Single-cell RNA-seq analysis reveals cell subsets and gene signatures associated with Rheumatoid Arthritis Disease Activity.

Rheumatoid arthritis (RA) management lean toward achieving remission or low-disease activity. In this study, we conducted single-cell RNA sequencing (scRNAseq) of peripheral blood mononuclear cells (PBMCs) from 36 individuals (18 RA patients and 18 matched controls, accounting for age, sex, race, and ethnicity), to identify disease-relevant cell subsets and cell type-specific signatures associated with disease activity. Our analysis revealed 18 distinct PBMC subsets, including an IFITM3 overexpressing Interferon-activated (IFN-activated) monocyte subset. We observed an increase in CD4+ T effector memory cells in patients with moderate to high disease activity (DAS28-CRP ≥ 3.2), and a decrease in non-classical monocytes in patients with low disease activity or remission (DAS28-CRP < 3.2). Pseudobulk analysis by cell type identified 168 differentially expressed genes between RA and matched controls, with a downregulation of pro-inflammatory genes in the gamma-delta T cells subset, alteration of genes associated with RA predisposition in the IFN-activated subset, and non-classical monocytes. Additionally, we identified a gene signature associated with moderate-high disease activity, characterized by upregulation of pro-inflammatory genes such as TNF, JUN, EGR1, IFIT2, MAFB, G0S2, and downregulation of genes including HLA-DQB1, HLA-DRB5, TNFSF13B. Notably, cell-cell communication analysis revealed an upregulation of signaling pathways, including VISTA, in both moderate-high and remission-low disease activity contexts. Our findings provide valuable insights into the systemic cellular and molecular mechanisms underlying RA disease activity.

Geographic distance to Commission on Cancer-accredited and nonaccredited hospitals in the United States.

PURPOSE: The Commission on Cancer (CoC) establishes standards to support multidisciplinary, comprehensive cancer care. CoC-accredited cancer programs diagnose and/or treat 73% of patients in the United States. However, rural patients may experience diminished access to CoC-accredited cancer programs. Our study evaluated distance to hospitals by CoC accreditation status, rurality, and Census Division. METHODS: All US hospitals were identified from public-use Homeland Infrastructure Foundation-Level Data, then merged with CoC-accreditation data. Rural-Urban Continuum Codes (RUCC) were used to categorize counties as metro (RUCC 1-3), large rural (RUCC 4-6), or small rural (RUCC 7-9). Distance from each county centroid to the nearest CoC and non-CoC hospital was calculated using the Great Circle Distance method in ArcGIS. FINDINGS: Of 1,382 CoC-accredited hospitals, 89% were in metro counties. Small rural counties contained a total of 30 CoC and 794 non-CoC hospitals. CoC hospitals were located 4.0, 10.1, and 11.5 times farther away than non-CoC hospitals for residents of metro, large rural, and small rural counties, respectively, while the average distance to non-CoC hospitals was similar across groups (9.4-13.6 miles). Distance to CoC-accredited facilities was greatest west of the Mississippi River, in particular the Mountain Division (99.2 miles). CONCLUSIONS: Despite similar proximity to non-CoC hospitals across groups, CoC hospitals are located farther from large and small rural counties than metro counties, suggesting rural patients have diminished access to multidisciplinary, comprehensive cancer care afforded by CoC-accredited hospitals. Addressing distance-based access barriers to high-quality, comprehensive cancer treatment in rural US communities will require a multisectoral approach.

The moderating role of early-life parental adverse and positive factors in the genetic and environmental contributions to objectively assessed sleep duration in middle childhood.

Early-life positive and adverse parental factors, such as positive parent personality and parental stress, affect the environmental context in which children develop and may influence individual differences in children's sleep health. This study examined the moderating role of early-life parental factors in the heritability (i.e., the extent to which individual differences are due to genetic influences) of objectively assessed childhood sleep duration. A total of 351 families from the Arizona Twin Project were studied. Primary caregivers (95% mothers) reported on multiple dimensions of stress and facets of their own personality when the twins were 12 months old. Seven years later (Mage = 8.43 years, SD = 0.68), families completed a home visit, and twins (51% female; 57% White, 29% Hispanic; 30% monozygotic, 39% same-sex dizygotic, 31% other-sex dizygotic) wore actigraph watches to assess their sleep, with caregivers completing similar assessments on their personality attributes and stress. Early-life positive parent personality moderated the heritability of sleep duration (Δ-2LL [-2 log likelihood] = 2.54, Δdf = 2, p = .28), such that as positive parent personality increased, the heritability of duration decreased. Early-life parental stress also moderated the genetic contribution to sleep duration (Δ-2LL = 2.02, Δdf = 2, p = .36), such that as stress increased, the heritability of duration increased. Concurrent positive parent personality and parental stress composites showed similar patterns of findings. Results highlight the likely contribution of parent positive traits and adverse experiences to the etiology of children's sleep health, with genetic influences on children's sleep more prominent in "riskier" environments. Understanding how genetics and environments work together to influence the etiology of sleep may inform prevention programs.

