Experiences of Stigma and Discrimination Compounded by Intersecting Identities among Individuals Receiving Medication for Opioid Use Disorder.

Stigma and discrimination create barriers to care among people receiving medication for opioid use disorder (MOUD). We report qualitative findings from a mixed methods study guided by three aims: to explore (1) intersecting identities of people receiving MOUD (2) how individuals experience stigma and discrimination and (3) helpful resources in addressing cumulative experiences of multiple forms of disadvantage. We conducted interviews with 25 individuals in three treatment centers in the Northeast United States and identified six themes: (1) Living with multiple socially marginalized identities and addiction; (2) Loss; (3) "It's everywhere": Discrimination and stigma; (4) A "damaged" identity, (5) Positive responses to negative experiences: Facing reality and becoming accountable, and (6) Experiencing treatment and identifying supportive interventions. Findings highlight the complexity of intersecting, marginalized social positions. Future work should look beyond one-size-fits-all approaches to care and recognize individual vulnerabilities and strengths for improving outcomes among those experiencing OUD.

Screen time, sleep, brain structural neurobiology, and sequential associations with child and adolescent psychopathology: Insights from the ABCD study.

Background and Aims: The precise roles of screen media activity (SMA) and sleep problems in relation to child/adolescent psychopathology remain ambiguous. We investigated temporal relationships among sleep problems, SMA, and psychopathology and potential involvement of thalamus-prefrontal-cortex (PFC)-brainstem structural covariation. Methods: This study utilized data from the Adolescent Brain Cognitive Development study (n = 4,641 ages 9-12) at baseline, Year1, and Year2 follow-up. Cross-Lagged Panel Models (CLPMs) investigated reciprocal predictive relationships between sleep duration/problems, SMA, and psychopathology symptoms. A potential mediating role of baseline Thalamus-PFC-brainstem covariation on SMA-externalizing relationships was examined. Results: Participants were divided into discovery (n = 2,359, 1,054 girls) and replication (n = 2,282, 997 girls) sets. CLPMs showed 1) bidirectional associations between sleep duration and SMA in late childhood, with higher frequency SMA predicting shorter sleep duration (ß = -0.10 [95%CI: -0.16, -0.03], p = 0.004) and vice versa (ß = -0.11 [95%CI: -0.18, -0.05], p < 0.001); 2) externalizing symptoms at age 10-11 predicting sleep problems (ß = 0.11 [95%CI: 0.04, 0.19], p = 0.002), SMA (ß = 0.07 [95%CI: 0.01, 0.13], p = 0.014), and internalizing symptoms (ß = 0.09 [95%CI: 0.05, 0.13], p < 0.001) at age 11-12; and 3) externalizing behavior at age 10-11 partially mediating the relationship between baseline thalamus-PFC-brainstem covariation and SMA at age 11-12 (indirect effect = 0.032 [95%CI: 0.003, 0.067], p-value = 0.030). Findings were replicable. Conclusion: We found bi-directional SMA-sleep-duration associations in late childhood. Externalizing symptoms preceded future SMA and sleep disturbances and partially mediated relationships between structural brain covariation and SMA. The findings emphasize the need for understanding individual differences and developing and implementing integrated strategies addressing both sleep concerns and screen time to mitigate potential impacts on psychopathology.

Vitamin D receptor gene polymorphism in Egyptian multiple sclerosis patients.

One of the most common neurological illnesses in the world is multiple sclerosis (MS), a chronic autoimmune demyelinating disease of the central nervous system (CNS). MS has both a genetic and an environmental origin. In terms of environmental factors, vitamin D deficiency is one of the most important risk factors and closely connected with gene polymorphisms involved in vitamin D metabolism, transport, or activity. Since vitamin D activity requires a receptor-mediated response, any changes to the vitamin D receptor (VDR) may have an effect on the pathophysiology of the disease. In this study, we aimed to identify the relationship between VDR gene polymorphisms, FokI A>G (rs2228570), ApaI A>C (rs7975232) and BsmI C>T (rs1544410) and MS. FokI, ApaI and BsmI genotypes were determined in 50 patients with relapsing remitting MS (RRMS) and in 50 control subjects. DNA was isolated from blood samples, and then FokI, ApaI and BsmI gene polymorphisms were identified using allelic discrimination real time polymerase chain reaction (PCR) assay. The distribution of FokI, ApaI and BsmI polymorphisms did not show any significant differences between MS patients and controls. Thus, we concluded that there is no association between the studied VDR gene polymorphisms and MS.

