Two Non-myeloablative HLA-Matched Related Donor Allogeneic Hematopoietic Cell Transplant Regimens in Patients with Severe Sickle Cell Disease

BACKGROUND: Non-myeloablative (NMA) conditioning is increasingly being used with success in matched related donor (MRD) and alternative donor allogeneic hematopoietic cell transplant (allo-HCT) in individuals with sickle cell disease (SCD). Advantages include decrease toxicity and applicability in patients otherwise unable to tolerate conditioning regimens due to end organ damage or age. OBJECTIVE(S): We aimed to add to published data outcomes of two similar NMA protocols Protocol 1 (clinicaltrials.gov ID: NCT00061568) and Protocol 2 (clinicaltrials.gov ID: NCT02105766)) in mainly adult patients with SCD to evaluate safety, toxicity, and success of these regimens in individuals at high-risk for poor transplant-related outcomes. We also evaluated the tolerability and outcomes of Protocol 2, which included pre-conditioning immuno-depletion, in patients at even higher risk of T-cell mediated rejection or plasma/B-cell mediated anti-donor erythrocyte antibody production-the latter due to ABO incompatibility or recipient red blood cell alloimmunization to a donor antigen. Lastly, we evaluated the incidence and trajectory of mixed donor myeloid chimerism over time following allo-HCT. STUDY DESIGN: In this retrospective analysis of the two prospective phase 2 NMA transplant protocols, 91 individuals with SCD or transfusion-dependent beta thalassemia underwent MRD allo-HCT at the National Heart, Lung, and Blood Institute; regimens contained alemtuzumab, low dose radiation, and sirolimus for graft-versus-host disease (GVHD) prophylaxis with or without preconditioning immuno-depletion with pentostatin and oral cyclophosphamide (Protocol 2). RESULTS: In the total cohort of 91 transplant recipients, outcomes were favorable with timely neutrophil and platelet engraftment (median: 21 days (range, 7-67) and 21 days (10-112), respectively), minimal high-grade acute and no chronic GVHD, overall survival of 90%, sickle-free survival of 85%, and mixed donor myeloid chimerism in 43% at a median follow up of 7.3 years (range, 0.8-20). Most patients with mixed myeloid chimerism at 2-years post-HCT remained stable in their values. In analyzing each protocol separately, outcomes were comparable except for higher cytomegalovirus reactivation requiring treatment in Protocol 2, without associated increase in graft failure. In the combined cohort, graft failure occurred in 11 patients and hematologic malignancy or abnormal cytogenetics on bone marrow evaluation developed in 7 recipients. On a sub-analysis of factors that may implicate transplant outcomes, the number of RBC units transfused post-HCT was significantly higher in recipients with pre-HCT history of alloimmunization to donor red blood cell antigens. There was no difference in RBC units transfused, duration of transfusion, or in red cell engraftment in those with major ABO incompatibility; pre-conditioning immune-depletion and pre-treatment with rituximab were likely helpful. CONCLUSION: Both NMA allo-HCT protocols were successful in achieving adequate engraftment and sickle-free survival with minimal toxicity, including in individuals with mixed donor myeloid chimerism. The addition of pre-conditioning immuno-depletion was well-tolerated and reduced graft failure rate in high-risk recipients

ACR Appropriateness Criteria® Cervical Pain or Cervical Radiculopathy: 2024 Update

Cervical spine pain is one of the most common reasons for seeking medical care as it ranks in the top 5 causes of global years lost to disability. The economic burden of cervical pain is also significant. Imaging is at the center of diagnosis of cervical pain and its causes. However, different symptoms and potential causes of cervical pain require different initial imaging to maximize the benefit of diagnostic usefulness of imaging. In this document we address different cervical pain variants with detailed assessment of the strengths and weaknesses of different modalities for addressing each specific variant. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation

A Proposed Framework for Ranking and Prioritizing Food Safety Risks in Low Resource Settings Using Foodborne Disease Burden Metrics: A Case Study in Ethiopia

Risk-based food safety systems are recognized as the best way to address food safety in an effective and efficient manner. Central to risk-based food safety systems is an assessment, ranking, and prioritization of risks associated with foodborne hazards that informs objective, evidence-based decisions on risk mitigation in a systematic and transparent manner. While the importance of such approaches is well recognized, many governments struggle with where to begin. We adapted and implemented a framework for risk-based decision-making in low resource settings using Ethiopia as an example, engaging Ethiopian stakeholders in a multi-phase process to identify food safety priorities. First, stakeholder representatives were engaged to define statements of concern and purpose; identify foodborne hazards of public health relevance in Ethiopia; and select appropriate risk metrics for risk ranking and prioritization. Second, estimates for each risk metric were calculated for selected foodborne hazards using World Health Organization (WHO) data and expert elicitation. Third, stakeholder representatives were engaged in ranking the hazards as High, Medium, or Low risk; notably, mortality was the preferred risk metric in decision-making. Fourth, attribution estimates to food groups were developed for hazards ranked as High risk using expert elicitation to supplement WHO data. Lastly, stakeholder representatives were engaged in a risk prioritization exercise that identified key control points in four food supply chains and quantified their impact on risk through mitigation of hazards or prevention of contamination. Our proposed framework provides a systematic, evidence-based and adaptable method for prioritizing allocation of public sector resources. The process can generate the evidence needed to strengthen regulatory systems and support efficient implementation of national-level food safety strategies that span from farm to fork to improve public health

