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BACKGROUND AND OBJECTIVES: Traumatic brain injury (TBI) is frequently characterized by chronic motor deficits. Therefore, this clinical trial assessed whether intracranial implantation of allogeneic modified mesenchymal stromal (SB623) cells can improve chronic motor deficits after TBI. METHODS: Post hoc analysis of the double-blind, randomized, prospective, surgical sham-controlled, phase 2, STEMTRA clinical trial (June 2016 and March 2019) with 48 weeks of follow-up was conducted. In this international, multicenter clinical trial, eligible participants had moderate-to-severe TBI, were ≥12 months postinjury, and had chronic motor deficits. Participants were randomized in a 1:1:1:1 ratio to stereotactic surgical intracranial implantation of SB623 cells (2.5 × 106, 5.0 × 106, 10 × 106) or surgical sham-controlled procedure. The prespecified primary efficacy end point was significantly greater change from baseline of the Fugl-Meyer Motor Scale (FMMS) score, a measure of motor status, for the SB623 pooled vs control arm at 24 weeks. RESULTS: A total of 211 participants were screened, 148 were excluded, and 63 underwent randomization, of which 61 (97%; mean age, 34 [SD, 12] years; 43 men [70.5%]) completed the trial. Single participants in the SB623 2.5 × 106 and 5.0 × 106 cell dose groups discontinued before surgery. Safety and efficacy (modified intent-to-treat) were assessed in participants who underwent surgery (N = 61; SB623 = 46, controls = 15). The primary efficacy end point (FMMS) was achieved (least squares mean [SE] SB623: +8.3 [1.4]; 95% CI 5.5-11.2 vs control: +2.3 [2.5]; 95% CI -2.7 to 7.3; p = 0.04), with faster improvement of the FMMS score in SB623-treated groups than in controls at 24 weeks and sustained improvement at 48 weeks. At 48 weeks, improvement of function and activities of daily living (ADL) was greater, but not significantly different in SB623-treated groups vs controls. The incidence of adverse events was equivalent in SB623-treated groups and controls. There were no deaths or withdrawals due to adverse events. DISCUSSION: Intraparenchymal implantation of SB623 cells was safe and significantly improved motor status at 24 weeks in participants with chronic motor deficits after TBI, with continued improvement of function and ADL at 48 weeks. Cell therapy can modify chronic neurologic deficits after TBI. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT02416492. Submitted to registry: April 15, 2015. First participant enrolled: July 6, 2016. Available at: classic.clinicaltrials.gov/ct2/show/NCT02416492. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that intracranial implantation of allogeneic stem (SB623) cells in adults with motor deficits from chronic TBI improves motor function at 24 weeks.

Identifying pan-tumor biomarkers that predict responses to immune checkpoint inhibitors (ICI) is critically needed. In the AMADEUS clinical trial (NCT03651271), patients with various advanced solid tumors were assessed for changes in intratumoral CD8 percentages and their response to ICI. Patients were grouped based on tumoral CD8 levels: those with CD8

Background and purposeClinicians use reference values to contextualize physical performance scores, but data are sparse in individuals 90 years and older and racial/ethnic diversity is limited in existing studies. Gait speed provides valuable information about an individual's health status. Slow gait speed is associated with falls, cognitive decline, and mortality. Here, we report gait speed reference values in a racially/ethnically diverse oldest-old cohort.MethodsLifeAfter90 is a multiethnic cohort study of individuals 90 years and older. Participants are long-term members of an integrated healthcare delivery system without a dementia diagnosis at enrollment. We assessed gait speed using the 4-m walk test and calculated means, standard deviations, and percentiles by age, sex, assistive device use, and device type. We used linear regression to compare means by sex, age, device use and type, living situation and arrangement, and race/ethnicity.Results and discussionThe mean age of the 502 participants was 92.9 (range 90.1-102.8) years. Of these, 62.6% were women, 34.7% were college educated, 90.8% lived in a private residence, 20.9% self-reported as Asian, 22.5% as Black, 11.8% as Hispanic, 35.7% as White, and 9.2% as multiple, "other," or declined to state. The overall mean gait speed was 0.54 m/s (women = 0.51 m/s, men = 0.58 m/s). Mean gait speeds were 0.58 m/s, 0.53 m/s, and 0.48 m/s in the 90 to 91, 92 to 93, and 94+ age categories, respectively. In those without a device, mean gait speed was 0.63 m/s compared to 0.40 m/s in those with a device (cane = 0.44 m/s, walker = 0.37 m/s). Mean gait speed was significantly slower in women compared to men, age category 94+ compared to 90 to 91, participants with a device compared to those without, participants with a walker compared to a cane, and Black participants compared to Asian and White participants. However, differences by race/ethnicity were attenuated when chronic health conditions were considered.ConclusionsReference values developed from this multiethnic 90+ cohort will help clinicians interpret gait speed measures and tailor recommendations toward a 90+ population that is growing in number and in racial/ethnic diversity.

Brain differences linked to autism spectrum disorder (ASD) can manifest before observable symptoms. Studying these early neural precursors in larger and more diverse cohorts is crucial for advancing our understanding of developmental pathways and potentially facilitating earlier identification. EEG is an ideal tool for investigating early neural differences in ASD, given its scalability and high tolerability in infant populations. In this context, we integrated EEG into an existing multi-site MRI study of infants with a higher familial likelihood of developing ASD. This paper describes the comprehensive protocol established to collect longitudinal, high-density EEG data from infants across five sites as part of the Infant Brain Imaging Study (IBIS) Network and reports interim feasibility and data quality results. We evaluated feasibility by measuring the percentage of infants from whom we successfully collected each EEG paradigm. The quality of task-free data was assessed based on the duration of EEG recordings remaining after artifact removal. Preliminary analyses revealed low data loss, with average in-session loss rates at 4.16 % and quality control loss rates at 11.66 %. Overall, the task-free data retention rate, accounting for both in-session issues and quality control, was 84.16 %, with high consistency across sites. The insights gained from this preliminary analysis highlight key sources of data attrition and provide practical considerations to guide similar research endeavors.

Lactate, a product of glycolysis, is formed under aerobic conditions. Extensive work has shown lactate flux in young and exercising humans; however, the effect of age is not known. We tested the hypothesis that postprandial lactate shuttling (PLS) would be diminished in older adults. We used [3-13C]lactate and [6,6-2H]glucose tracers, an oral glucose tolerance test (OGTT), and arterialized blood sampling to determine postprandial lactate rates of appearance (Ra), disappearance (Rd), and oxidation (Rox) in 15 young (28.1 ± 1.4 yr) and 13 older (70.6 ± 2.4 yr) healthy men and women. In young participants, fasting blood [lactate] (≈0.5 mM) rose after the glucose challenge, peaked at 15 min, dipped to a nadir at 30 min, and rose again peaking at 60 min (≈1.0 mM). Initial responses in lactate Ra of older participants were delayed and diminished until 90 min rising by 0.83 mg·kg-1·min-1. Lactate Rox was higher throughout the entire trial in young participants by a difference of ∼0.5 mg·kg-1·min-1. Initial peaks in lactate Ra and concentration in all volunteers demonstrated the presence of an enteric PLS following an OGTT. Notably, in the systemic, but not enteric, PLS phase, lactate Ra correlated highly with glucose Rd (r2 = 0.92). Correspondence of second peaks in lactate Ra and concentration and glucose Rd shows dependence of lactate Ra on glucose Rd. Although results show both enteric and systemic PLS phases in young and older study cohorts, metabolic responses were delayed and diminished in healthy older individuals.NEW & NOTEWORTHY We used isotope tracers, an oral glucose tolerance test, and arterialized blood sampling to determine postprandial lactate flux rates in healthy young and older men and women. Lactate rates of appearance and oxidation and the lactate-pyruvate exchange were delayed and diminished in both enteric and systemic postprandial lactate shuttle phases in older participants.