Obstetrical and neonatal complications, prematurity, and childhood effortful control development: A longitudinal twin study.

Premature infants may be at risk for lower effortful control, and subsequent lower academic achievement, peer competence, and emotional and physical wellness throughout the lifespan. However, because prematurity is related to obstetrical and neonatal complications, it is unclear what may drive the effect. Effortful control also has a strong heritable component; therefore, environmental factors during pregnancy and the neonatal period may interact with genetic factors to predict effortful control development. In this study, we aimed to dissect the influences of genetics, prematurity, and neonatal and obstetrical complications on the development of effortful control from 12 months to 10 years using a twin cohort. This study used data from the Arizona Twin Project, an ongoing longitudinal study of approximately 350 pairs of twins. Twins were primarily Hispanic/Latinx (23.8%-27.1%) and non-Hispanic/Latinx White (53.2%-57.8%), and families ranged in socioeconomic status with around one third falling below or near the poverty line. Of the twins, 62.6% were born prematurely. Effortful control was assessed via parent report at six waves. There was not a significant relationship between gestational age and effortful control regardless of whether obstetrical and neonatal complications were controlled for. Biometric twin modeling revealed that the attentional focusing subdomain of effortful control was highly heritable. Gestational age did not moderate genetic and environmental estimates. Our findings help inform the risk assessment of prematurity and provide evidence for the differing etiology of each subdomain of effortful control and the strong role of genetics in effortful control development. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Comparative single-cell transcriptional and proteomic atlas of clinical-grade injectable mesenchymal source tissues.

Bone marrow aspirate concentrate (BMAC) and adipose-derived stromal vascular fraction (ADSVF) are the most marketed stem cell therapies to treat a variety of conditions in the general population and elite athletes. Both tissues have been used interchangeably clinically even though their detailed composition, heterogeneity, and mechanisms of action have neither been rigorously inventoried nor compared. This lack of information has prevented investigations into ideal dosages and has facilitated anecdata and misinformation. Here, we analyzed single-cell transcriptomes, proteomes, and flow cytometry profiles from paired clinical-grade BMAC and ADSVF. This comparative transcriptional atlas challenges the prevalent notion that there is one therapeutic cell type present in both tissues. We also provide data of surface markers that may enable isolation and investigation of cell (sub)populations. Furthermore, the proteome atlas highlights intertissue and interpatient heterogeneity of injected proteins with potentially regenerative or immunomodulatory capacities. An interactive webtool is available online.

Patient and Caregiver Experience With the Hope and Prognostic Uncertainty of Immunotherapy: A Qualitative Study.

PURPOSE: Immunotherapy has improved survival for patients with melanoma and non-small cell lung cancer (NSCLC). Yet, as responses vary widely, immunotherapy also introduces challenges in prognostic communication. In this study, we sought to explore how patients and caregivers learned about the goal of immunotherapy and their experience of living with uncertainty. MATERIALS AND METHODS: We conducted a qualitative study of patients with stage III or IV melanoma or stage IV NSCLC within 12 weeks of initiating or 12 months of discontinuing immunotherapy, and their caregivers. We conducted in-depth interviews with participants to explore how they learned about immunotherapy from oncology clinicians and how they experienced uncertainty. We used a framework approach to analyze interview transcripts and synthesized concepts into themes. RESULTS: Forty-two patients and 10 caregivers participated; median age was 67 years and most were male (68%), white (95%), married (61%), and had melanoma (62%). We identified four themes: (1) the oncology team shaped participants' hopeful expectations of immunotherapy, including as a potential cure among those with melanoma; (2) distress related to prognostic uncertainty particularly affected patients who experienced toxicity or progressive disease; (3) patients who did not have long-term responses experienced overwhelming disappointment; and (4) some patients and caregivers had conflicting preferences for prognostic information. Participants provided suggestions to improve education and underscored unmet psychosocial needs. CONCLUSION: Patients and caregivers held optimistic expectations of immunotherapy, which resulted in heightened disappointment among the subset with progression or toxicity. Clinicians should elicit information preferences of both patients and caregivers, as these may be disparate. Our results highlight the need to optimize prognostic communication and support for living with uncertainty among patients receiving immunotherapy.