Occupational Therapy Assessment Practice Patterns for Core Domains in Adult Populations

Practitioners need to demonstrate the value of occupational therapy services in achieving effective patient outcomes. To intervene effectively, we must have adequate assessment practices. This study examines variation in occupational therapy assessment practices by facility type, areas addressed, and types of instruments. The study characterizes commonly and frequently used assessment practices in core occupational domains and identifies potential practice gaps related to assessment. A cross-sectional online survey across six domains central to adult occupational therapy practice (activities of daily living [ADL], instrumental activities of daily living [IADL], fear of falling, functional cognition, psychosocial, and vision) was administered to practitioners in various settings. Surveys were obtained from 1,198 respondent. Survey responses identified differences in domains being assessed and assessment methods used by occupational therapy practitioners across hospital inpatient post-acute care facilities and community settings. There is variability in the methods used to assess domains critical to occupational therapy practice and the degree to which occupational therapists evaluate domains in practice settings

Rapid and Simultaneous Initiation of Guideline-Directed Kidney Therapies in Patients with CKD and Type 2 Diabetes

The global incidence of chronic kidney disease (CKD) continues to rise, with type 2 diabetes as a major contributor. At any stage of CKD, patients with concurrent CKD and type 2 diabetes are at heightened cardiovascular risk and have a greater likelihood of dying from cardiovascular causes than progressing to kidney failure. Consequently, the use of \u27four pillars\u27 of CKD therapy, including renin-angiotensin system inhibitors (RASi), sodium-glucose cotransporter 2 inhibitors (SGLT2i), nonsteroidal mineralocorticoid receptor antagonists (ns-MRA), and glucagon-like peptide-1 receptor agonists (GLP1-RAs), has been advocated to reduce cardiovascular-kidney risk. While these therapies can mitigate cardiovascular and kidney events when used individually, the residual risks of these events remain high across major clinical trials testing these therapies separately as well as in real-world clinical settings. This raises the question about when to optimally initiate these therapies, including strategies that start these agents in rapid sequence, or even simultaneously, in order to reduce long-term risk, thereby mirroring best-practices with rapid titration schedules in patients with heart failure. However, initiating all four therapies simultaneously in the setting of CKD has not yet been tested due to lack of data on safety and tolerability in this high risk population. Data regarding the safety profile of rapid sequence initiation remain limited. Therefore, our aim was to review the existing evidence on the safety profiles of guideline-recommended therapies and discuss the challenges associated with rapid sequence initiation of these treatments in patients with CKD

Emergency Department Interventions for Youth With Assault-Related Injuries: A Scoping Review

Assault-related injuries in youth are associated with poor outcomes related to physical and mental health. These youth often seek acute injury-related care in the emergency department (ED), making this an important location for violence prevention and intervention efforts. This scoping review sought to describe ED-initiated and ED-based interventions for youth with assault-related injury. We searched 6 databases from their inception to October 2023: Ovid MEDLINE, Cochrane Library, Embase, Web of Science, PsycInfo, and CINAHL. We included original research on interventions for youth (0 to 18 years) presenting to the ED with assault-related injury (including firearm-related injury). We excluded non-English studies, conference proceedings, and editorials. Two independent reviewers performed title and abstract screening, full text review, and data abstraction and synthesis. We found 5,021 unique articles and excluded 4,955 after the title and abstract screening. The remaining 66 articles underwent full text review, and 25 were included. The primary types of ED interventions identified were case management, behavioral and psychosocial interventions, and mentorship. Although all interventions were initiated in the ED, the majority primarily occurred following discharge, required high levels of resources, and were often performed by hospital-based personnel in partnership with community-based organizations. Most studies described outcomes related to injury recidivism, criminal justice involvement, violence-related risk factors, health care usage, and mortality. Few described strengths-based and other quality-of-life outcomes. Although many studies demonstrated improved outcomes with interventions, they were often limited by sample size, study attrition, and short-term follow-up. Overall, our findings indicate that current research on ED interventions for youth with assault-related injuries is skewed toward resource-intensive services such as hospital-based violence intervention programs. Further work is needed to develop, implement, and rigorously evaluate community-informed ED-based interventions that could complement these resource-intensive interventions. Future studies should also examine strengths-based and patient-centered outcomes