First-Line Respiratory Support for Children With Hematologic Malignancy and Acute Respiratory Failure.

OBJECTIVES: To characterize trends in noninvasive ventilation (NIV) and invasive mechanical ventilation (IMV) use over time in children with hematologic malignancy admitted to the PICU with acute respiratory failure (ARF), and to identify risk factors associated with NIV failure requiring transition to IMV. DESIGN: Retrospective cohort analysis using the Virtual Pediatric Systems (VPS, LLC) between January 1, 2010 and December 31, 2019. SETTING: One hundred thirteen North American PICUs participating in VPS. PATIENTS: Two thousand four hundred eighty children 0-21 years old with hematologic malignancy admitted to participating PICUs for ARF requiring respiratory support. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were 3013 total encounters, of which 868 (28.8%) received first-line NIV alone (NIV only), 1544 (51.2%) received first-line IMV (IMV only), and 601 (19.9%) required IMV after a failed NIV trial (NIV failure). From 2010 to 2019, the NIV only group increased from 9.6% to 43.1% and the IMV only group decreased from 80.1% to 34.2% (p < 0.001). The NIV failure group had the highest mortality compared with NIV only and IMV only (36.6% vs. 8.1%, vs. 30.5%, p < 0.001). However, risk-of-mortality (ROM) was highest in the IMV only group compared with NIV only and NIV failure (median Pediatric Risk of Mortality III ROM 8.1% vs. 2.8% vs. 5.5%, p < 0.001). NIV failure patients also had the longest median PICU length of stay compared with the other two study groups (15.2 d vs. 6.1 and 9.0 d, p < 0.001). Higher age was associated with significantly decreased odds of NIV failure, and diagnosis of non-Hodgkin lymphoma was associated with significantly increased odds of NIV failure compared with acute lymphoid leukemia. CONCLUSIONS: For children with hematologic malignancy admitted to the PICU with ARF, NIV has replaced IMV as the most common initial therapy. NIV failure rate remains high with high-observed mortality despite lower PICU admission ROM.

Variation in Specialist Palliative Care Reach and Associated Factors Among People With Advanced Heart Failure in the Department of Veterans Affairs.

CONTEXT: Clinical practice guidelines recommend palliative care for people with advanced heart failure (aHF), yet it remains underutilized. OBJECTIVES: We examined medical center variation in specialist palliative care (SPC) and identified factors associated with variation among people with aHF. METHODS: We conducted a retrospective cohort study of 21,654 people with aHF who received healthcare in 83 Veterans Affairs Medical Centers (VAMCs) from 2018-2020. We defined aHF with ICD-9/10 codes and hospitalizations. We used random intercept multilevel logistic regression to derive SPC reach (i.e., predicted probability) for each VAMC adjusting for demographic and clinical characteristics. We then examined VAMC-level SPC delivery characteristics associated with predicted SPC reach including the availability of outpatient SPC (proportion of outpatient consultations), cardiology involvement (number of outpatient cardiology-initiated referrals), and earlier SPC (days from aHF identification to consultation). RESULTS: Of the sample the mean age = 72.9+/-10.9 years, 97.9% were male, 61.6% were White, and 32.2% were Black. The predicted SPC reach varied substantially across VAMCs from 9% to 57% (mean: 28% [95% Confidence Interval: 25%-30%]). Only the availability of outpatient SPC was independently associated with higher SPC reach. VAMCs, in which outpatient delivery made up the greatest share of SPC consultations (9% or higher) had 11% higher rates of SPC reach relative to VAMCs with a lower proportion of outpatient SPC. CONCLUSION: SPC reach varies widely across VAMCs for people with aHF. Outpatient palliative is common among high-reach VAMCs but its role in reach warrants further investigation. Strategies used by high-reach VAMCs may be potential targets to test for implementation and dissemination.

Effect of Positive Deviance Approach on Promotion of Safe Disposal of Child's Feces in Rural Tamil Nadu: A Community-Based Quasi-Experimental Study.