Many animals use visual information to navigate1-4, but how such information is encoded and integrated by the navigation system remains incompletely understood. In Drosophila melanogaster, EPG neurons in the central complex compute the heading direction5 by integrating visual input from ER neurons6-12, which are part of the anterior visual pathway (AVP)10,13-16. Here we densely reconstruct all neurons in the AVP using electron-microscopy data17. The AVP comprises four neuropils, sequentially linked by three major classes of neurons: MeTu neurons10,14,15, which connect the medulla in the optic lobe to the small unit of the anterior optic tubercle (AOTUsu) in the central brain; TuBu neurons9,16, which connect the AOTUsu to the bulb neuropil; and ER neurons6-12, which connect the bulb to the EPG neurons. On the basis of morphologies, connectivity between neural classes and the locations of synapses, we identify distinct information channels that originate from four types of MeTu neurons, and we further divide these into ten subtypes according to the presynaptic connections in the medulla and the postsynaptic connections in the AOTUsu. Using the connectivity of the entire AVP and the dendritic fields of the MeTu neurons in the optic lobes, we infer potential visual features and the visual area from which any ER neuron receives input. We confirm some of these predictions physiologically. These results provide a strong foundation for understanding how distinct sensory features can be extracted and transformed across multiple processing stages to construct higher-order cognitive representations.

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.

Older adults aged 70 and older who drive have higher crash death rates per mile driven compared to middle aged (35-54 years) adults who drive in the US. Prior studies have found that depression and or antidepressant medication use in older adults are associated with an increase in the vehicular crash rate. Using data from the prospective multi-site AAA Longitudinal Research on Aging Drivers Study, this analysis examined the independent and interdependent associations of self-reported depression and antidepressant use with driving behaviors that can increase motor vehicle crash risk such as hard braking, speeding, and night-time driving in adults over age 65. Of the 2951 participants, 6.4% reported having depression and 21.9% were on an antidepressant medication. Correcting for age, race, gender, and education level, participants on an antidepressant had increased hard braking events (1.22 [1.10-1.34]) but self-reported depression alone was not associated with changes in driving behaviors.

Child abuse has intergenerational consequences for psychopathology, however, there remains a paucity of research regarding how these experiences affect Latinx families, particularly those at risk for additional negative life events, such as racial discrimination. This study aims to contribute to this gap in the literature by examining the impact maternal child abuse exposure has on youth and maternal psychopathology, as well as whether these associations are moderated by racial discrimination, in a sample of 224 Latinx mother-youth dyads. Hierarchical regressions revealed small but significant maternal child abuse exposure x racial discrimination interactions for youth depression and anxiety, but not maternal depression or anxiety, which were solely positively associated with maternal child abuse exposure. Findings highlight the multifarious, and at times convergent, nature of trauma and oppression among Latinx families, as well as the impact across generations. Future work is needed to further elucidate developmental pathways of intergenerational trauma in understudied populations.

This study investigated posttraumatic stress disorder (PTSD) prevalence among a sample of intimate partner violence (IPV) survivors (n  =  77) who filed for restraining orders in rural Louisiana during the COVID-19 pandemic. IPV survivors were individually interviewed to assess their self-reported levels of perceived stress, resilience, potential PTSD, COVID-19-related experiences, and sociodemographic characteristics. Data were analyzed to differentiate group membership between two groups; non-PTSD and probable PTSD. Results suggest the probable PTSD group had lower levels of resilience and higher levels of perceived stress compared to the non-PTSD group. Findings suggest the importance of providing services during disaster to reduce PTSD for IPV survivors.

PurposeTraumatic brain injury (TBI) and potentially traumatic events (PTEs) contribute to increased substance use, mental health issues, and cognitive impairments. However, there's not enough research on how TBI and PTEs combined impact mental heath, substance use, and neurocognition.MethodsThis study leverages a subset of The National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) multi-site dataset with 551 adolescents to assess the combined and distinctive impacts of TBI, PTEs, and TBI+PTEs (prior to age 18) on substance use, mental health, and neurocognitive outcomes at age 18.ResultsTBI, PTEs, and TBI+PTEs predicted greater lifetime substance use and past-year alcohol and cannabis use. PTEs predicted greater internalizing symptoms, while TBI+PTEs predicted greater externalizing symptoms. Varying effects on neurocognitive outcomes included PTEs influencing attention accuracy and TBI+PTEs predicting faster speed in emotion tasks. PTEs predicted greater accuracy in abstraction-related tasks. Associations with working memory were not detected.ConclusionThis exploratory study contributes to the growing literature on the complex interplay between TBI, PTEs, and adolescent mental health, substance use, and neurocognition. The developmental implications of trauma via TBIs and/or PTEs during adolescence are considerable and worthy of further investigation.

Early adolescent drinking onset is linked to myriad negative consequences. Using the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA) baseline to year 8 data, this study (1) leveraged best subsets selection and Cox Proportional Hazards regressions to identify the most robust predictors of adolescent first and regular drinking onset, and (2) examined the clinical utility of drinking onset in forecasting later binge drinking and withdrawal effects. Baseline predictors included youth psychodevelopmental characteristics, cognition, brain structure, family, peer, and neighborhood domains. Participants (N=538) were alcohol-naïve at baseline. The strongest predictors of first and regular drinking onset were positive alcohol expectancies (Hazard Ratios [HRs]=1.67-1.87), easy home alcohol access (HRs=1.62-1.67), more parental solicitation (e.g., inquiring about activities; HRs=1.72-1.76), and less parental control and knowledge (HRs=.72-.73). Robust linear regressions showed earlier first and regular drinking onset predicted earlier transition into binge and regular binge drinking (βs=0.57-0.95). Zero-inflated Poisson regressions revealed that delayed first and regular drinking increased the likelihood (Incidence Rate Ratios [IRR]=1.62 and IRR=1.29, respectively) of never experiencing withdrawal. Findings identified behavioral and environmental factors predicting temporal paths to youthful drinking, dissociated first from regular drinking initiation, and revealed adverse sequelae of younger drinking initiation, supporting efforts to delay drinking onset.

Excessive growth hormone (GH) has been shown to promote joint degeneration in both preclinical and clinical studies. Little is known about the effect of disrupted GH or GH receptor (GHR) on joint health. The goal of this study is to investigate joint pathology in mice with either germline (GHR-/-) or adult inducible (iGHR-/-) GHR deficiency. Knee joints from male and female GHR-/- and WT mice at 24 months of age were processed for histological analysis. Also, knee joints from male and female iGHR-/- and WT mice at 22 months of age were scanned by micro-CT (μCT) for subchondral bone changes and characterized via histology for cartilage degeneration. Joint sections were also stained for the chondrocyte hypertrophy marker, COLX, and the cartilage degeneration marker, ADAMTS-5, using immunohistochemistry. Compared to WT mice, GHR-/- mice had remarkably smooth articular joint surfaces and an even distribution of proteoglycan with no signs of degeneration. Quantitatively, GHR-/- mice had lower OARSI and Mankin scores compared to WT controls. By contrast, iGHR-/- mice were only moderately protected from developing aging-associated OA. iGHR-/- mice had a significantly lower Mankin score compared to WT. However, Mankin scores were not significantly different between iGHR-/- and WT when males and females were analyzed separately. OARSI scores did not differ significantly between WT and iGHR-/- in either individual or combined sex analyses. Both GHR-/- and iGHR-/- mice had fewer COLX+ hypertrophic chondrocytes compared to WT, while no significant difference was observed in ADAMTS-5 staining. Compared to WT, a significantly lower trabecular thickness in the subchondral bone was observed in the iGHR-/- male mice but not in the female mice. However, there were no significant differences between WT and iGHR-/- mice in the bone volume to total tissue volume (BV/TV), bone mineral density (BMD), and trabecular number in either sex. This study identified that both germline and adult-induced GHR deficiency protected mice from developing aging-associated OA with more effective protection in GHR-/- mice.

Genetically heterogeneous UM-HET3 mice born in 2020 were used to test possible lifespan effects of alpha-ketoglutarate (AKG), 2,4-dinitrophenol (DNP), hydralazine (HYD), nebivolol (NEBI), 16α-hydroxyestriol (OH_Est), and sodium thiosulfate (THIO), and to evaluate the effects of canagliflozin (Cana) when started at 16 months of age. OH_Est produced a 15% increase (p = 0.0001) in median lifespan in males but led to a significant (7%) decline in female lifespan. Cana, started at 16 months, also led to a significant increase (14%, p = 0.004) in males and a significant decline (6%, p = 0.03) in females. Cana given to mice at 6 months led, as in our previous study, to an increase in male lifespan without any change in female lifespan, suggesting that this agent may lead to female-specific late-life harm. We found that blood levels of Cana were approximately 20-fold higher in aged females than in young males, suggesting a possible mechanism for the sex-specific disparities in its effects. NEBI was also found to produce a female-specific decline (4%, p = 0.03) in lifespan. None of the other tested drugs provided a lifespan benefit in either sex. These data bring to 7 the list of ITP-tested drugs that induce at least a 10% lifespan increase in one or both sexes, add a fourth drug with demonstrated mid-life benefits on lifespan, and provide a testable hypothesis that might explain the sexual dimorphism in lifespan effects of the SGLT2 inhibitor Cana.

