Severe Granulomatosis With Polyangiitis Treated With Low-Dose Cyclophosphamide, Rituximab, Glucocorticoids, and Plasma Exchange: A Case Report.

Granulomatosis with polyangiitis (GPA) is a systemic vasculitis that affects blood vessels and presents with vague constitutional symptoms, but more serious manifestations can develop, including pulmonary complications and glomerulonephritis. Currently, there are no definitive treatment guidelines. We present a case of a 66-year-old male with no previous medical history who was admitted for generalized constitutional symptoms for the past month. Imaging of the patient's brain revealed dural enhancement. Bronchoalveolar lavage was done and revealed diffuse alveolar hemorrhage (DAH). A kidney biopsy revealed granulomatosis with polyangiitis. The patient's hospital course was complicated by acute renal failure and required hemodialysis. Due to the patient's multi-organ involvement, the patient was treated aggressively with cyclophosphamide, rituximab, plasma exchange (PE), and steroids. GPA is a systemic vasculitis that can present with multi-organ involvement. A prompt diagnosis is necessary to initiate treatment and preserve organ function. More research is needed to determine which combination therapies are the best treatment modalities in cases of severe multi-organ system involvement.

Association between JAK2V617F variable allele frequency and risk of thrombotic events in patients with myeloproliferative neoplasms.

BACKGROUND: Myeloproliferative neoplasms (MPNs) are a group of chronic disorders of the bone marrow characterised by the overproduction of clonal myeloid stem cells. The most common driver mutation found in MPNs is a point mutation on exon 14 of the JAK2 gene, JAK2V617F. Various studies have suggested that measuring the variable allele frequency (VAF) of JAK2V617F may provide useful insight regarding diagnosis, treatment, risks and outcomes in MPN patients. In particular, JAK2V617F has been associated with increased risk of thrombotic events, a leading cause of mortality in MPNs. AIMS: The aim of this study was to determine if JAK2V617F VAF was associated with clinical outcomes in patients with MPN. METHODS: JAK2V617F VAF was determined by quantitative PCR (qPCR) in a cohort of 159 newly diagnosed MPN patients, and the association of JAK2V617F VAF and risk of thrombosis was examined in this cohort. RESULTS: We observed a significantly higher JAK2V617F VAF in PV and PMF versus ET. A significant association was observed between JAK2V617F VAF and risk of thrombotic events. When patients were stratified by thrombotic events prior to and post diagnosis, an association with JAK2V617F VAF was only observed with post diagnosis thrombotic events. Of note, these associations were not observed when looking at each MPN subtype in isolation. CONCLUSIONS: We have shown that a higher JAK2V617F VAF is associated with thrombotic events post MPN diagnosis. JAK2V617F VAF may therefore provide a valuable prognostic indicator for risk of thrombosis in MPNs.

FTY720/Fingolimod mitigates paclitaxel-induced Sparcl1-driven neuropathic pain and breast cancer progression.

Paclitaxel is among the most active chemotherapy drugs for the aggressive triple negative breast cancer (TNBC). Unfortunately, it often induces painful peripheral neuropathy (CIPN), a major debilitating side effect. Here we demonstrate that in naive and breast tumor-bearing immunocompetent mice, a clinically relevant dose of FTY720/Fingolimod that targets sphingosine-1-phosphate receptor 1 (S1PR1), alleviated paclitaxel-induced neuropathic pain. FTY720 also significantly attenuated paclitaxel-stimulated glial fibrillary acidic protein (GFAP), a marker for activated astrocytes, and expression of the astrocyte-secreted synaptogenic protein Sparcl1/Hevin, a key regulator of synapse formation. Notably, the formation of excitatory synapses containing VGluT2 in the spinal cord dorsal horn induced by paclitaxel was also inhibited by FTY720 treatment, supporting the involvement of astrocytes and Sparcl1 in CIPN. Furthermore, in this TNBC mouse model that mimics human breast cancer, FTY720 administration also enhanced the anti-tumor effects of paclitaxel, leading to reduced tumor progression and lung metastasis. Taken together, our findings suggest that targeting the S1P/S1PR1 axis with FTY720 is a multipronged approach that holds promise as a therapeutic strategy for alleviating both CIPN and enhancing the efficacy of chemotherapy in TNBC treatment.

antiCD49d Ab treatment ameliorates age-associated inflammatory response and mitigates CD8+ T-cell cytotoxicity after traumatic brain injury.