Introduction: Safe disposal of feces is ensured when it is deposited into a toilet, whereas unsafe disposal of child's feces plays a crucial role in disease transmission and environmental pollution. These areas are overlooked by many sanitation promotion interventions. Objective: To determine the effect of positive deviance (PD) approach on safe disposal of child's feces among households who owned a toilet. Materials and Methods: A community-based quasi-experimental study was conducted in the four field practice villages of the Urban Health Training Center, Villupuram, for 18 months. Households who owned a toilet and had a child less than 5 years old were included. After IEC clearance, information was collected from a representative sample of 100 households before intervention and another 100 households after intervention. PD approach was applied for 6 months to promote safe disposal practices in the study villages. Data were analyzed using the Statistical Package for the Social Sciences (SPSS) software (version 24). The Chi-square test was used to determine the significance of difference between baseline and endline data. The effect size was calculated to estimate the magnitude of difference between baseline and endline data. Results: Before intervention, only 3% of households disposed the feces into a toilet, while after intervention, almost 38% of households disposed in the toilet (χ2 = 37.39; df = 1; P = 0.001). The effect size (Cramer's V) was found to be 0.43. Conclusion: PD approach demonstrated considerable improvements in safe disposal of child's feces in rural settings. Further, to sustain the behavior change, frequent reinforcement of key messages at frequent intervals needs to be emphasized.

Impact of external female urinary catheter use on urine chemistry test results.

BACKGROUND: We aimed to evaluate how urine chemistry tests are impacted by collection using a female external urinary catheter employing wicking and suction, to assess this catheter's potential as an alternative to transurethral catheters for collecting urine samples from incontinent patients. METHODS: We obtained 50 random 40 mL refrigerated urine specimens from excess volume submitted to the Michigan Medicine Biochemical Laboratory. Specimens were split into a 10 mL "control" sample simulating voided urine, and a 30 mL paired "wicked" sample applied dropwise to and collected from a fresh PureWick system simulating collection from an incontinent patient. Each sample pair was tested for glucose, sodium, potassium, creatinine, urea, total protein, and derived ratios of sodium/creatinine, urea/creatinine, and protein/creatinine, then compared using Pearson correlation coefficients. Wicking materials were imaged via absorption contrast tomography on a laboratory X-ray microscope, to study the structure through which urine passes. RESULTS: Control and wicked urine samples had very similar results for all chemical tests evaluated: strong Pearson correlation coefficients ranging from 0.955 (potassium) to 0.997 (glucose). Microscopic assessment of the amorphous wicking materials demonstrated an average pore spacing of 95.38 µm. CONCLUSIONS: Common urine chemistry tests were unaltered by collection using the PureWick female external catheter system. This external device can be used to collect urine for chemistry tests as an alternative to transurethral catheters.

Investigating brain dynamics and their association with cognitive control in opioid use disorder using naturalistic and drug cue paradigms.

Objectives: Opioid use disorder (OUD) impacts millions of people worldwide. The prevalence and debilitating effects of OUD present a pressing need to understand its neural mechanisms to provide more targeted interventions. Prior studies have linked altered functioning in large-scale brain networks with clinical symptoms and outcomes in OUD. However, these investigations often do not consider how brain responses change over time. Time-varying brain network engagement can convey clinically relevant information not captured by static brain measures. Methods: We investigated brain dynamic alterations in individuals with OUD by applying a new multivariate computational framework to movie-watching (i.e., naturalistic; N=76) and task-based (N=70) fMRI. We further probed the associations between cognitive control and brain dynamics during a separate drug cue paradigm in individuals with OUD. Results: Compared to healthy controls (N=97), individuals with OUD showed decreased variability in the engagement of recurring brain states during movie-watching. We also found that worse cognitive control was linked to decreased variability during the rest period when no opioid-related stimuli were present. Conclusions: These findings suggest that individuals with OUD may experience greater difficulty in effectively engaging brain networks in response to evolving internal or external demands. Such inflexibility may contribute to aberrant response inhibition and biased attention toward opioid-related stimuli, two hallmark characteristics of OUD. By incorporating temporal information, the current study introduces novel information about how brain dynamics are altered in individuals with OUD and their behavioral implications.

Determining the cost and cost-effectiveness of childhood cancer treatment in Haiti.