The presence of HIV in sequestered reservoirs is a central impediment to a functional cure, allowing HIV to persist despite life-long antiretroviral therapy (ART), and driving a variety of comorbid conditions. Our understanding of the latent HIV reservoir in the central nervous system is incomplete, because of difficulties in accessing human central nervous system tissues. Microglia contribute to HIV reservoirs, but the molecular phenotype of HIV-infected microglia is poorly understood. We leveraged the unique "Last Gift" rapid autopsy program, in which people with HIV are closely followed until days or even hours before death. Microglial populations were heterogeneous regarding their gene expression profiles but showed similar chromatin accessibility landscapes. Despite ART, we detected occasional microglia containing cell-associated HIV RNA and HIV DNA integrated into open regions of the host's genome (∼0.005%). Microglia with detectable HIV RNA showed an inflammatory phenotype. These results demonstrate a distinct myeloid cell reservoir in the brains of people with HIV despite suppressive ART. Strategies for curing HIV and neurocognitive impairment will need to consider the myeloid compartment to be successful.

Substance use disparities among sexual and gender minority (SGM) people are attributed to minority stress, but few studies have examined minority stress and cannabis use over time or investigated differences in cannabis use trajectories by less-studied gender subgroups. We examined if longitudinal cannabis use trajectories are related to baseline minority stressors and if gender differences persisted after accounting for minority stress. Cannabis use risk was measured annually over four years (2017-2021) within a longitudinal cohort study of SGM adults in the United States (N = 11,813). Discrimination and victimization, internalized stigma, disclosure and concealment, and safety and acceptance comprised minority stress (n = 5,673). Latent class growth curve mixture models identified five cannabis use trajectories: 'low or no risk', 'low moderate risk', 'high moderate risk', 'steep risk increase', and 'highest risk'. Participants who reported past-year discrimination and/or victimization at baseline had greater odds of membership in any cannabis risk category compared to the 'low risk' category (odds ratios [OR] 1.17-1.33). Internalized stigma was related to 'high moderate' and 'highest risk' cannabis use (ORs 1.27-1.38). After accounting for minority stress, compared to cisgender men, gender expansive people and transgender men had higher odds of 'low moderate risk' (ORs 1.61, 1.67) or 'high moderate risk' (ORs 2.09, 1.99), and transgender men had higher odds of 'highest risk' (OR 2.36) cannabis use. This study indicates minority stress is related to prospective cannabis use risk trajectories among SGM people, and transgender men and gender expansive people have greater odds of trajectories reflecting cannabis use risk.

IntroductionThe COVID-19 pandemic raised significant concerns about fitness to dive due to potential damage to the pulmonary and cardiovascular systems. Our group previously published guidelines (original and revised) for assessment of these divers. Here, we report a prospective, observational study to evaluate the utility of these guidelines.MethodsRecreational, commercial, and scientific divers with a history of COVID-19 were consented and enrolled. Subjects were evaluated according to the aforementioned guidelines and followed for any additional complications or diving related injuries.ResultsOne-hundred and twelve divers (56 male, 56 female, ages 19-68) were enrolled: 59 commercial, 30 scientific, 20 recreational, two unknown (not documented), one military. Cases were categorised according to two previous guidelines ('original' n = 23 and 'revised' n = 89): category 0 (n = 6), category 0.5 (n = 64), category 1 (n = 38), category 2 (n = 2), category 3 (n = 1), uncategorisable due to persistent symptoms (n = 1). One hundred divers (89.3%) were cleared to return to diving, four (3.6%) were unable to return to diving, four (3.6%) were able to return to diving with restrictions, and four (3.6%) did not complete testing. Regarding diving related complications, one diver had an episode of immersion pulmonary oedema one year later and one diver presented with decompression sickness and tested positive for COVID-19.ConclusionsMost divers who presented for evaluation were able to return to diving safely. Abnormalities were detected in a small percentage of divers that precluded them from being cleared to dive. Guidelines were easily implemented by a variety of clinicians.

BackgroundColorectal cancer (CRC) screening is underused, particularly among low-income and minoritized populations, for whom the coronavirus disease 2019 (COVID-19) pandemic has challenged progress in achieving equity.MethodsA hub-and-spoke model was used. The hub was a nonacademic organization and the spokes were three community health center (CHC) systems overseeing numerous clinic sites. Via a cluster-randomized trial design, nine clinic sites were randomized to intervention and 16 clinic sites were randomized to usual care. Patient-level interventions included invitation letters, mailed fecal immunochemical tests (FITs), and call/text-based reminders. Year 1 intervention impact, which took place during the COVID-19 pandemic, was assessed as the proportion completing screening among individuals not up to date at baseline, which compared intervention and nonintervention clinics accounting for intraclinic cluster variation; confidence intervals (CIs) around differences not including 0 were interpreted as statistically significant.ResultsAmong 26,736 patients who met eligibility criteria, approximately 58% were female, 55% were Hispanic individuals, and 44% were Spanish speaking. The proportion completing screening was 11.5 percentage points (ppts) (95% CI, 6.1-16.9 ppts) higher in intervention versus usual care clinics. Variation in differences between intervention and usual care clinics was observed by sex (12.6 ppts [95% CI, 7.2-18.0 ppts] for females; 8.8 ppts [95% CI, 4.7-13.9 ppts] for males) and by racial and ethnic group (13.8 ppts [95% CI, 7.0-20.6 ppts] for Hispanic individuals; 13.0 ppts [95% CI, 3.6-22.4 ppts] for Asian individuals; 11.3 ppts [95% CI, 5.8-16.8 ppts] for non-Hispanic White individuals; 6.1 ppts [95% CI, 0.8-10.4 ppts] for Black individuals).ConclusionsA regional mailed FIT intervention was effective for increasing CRC screening rates across CHC systems serving diverse, low-income populations.

PurposeTo assess the safety and efficacy of the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor osimertinib as neoadjuvant therapy in patients with surgically resectable stage I-IIIA EGFR-mutated non-small cell lung cancer (NSCLC).Patients and methodsThis was a multi-institutional phase II trial of neoadjuvant osimertinib for patients with surgically resectable stage I-IIIA (American Joint Committee on Cancer [AJCC] V7) EGFR-mutated (L858R or exon 19 deletion) NSCLC (ClinicalTrials.gov identifier: NCT03433469). Patients received osimertinib 80 mg orally once daily for up to two 28-day cycles before surgical resection. The primary end point was major pathological response (MPR) rate. Secondary safety and efficacy end points were also assessed. Exploratory end points included pretreatment and post-treatment tumor mutation profiling.ResultsA total of 27 patients were enrolled and treated with neoadjuvant osimertinib for a median 56 days before surgical resection. Twenty-four (89%) patients underwent subsequent surgery; three (11%) patients were converted to definitive chemoradiotherapy. The MPR rate was 14.8% (95% CI, 4.2 to 33.7). No pathological complete responses were observed. The ORR was 52%, and the median DFS was 40.9 months. One treatment-related serious adverse event (AE) occurred (3.7%). No patients were unable to undergo surgical resection or had surgery delayed because of an AE. The most common co-occurring tumor genomic alterations were in TP53 (42%) and RBM10 (21%).ConclusionTreatment with neoadjuvant osimertinib in surgically resectable (stage IA-IIIA, AJCC V7) EGFR-mutated NSCLC did not meet its primary end point for MPR rate. However, neoadjuvant osimertinib did not lead to unanticipated AEs, surgical delays, nor result in a significant unresectability rate.