Classification of Force-Time Metrics Into Lower-Body Strength Domains.

ABSTRACT: Geneau, MC, Carey, DL, Gastin, PB, Robertson, S, and James, LP. Classification of force-time metrics into lower-body strength domains. J Strength Cond Res XX(X): 000-000, 2024-The purpose of this study was to classify force-time metrics into distinct lower-body strength domains using a systematic data reduction analysis. A cross-sectional design was used, whereby competitive field sport athletes (F = 39, M = 96) completed a series of drop jumps, squat jumps, countermovement jumps (CMJs), loaded CMJs, and 2 isometric tasks on portable force platforms, resulting in a total of 285 force-time performance metrics. The metrics were split into 4 test "families" and each was entered into a sparse principal component analysis (sPCA) model. A single metric from each component of each family-specific sPCA were selected based on the loading, reliability, and simplicity of the metric and entered into a second sPCA that included metrics across all tests. The final sPCA revealed 7 principal components each containing 2 metrics and explained a total of 53% variance of the dataset. The final principal components were interpreted as 7 lower-body strength domains: (a) dynamic force, (b) dynamic timing, (c) early isometric, (d) maximal isometric, (e) countermovement velocity, (f) reactive output, and (g) reactive timing. The findings demonstrate that a total of 7 metrics from a drop jump, CMJ, and isometric test can be used to represent ∼50% of variance in lower-body strength performance of field sport athletes. These results can help guide and simplify the lower-body strength diagnosis process in field sport athletes.

Characterization of the family-level Borreliaceae pan-genome and development of an episomal typing protocol.

Background: The Borreliaceae family includes many obligate parasitic bacterial species which are etiologically associated with a myriad of zoonotic borrelioses including Lyme disease and vector-borne relapsing fevers. Infections by the Borreliaceae are difficult to detect by both direct and indirect methods, often leading to delayed and missed diagnoses. Efforts to improve diagnoses center around the development of molecular diagnostics (MDx), but due to deep tissue sequestration of the causative spirochaetes and the lack of persistent bacteremias, even MDx assays suffer from a lack of sensitivity. Additionally, the highly extensive genomic heterogeneity among isolates, even within the same species, contributes to the lack of assay sensitivity as single target assays cannot provide universal coverage. This within-species heterogeneity is partly due to differences in replicon repertoires and genomic structures that have likely arisen to support the complex Borreliaceae lifecycle in which these parasites have to survive in multiple hosts each with unique immune responses. Results: We constructed a Borreliaceae family-level pangenome and characterized the phylogenetic relationships among the constituent taxa which supports the recent taxonomy of splitting the family into at least two genera. Gene content pro les were created for the majority of the Borreliaceae replicons, providing for the first time their unambiguous molecular typing. Conclusion: Our characterization of the Borreliaceae pan-genome supports the splitting of the former Borrelia genus into two genera and provides for the phylogenetic placement of several non-species designated isolates. Mining this family-level pangenome will enable precision diagnostics corresponding to gene content-driven clinical outcomes while also providing targets for interventions.

Expanding the genetics and phenotypes of ocular congenital cranial dysinnervation disorders.

