.1 RECIST 1.1), an Eastern Cooperative Oncology Group performance status of 0–2, DDR-HRR gene alterations reported to sensitise to PARP inhibitors (ie, ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C), had received one or two taxane-based chemotherapy regimens for metastatic disease, and progressed on enzalutamide or abiraterone, or both, for metastatic castration-resistant prostate cancers. Eligible patients were given oral talazoparib (1 mg per day; or 0·75 mg per day in patients with moderate renal impairment) until disease progression, unacceptable toxicity, investigator decision, withdrawal of consent, or death. The primary endpoint was confirmed objective response rate, defined as best overall soft-tissue response of complete or partial response per RECIST 1.1, by blinded independent central review. The primary endpoint was assessed in patients who received study drug, had measurable soft-tissue disease, and had a gene alteration in one of the predefined DDR-HRR genes. Safety was assessed in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, NCT03148795, and is ongoing.
Between Oct 18, 2017, and March 20, 2020, 128 patients were enrolled, of whom 127 received at least one dose of talazoparib (safety population) and 104 had measurable soft-tissue disease (antitumour activity population). Data cutoff for this analysis was Sept 4, 2020. After a median follow-up of 16·4 months (IQR 11·1–22·1), the objective response rate was 29·8% (31 of 104 patients; 95% CI 21·2–39·6). The most common grade 3–4 treatment-emergent adverse events were anaemia (39 31% of 127 patients), thrombocytopenia (11 9%), and neutropenia (ten 8%). Serious treatment-emergent adverse events were reported in 43 (34%) patients. There were no treatment-related deaths.
Talazoparib showed durable antitumour activity in men with advanced metastatic castration-resistant prostate cancers with DDR-HRR gene alterations who had been heavily pretreated. The favourable benefit–risk profile supports the study of talazoparib in larger, randomised clinical trials, including in patients with non-BRCA alterations.
Pfizer/Medivation.
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