PURPOSE: Merkel cell carcinoma (MCC) is an aggressive skin cancer with a 40% recurrence rate, lacking effective prognostic biomarkers and surveillance methods. This prospective, multicenter, observational study aimed to evaluate circulating tumor DNA (ctDNA) as a biomarker for detecting MCC recurrence. METHODS: Plasma samples, clinical data, and imaging results were collected from 319 patients. A tumor-informed ctDNA assay was used for analysis. Patients were divided into discovery (167 patients) and validation (152 patients) cohorts. Diagnostic performance, including sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), was assessed. RESULTS: ctDNA showed high sensitivity, 95% (discovery; 95% CI, 87 to 99) and 94% (validation; 95% CI, 85 to 98), for detecting disease at enrollment, with corresponding specificities of 90% (95% CI, 82 to 95) and 86% (95% CI, 77 to 93). A positive ctDNA during surveillance indicated increased recurrence risk, with hazard ratios (HRs) of 6.8 (discovery; 95% CI, 2.9 to 16) and 20 (validation; 95% CI, 8.3 to 50). The PPV for clinical recurrence at 1 year after a positive ctDNA test was 69% (discovery; 95% CI, 32 to 91) and 94% (validation; 95% CI, 71 to 100), respectively. The NPV at 135 days after a negative ctDNA test was 94% (discovery; 95% CI, 90 to 97) and 93% (validation; 95% CI, 89 to 97), respectively. Patients positive for ctDNA within 4 months after treatment had higher rates of recurrence, with 1-year rates of 74% versus 21% (adjusted HR, 7.4 [95% CI, 2.7 to 20]). CONCLUSION: ctDNA testing exhibited high prognostic accuracy in detecting MCC recurrence, suggesting its potential to reduce frequent surveillance imaging. ctDNA also identifies high-risk patients who need more frequent imaging and may be best suited for adjuvant therapy trials.

BACKGROUND AND OBJECTIVES: It is widely cited that dementia occurs in up to 80% of patients with Parkinson disease (PD), but studies reporting such high rates were published over two decades ago, had relatively small samples, and had other limitations. We aimed to determine long-term dementia risk in PD using data from two large, ongoing, prospective, observational studies. METHODS: Participants from the Parkinsons Progression Markers Initiative (PPMI), a multisite international study, and a long-standing PD research cohort at the University of Pennsylvania (Penn), a single site study at a tertiary movement disorders center, were recruited. PPMI enrolled de novo, untreated PD participants and Penn a convenience cohort from a large clinical center. For PPMI, a cognitive battery is administered annually, and a site investigator makes a cognitive diagnosis. At Penn, a comprehensive cognitive battery is administered either annually or biennially, and a cognitive diagnosis is made by expert consensus. Interval-censored survival curves were fit for time from PD diagnosis to stable dementia diagnosis for each cohort, using cognitive diagnosis of dementia as the primary end point and Montreal Cognitive Assessment (MoCA) score

BACKGROUND: Fragile X syndrome (FXS) and autism spectrum disorder (ASD) are neurodevelopmental conditions that often have a substantial impact on daily functioning and quality of life. FXS is the most common cause of inherited intellectual disability (ID) and the most common monogenetic cause of ASD. Previous literature has shown that electrophysiological activity measured by electroencephalogram (EEG) during resting state is perturbated in FXS and ASD. However, whether electrophysiological profiles of participants with FXS and ASD are similar remains unclear. The aim of this study was to compare EEG alterations found in these two clinical populations presenting varying degrees of cognitive and behavioral impairments. METHODS: Resting state EEG signal complexity, alpha peak frequency (APF) and power spectral density (PSD) were compared between 47 participants with FXS (aged between 5-20), 49 participants with ASD (aged between 6-17), and 52 neurotypical (NT) controls with a similar age distribution using MANCOVAs with age as covariate when appropriate. MANCOVAs controlling for age, when appropriate, and nonverbal intelligence quotient (NVIQ) score were subsequently performed to determine the impact of cognitive functioning on EEG alterations. RESULTS: Our results showed that FXS participants manifested decreased signal complexity and APF compared to ASD participants and NT controls, as well as altered power in the theta, alpha and low gamma frequency bands. ASD participants showed exaggerated beta power compared to FXS participants and NT controls, as well as enhanced low and high gamma power compared to NT controls. However, ASD participants did not manifest altered signal complexity or APF. Furthermore, when controlling for NVIQ, results of decreased complexity in higher scales and lower APF in FXS participants compared to NT controls and ASD participants were not replicated. CONCLUSIONS: These findings suggest that signal complexity and APF might reflect cognitive functioning, while altered power in the low gamma frequency band might be associated with neurodevelopmental conditions, particularly FXS and ASD.

BACKGROUND: The incidence of breast and colorectal cancer (CRC) in younger-than-average-age patients is rising and poorly understood. This is the largest study on patients with both cancers who are less than 60 years old and aims to characterize demographic, clinicopathologic, and genetic features and describe therapeutic dilemmas and management strategies. MATERIALS AND METHODS: This is a retrospective medical records review of patients at the University of California San Francisco with both primary breast and CRC before age 60. RESULTS: Fifty-one patients were identified; 41 had detailed medical records. Median age of diagnosis with breast cancer was 43 (range 27-59) and CRC was 50 (28-59). Most were Caucasian (38, 74.5%) and never smokers (23, 56.1%); about half were current alcohol consumers (20, 48.8%) and about one-third had sedentary jobs (14, 34.1%). Average BMI was 25.8 (range: 14-49), and 30% were overweight or obese. Breast was the first cancer diagnosed in 36 patients (70.6%) and 44 (86.3%) had a metachronous CRC diagnosis. Breast cancer was early stage (0-2) in 32 (78.0%) patients whereas CRC was split between early stage (1-2) in 14 (34.1%) and later stage (3-4) in 19 (46.2%). Ten patients (24.3%) had a known germline mutation, although 23 (56.1%) had a family history of cancer in a first-degree relative. CONCLUSION: Younger patients with both breast and CRC are a unique cohort, often without known risk factors. Alcohol consumption and sedentary jobs were the most common risk factors, and about one-quarter had a known genetic predisposition. Comanagement of both cancers requires individualized, multidisciplinary care.

Konzo is a neglected paralytic neurological disease associated with food (cassava) poisoning that affects the worlds poorest children and women of childbearing ages across regions of sub-Saharan Africa. Despite understanding the dietary factors that lead to konzo, the molecular markers and mechanisms that trigger this disease remain unknown. To identify potential protein biomarkers associated with a disease status, plasma was collected from two independent Congolese cohorts, a discovery cohort (n = 60) and validation cohort (n = 204), sampled 10 years apart and subjected to multiple high-throughput assays. We identified that Glutathione Peroxidase 3 (GPx3), a critical plasma-based antioxidant enzyme, was the sole protein examined that was both significantly and differentially abundant between affected and non-affected participants in both cohorts, with large reductions observed in those affected with konzo. Our findings raise the notion that reductions in key antioxidant mechanisms may be the biological risk factor for the development of konzo, particularly those mediated through pathways involving the glutathione peroxidase family.

ImportanceHousing deposits and tenancy supports have become new Medicaid benefits in multiple states; however, evidence on impacts from these specific housing interventions is limited.ObjectiveTo evaluate the association of rental housing deposits and health care use among Medicaid beneficiaries receiving social needs case management as part of a Whole-Person Care (Medicaid 1115 waiver) pilot program in California.Design, setting, and participantsThis cohort study compared changes in health care use among a group of adults who received a housing deposit between October 2018 and December 2021 along with case management vs a matched comparison group who received case management only in Contra Costa County, California, a large county in the San Francisco Bay Area. All participants were enrolled in health and social needs case management based on elevated risk of acute care use. Data analysis took place from March 2023 to June 2024.ExposureRental housing deposit funds that covered 1-time moving transition costs. Funds averaged $1750 per recipient.Main outcomes and measuresChanges in hospitalizations, emergency department visits, primary care visits, specialty care visits, behavioral health visits, psychiatric emergency services, or detention intakes during the 6 months before vs 6 months after deposit receipt. Changes 12 months before and after deposit receipt were examined as a sensitivity analysis.ResultsOf 1690 case management participants, 845 received a housing deposit (362 [42.8%]

Pregnancies ending before 26 weeks contribute 1% of births but 40% of infant deaths in the United States. The rate of these periviable births to non-Hispanic (NH) Black women exceeds four times that for NH whites. Small male periviable infants remain most likely to die. NH white periviable males weigh more than their NH Black counterparts. We argue that male infants born from twin gestations, in which one fetus died in utero (i.e., the vanishing twin syndrome), contribute to the disparity. We cannot directly test our argument because vanishing typically occurs before clinical recognition of pregnancy. We, however, describe and find associations that would emerge in vital statistics were our argument correct. Among male periviable singleton births from 288 monthly conception cohorts (January 1995 through December 2018), we found an average NH white advantage of 30 grams (759 grams versus 729 grams). Consistent with our argument, however, cohorts signaling relatively few survivors of the vanishing twin syndrome showed no disparity.