Patients aged 65 years and older account for an increasing proportion of patients with traumatic brain injury (TBI). Older TBI patients experience increased morbidity and mortality compared to their younger counterparts. Our prior data demonstrated that by blocking α4 integrin, anti-CD49d antibody (aCD49d Ab) abrogates CD8+ T-cell infiltration into the injured brain, improves survival, and attenuates neurocognitive deficits. Here, we aimed to uncover how aCD49d Ab treatment alters local cellular responses in the aged mouse brain. Consequently, mice incur age-associated toxic cytokine and chemokine responses long-term post-TBI. aCD49d Ab attenuates this response along with a T helper (Th)1/Th17 immunological shift and remediation of overall CD8+ T cell cytotoxicity. Furthermore, aCD49d Ab reduces CD8+ T cells exhibiting higher effector status, leading to reduced clonal expansion in aged, but not young, mouse brains with chronic TBI. Together, aCD49d Ab is a promising therapeutic strategy for treating TBI in the older people. Graphic abstract: Aged brains after TBI comprise two pools of CD8 + T cells . The aged brain has long been resided by a population of CD8 + T cells that's exhaustive and dysfunctional. Post TBI, due to BBB impairment, functional CD8 + T cells primarily migrate into the brain parenchyma. Aged, injury-associated microglia with upregulated MHC class I molecules can present neoantigens such as neuronal and/or myelin debris in the injured brains to functional CD8+ T, resulting in downstream CD8+ T cell cytotoxicity. aCD49d Ab treatment exerts its function by blocking the migration of functional effector CD8 + T cell population, leading to less cytotoxicity and resulting in improved TBI outcomes in aged mice.

Beyond the Dichotomy: Creation and Validation of a Continuous Statewide Index of U.S. Honor Culture.

Honor cultures are characterized by a heightened sensitivity to reputation threats and strong expectations for the defense of honor. U.S. states vary in the extent to which they express the cultural norms of honor, but researchers have frequently relied upon a dichotomous classification that differentiates states as honor or dignity states. We created and validated a continuous, six-item index of honor norms and values across all U.S. states (Study 1). In Study 2, our honor index was correlated with historical variables theoretically associated with the genesis of honor cultures. In Study 3, we validated our honor index further by showing that it predicted several race-/ethnicity-specific outcomes that prior research has connected with honor (e.g., homicide rates, suicide rates). This new index equips researchers with a more nuanced understanding of U.S. honor cultures and a measure that can be used in future investigations.

Development and validation of the Global Adolescent and Child Physical Activity Questionnaire (GAC-PAQ) in 14 countries: study protocol.

INTRODUCTION: Global surveillance of physical activity (PA) of children and adolescents with questionnaires is limited by the use of instruments developed in high-income countries (HICs) lacking sociocultural adaptation, especially in low- and middle-income countries (LMICs); under-representation of some PA domains; and omission of active play, an important source of PA. Addressing these limitations would help improve international comparisons, and facilitate the cross-fertilisation of ideas to promote PA. We aim to develop and assess the reliability and validity of the app-based Global Adolescent and Child Physical Activity Questionnaire (GAC-PAQ) among 8-17 years old in 14 LMICs and HICs representing all continents; and generate the 'first available data' on active play in most participating countries. METHODS AND ANALYSIS: Our study involves eight stages: (1) systematic review of psychometric properties of existing PA questionnaires for children and adolescents; (2) development of the GAC-PAQ (first version); (3) content validity assessment with global experts; (4) cognitive interviews with children/adolescents and parents in all 14 countries; (5) development of a revised GAC-PAQ; (6) development and adaptation of the questionnaire app (application); (7) pilot-test of the app-based GAC-PAQ; and, (8) main study with a stratified, sex-balanced and urban/rural-balanced sample of 500 children/adolescents and one of their parents/guardians per country. Participants will complete the GAC-PAQ twice to assess 1-week test-retest reliability and wear an ActiGraph wGT3X-BT accelerometer for 9 days to test concurrent validity. To assess convergent validity, subsamples (50 adolescents/country) will simultaneously complete the PA module from existing international surveys. ETHICS AND DISSEMINATION: Approvals from research ethics boards and relevant organisations will be obtained in all participating countries. We anticipate that the GAC-PAQ will facilitate global surveillance of PA in children/adolescents. Our project includes a robust knowledge translation strategy sensitive to social determinants of health to inform inclusive surveillance and PA interventions globally.

Psychosocial Disadvantage During Childhood and Midlife Health: NIMHD Social Epigenomics Program.

