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.

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.

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.

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.

Medical neutrality and structural competency in conflict zones: Israeli healthcare professionals' reaction to political violence.

ABSTRACTThis 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.

Single-cell multi-omics of mitochondrial DNA disorders reveals dynamics of purifying selection across human immune cells.

Pathogenic mutations in mitochondrial DNA (mtDNA) compromise cellular metabolism, contributing to cellular heterogeneity and disease. Diverse mutations are associated with diverse clinical phenotypes, suggesting distinct organ- and cell-type-specific metabolic vulnerabilities. Here we establish a multi-omics approach to quantify deletions in mtDNA alongside cell state features in single cells derived from six patients across the phenotypic spectrum of single large-scale mtDNA deletions (SLSMDs). By profiling 206,663 cells, we reveal the dynamics of pathogenic mtDNA deletion heteroplasmy consistent with purifying selection and distinct metabolic vulnerabilities across T-cell states in vivo and validate these observations in vitro. By extending analyses to hematopoietic and erythroid progenitors, we reveal mtDNA dynamics and cell-type-specific gene regulatory adaptations, demonstrating the context-dependence of perturbing mitochondrial genomic integrity. Collectively, we report pathogenic mtDNA heteroplasmy dynamics of individual blood and immune cells across lineages, demonstrating the power of single-cell multi-omics for revealing fundamental properties of mitochondrial genetics.

Between health care and social services: Boundary objects and cross-sector collaboration.

Health care systems throughout the United States are initiating collaborations with social services agencies. These cross-sector collaborations aim to address patients' social needs-such as housing, food, income, and transportation-in health care settings. However, such collaborations can be challenging as health care and social service sectors are composed of distinct missions, institutions, professional roles, and modes of distributing resources. This paper examines how the "high-risk" patient with both medical and social needs is constructed as a shared object of intervention across sectors. Using the concept of boundary object, we illustrate how the high-risk patient category aggregates and represents multiple types of information-medical, social, service utilization, and cost-in ways that facilitate its use across sectors. The high-risk patient category works as a boundary object, in part, by the differing interpretations of "risk" available to collaborators. During 2019-2021, we conducted 75 semi-structured interviews and 31 field observations to investigate a relatively large-scale, cross-sector collaboration effort in California known as CommunityConnect. This program uses a predictive algorithm and big data sets to assign risk scores to the population and directs integrated health care and social services to patients identified as high risk. While the high-risk patient category worked well to foster collaboration in administrative and policy contexts, we find that it was less useful for patient-level interactions, where frontline case managers were often hesitant or unable to communicate information about the risk-based eligibility process. We suggest that the predominance of health care utilization (and its impacts on costs) in constructing the high-risk patient category may be medicalizing social services, with the potential to deepen inequities.

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.

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.

Management of double carotid blowout with definitive repair after temporizing stent graft placement.

Carotid blowout syndrome is a life-threatening complication for patients with head and neck cancer. Temporizing stent graft procedures improve short-term survival and can be the definitive treatment for various reasons, including a poor oncologic prognosis, unsuitability for definitive reconstruction, or a lack of operative options. A second carotid blowout will often be fatal. Preventing such events requires multidisciplinary strategic planning because of a hostile reoperative field. We have described a case of a 44-year-old man with a history of laryngeal cancer who had experienced a carotid blowout. Treated with a stent graft, the patient had experienced a second event 6 weeks later. Treatment involved excision and suture ligation with rotational muscle flap coverage.

DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling.

Dipeptidyl peptidase 9 (DPP9) is a direct inhibitor of NLRP1, but how it affects inflammasome regulation in vivo is not yet established. Here, we report three families with immune-associated defects, poor growth, pancytopenia, and skin pigmentation abnormalities that segregate with biallelic DPP9 rare variants. Using patient-derived primary cells and biochemical assays, these variants were shown to behave as hypomorphic or knockout alleles that failed to repress NLRP1. The removal of a single copy of Nlrp1a/b/c, Asc, Gsdmd, or Il-1r, but not Il-18, was sufficient to rescue the lethality of Dpp9 mutant neonates in mice. Similarly, dpp9 deficiency was partially rescued by the inactivation of asc, an obligate downstream adapter of the NLRP1 inflammasome, in zebrafish. These experiments suggest that the deleterious consequences of DPP9 deficiency were mostly driven by the aberrant activation of the canonical NLRP1 inflammasome and IL-1ß signaling. Collectively, our results delineate a Mendelian disorder of DPP9 deficiency driven by increased NLRP1 activity as demonstrated in patient cells and in two animal models of the disease.

Association of Shelter-in-Place Hotels With Health Services Use Among People Experiencing Homelessness During the COVID-19 Pandemic.