Sterile inflammation after myocardial infarction is classically credited to myeloid cells interacting with dead cell debris in the infarct zone1,2. Here we show that cardiomyocytes are the dominant initiators of a previously undescribed type I interferon response in the infarct borderzone. Using spatial transcriptomics analysis in mice and humans, we find that myocardial infarction induces colonies of interferon-induced cells (IFNICs) expressing interferon-stimulated genes decorating the borderzone, where cardiomyocytes experience mechanical stress, nuclear rupture and escape of chromosomal DNA. Cardiomyocyte-selective deletion of Irf3 abrogated IFNIC colonies, whereas mice lacking Irf3 in fibroblasts, macrophages, neutrophils or endothelial cells, Ccr2-deficient mice or plasmacytoid-dendritic-cell-depleted mice did not. Interferons blunted the protective matricellular programs and contractile function of borderzone fibroblasts, and increased vulnerability to pathological remodelling. In mice that died after myocardial infarction, IFNIC colonies were immediately adjacent to sites of ventricular rupture, while mice lacking IFNICs were protected from rupture and exhibited improved survival3. Together, these results reveal a pathological borderzone niche characterized by a cardiomyocyte-initiated innate immune response. We suggest that selective inhibition of IRF3 activation in non-immune cells could limit ischaemic cardiomyopathy while avoiding broad immunosuppression.

BackgroundStandard treatment for patients with newly diagnosed glioblastoma includes surgery, radiotherapy (RT), and temozolomide (TMZ) chemotherapy (TMZ/RT→TMZ). The proteasome has long been considered a promising therapeutic target because of its role as a central biological hub in tumor cells. Marizomib is a novel pan-proteasome inhibitor that crosses the blood-brain barrier.MethodsEuropean Organisation for Research and Treatment of Cancer 1709/Canadian Cancer Trials Group CE.8 was a multicenter, randomized, controlled, open-label phase 3 superiority trial. Key eligibility criteria included newly diagnosed glioblastoma, age > 18 years and Karnofsky performance status > 70. Patients were randomized in a 1:1 ratio. The primary objective was to compare overall survival (OS) in patients receiving marizomib in addition to TMZ/RT→TMZ with patients receiving the only standard treatment in the whole population and in the subgroup of patients with MGMT promoter-unmethylated tumors.ResultsThe trial was opened at 82 institutions in Europe, Canada, and the U.S. A total of 749 patients (99.9% of the planned 750) were randomized. OS was not different between the standard and the marizomib arm (median 17 vs. 16.5 months; HR = 1.04; P = .64). PFS was not statistically different either (median 6.0 vs. 6.3 months; HR = 0.97; P = .67). In patients with MGMT promoter-unmethylated tumors, OS was also not different between standard therapy and marizomib (median 14.5 vs. 15.1 months, HR = 1.13; P = .27). More CTCAE grade 3/4 treatment-emergent adverse events were observed in the marizomib arm than in the standard arm.ConclusionsAdding marizomib to standard temozolomide-based radiochemotherapy resulted in more toxicity, but did not improve OS or PFS in patients with newly diagnosed glioblastoma.

Single-dose azithromycin is being considered by the WHO as an intervention for prevention of child mortality. However, concerns have emerged related to longer term unintended consequences of early life antibiotic use, particularly among infants. We conducted a long-term follow-up in a random sample of children who had been enrolled in a trial of neonatal azithromycin versus placebo for prevention of mortality to assess whether neonatal azithromycin exposure led to differences in child growth up to 4 years of age. We found no evidence of a difference in any anthropometric outcome among children who had received a single oral dose of azithromycin compared with placebo during the neonatal period. These results do not support long-term growth-promoting or deleterious effects of early life azithromycin exposure.

We lack the fundamental information needed to understand how DNA damage in the brain is generated and how it is controlled over a lifetime in the absence of replication check points. To address these questions, here, we integrate cell-type and region-specific features of DNA repair activity in the normal brain. The brain has the same repair proteins as other tissues, but normal, canonical repair activity is unequal and is characterized by high base excision repair (BER) and low double strand break repair (DSBR). The natural imbalance creates conditions where single strand breaks (SSBs) can convert to double strand breaks (DSBs) and reversibly switch between states in response to oxidation both in vivo and in vitro. Our data suggest that, in a normal background of repair, SSBs and DSBs are in an equilibrium which is pushed or pulled by metabolic state. Interconversion of SSB to DSBs provides a physiological check point, which would allow the formation of unrepaired DSBs for productive functions, but would also restrict them from exceeding tolerable limits.

This research explores prospective determinants of trust in the recommendations of artificial agents regarding decisions to kill, using a novel visual challenge paradigm simulating threat-identification (enemy combatants vs. civilians) under uncertainty. In Experiment 1, we compared trust in the advice of a physically embodied versus screen-mediated anthropomorphic robot, observing no effects of embodiment; in Experiment 2, we manipulated the relative anthropomorphism of virtual robots, observing modestly greater trust in the most anthropomorphic agent relative to the least. Across studies, when any version of the agent randomly disagreed, participants reversed their threat-identifications and decisions to kill in the majority of cases, substantially degrading their initial performance. Participants subjective confidence in their decisions tracked whether the agent (dis)agreed, while both decision-reversals and confidence were moderated by appraisals of the agents intelligence. The overall findings indicate a strong propensity to overtrust unreliable AI in life-or-death decisions made under uncertainty.

Infectious keratitis is a leading cause of corneal blindness worldwide with little information known about causative etiologies in Malawi, Africa. This area is resource-limited with ophthalmologist and microbiology services. The Department of Ophthalmology at the Kamuzu College of Health Sciences in Blantyre, Malawi, is a participating site of an international corneal ulcer consortium, capriCORN (Comprehensive Analysis of Pathogens, Resistomes, and Inflammatory-markers in the CORNea). In this study, 50 patients with corneal ulcers were swabbed for pathogen identification using RNA-sequencing. Corneal trauma was reported in 41% and 19% of the patients worked in agriculture. A pathogen was identified in 58% of the cases. Fungal pathogens predominated, followed by viruses and bacteria. Aspergillus, Fusarium, HSV-1, and Gardnerella were the most common pathogens detected. 50% of patients reported treatment with an antibiotic before presentation. Pathogens unusual for infectious keratitis, such as Subramaniula asteroids, Aureobasidium pullulans, and Gardnerella vaginalis, were also detected.

In frontotemporal lobar degeneration (FTLD), pathological protein aggregation in specific brain regions is associated with declines in human-specialized social-emotional and language functions. In most patients, disease protein aggregates contain either TDP-43 (FTLD-TDP) or tau (FTLD-tau). Here, we explored whether FTLD-associated regional degeneration patterns relate to regional gene expression of human accelerated regions (HARs), conserved sequences that have undergone positive selection during recent human evolution. To this end, we used structural neuroimaging from patients with FTLD and human brain regional transcriptomic data from controls to identify genes expressed in FTLD-targeted brain regions. We then integrated primate comparative genomic data to test our hypothesis that FTLD targets brain regions linked to expression levels of recently evolved genes. In addition, we asked whether genes whose expression correlates with FTLD atrophy are enriched for genes that undergo cryptic splicing when TDP-43 function is impaired. We found that FTLD-TDP and FTLD-tau subtypes target brain regions with overlapping and distinct gene expression correlates, highlighting many genes linked to neuromodulatory functions. FTLD atrophy-correlated genes were strongly enriched for HARs. Atrophy-correlated genes in FTLD-TDP showed greater overlap with TDP-43 cryptic splicing genes and genes with more numerous TDP-43 binding sites compared with atrophy-correlated genes in FTLD-tau. Cryptic splicing genes were enriched for HAR genes, and vice versa, but this effect was due to the confounding influence of gene length. Analyses performed at the individual-patient level revealed that the expression of HAR genes and cryptically spliced genes within putative regions of disease onset differed across FTLD-TDP subtypes. Overall, our findings suggest that FTLD targets brain regions that have undergone recent evolutionary specialization and provide intriguing potential leads regarding the transcriptomic basis for selective vulnerability in distinct FTLD molecular-anatomical subtypes.