PURPOSE: To identify genetic etiologies and genotype/phenotype associations for unsolved ocular congenital cranial dysinnervation disorders (oCCDDs). METHODS: We coupled phenotyping with exome or genome sequencing of 467 probands (550 affected and 1108 total individuals) with genetically unsolved oCCDDs, integrating analyses of pedigrees, human and animal model phenotypes, and de novo variants to identify rare candidate single nucleotide variants, insertion/deletions, and structural variants disrupting protein-coding regions. Prioritized variants were classified for pathogenicity and evaluated for genotype/phenotype correlations. RESULTS: Analyses elucidated phenotypic subgroups, identified pathogenic/likely pathogenic variant(s) in 43/467 probands (9.2%), and prioritized variants of uncertain significance in 70/467 additional probands (15.0%). These included known and novel variants in established oCCDD genes, genes associated with syndromes that sometimes include oCCDDs (e.g., MYH10, KIF21B, TGFBR2, TUBB6), genes that fit the syndromic component of the phenotype but had no prior oCCDD association (e.g., CDK13, TGFB2), genes with no reported association with oCCDDs or the syndromic phenotypes (e.g., TUBA4A, KIF5C, CTNNA1, KLB, FGF21), and genes associated with oCCDD phenocopies that had resulted in misdiagnoses. CONCLUSION: This study suggests that unsolved oCCDDs are clinically and genetically heterogeneous disorders often overlapping other Mendelian conditions and nominates many candidates for future replication and functional studies.

Learning About and Living With Toxicity: A Qualitative Study of Patients Receiving Immune Checkpoint Inhibitors For Melanoma or Lung Cancer and Their Caregivers.

Background/Objective: Immune checkpoint inhibitors (ICIs) have revolutionized treatment for melanoma and lung cancer and are in widespread use. This study aims to describe how patients and caregivers learn about ICI toxicities and their perceptions and experiences of toxicity. Methods: We conducted a qualitative study of 42 patients with advanced non-small cell lung cancer (NSCLC; n = 16) or melanoma (n = 26) who were initiating or discontinuing an ICI and their caregivers (n = 9). We conducted in-depth interviews to explore patients' and caregivers' experiences learning about and living with ICI side effects. We audio-recorded the first oncology visit after enrollment. We used a framework approach to code interview and visit transcripts and synthesized codes into themes. Results: The median age of patients was 67; 68% were male. Themes of participant interviews and clinician-patient dialogue included: i) Patients initiating an ICI received extensive information about side effects, which some patients found overwhelming or scary and difficult to absorb; ii) Patients who were deterred by fear of toxicity ultimately proceeded with treatment because of oncologist encouragement or the sense of no alternative; iii) participants found hope in the association between toxicity and ICI efficacy; iv) caregivers helped patients navigate the deluge of information and uncertainty related to ICIs. Participants suggested ways to improve ICI side effect education, such as incorporating patient stories. Conclusion: Patients perceived that ICI toxicity counseling was overwhelming yet were encouraged by oncologists' reassurance that serious side effects were manageable and by the framing of toxicity as a sign of efficacy. We identified opportunities to improve communication of ICI risks and benefits.

Dual species transcriptomics reveals conserved metabolic and immunologic processes in interactions between human neutrophils and Neisseria gonorrhoeae.

Neisseria gonorrhoeae (the gonococcus, Gc) causes the sexually transmitted infection gonorrhea. Gc is a prominent threat to human health by causing severe lifelong sequelae, including infertility and chronic pelvic pain, which is amplified by the emergence of "superbug" strains resistant to all current antibiotics. Gc is highly adapted to colonize human mucosal surfaces, where it survives despite initiating a robust inflammatory response and influx of polymorphonuclear leukocytes (PMNs, neutrophils) that typically clear bacteria. Here, dual-species RNA-sequencing was used to define Gc and PMN transcriptional profiles alone and after infection. Core host and bacterial responses were assessed for two strains of Gc and three human donors' PMNs. Comparative analysis of Gc transcripts revealed overlap between Gc responses to PMNs, iron, and hydrogen peroxide; 98 transcripts were differentially expressed across both Gc strains in response to PMN co-culture, including iron-responsive and oxidative stress response genes. We experimentally determined that the iron-dependent TbpB is suppressed by PMN co-culture, and iron-limited Gc have a survival advantage when cultured with PMNs. Analysis of PMN transcripts modulated by Gc infection revealed differential expression of genes driving cell adhesion, migration, inflammatory responses, and inflammation resolution pathways. Production of pro-inflammatory cytokines, including IL1B and IL8, the adhesion factor ICAM1, and prostaglandin PGE2 were induced in PMNs in response to Gc. Together, this study represents a comprehensive and experimentally validated dual-species transcriptomic analysis of two isolates of Gc and primary human PMNs that gives insight into how this bacterium survives innate immune onslaught to cause disease.