Importance: Some jurisdictions used hotels to provide emergency noncongregate shelter and support services to reduce the risk of COVID-19 infection among people experiencing homelessness (PEH). A subset of these shelter-in-place (SIP) hotel guests were high users of acute health services, and the association of hotel placement with their service use remains unknown. Objective: To evaluate the association of SIP hotel placements with health services use among a subset of PEH with prior high acute health service use. Design, Setting, and Participants: This study used a matched retrospective cohort design comparing health services use between PEH with prior high service use who did and did not receive a SIP hotel placement, from April 2020 to April 2021. The setting was 25 SIP hotels in San Francisco, California, with a daily capacity of 2500 people. Participants included PEH who were among the top 10% high users of acute medical, mental health, and substance use services and who had 3 or more emergency department (ED) visits in the 9 months before the implementation of the SIP hotel program. Data analysis for this study was performed from February 2021 to May 2022. Exposures: SIP hotel placement with on-site supportive services. Main Outcomes and Measures: The primary outcomes were ED visits, hospitalizations and bed days, psychiatric emergency visits, psychiatric hospitalizations, outpatient mental health and substance use visits, and outpatient medical visits. Results: Of 2524 SIP guests with a minimum of 90-day stays, 343 (13.6%) met criteria for high service use. Of 686 participants with high service use (343 SIP group; 343 control), the median (IQR) age was 54 (43-61) years, 485 (70.7%) were male, 283 (41.3%) were Black, and 337 (49.1%) were homeless for more than 10 years. The mean number of ED visits decreased significantly in the high-user SIP group (1.84 visits [95% CI, 1.52-2.17 visits] in the 90 days before SIP placement to 0.82 visits [95% CI, 0.66-0.99 visits] in the 90 days after SIP placement) compared with high-user controls (decrease from 1.33 visits [95% CI, 1.39-1.58 visits] to 1.00 visits [95% CI, 0.80-1.20 visits]) (incidence rate ratio [IRR], 0.60; 95% CI, 0.47-0.75; P < .001). The mean number of hospitalizations decreased significantly from 0.41 (95% CI, 0.30-0.51) to 0.14 (95% CI, 0.09-0.19) for SIP guests vs 0.27 (95% CI, 0.19-0.34) to 0.22 (95% CI, 0.15-0.29) for controls (IRR, 0.41; 95% CI, 0.27-063; P < .001). Inpatient hospital days decreased significantly from a mean of 4.00 (95% CI, 2.44-5.56) to 0.81 (95% CI, 0.40-1.23) for SIP guests vs 2.27 (95% CI, 1.27-3.27) to 1.85 (95% CI, 1.06-2.65) for controls (IRR, 0.25; 95% CI, 0.12-0.54; P < .001), as did psychiatric emergency visits, from a mean of 0.03 (95% CI, 0.01-0.05) to 0.01 (95% CI, 0.00-0.01) visits for SIP guests vs no change in the control group (IRR, 0.25; 95% CI, 0.11-0.51; P < .001). Conclusions and Relevance: These findings suggest that in a population of PEH with high use of acute health services, SIP hotel placement was associated with significantly reduced acute care use compared with high users without a placement.

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.

Defining case management success: a qualitative study of case manager perspectives from a large-scale health and social needs support program.

OBJECTIVE: Health systems are expanding efforts to address health and social risks, although the heterogeneity of early evidence indicates need for more nuanced exploration of how such programs work and how to holistically assess program success. This qualitative study aims to identify characteristics of success in a large-scale, health and social needs case management program from the perspective of interdisciplinary case managers. SETTING: Case management program for high-risk, complex patients run by an integrated, county-based public health system. PARTICIPANTS: 30 out of 70 case managers, purposively sampled to represent their interdisciplinary health and social work backgrounds. Interviews took place in March-November 2019. PRIMARY AND SECONDARY OUTCOME MEASURES: The analysis intended to identify characteristics of success working with patients. RESULTS: Case managers described three characteristics of success working with patients: (1) establishing trust; (2) observing change in patients' mindset or initiative and (3) promoting stability and independence. Cross-cutting these characteristics, case managers emphasised the importance of patients defining their own success, often demonstrated through individualised, incremental progress. Thus, moments of success commonly contrasted with external perceptions and operational or productivity metrics. CONCLUSIONS: Themes emphasise the importance of compassion for complexity in patients' lives, and success as a step-by-step process that is built over longitudinal relationships.

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.

Hematologic complications with age in Shwachman-Diamond syndrome.

Shwachman-Diamond syndrome (SDS) is an inherited bone marrow failure syndrome with leukemia predisposition. An understanding of the hematologic complications of SDS with age could guide clinical management, but data are limited for this rare disease. We conducted a cohort study of 153 subjects from 143 families with confirmed biallelic SBDS mutations enrolled on the North American Shwachman Diamond Registry or Bone Marrow Failure Registry. The SBDS c.258 + 2T>C variant was present in all but 1 patient. To evaluate the association between blood counts and age, 2146 blood counts were analyzed for 119 subjects. Absolute neutrophil counts were positively associated with age (P < .0001). Hemoglobin was also positively associated with age up to 18 years (P < .0001), but the association was negative thereafter (P = .0079). Platelet counts and marrow cellularity were negatively associated with age (P < .0001). Marrow cellularity did not correlate with blood counts. Severe marrow failure necessitating transplant developed in 8 subjects at a median age of 1.7 years (range, 0.4-39.5), with 7 of 8 requiring transplant prior to age 8 years. Twenty-six subjects (17%) developed a myeloid malignancy (16 myelodysplasia and 10 acute myeloid leukemia) at a median age of 12.3 years (range, 0.5-45.0) and 28.4 years (range, 14.4-47.3), respectively. A lymphoid malignancy developed in 1 patient at the age of 16.9 years. Hematologic complications were the major cause of mortality (17/20 deaths; 85%). These data inform surveillance of hematologic complications in SDS.