Immunotherapies, especially checkpoint inhibitors such as anti-programmed cell death protein 1 (anti-PD-1) antibodies, have transformed cancer treatment by enhancing the immune systems capability to target and kill cancer cells. However, predicting immunotherapy response remains challenging. 18F-arabinosyl guanine ([18F]F-AraG) is a molecular imaging tracer targeting activated T cells, which may facilitate therapy response assessment by noninvasive quantification of immune cell activity within the tumor microenvironment and elsewhere in the body. The aim of this study was to obtain preliminary data on total-body pharmacokinetics of [18F]F-AraG as a potential quantitative biomarker for immune response evaluation. Methods: The study consisted of 90-min total-body dynamic scans of 4 healthy subjects and 1 non-small cell lung cancer patient who was scanned before and after anti-PD-1 immunotherapy. Compartmental modeling with Akaike information criterion model selection was used to analyze tracer kinetics in various organs. Additionally, 7 subregions of the primary lung tumor and 4 mediastinal lymph nodes were analyzed. Practical identifiability analysis was performed to assess the reliability of kinetic parameter estimation. Correlations of the SUVmean, the tissue-to-blood SUV ratio (SUVR), and the Logan plot slope (K Logan) with the total volume of distribution (V T) were calculated to identify potential surrogates for kinetic modeling. Results: Strong correlations were observed between K Logan and SUVR with V T, suggesting that they can be used as promising surrogates for V T, especially in organs with a low blood-volume fraction. Moreover, practical identifiability analysis suggested that dynamic [18F]F-AraG PET scans could potentially be shortened to 60 min, while maintaining quantification accuracy for all organs of interest. The study suggests that although [18F]F-AraG SUV images can provide insights on immune cell distribution, kinetic modeling or graphical analysis methods may be required for accurate quantification of immune response after therapy. Although SUVmean showed variable changes in different subregions of the tumor after therapy, the SUVR, K Logan, and V T showed consistent increasing trends in all analyzed subregions of the tumor with high practical identifiability. Conclusion: Our findings highlight the promise of [18F]F-AraG dynamic imaging as a noninvasive biomarker for quantifying the immune response to immunotherapy in cancer patients. Promising total-body kinetic modeling results also suggest potentially wider applications of the tracer in investigating the role of T cells in the immunopathogenesis of diseases.

PURPOSE: This study uses deep neural network-generated rim-to-disc area ratio (RADAR) measurements and the disc damage likelihood scale (DDLS) to measure the rate of optic disc rim loss in a large cohort of glaucoma patients. METHODS: A deep neural network was used to calculate RADAR and DDLS for each optic disc photograph (ODP). Patient demographics, diagnosis, intraocular pressure (IOP), and mean deviation (MD) from perimetry were analyzed as risk factors for faster progression of RADAR. Receiver operating characteristic (ROC) curves were used to compare RADAR and DDLS in their utility to distinguish glaucoma from glaucoma suspect (GS) and for detecting glaucoma progression. RESULTS: A total of 13,679 ODPs with evidence of glaucomatous optic nerve damage from 4106 eyes of 2407 patients with glaucoma or GS were included. Of these eyes, 3264 (79.5%) had a diagnosis of glaucoma, and 842 (20.5%) eyes were GS. Mean ± SD baseline RADAR of GS and glaucoma were 0.67 ± 0.13 and 0.57 ± 0.18, respectively (P < 0.001). Older age, greater IOP fluctuation, baseline MD, right eye, and diagnosis of secondary open-angle glaucoma were associated with slope of RADAR. The mean baseline DDLS of GS and glaucoma were 3.78 and 4.39, respectively. Both RADAR and DDLS showed a less steep slope in advanced glaucoma. In glaucoma, the change of RADAR and DDLS correlated with the corresponding change in MD. RADAR and DDLS had a similar ability to discriminate glaucoma from GS and detect disease progression. Area under the ROC curve of RADAR and DDLS was 0.658 and 0.648. CONCLUSIONS: Automated calculation of RADAR and DDLS with a neural network can be used to evaluate the extent and long-term rate of optic disc rim loss and is further evidence of long-term nerve fiber loss in treated patients with glaucoma. TRANSLATIONAL RELEVANCE: Our study provides a large clinic-based experience for RADAR and DDLS measurements in GS and glaucoma with a neural network.

OBJECTIVES: To determine the role of keratin 17 (K17) as a predictive biomarker for response to chemotherapy by defining thresholds of K17 expression based on immunohistochemical tests that could be used to optimize therapeutic intervention for patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: We profiled K17 expression, a hallmark of the basal molecular subtype of PDAC, by immunohistochemistry in 2 cohorts of formalin-fixed, paraffin-embedded PDACs (n = 305). We determined a K17 threshold of expression to optimize prognostic stratification according to the lowest Akaike information criterion and explored the potential relationship between K17 and chemoresistance by multivariate predictive analyses. RESULTS: Patients with advanced-stage, low K17 PDACs treated using 5-fluorouracil (5-FU)-based chemotherapeutic regimens had 3-fold longer survival than corresponding cases treated with gemcitabine-based chemotherapy. By contrast, PDACs with high K17 did not respond to either regimen. The predictive value of K17 was independent of tumor mutation status and other clinicopathologic variables. CONCLUSIONS: The detection of K17 in 10% or greater of PDAC cells identified patients with shortest survival. Among patients with low K17 PDACs, 5-FU-based treatment was more likely than gemcitabine-based therapies to extend survival.

BackgroundPrenatal folate supplementation has been consistently associated with a reduced risk of childhood acute lymphoblastic leukemia (ALL). Previous germline genetic studies examining the one carbon (folate) metabolism pathway were limited in sample size, scope, and population diversity and led to inconclusive results.MethodsWe evaluated whether ∼2,900 single-nucleotide polymorphisms (SNP) within 46 candidate genes involved in the folate metabolism pathway influence the risk of childhood ALL, using genome-wide data from nine case-control studies in the Childhood Cancer and Leukemia International Consortium (n = 9,058 cases including 4,510 children of European ancestry, 3,018 Latinx, and 1,406 Asians, and 92,364 controls). Each study followed a standardized protocol for quality control and imputation of genome-wide data and summary statistics were meta-analyzed for all children combined and by major ancestry group using METAL software.ResultsNone of the selected SNPs reached statistical significance, overall and for major ancestry groups (using adjusted Bonferroni P-value of 5 × 10-6 and less-stringent P-value of 3.5 × 10-5 accounting for the number of "independent" SNPs). None of the 10 top (nonsignificant) SNPs and corresponding genes overlapped across ancestry groups.ConclusionsThis large meta-analysis of original data does not reveal associations between many common genetic variants in the folate metabolism pathway and childhood ALL in various ancestry groups.ImpactGenetic variants in the folate pathway alone do not appear to substantially influence childhood acute lymphoblastic leukemia risk. Other mechanisms such as gene-folate interaction, DNA methylation, or maternal genetic effects may explain the observed associations with self-reported prenatal folate intake.