Haiti is a low-income country with one of the lowest human development index rankings in the world. Its childhood cancer services are provided by a single hospital with the only dedicated paediatric oncology department in the country. Our objective was to assess the cost and cost-effectiveness of all types of childhood cancer in Haiti to help prioritise investments and to support national cancer control planning. All costing data were collected from the year 2017 or 2018 hospital records. Costs were classified into 11 cost categories, and the proportion of the overall budget represented by each was calculated and converted from Haitian Gourde to United States dollars. The 5-year survival rate was retrieved from hospital records and used to calculate the cost-effectiveness of disability-adjusted life year (DALY) averted, using a healthcare costing perspective. Additional sensitivity analyses were conducted accounting for late-effect morbidity and early mortality and discounting rates of 0%, 3% and 6%. The annual cost of operating a paediatric oncology unit in Haiti treating 74 patients with newly diagnosed cancer was $803,184 overall or $10,854 per patient. The largest cost category was pharmacy, constituting 25% of the overall budget, followed by medical personnel (20%) and administration (12%). The cost per DALY averted in the base-case scenario was $1,128, which is 76% of the gross domestic product per capita, demonstrating that treating children with cancer in Haiti is very cost-effective according to the World Health Organisation Choosing Interventions that are Cost-Effective (WHO-CHOICE) threshold. In the most conservative scenario, the cost per DALY averted was cost-effective by WHO-CHOICE criteria. Our data will add to the growing body of literature illustrating a positive return on investment associated with diagnosing and treating children with cancer in even the most resource-limited environments. We anticipate that these data will aid local stakeholders and policymakers when identifying cancer control priorities and making budgetary decisions.

Levels of procoagulant factors and peak thrombin generation in relation to dementia risk in older adults: The Cardiovascular Health Study.

INTRODUCTION: Markers of hemostasis such as procoagulant factors and peak thrombin generation are associated with cardiovascular outcomes, but their associations with dementia risk are unclear. We aimed to evaluate prospective associations of selected procoagulant factors and peak thrombin generation with dementia risk. METHODS: We measured levels of 7 hemostatic factors (fibrinogen, factor VII coagulant activity [FVIIc], activated factor VII [FVIIa], factor VIIa-antithrombin [FVIIa-AT], factor XI antigen [FXI], peak thrombin generation, and platelet count) among participants in the Cardiovascular Health Study, a cohort of older adults free of dementia in 1992/1993 (n = 3185). Dementia was adjudicated and classified by DSM-IV criteria through 1998/1999. Cox proportional hazards models estimated hazard ratios (HRs) for any dementia associated with 1-standard deviation (SD) differences, adjusting for sociodemographic and clinical factors and APOE genotype. Secondary analyses separately evaluated the risk of vascular dementia, Alzheimer's disease, and mixed dementia. RESULTS: At baseline, participants had a median age of 73 years. Over 5.4 years of follow-up, we identified 448 dementia cases. There was no evidence of linear associations between levels of these hemostatic factors with any dementia risk (HRs per 1-SD difference ranged from 1.0 to 1.1; 95 % confidence intervals included 1.0). Results of secondary analyses by dementia subtype were similar. CONCLUSIONS: In this prospective study, there was no strong evidence of linear associations between levels of fibrinogen, FVIIc, FVIIa, FVIIa-AT, FXI, peak thrombin generation, or platelet count with dementia risk. Despite their associations with cardiovascular disease, higher levels of these biomarkers measured among older adults may not reflect dementia risk.

Hydroxyurea Adherence for Personal Best in Sickle Cell Treatment (HABIT) efficacy trial: Community health worker support may increase hydroxyurea adherence of youth with sickle cell disease.