Association of Race and Ethnicity With Emergency Room Rate of Migraine Diagnosis, Testing, and Management in Children With Headache

BACKGROUND AND OBJECTIVES: Headache evaluation and treatment are believed to be influenced by race and ethnicity. Specific headache diagnosis assigned in the pediatric emergency department (ED) may compound disparities. We sought to investigate racial and ethnic disparities in the diagnosis, testing, and treatment of pediatric patients with headache presenting to the ED. METHODS: We performed a cross-sectional analysis of ED visits from 49 children\u27s hospitals between 2016 and 2022 from the Pediatric Health Information System, an administrative database of ED and hospitalized encounters within children\u27s hospitals in the United States. Index encounters in the ED from patients (aged 5-21 years, median age 13 [10-15]) with a primary diagnosis of migraine, headache, new daily persistent headache, or tension-type headache were included. Encounters with trauma, infection, and malignancy where secondary headache was possible were excluded. The primary outcomes were the rates of migraine diagnosis, testing, and treatment. We used generalized estimating equations to estimate associations between race and ethnicity and outcomes after adjusting for demographic factors, medical complexity, visit timing, and final headache diagnosis. RESULTS: A total of 309,678 encounters were included while 61,677 repeat visits, 81,821 visits with diagnoses suggestive of secondary headache, and 5,714 visits from 3 hospitals with sparse data on patient race/ethnicity were excluded. Of 160,466 eligible visits (59.8% female), 41% were by non-Hispanic White (NHW) children, 24.8% non-Hispanic Black (NHB), and 26.0% Hispanic/Latino (HL). NHW children were more frequently diagnosed with migraine (45.5% vs NHB 28.2% and HL 28.3%, p \u3c 0.001). NHB and HL children compared with NHW children received less testing including brain MRI scans (adjusted odds ratio [aOR]: NHB 0.56 [95% CI 0.46-0.69] and HL 0.54 [0.36-0.82]). There was no difference in the proportion of visits without administration of headache-related medications (NHW 23.3% vs NHB 24.6% and HL 23.4%, p = 0.64). NHB and HL children were more likely to receive only oral medications (aOR: NHB 1.37 [1.2-1.56] and HL 1.54 [1.34-1.76]) and less likely to be admitted inpatient (aOR: NHB 0.8 [0.66-0.97] and HL 0.65 [0.44-0.94]). DISCUSSION: NHB and HL children in the pediatric ED with headache receive fewer migraine diagnoses, less testing, and less intensive treatment compared with NHW children. Beyond affecting headache management, this inequity in migraine diagnosis requires further consideration to include children from marginalized racial and ethnic groups in future migraine research

Prevalence, Risk Factors, and Prognosis for Fontan-Associated Liver Disease: A Systematic Review and Exploratory Meta-Analysis

BACKGROUND: Patients with Fontan circulation are at risk of progressive liver disease, but the prevalence and risk factors for Fontan-associated liver disease (FALD) remain unclear. OBJECTIVES: The aim of the study was to review unbiased data on FALD prevalence, diagnostic methods, risk factors, and prognostic significance, and to undertake exploratory meta-analysis on available data. METHODS: This systematic review included studies with unselected FALD screening. Outcomes were imaging or biopsy-proven cirrhosis, advanced fibrosis, portal hypertension, and hepatocellular carcinoma. Exploratory meta-analysis was performed, as well as subgroup analyses and meta-regression to explore contributors towards outcome heterogeneity. RESULTS: Thirty-seven studies comprising 5,701 patients were included, with a median of 17 years of follow-up post-Fontan completion. All estimates of FALD were highly heterogeneous, reflecting variable patient factors and institutional practices. Cirrhosis was diagnosed in 21% of patients, but ranged from 0% to 76%. Advanced fibrosis without cirrhosis was noted in 30%, portal hypertension in 17%, and hepatocellular carcinoma in 2%, also with significant heterogeneity. Subgroup analysis and meta-regression highlighted several factors that contributed to such heterogeneity. It was found that cirrhosis was less commonly diagnosed by biopsy than by imaging (10% vs 26%). Other risk factors for cirrhosis included years post-Fontan completion, atriopulmonary Fontan, moderate or greater ventricular dysfunction, and higher pulmonary capillary wedge pressure. Qualitative synthesis noted FALD to be associated with elevated risk of cardiovascular and all-cause mortality. CONCLUSIONS: Liver disease is common post-Fontan completion, though prevalence varies widely. Several risk factors should guide patient screening. A universal, prognostically meaningful FALD definition is needed to advance research and clinical care