ObjectiveDiabetic foot ulcers (DFUs) present a significant global health challenge, resulting in high morbidity and economic costs. Current available treatments often fail to achieve satisfactory healing rates, highlighting the need for novel therapies. This study evaluated the safety and efficacy of a novel autologous whole blood clot (AWBC)-a blood-based, biodegradable provisional matrix-in conjunction with standard of care (SoC) when compared to SoC alone in the treatment of hard-to-heal DFUs.MethodA multicentre, prospective, blinded assessor, randomised controlled trial was conducted at 16 sites across the US, South Africa and Turkey. A cohort of patients with hard-to-heal DFUs was enrolled and randomised to either the AWBC group or the control group. The primary endpoint was complete wound closure at 12 weeks, while secondary endpoints included time to heal and percentage area reduction (PAR) at four and eight weeks. Data were analysed using both intention-to-treat (ITT) and per-protocol (PP) populations.ResultsThe cohort included 119 patients. AWBC treatment resulted in a significantly higher healing rate compared to the control in both ITT (41% versus 15%, respectively; p=0.002) and PP populations (51% versus 18%, respectively; p=0.0075). AWBC treatment also resulted in a shorter mean time to heal and higher durability of wound closure. Safety analysis showed a similar incidence of adverse events (AEs) between groups, with no device-related AEs.ConclusionThe AWBC system, by modulating the wound microenvironment and providing a functional extracellular matrix, offered a promising new approach to treating hard-to-heal DFUs, demonstrating superior healing outcomes compared to SoC alone in this study.

Improvement of water and sanitation conditions may reduce infant mortality, particularly in countries like India where open defecation is highly prevalent. We conducted a quasi-experimental study to investigate the association between the Swachh Bharat Mission (SBM)-a national sanitation program initiated in 2014-and infant (IMR) and under five mortality rates (U5MR) in India. We analyzed data from thirty-five Indian states and 640 districts spanning 10 years (2011-2020), with IMR and U5MR per thousand live births as the outcomes. Our main exposure was the district-level annual percentage of households that received a constructed toilet under SBM. We mapped changes in IMR and U5MR and toilet access at the district level over time. We fit two-way fixed effects regression models controlling for sociodemographic, wealth, and healthcare-related confounders at the district-level to estimate the association between toilets constructed and child mortality. Toilet access and child mortality have a historically robust inverse association in India. Toilets constructed increased dramatically across India following the implementation of SBM in 2014. Results from panel data regression models show that districts with > 30% toilets constructed under SBM corresponds with 5.3 lower IMR (p

RATIONALE: Research studies typically quantify acute respiratory exacerbation episodes (AECOPD) among people with chronic obstructive pulmonary disease (COPD) based on self-report elicited by survey questionnaire. However, AECOPD quantification by self-report could be inaccurate, potentially rendering it an imprecise tool for identification of those with exacerbation tendency. OBJECTIVE: Determine the agreement between self-reported and health records-documented quantification of AECOPD and their association with airway inflammation. METHODS: We administered a questionnaire to elicit the incidence and severity of respiratory exacerbations in the three years preceding the survey among current or former heavy smokers with or without diagnosis of COPD. We then examined electronic health records (EHR) of those with COPD and those without (tobacco-exposed persons with preserved spirometry or TEPS) to determine whether the documentation of the three-year incidence of moderate to very severe respiratory exacerbations was consistent with self-report using Kappa Interrater statistic. A subgroup of participants also underwent bronchoalveolar lavage (BAL) to quantify their airway inflammatory cells. We further used multivariable regressions analysis to estimate the association between respiratory exacerbations and BAL inflammatory cell composition with adjustment for covariates including age, sex, height, weight, smoking status (current versus former) and burden (pack-years). RESULTS: Overall, a total of 511 participants completed the questionnaire, from whom 487 had EHR available for review. Among the 222 participants with COPD (70 ± 7 years-old; 96% male; 70 ± 38 pack-years smoking; 42% current smoking), 57 (26%) reported having any moderate to very severe AECOPD (m/s-AECOPD) while 66 (30%) had EHR documentation of m/s-AECOPD. However, 42% of those with EHR-identified m/s-AECOPD had none by self-report, and 33% of those who reported m/s-AECOPD had none by EHR, suggesting only moderate agreement (Cohens Kappa = 0.47 ± 0.07; P

ObjectiveTo test the effect of proactive home visits by trained community health workers (CHWs) on child survival.MethodsWe conducted a two arm, parallel, unmasked cluster-randomized trial in 137 village-clusters in rural Mali. From February 2017 to January 2020, 31 761 children enrolled at the trial start or at birth. Village-clusters received either primary care services by CHWs providing regular home visits (intervention) or by CHWs providing care at a fixed site (control). In both arms, user fees were removed and primary health centres received staffing and infrastructure improvements before trial start. Using lifetime birth histories from women aged 15-49 years surveyed annually, we estimated incidence rate ratios (IRR) for intention-to-treat and per-protocol effects on under-five mortality using Poisson regression models.FindingsOver three years, we observed 52 970 person-years (27 332 in intervention arm; 25 638 in control arm). During the trial, 909 children in the intervention arm and 827 children in the control arm died. The under-five mortality rate declined from 142.8 (95% CI: 133.3-152.9) to 56.7 (95% CI: 48.5-66.4) deaths per 1000 live births in the intervention arm; and from 154.3 (95% CI: 144.3-164.9) to 54.9 (95% CI: 45.2-64.5) deaths per 1000 live births in the control arm. Intention-to-treat (IRR: 1.02; 95% CI: 0.88-1.19) and per-protocol estimates (IRR: 1.01; 95% CI: 0.87-1.18) showed no difference between study arms.ConclusionThough proactive home visits did not reduce under-five mortality, system-strengthening measures may have contributed to the decline in under-five mortality in both arms.

BackgroundSphingosine-1-phosphate lyase insufficiency syndrome (SPLIS) is a recently recognized inborn error of metabolism associated with steroid-resistant nephrotic syndrome as well as adrenal insufficiency and immunological, neurological, and skin manifestations. SPLIS is caused by inactivating mutations in SGPL1, encoding the pyridoxal 5'phosphate-dependent enzyme sphingosine-1-phosphate lyase, which catalyzes the final step of sphingolipid metabolism. Some SPLIS patients have undergone kidney transplantation, and others have been treated with vitamin B6 supplementation. In addition, targeted therapies including gene therapy are in preclinical development. In anticipation of clinical trials, it will be essential to characterize the full spectrum and natural history of SPLIS. We performed a retrospective analysis of 76 patients in whom the diagnosis of SPLIS was established in a proband with at least one suggestive finding and biallelic SGPL1 variants identified by molecular genetic testing. The main objective of the study was to identify factors influencing survival in SPLIS subjects.ResultsOverall survival at last report was 50%. Major influences on survival included: (1) age and organ involvement at first presentation; (2) receiving a kidney transplant, and (3) SGPL1 genotype. Among 48 SPLIS patients with nephropathy who had not received a kidney transplant, two clinical subgroups were distinguished. Of children diagnosed with SPLIS nephropathy before age one (n = 30), less than 30% were alive 2 years after diagnosis, and 17% were living at last report. Among those diagnosed at or after age one (n = 18), ~ 70% were alive 2 years after diagnosis, and 72% were living at time of last report. SPLIS patients homozygous for the SPL R222Q variant survived longer compared to patients with other genotypes. Kidney transplantation significantly extended survival outcomes.ConclusionOur results demonstrate that SPLIS is a phenotypically heterogeneous condition. We find that patients diagnosed with SPLIS nephropathy in the first year of life and patients presenting with prenatal findings represent two high-risk subgroups, whereas patients harboring the R222Q SGPL1 variant fare better than the rest. Time to progression from onset of proteinuria to end stage kidney disease varies from less than one month to five years, and kidney transplantation may be lifesaving.