Importance: Low childhood socioeconomic status (SES) is a social hallmark of aging that contributes to adult health disparities and earlier morbidity and mortality. Childhood perceptions of stress are associated with child health outcomes and may contribute to premature biological aging into adulthood. Objective: To describe the association of childhood SES and perceived stress with midlife insulin resistance and epigenetic age and to explore whether late adolescent adiposity mediates the observed associations. Design, Setting, and Participants: The longitudinal cohort National Heart, Lung, and Blood Institute Growth and Health Study enrolled girls aged 10 years from January 1987 to May 1988, and followed them up to 19 years of age. Participants from Richmond, California, were recruited again at midlife in 2016 to assess insulin resistance and epigenetic age. Analyses were conducted from August 2, 2023, to March 18, 2024. A total of 433 participants were eligible and included in the analyses (specific sample sizes ranged across analyses from 303 to 391). Exposures: Childhood levels of SES at 10 years of age (parental educational level and income) and perceived stress at 11 years of age. Main Outcomes and Measures: The hypotheses tested were formulated after data collection. Outcomes included the homeostatic model assessment of insulin resistance (HOMA-IR) and the GrimAge and DunedinPACE epigenetic clocks. Waist circumference in late adolescence was tested as a mediator. Results: Among the 433 participants, the mean (SD) age was 39.4 (1.2) years; 218 (50.3%) were Black and 215 (49.7%) were White; and 135 (31.2%) had parents with a college degree or higher. Higher parental educational level was associated with lower HOMA-IR (B = -0.22 [95% CI, -0.41 to -0.02]; P = .03), lower midlife GrimAge (B = -1.76 [95% CI, -2.85 to -0.66] years; P = .002), and slower midlife DunedinPACE (B = -0.03 [95% CI, -6.29 to -0.002]; P = .04). Childhood perceived stress was indirectly associated through late adolescent adiposity with midlife HOMA-IR (B = 0.01 [95% CI, 0.001-0.01]; P = .02) and midlife GrimAge (B = 0.02 [95% CI, 0.003-0.04] years; P = .01). Conclusions and Relevance: In this longitudinal cohort study of midlife health and aging, childhood social hallmarks of aging were associated with midlife insulin resistance and epigenetic age (GrimAge and DunedinPACE). Future studies should identify malleable factors that may slow the impact of social hallmarks of aging.

The erector spinae plane block vs. usual care for treatment of mechanical back pain in the emergency department: a pilot study.

BACKGROUND: The ultrasound-guided erector spinae plane block (ESPB), traditionally utilized for thoracic regional pain control, has been reported as an effective analgesic option for mechanical back pain, renal colic, and rib fractures in the emergency department (ED). This pilot study aims to compare the effectiveness of the ESPB to usual analgesic treatment for patients presenting to the ED with mechanical back pain. METHODS: A prospective, single-blind randomized controlled trial was conducted at a Canadian community hospital from March 2020 to December 2022. Adult patients presenting to the ED with mechanical back pain of at least 7 out of 10 on the Numeric Pain Rating Scale (NPRS) were randomized to receive either the ESPB or usual care. The primary outcome was the difference in NPRS score reduction at ED discharge. Secondary outcomes included ED length of stay, ED opiate use, follow-up NPRS and Brief Pain Inventory (BPI) scores, back pain-related return ED visits, and ongoing opiate use. RESULTS: A total of 30 patients were enrolled, with 19 randomized to the ESPB cohort and 11 to the usual care cohort. The mean NPRS reduction at ED discharge was significantly higher in the ESPB group compared to the usual care group (5.4 vs. 2.2), with a difference of 3.2 (95% confidence interval 1.4-5.1). ED opiate use was lower in the ESPB group. The ESPB also resulted in a significant reduction in ED length of stay (160 min vs. 235 min). There were no reported adverse effects related to the research interventions. CONCLUSION: This pilot study suggests that the ESPB may be an effective opioid-sparing analgesic option for patients presenting to the ED with mechanical back pain. GOV IDENTIFIER: NCT05982483.