Bilateral Oophorectomy Prevalence Among U.S. Women.

Background: Bilateral oophorectomy has been linked to numerous health outcomes, some of which can have a long latency period. Limited data are available on bilateral oophorectomy prevalence among U.S. women. Methods: The National Health Interview Survey fielded measures of bilateral oophorectomy most recently in 2010 and 2015. We pooled these 2 data years to present bilateral oophorectomy prevalence estimates by age-group, race, ethnicity, geographic region, and hysterectomy status. Results: Our study found bilateral oophorectomy was common among older women. Among women aged 70-79 years, 29% reported a bilateral oophorectomy, compared with <1% for women aged 20-29 years. By geographic region, bilateral oophorectomy prevalence among women 20-84 years was 12.3% in the South, 10.8% in the Midwest, 9.4% in the West, and 8.0% in the Northeast. Small numbers limited our ability to generate age-specific estimates for American Indian and Alaska Native women and subgroups of Asian and Hispanic women. Nearly half of women who had a bilateral oophorectomy reported their procedure occurred more than 20 years ago. Among women aged 20-84 years who reported a hysterectomy, 57% reported they also had both of their ovaries removed. Conclusion: Standard measures of incidence rates for ovarian cancer are not adjusted for oophorectomy status. These findings suggest that ovarian cancer incidence rates may be underestimated among older women. Continued monitoring of bilateral oophorectomy prevalence will be needed to track its potential impact on ovarian cancer incidence and numerous other chronic health outcomes.

The acute effects of nonsleep deep rest on perceptual responses, physical, and cognitive performance in physically active participants.

This study aimed to examine the effect of nonsleep deep rest (NSDR) on physical and cognitive performance, as well as sleepiness, acute readiness, recovery, stress, and mood state in physically active participants. A total of 65 physically active participants (42 male, 23 female) were randomly assigned into two groups: an experimental group (NSDR, n = 34), in which participants completed a 10-min NSDR intervention, and a control group (CON, n = 31), whereby participants sat passively for 10 min. Testing measures were assessed immediately pre and 10 min post each condition and comprised completing a hand grip strength dynamometer test and a countermovement jump test on force plates, cognitive function measures via a psychomotor vigilance task (PVT-B), and a Simon task test, along with four questionnaires to assess sleep, recovery, and mood state. A significant Group × Time interaction favored the NSDR condition for handgrip strength, median reaction time during the PVT-B, and accuracy percentage during the Simon task. Questionnaire responses demonstrated NSDR to be associated with significant benefits to physical readiness, emotional balance, overall recovery, negative emotional state, overall stress, and tension in comparison to CON (p < .05). The NSDR intervention could be a valuable strategy for acutely enhancing overall well-being and readiness.

A prognostic matrix gene expression signature defines functional glioblastoma phenotypes and niches.

Background: Interactions among tumor, immune, and vascular niches play major roles in driving glioblastoma (GBM) malignancy and treatment responses. The composition, heterogeneity, and localization of extracellular core matrix proteins (CMPs) that mediate such interactions, however, are not well understood. Methods: Here, through computational genomics and proteomics approaches, we analyzed the functional and clinical relevance of CMP expression in GBM at bulk, single cell, and spatial anatomical resolution. Results: We identified genes encoding CMPs whose expression levels categorize GBM tumors into CMP expression-high (M-H) and CMP expression-low (M-L) groups. CMP enrichment is associated with worse patient survival, specific driver oncogenic alterations, mesenchymal state, infiltration of pro-tumor immune cells, and immune checkpoint gene expression. Anatomical and single-cell transcriptome analyses indicate that matrisome gene expression is enriched in vascular and leading edge/infiltrative niches that are known to harbor glioma stem cells driving GBM progression. Finally, we identified a 17-gene CMP expression signature, termed Matrisome 17 (M17) signature that further refines the prognostic value of CMP genes. The M17 signature is a significantly stronger prognostic factor compared to MGMT promoter methylation status as well as canonical subtypes, and importantly, potentially predicts responses to PD1 blockade. Conclusion: The matrisome gene expression signature provides a robust stratification of GBM patients by survival and potential biomarkers of functionally relevant GBM niches that can mediate mesenchymal-immune cross talk. Patient stratification based on matrisome profiles can contribute to selection and optimization of treatment strategies.