The financial impact of liver transplantation has been underexplored. We aimed to identify associations between high financial burden (≥10% annual income spent on out-of-pocket medical costs) and work productivity, financial distress (coping behaviors in response to the financial burden), and financial toxicity (health-related quality of life, HRQOL) among adult recipients of liver transplant. Between June 2021 and May 2022, we surveyed 207 adult recipients of liver transplant across 5 US transplant centers. Financial burden and distress were measured by 25 items adapted from national surveys of cancer survivors. Participants also completed the Work Productivity and Activity Impairment and EQ-5D-5L HRQOL questionnaires. In total, 23% of recipients reported high financial burden which was significantly associated with higher daily activity impairment (32.9% vs. 23.3%, p =0.048). In adjusted analyses, the high financial burden was significantly and independently associated with delayed or foregone medical care (adjusted odds ratio, 3.95; 95% CI, 1.85-8.42) and being unable to afford basic necessities (adjusted odds ratio, 5.12; 95% CI: 1.61-16.37). Recipients experiencing high financial burden had significantly lower self-reported HRQOL as measured by the EQ-5D-5L compared to recipients with low financial burden (67.8 vs. 76.1, p =0.008) and an age-matched and sex-matched US general population (67.8 vs. 79.1, p

Measures of attention and memory were evaluated in 6- to 9-month-old infants from two diverse contexts. One sample consisted of African infants residing in rural Malawi (N = 228, 118 girls, 110 boys). The other sample consisted of racially diverse infants residing in suburban California (N = 48, 24 girls, 24 boys). Infants were tested in an eye-tracking version of the visual paired comparison procedure and were shown racially familiar faces. The eye tracking data were parsed into individual looks, revealing that both groups of infants showed significant memory performance. However, how a look was operationally defined impacted some-but not other-measures of infant VPC performance. RESEARCH HIGHLIGHTS: In both the US and Malawi, 6- to 9-month-old infants showed evidence of memory for faces they had previously viewed during a familiarization period. Infant age was associated with peak look duration and memory performance in both contexts. Different operational definitions of a look yielded consistent findings for peak look duration and novelty preference scores-but not shift rate. Operationalization of look-defined measures is an important consideration for studies of infants in different cultural contexts.

Although caregiving responsibilities and need for support persist and evolve across the life course in families with autistic youth or youth with other developmental disabilities (DDs), little is known about support during their childs adulthood years. Therefore, the present study used a mixed-methods approach to examine change and stability in formal and informal family support across the transition to adulthood. Caregivers of 126 individuals with autism or DDs completed a modified version of the Family Support Scale, including open-ended questions, at five time points from adolescence (age 16) into young adulthood (age 22). Caregivers reported that informal support from family members was the most frequently used, helpful, and valued source of support with relative stability across time. In contrast, the reported helpfulness, use, and value of formal support (e.g., professionals, schools) for caregivers declined over time. Qualitative content analyses revealed characteristics of highly valued support included support type (e.g., instrumental or emotional) and features of the support source (e.g., their understanding). There was a shift to valuing emotional support more than instrumental support over time, especially for caregivers of less able adults. Partnership and dependability emerged as highly valued features of the support source. These findings fit within a social convoy perspective and likely reflect the service cliff experienced by autistic individuals or people with DDs and their families. As social networks shrink over time and formal services are less readily available in adulthood, remaining sources of support, particularly from family members, become increasingly important.

Motivation in general, and social motivation in particular are important for interpersonal functioning in individuals with schizophrenia. Still, their roles after accounting for social cognition, are not well understood. The sample consisted of 147 patients with schizophrenia. General motivation was measured using the Behavioral inhibition/activation scale (BIS/BAS). Social motivation was measured by Passive social withdrawal and Active social avoidance items from PANSS. Interpersonal functioning was evaluated with Birchwoods Social Functioning Scale (SFS). We used Exploratory Graph Analysis for network estimation and community detection. Active social avoidance, passive social withdrawal, and social withdrawal/engagement (from SFS) were the most important nodes. In addition, three distinct communities were identified: Social cognition, Social motivation, and Interpersonal functioning. Notably, the BIS and BAS measures of general motivation were not part of any community. BAS showed stronger links to functioning than BIS. Passive social withdrawal was more strongly linked to interpersonal functioning than social cognitive abilities. Results suggest that social motivation, especially social approach, is more closely related to interpersonal functioning in schizophrenia than general motivation. In contrast, we found that general motivation was largely unrelated to social motivation. This pattern highlights the importance of type of motivation for understanding variability in interpersonal difficulties in schizophrenia.

PURPOSE: Population-based studies on the associations of plant-based foods, red meat or dairy with gut microbiome are scarce. We examined whether the consumption of plant-based foods (vegetables, potatoes, fruits, cereals), red and processed meat (RPM) or dairy (fermented milk, cheese, other dairy products) are related to gut microbiome in Finnish adults. METHODS: We utilized data from the National FINRISK/FINDIET 2002 Study (n = 1273, aged 25-64 years, 55% women). Diet was assessed with 48-hour dietary recalls. Gut microbiome was analyzed using shallow shotgun sequencing. We applied multivariate analyses with linear models and permutational ANOVAs adjusted for relevant confounders. RESULTS: Fruit consumption was positively (beta = 0.03, SE = 0.01, P = 0.04), while a dairy subgroup including milk, cream and ice-creams was inversely associated (beta=-0.03, SE 0.01, P = 0.02) with intra-individual gut microbiome diversity (alpha-diversity). Plant-based foods (R2 = 0.001, P = 0.03) and dairy (R2 = 0.002, P = 0.01) but not RPM (R2 = 0.001, P = 0.38) contributed to the compositional differences in gut microbiome (beta-diversity). Plant-based foods were associated with several butyrate producers/cellulolytic species including Roseburia hominis. RPM associations included an inverse association with R. hominis. Dairy was positively associated with several lactic producing/probiotic species including Lactobacillus delbrueckii and potentially opportunistic pathogens including Citrobacter freundii. Dairy, fermented milk, vegetables, and cereals were associated with specific microbial functions. CONCLUSION: Our results suggest a potential association between plant-based foods and dairy or their subgroups with microbial diversity measures. Furthermore, our findings indicated that all the food groups were associated with distinct overall microbial community compositions. Plant-based food consumption particularly was associated with a larger number of putative beneficial species.

BACKGROUND: Ileal neuroendocrine tumors (i-NETs) are characterized by their multifocality and bulky mesenteric mass. Having shown that minimally invasive surgery (MIS) utilizing a hand-access port device has favorable short-term outcomes and achieves the goals of surgery for i-NETs, we sought to analyze long-term survival outcomes of MIS. METHODS: One hundred and sixty-eight patients who underwent resection of primary i-NETs at a single institution between January 2007 and February 2023 were retrospectively studied. Patients were categorized into the MIS or open surgery cohorts on an intention-to-treat basis. Open surgery was selected mainly based on the need for hepatectomy or bulky mesenteric mass resection. Overall survival was analyzed using log-rank tests with propensity score matching (PSM) and Cox proportional hazards regression. PSM was performed to reduce standardized mean differences of the variables to

BACKGROUND/OBJECTIVES: The phase 3 REGAIN study and its open-label extension demonstrated the efficacy of the complement C5 inhibitor eculizumab in patients with treatment-refractory, acetylcholine receptor antibody-positive generalized myasthenia gravis (gMG). The aim of the ELEVATE study was to assess the effectiveness of eculizumab in clinical practice in adults with MG in the United States. METHODS: A retrospective chart review was conducted in adults with MG who initiated eculizumab treatment between October 23, 2017 and December 31, 2019. Outcomes assessed before and during eculizumab treatment using a pre- versus post-treatment study design included Myasthenia Gravis-Activities of Daily Living (MG-ADL) total scores; minimal symptom expression (MSE); physician impression of clinical change; minimal manifestation status (MMS); and concomitant medication use. RESULTS: In total, 119 patients were included in the study. A significant reduction was observed in mean MG-ADL total score, from 8.0 before eculizumab initiation to 5.4 at 3 months and to 4.7 at 24 months after eculizumab initiation (both p

Food cue reactivity (FCR) is an appetitive trait associated with overeating and weight gain. We developed a laboratory craving assessment to objectively evaluate cognitive aspects of FCR. This study examined the preliminary construct and criterion validity of this craving assessment and evaluated 4 different interventions, 2 of which incorporated cue-exposure treatment for food, on craving over treatment and follow-up. 271 treatment-seeking adults with overweight/obesity (body mass index = 34.6[5.2]; age = 46.5[11.8]; 81.2% female; 61.6% non-Latinx White) completed the Food Cue Responsivity Scale and the laboratory craving assessment, during which they alternated holding and smelling a highly craved food and provided craving ratings over 5 min. Participants were subsequently randomized to 26 treatment sessions over 12-months of ROC, Behavioral Weight Loss (BWL), a combined arm (ROC+) and an active comparator (AC), and repeated the craving assessment at post-treatment and 12-month follow-up. Linear mixed-effects models assessed associations between trial type (holding vs. smelling), trial number, pre-treatment FCR, treatment arm, assessment time point, and craving. Cravings were greater when smelling vs. holding food (b = 0.31, p