RéSUMé: CONTEXTE: Le bloc raboteux spina érectile guidé par ultrasons (ESPB), traditionnellement utilisé pour le contrôle de la douleur régionale thoracique, a été signalé comme une option analgésique efficace pour les maux de dos mécaniques, les coliques rénales et les fractures des côtes au service des urgences (ED). Cette étude pilote vise à comparer l'efficacité de l'ESPB au traitement analgésique habituel pour les patients présentant à l'urgence des douleurs dorsales mécaniques. MéTHODES: Un essai contrôlé randomisé prospectif en aveugle a été mené dans un hôpital communautaire canadien de mars 2020 à décembre 2022. Les patients adultes se présentant à l'urgence avec une douleur dorsale mécanique d'au moins 7 sur 10 sur l'échelle numérique d'évaluation de la douleur (NPRS) ont été randomisés pour recevoir soit la ESPB ou les soins habituels. Le critère de jugement principal était la différence dans la réduction du score NPRS à la sortie de l'urgence. Les critères de jugement secondaires comprenaient la durée du séjour à l'urgence, l'utilisation d'opiacés à l'urgence, les scores de suivi à l'INRP et au Brief Pain Inventory (BPI), les visites de retour à l'urgence liées à la douleur dorsale et l'utilisation continue d'opiacés. RéSULTATS: Au total, 30 patients ont été recrutés, dont 19 randomisés dans la cohorte de la DGPSE et 11 dans la cohorte de soins habituels. La réduction moyenne du NPRS à la sortie de l'urgence était significativement plus élevée dans le groupe ESPB que dans le groupe de soins habituels (5,4 vs. 2,2), avec une différence de 3,2 (intervalle de confiance à 95 % 1,4-5,1). La consommation d'opiacés aux urgences était plus faible dans le groupe ESPB. La ESPB a également entraîné une réduction significative de la durée du séjour aux urgences (160 min contre 235 min). Aucun effet indésirable lié aux interventions de recherche n'a été signalé. CONCLUSION: Cette étude pilote suggère que l'ESPB peut être une option analgésique efficace épargnant les opioïdes pour les patients se présentant à l'urgence avec des douleurs dorsales mécaniques.

Sleep Problems and Health Outcomes Among Urban American Indian and Alaska Native Adolescents.

Importance: Adolescent sleep problems are prevalent, particularly among racial and ethnic minority groups, and can increase morbidity. Despite the numerous strengths of their racial and ethnic group, urban American Indian and Alaska Native adolescents face significant health disparities but are rarely included in health research. Understanding how sleep problems are associated with health outcomes among American Indian and Alaska Native adolescents may elucidate novel targets for interventions to promote health equity. Objective: To assess whether baseline sleep problems are associated with changes in behavioral and cardiometabolic health outcomes among urban American Indian and Alaska Native adolescents 2 years later. Design, Setting, and Participants: American Indian and Alaska Native adolescents were recruited via flyers and community events for an observational cohort study in California. Baseline assessments were conducted among 142 adolescents from March 1, 2018, to March 31, 2020, and follow-ups were conducted among 114 adolescents from December 1, 2020, to June 30, 2022. Exposures: Baseline actigraphy-assessed sleep duration and efficiency and self-reported sleep disturbances and social jet lag (absolute value of the difference in sleep midpoint on weekends vs weekdays; indicator of circadian misalignment). Main Outcomes and Measures: Main outcome measures included self-reported depression (measured using the Patient Health Questionnaire), anxiety (measured using the Generalized Anxiety Disorder 7-item scale), past year alcohol and cannabis use, body mass index, systolic blood pressure (SBP) and diastolic blood pressure (DBP), waist circumference, and glycosylated hemoglobin (HbA1c). Analyses examined whether baseline sleep was associated with health outcomes at follow-up, controlling for age, sex, and baseline outcome measures. Results: The baseline sample included 142 urban American Indian and Alaska Native adolescents (mean [SD] age, 14.0 [1.4] years; 84 girls [59%]), 80% of whom (n = 114; mean [SD] age, 14.1 [1.3] years; 71 girls [62%]) completed follow-ups. Linear or logistic regressions showed significant negative associations between shorter sleep duration and depression (ß = -1.21 [95% CI, -2.19 to -0.24]), anxiety (ß = -0.89 [95% CI, -1.76 to -0.03]), DBP (ß = -2.03 [95% CI, -3.79 to -0.28]), and HbA1c level (ß = -0.15 [95% CI, -0.26 to -0.04]) and likelihood of alcohol (odds ratio [OR], 0.57 [95% CI, 0.36-0.91]) and cannabis use (full week: OR, 0.59 [95% CI, 0.35-0.99]) at follow-up. Greater social jet lag was associated with significantly higher SBP (ß = 0.06 [95% CI, 0.01-0.11]) at follow-up. Conclusions and Relevance: This cohort study found significant associations between poor sleep and adverse changes in health outcomes. Findings highlight the importance of developing culturally responsive interventions that target sleep as a key modifiable risk factor to improve the health of American Indian and Alaska Native adolescents.