Advances in Human Leukocyte Antigen Testing Technologies and Management Strategies for Platelet Transfusion Refractoriness.

CONTEXT.­: The blood bank is often consulted for transfusion support of patients with suspected platelet transfusion refractoriness (PTR). The workup is complex because testing includes specialized assays that are uncommonly ordered with limited availability. Add to this the variety of possible products-crossmatched platelets, human leukocyte antigen (HLA)-matched platelets, HLA antigen-negative platelets-and the approach to PTR can be overwhelming. Moreover, most literature on the subject is published in transfusion medicine journals aimed at transfusion medicine physicians and blood bank specialists in academic settings. Resources tailored to community hospital blood banks are lacking. OBJECTIVE.­: To provide pathologists who may not have subspecialized training in transfusion medicine and who direct blood banks algorithmic workflows based on clinical scenario and test availability to provide appropriate transfusion support for patients with PTR. DATA SOURCES.­: This review is a comprehensive overview of terminology, HLA testing procedures, interpretations, and practical recommendations for managing PTR in various scenarios based on expert opinion as well as relevant medical literature published from 2007 to 2022. CONCLUSIONS.­: Consultation on PTR is complicated and encompasses many clinical and laboratory aspects. The lack of guidelines derived from high-quality prospective studies poses challenges in the workup and management of PTR. Hindering the process further are limited test availability, unfamiliarity with the technical assays, and the various specialized platelet products. The clinical evaluation algorithm presented herein along with the workflow pathways offer pathologists user-friendly and best-practice guidelines with different options based on the clinical scenario and the tests available.

Technical Success and Serious Adverse Events for Fetal Aortic Valvuloplasty in a Large 20-Year Cohort.

Background: FAV is offered to fetuses with severe aortic valve stenosis and evolving hypoplastic left heart syndrome. An inferential analysis of TS and SAE in a large series has not been reported. Objectives: The purpose of this study was to determine factors associated with fetal aortic valvuloplasty (FAV) technical success (TS) and serious adverse events (SAEs). Methods: Retrospective, single-center, cohort analysis of attempted FAV from March 1, 2000, to December 31, 2020. The primary outcome was the TS of FAV, and the secondary outcome was the presence of an SAE. Results: A total of 165 FAVs were attempted in 163 patients with a median gestational age of 24.6 weeks (IQR: 22.9-27.1 weeks). FAV TS was 85% (141/165) and was higher in the 2010 to 2020 era (94% [85/90] vs 75% [56/75]; P < 0.001). Pre-FAV echocardiographic left ventricle (LV) long axis dimension z-score >-0.10 (P < 0.001) and higher LV ejection fraction (P = 0.037) were independently associated with a higher odds of TS. There were 117 SAEs in 67 attempted FAVs (41%), 13 of which were fetal deaths (7.9%). By classification and regression tree analysis, gestational age <21 weeks or in older fetuses, a procedure time of ≥39.6 minutes was associated with higher SAE rate. In the multivariable logistic regression model correcting for gestational age, fetuses with an LV end-diastolic volume <4.09 mL had an age-adjusted OR of 4.71 (95% CI: 1.67-13.29; P = 0.004) for experiencing an SAE. Conclusions: TS of FAV has improved over time, and failure is associated with smaller fetal left heart sizes. SAEs are common and are associated with smaller left hearts and longer procedure times.

Consolidation with First and Second Allogeneic Transplants in Adults with Relapsed/Refractory B-ALL Following Response to CD19CAR T Cell Therapy.

CD19-targeted chimeric antigen receptor T cell (CAR-T) therapy has led to unprecedented rates of complete remission (CR) in children and adults with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL), yet the majority of adults relapse after initial response. One proposed method to extend the durability of remission in adults following response to CAR-T therapy is consolidation with allogeneic hematopoietic cell transplantation (alloHCT). Considering the limited published data for the utility of post CAR-T therapy consolidative alloHCT in r/r B-ALL, especially data related to patients receiving a second alloHCT, we sought to describe outcomes of patients with r/r B-ALL at our institution who received their first or second alloHCT following response to CAR-T therapy. We performed a retrospective analysis of adult patients with r/r B-ALL who responded to either investigational or standard of care (SOC) CD19-targeted CAR-T therapy and underwent consolidation with alloHCT while in CR without interim therapy. We identified 45 patients, of whom 26 (58%) and 19 (42%) received their first and second alloHCT as consolidation post CAR-T therapy, respectively. The median age was 31 years (range: 19-67) and 31 (69%) patients were Hispanic. Ph-like was the most common genetic subtype and comprised over half of cases (53%; n = 24). The median number of prior therapies pre-transplant was 5 (range: 2-7), and disease status at the time of alloHCT was CR1, CR2 or ≥CR3 in 7 (16%), 22 (49%) and 16 (35%) patients, respectively. The median time from CAR-T therapy until alloHCT was 93 (range: 42-262) days. The conditioning regimen was radiation-based myeloablative (MAC) in 22 (49%) patients. With a median follow-up of 2.47 years (range: 0.13-6.93), 2-year overall survival (OS), relapse free survival (RFS), cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were 57.3% (95% CI: 0.432-0.760), 56.2% (95% CI: 0.562-0.745), 23.3% (95% CI: 0.13-0.42), and 20.4% (95% CI: 0.109-0.384), respectively. Two-year OS (52% vs. 68%, P = .641), RFS (54% vs. 59%, P = .820), CIR (33.5% vs. 8.5%, P = .104), and NRM (12.5% vs. 32.2%, P = .120) were not significantly different between patients who underwent their first vs. second transplant, respectively. In univariate analysis, only Ph-like genotype was associated with inferior RFS (P = .03). AlloHCT post CAR-T response is associated with a relatively low early mortality rate and encouraging survival results in high-risk adults with r/r B-ALL, extending to the second alloHCT for fit and eligible patients.

Predicting Post-Disaster Post-Traumatic Stress Disorder Symptom Trajectories: The Role of Pre-Disaster Traumatic Experiences.

The mental health impact of disasters is substantial, with 30-40% of direct disaster victims developing post-traumatic stress disorder (PTSD). It is not yet clear why some people cope well with disaster-related trauma while others experience chronic dysfunction. Prior research on non-disaster trauma suggests that an individual's history of traumatic experiences earlier in the life course, prior to the disaster, may be a key factor in explaining variability in psychological responses to disasters. This study evaluated the extent to which pre-disaster trauma predicts PTSD trajectories in a sample of Hurricane Katrina survivors followed for 12 years after the storm. Four PTSD trajectories were identified using latent class growth analysis: Resistant (49.0%), Recovery (29.3%), Delayed-Onset (8.0%), and Chronic-High (13.7%). After adjusting for covariates, pre-Katrina trauma had only a small, positive impact on the probability of long-term, chronic Katrina-specific PTSD, and little effect on the probability of the Resistant and Delayed-Onset trajectories. Higher pre-Katrina trauma exposure moderately decreased the probability of being in the Recovery trajectory, in which Katrina-specific PTSD symptoms are initially high before declining over time. When covariates were added to the model one at a time, the association between pre-Katrina trauma and Chronic-High PTSD was attenuated most by the addition of Katrina-related trauma. Our findings suggest that while pre-disaster trauma exposure does not have a strong direct effect on chronic Katrina-specific PTSD, pre-Katrina trauma may impact PTSD through other factors that affect Katrina-related PTSD, such as by increasing the severity of Katrina-related trauma. These findings have important implications for the development of disaster preparedness strategies to diminish the long-term burden of disaster-related PTSD.

Congenital cranial dysinnervation disorder with homozygous KIF26A variant.

Congenital fibrosis of the extraocular muscles (CFEOM) type 1 is associated with heterozygous missense variants in KIF21A, which encodes a kinesin-like motor protein. Individuals with CFEOM1 have severe paralysis of upgaze and ptosis, resulting in a pronounced chin-up head posture. There can also be limitations of horizontal eye movements. Loss of function of KIF26A, an unconventional kinesin motor protein that lacks ATP-dependent motor activity, has been recently reported to cause a spectrum of congenital brain malformations associated with defects in migration, localization, and growth of excitatory neurons. It has also been associated with megacolon resembling Hirschsprung's disease. We report the case of a boy with homozygous loss of function of KIF26A with restricted eye movements, specifically restricted upgaze and downgaze with variable nystagmus and dissociated vertical eye movements. This case represents a congenital cranial dysinnervation disorder, most similar to CFEOM, and is the first report of a congenital cranial dysinnervation disorder caused by a kinesin other than KIF21A.