Sphingosine kinase 2 and p62 regulation are determinants of sexual dimorphism in hepatocellular carcinoma.

OBJECTIVE: Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality, and its incidence is increasing due to endemic obesity. HCC is sexually dimorphic in both humans and rodents with higher incidence in males, although the mechanisms contributing to these correlations remain unclear. Here, we examined the role of sphingosine kinase 2 (SphK2), the enzyme that regulates the balance of bioactive sphingolipid metabolites, sphingosine-1-phosphate (S1P) and ceramide, in gender specific MASH-driven HCC. METHODS: Male and female mice were fed a high fat diet with sugar water, a clinically relevant model that recapitulates MASH-driven HCC in humans followed by physiological, biochemical cellular and molecular analyses. In addition, correlations with increased risk of HCC recurrence were determined in patients. RESULTS: Here, we report that deletion of SphK2 protects both male and female mice from Western diet-induced weight gain and metabolic dysfunction without affecting hepatic lipid accumulation or fibrosis. However, SphK2 deficiency decreases chronic diet-induced hepatocyte proliferation in males but increases it in females. Remarkably, SphK2 deficiency reverses the sexual dimorphism of HCC, as SphK2-/- male mice are protected whereas the females develop liver cancer. Only in male mice, chronic western diet induced accumulation of the autophagy receptor p62 and its downstream mediators, the antioxidant response target NQO1, and the oncogene c-Myc. SphK2 deletion repressed these known drivers of HCC development. Moreover, high p62 expression correlates with poor survival in male HCC patients but not in females. In hepatocytes, lipotoxicity-induced p62 accumulation is regulated by sex hormones and prevented by SphK2 deletion. Importantly, high SphK2 expression in male but not female HCC patients is associated with a more aggressive HCC differentiation status and increased risk of cancer recurrence. CONCLUSIONS: This work identifies SphK2 as a potential regulator of HCC sexual dimorphism and suggests SphK2 inhibitors now in clinical trials could have opposing, gender-specific effects in patients.

Preliminary Experience with Three Alternative Motion Sensors for 0.55 Tesla MR Imaging.

Due to limitations in current motion tracking technologies and increasing interest in alternative sensors for motion tracking both inside and outside the MRI system, in this study we share our preliminary experience with three alternative sensors utilizing diverse technologies and interactions with tissue to monitor motion of the body surface, respiratory-related motion of major organs, and non-respiratory motion of deep-seated organs. These consist of (1) a Pilot-Tone RF transmitter combined with deep learning algorithms for tracking liver motion, (2) a single-channel ultrasound transducer with deep learning for monitoring bladder motion, and (3) a 3D Time-of-Flight camera for observing the motion of the anterior torso surface. Additionally, we demonstrate the capability of these sensors to simultaneously capture motion data outside the MRI environment, which is particularly relevant for procedures like radiation therapy, where motion status could be related to previously characterized cyclical anatomical data. Our findings indicate that the ultrasound sensor can track motion in deep-seated organs (bladder) as well as respiratory-related motion. The Time-of-Flight camera offers ease of interpretation and performs well in detecting surface motion (respiration). The Pilot-Tone demonstrates efficacy in tracking bulk respiratory motion and motion of major organs (liver). Simultaneous use of all three sensors could provide complementary motion information outside the MRI bore, providing potential value for motion tracking during position-sensitive treatments such as radiation therapy.

The transcription factor sex-determining region Y-box 2 (SOX2) in bladder cancer.

Sex-determining region Y-box 2 (SOX2) is a transcription factor with a central role in embryologic development. SOX2 is also an oncogene in several cancer types. Prior work by our group has shown SOX2 activity associates with cell cycle dysregulation in early-stage bladder cancer. The present study was thus undertaken to broadly investigate SOX2 in bladder cancer, with emphasis on associations with tumor stage, clinical outcomes, and tumorigenicity. Gene expression was quantified by immunohistochemistry in an established tissue microarray (n=303 cystectomy specimens, all stages) and whole tissue sections of noninvasive papillary urothelial carcinoma (n=25). Gene expression by RNA sequencing was evaluated in non-muscle invasive and muscle-invasive cohorts from publicly available repositories. By immunohistochemistry, SOX2 was expressed in 40% of whole tissue sections of noninvasive papillary carcinoma, which correlated with SOX2 expression by RNA sequencing (r=0.6, P=0.001, Spearman correlation). Expression tended to be focal (median H-score =6). SOX2 was expressed in only 9% of TMA cases, consistent with focal expression. SOX2 expression was substantially higher in muscle-invasive compared with noninvasive papillary urothelial carcinoma by RNA sequencing (P<0.001, Wilcoxon rank sum test). SOX2 expression associated with stage progression in lamina-propria invasive cancers (hazard ratio =2, P=0.05, Cox model, binary, RNA sequencing) but not noninvasive papillary cancers (P=0.5, Cox model, binary, RNA sequencing). SOX2 expression did not associate with overall survival in muscle-invasive carcinoma. Activity of SOX2 in bladder cancer was tested in vivo using murine allografts created with MB49 cells that express human SOX2 (MB49-SOX). MB49-SOX allografts expressed this protein focally by immunohistochemistry, much like human tumors. Compared with controls, MB49 allografts demonstrated larger tumor size (P=0.03, Wilcoxon rank sum test) and higher tumor burden in mesenteric metastases (P=0.009, Wilcoxon rank sum test). Though SOX2 expression is focal within tumors, it may drive tumorigenesis, increase growth rate, and promote aggressive features of bladder cancer, particularly stage progression of early-stage disease.

Highly Efficient and Scalable p-i-n Perovskite Solar Cells Enabled by Poly-metallocene Interfaces.

Inverted p-i-n perovskite solar cells (PSCs) are easy to process but need improved interface characteristics with reduced energy loss to prevent efficiency drops when increasing the active photovoltaic area. Here, we report a series of poly ferrocenyl molecules that can modulate the perovskite surface enabling the construction of small- and large-area PSCs. We found that the perovskite-ferrocenyl interaction forms a hybrid complex with enhanced surface coordination strength and activated electronic states, leading to lower interfacial nonradiative recombination and charge transport resistance losses. The resulting PSCs achieve an enhanced efficiency of up to 26.08% for small-area devices and 24.51% for large-area devices (1.0208 cm2). Moreover, the large-area PSCs maintain >92% of the initial efficiency after 2000 h of continuous operation at the maximum power point under 1-sun illumination and 65 °C.

Physical pain among urban Native American emerging adults: Socio-cultural risk and protective factors.

OBJECTIVE: American Indian/Alaska Native (AI/AN) people have high rates of physical pain. Pain is understudied in urban-dwelling, AI/AN emerging adults, a group with unique socio-cultural risk and protective factors. We explore associations between socioeconomic disadvantage, additional socio-cultural factors, and pain among urban AI/AN emerging adults. METHODS: AI/AN participants aged 18-25 (N = 417) were recruited via social media. Regression models tested associations between socioeconomic disadvantage (income and ability to afford healthcare) and pain as well as additional socio-cultural factors (discrimination, historical loss, cultural pride and belonging, visiting tribal lands) and pain. Multi-group regression models tested whether associations between socio-cultural factors and pain differed between participants who were socioeconomically disadvantaged and those who were less disadvantaged. RESULTS: In the full sample, lower income (b = 1.00 - 1.48, p < .05), inability to afford healthcare (b = 1.00, p = .011), discrimination (b = 0.12, p = .001), and historical loss (b = 0.24, p = .006) were positively associated with pain, whereas visiting tribal lands was negatively associated with pain (b = -0.86 - -0.42, p < .05). In the multi-group model, visiting tribal lands 31+ days was negatively associated with pain only among the less socioeconomically disadvantaged group (b = -1.48, p < .001). CONCLUSIONS: Socioeconomic disadvantage may, in part, drive pain disparities among AI/AN emerging adults and act as a barrier to benefitting from visiting tribal lands. Results support a biopsychosocial approach to targeting pain in this population, including addressing socioeconomic challenges and developing culturally informed, strengths-based interventions.

Voices of Identity: Exploring Identity Development and Transformation among Urban American Indian/Alaska Native Emerging Adults.

Emerging adulthood shapes personal, professional, and overall well-being through identity exploration. This study addresses a gap in the minority identity literature by investigating how urban AI/AN emerging adults think about their identity and discussing challenges and protective factors associated with exploring their identity holistically. This mixed-methods study created a sampling framework based on discrimination experiences, cultural identity, social network support, mental health, and problematic substance use. We recruited 20 urban AI/AN emerging adults for interviews. We sought to gain deeper insights into their experiences and discussions surrounding identity formation and exploration. We provide descriptives for demographic characteristics and conducted a thematic analysis of the qualitative data from the interviews. Four themes emerged: a) being an urban AI/AN emerging adult means recognizing that one's identity is multifaceted; b) a multifaceted identity comes with tension of living in multiple worlds; c) the trajectory of one's identity grows over time to a deeper desire to connect with Native American culture; and d) understanding one's Native American background affects one's professional trajectory. Findings underscore the importance of developing programs to support well-being and identity development through cultural connection for urban AI/AN emerging adults.

Enhancing sleep health in urban American Indian/Alaska Native adolescents: Implications for culturally tailored interventions.

BACKGROUND: Urban American Indian/Alaska Native (AI/AN) adolescents are vulnerable to sleep and other health-related disparities due to numerous social drivers, including historical trauma and relocation to urban areas. This study aims to identify strategies to increase protective factors and culturally tailor sleep health interventions for this population. METHODS: Using community-based participatory research, the NAYSHAW study conducted in-depth interviews with urban AI/AN adolescents aged 12-19 years to understand critical components needed for developing a culturally sensitive sleep health intervention. Data from two qualitative subsamples (N = 46) and parent surveys (N = 110) were analyzed, focusing on factors that affect sleep health behaviors, including parental involvement, technology, and traditional practices. RESULTS: Key findings include the detrimental impact of electronics use at night and protective effects of traditional practices on sleep. Parental involvement in sleep routines varied by adolescent's age. Adolescents desired sleep health education in interactive formats, whereas parents preferred workshops and digital applications for sleep health strategies. Findings suggest that interventions need to address electronics use and should also be culturally tailored to address the unique experiences of urban AI/AN adolescents. CONCLUSIONS: Results underscore the importance of utilizing community-based strategies to develop culturally tailored sleep interventions for underserved populations, specifically urban AI/AN adolescents. Integrating traditional practices with evidence-based sleep health strategies can provide a holistic approach to improving sleep and overall well-being. Parental education and involvement will be critical to the success of such interventions.

ORMDL mislocalization by impaired autophagy in Niemann-Pick type C disease leads to increased de novo sphingolipid biosynthesis.

Niemann-Pick type C1 (NPC1) disease is a rare neurodegenerative cholesterol and sphingolipid storage disorder primarily due to mutations in the cholesterol-trafficking protein NPC1. In addition to catabolic-derived sphingolipids, NPC1 dysfunction also leads to an increase in de novo sphingolipid biosynthesis, yet little is known about the cellular mechanism involved. Although deletion of NPC1 or inhibition of the NPC1 sterol binding domain enhanced de novo sphingolipid biosynthesis, surprisingly levels of the ORMDLs, the regulatory subunits of serine palmitoyltransferase (SPT), the rate-limiting step in sphingolipid biosynthesis, were also greatly increased. Nevertheless, less ORMDL was bound in the SPT-ORMDL complex despite elevated ceramide levels. Instead, ORMDL colocalized with p62, the selective autophagy receptor, and accumulated in stalled autophagosomes due to defective autophagy in NPC1 disease cells. Restoration of autophagic flux with N-acetyl-L-leucine in NPC1 deleted cells decreased ORMDL accumulation in autophagosomes and reduced de novo sphingolipid biosynthesis and their accumulation. This study revealed a previously unknown link between de novo sphingolipid biosynthesis, ORMDL, and autophagic defects present in NCP1 disease. In addition, we provide further evidence and mechanistic insight for the beneficial role of N-acetyl-L-leucine treatment for NPC1 disease which is presently awaiting approval from the Food and Drug Administration and the European Medicines Agency.

Stress-induced mucin 13 reductions drive intestinal microbiome shifts and despair behaviors.

Depression is a prevalent psychological condition with limited treatment options. While its etiology is multifactorial, both chronic stress and changes in microbiome composition are associated with disease pathology. Stress is known to induce microbiome dysbiosis, defined here as a change in microbial composition associated with a pathological condition. This state of dysbiosis is known to feedback on depressive symptoms. While studies have demonstrated that targeted restoration of the microbiome can alleviate depressive-like symptoms in mice, translating these findings to human patients has proven challenging due to the complexity of the human microbiome. As such, there is an urgent need to identify factors upstream of microbial dysbiosis. Here we investigate the role of mucin 13 as an upstream mediator of microbiome composition changes in the context of stress. Using a model of chronic stress, we show that the glycocalyx protein, mucin 13, is selectively reduced after psychological stress exposure. We further demonstrate that the reduction of Muc13 is mediated by the Hnf4 transcription factor family. Finally, we determine that deleting Muc13 is sufficient to drive microbiome shifts and despair behaviors. These findings shed light on the mechanisms behind stress-induced microbial changes and reveal a novel regulator of mucin 13 expression.

CBCT-DRRs superior to CT-DRRs for target-tracking applications for pancreatic SBRT.

Objective.In current radiograph-based intra-fraction markerless target-tracking, digitally reconstructed radiographs (DRRs) from planning CTs (CT-DRRs) are often used to train deep learning models that extract information from the intra-fraction radiographs acquired during treatment. Traditional DRR algorithms were designed for patient alignment (i.e.bone matching) and may not replicate the radiographic image quality of intra-fraction radiographs at treatment. Hypothetically, generating DRRs from pre-treatment Cone-Beam CTs (CBCT-DRRs) with DRR algorithms incorporating physical modelling of on-board-imagers (OBIs) could improve the similarity between intra-fraction radiographs and DRRs by eliminating inter-fraction variation and reducing image-quality mismatches between radiographs and DRRs. In this study, we test the two hypotheses that intra-fraction radiographs are more similar to CBCT-DRRs than CT-DRRs, and that intra-fraction radiographs are more similar to DRRs from algorithms incorporating physical models of OBI components than DRRs from algorithms omitting these models.Approach.DRRs were generated from CBCT and CT image sets collected from 20 patients undergoing pancreas stereotactic body radiotherapy. CBCT-DRRs and CT-DRRs were generated replicating the treatment position of patients and the OBI geometry during intra-fraction radiograph acquisition. To investigate whether the modelling of physical OBI components influenced radiograph-DRR similarity, four DRR algorithms were applied for the generation of CBCT-DRRs and CT-DRRs, incorporating and omitting different combinations of OBI component models. The four DRR algorithms were: a traditional DRR algorithm, a DRR algorithm with source-spectrum modelling, a DRR algorithm with source-spectrum and detector modelling, and a DRR algorithm with source-spectrum, detector and patient material modelling. Similarity between radiographs and matched DRRs was quantified using Pearson's correlation and Czekanowski's index, calculated on a per-image basis. Distributions of correlations and indexes were compared to test each of the hypotheses. Distribution differences were determined to be statistically significant when Wilcoxon's signed rank test and the Kolmogorov-Smirnov two sample test returnedp≤ 0.05 for both tests.Main results.Intra-fraction radiographs were more similar to CBCT-DRRs than CT-DRRs for both metrics across all algorithms, with allp≤ 0.007. Source-spectrum modelling improved radiograph-DRR similarity for both metrics, with allp< 10-6. OBI detector modelling and patient material modelling did not influence radiograph-DRR similarity for either metric.Significance.Generating DRRs from pre-treatment CBCT-DRRs is feasible, and incorporating CBCT-DRRs into markerless target-tracking methods may promote improved target-tracking accuracies. Incorporating source-spectrum modelling into a treatment planning system's DRR algorithms may reinforce the safe treatment of cancer patients by aiding in patient alignment.

Three-row MRI receive array with remote circuitry to preserve radiation transparency.

Objective.Up to this point, 1.5 T linac-compatible coil array layouts have been restricted to one or two rows of coils because of the desire to place radiation-opaque circuitry adjacent to the coils and outside the window through which the linac beam travels. Such layouts can limit parallel imaging performance. The purpose of this work was to design and build a three-row array in which remotely located circuits permitted a central row of coils while preserving the radiolucent window.Approach.The remote circuits consisted of a phase shifter to cancel the phase introduced by the coaxial link between the circuit and coil, followed by standard components for tuning, matching, detuning, and preamplifier decoupling. Tests were performed to compare prototype single-channel coils with remote or local circuits, which were followed by tests comparing two and three-row arrays .Main results.The single-channel coil with the remote circuit maintained 85% SNR at depths of 30 mm or more as compared to a coil with local circuit. The three-row array provided similar SNR as the two-row array, along with geometry factor advantages for parallel imaging acceleration in the head-foot direction.Significance.The remote circuit strategy could potentially support future MR-linac arrays by allowing greater flexibility in array layout compared to those confined by local circuits, which can be leveraged for parallel imaging acceleration.