Despite disease-modifying effects of hydroxyurea on sickle cell disease (SCD), poor adherence among affected youth commonly impedes treatment impact. Following our prior feasibility trial, the "Hydroxyurea Adherence for Personal Best in Sickle Cell Treatment (HABIT)" multi-site randomized controlled efficacy trial aimed to increase hydroxyurea adherence for youth with SCD ages 10-18 years. Impaired adherence was identified primarily through flagging hydroxyurea-induced fetal hemoglobin (HbF) levels compared to prior highest treatment-related HbF. Eligible youth were enrolled as dyads with their primary caregivers for the 1-year trial. This novel semi-structured supportive, multidimensional dyad intervention led by community health workers (CHW), was augmented by daily tailored text message reminders, compared to standard care during a 6-month intervention phase, followed by a 6-month sustainability phase. Primary outcomes from the intervention phase were improved Month 6 HbF levels compared to enrollment and proportion of days covered (PDC) for hydroxyurea versus pre-trial year. The secondary outcome was sustainability of changes up to Month 12. The 2020-2021 peak coronavirus disease 2019 (COVID-19) pandemic disrupted enrollment and clinic-based procedures; CHW in-person visits shifted to virtual scheduled interactions. We enrolled 50 dyads, missing target enrollment. Compared to enrollment levels, both HbF level and PDC significantly - but not sustainably - improved within the intervention group (p = .03 and .01, respectively) with parallel increased mean corpuscular volume (MCV) (p = .05), but not within controls. No significant between-group differences were found at Months 6 or 12. These findings suggest that our community-based, multimodal support for youth-caregiver dyads had temporarily improved hydroxyurea usage. Durability of impact should be tested in a trial with longer duration of CHW-led and mobile health support.

Digital Humans to Combat Loneliness and Social Isolation: Ethics Concerns and Policy Recommendations.

Social isolation and loneliness are growing concerns around the globe that put people at increased risk of disease and early death. One much-touted approach to addressing them is deploying artificially intelligent agents to serve as companions for socially isolated and lonely people. Focusing on digital humans, we consider evidence and ethical arguments for and against this approach. We set forth and defend public health policies that respond to concerns about replacing humans, establishing inferior relationships, algorithmic bias, distributive justice, and data privacy.

Monitoring of Fabric Integrity and Attrition Rate of Dual-Active Ingredient Long-Lasting Insecticidal Nets in Tanzania: A Prospective Cohort Study Nested in a Cluster Randomized Controlled Trial.

Pyrethroid-treated long-lasting insecticidal nets (LLINs) have been the main contributor to the reduction in malaria in the past two decades in sub-Saharan Africa. The development of pyrethroid insecticide resistance threatens the future of LLINs, especially when nets become holed and pyrethroid decays. In this study, three new classes of dual-active ingredient (AI) LLINs were evaluated for their physical durability: (1) Royal Guard, combining pyriproxyfen, which disrupts female fertility, and a pyrethroid, alpha-cypermethrin; (2) Interceptor G2, which combines the pyrrole chlorfenapyr and a pyrethroid (alpha-cypermethrin); (3) Olyset Plus, which incorporates the pyrethroid permethrin and the synergist piperonyl butoxide, to enhance the pyrethroid potency; and Interceptor, a reference net that contains alpha-cypermethrin as the sole active ingredient. About 40,000 nets of each type were distributed in February 2019 to different villages in Misungwi. A total of 3072 LLINs were followed up every 6-12 months up to 36 months to assess survivorship and fabric integrity. The median functional survival was less than three years with Interceptor, Interceptor G2, and Royal Guard showing 1.9 years each and Olyset Plus showing 0.9 years. After 36 months, 90% of Olyset Plus and Royal Guard and 87% of Interceptor G2 were no longer in use (discarded) due to wear and tear, compared to 79% for Interceptor. All dual-AI LLINs exhibited poor textile durability, with Olyset Plus being the worst.

Ameliorative effects of vanillin against pentylenetetrazole-induced epilepsy and associated memory loss in mice: The role of Nrf2/HO-1/NQO1 and HMGB1/RAGE/TLR4/NFκB pathways.

BACKGROUND: Epilepsy is a severe neurological disorder associated with substantial morbidity and mortality. Vanillin (Van) is a natural phenolic aldehyde with beneficial pharmacological properties. This study investigated the neuroprotective effects of Van in epilepsy and elucidated its mechanism of action. METHODS: Swiss albino mice were divided into the following five groups: "normal group", 0.9 % saline; "pentylenetetrazole (PTZ) group", intraperitoneal administration of 35 mg/kg PTZ on alternate days up to 42 days; and "PTZ + Van 20", "PTZ + Van 40", and "PTZ + sodium valproate (Val)" groups received PTZ injections in conjunction withVan 20 mg, Van 40 mg/kg, and Val 300 mg/kg, respectively. Behavioural tests and hippocampal histopathological analysis were performed in all groups. The Nrf2/HO-1/NQO1 and HMGB1/RAGE/TLR4/NFκB pathways, oxidative stress, neuro-inflammation, and apoptotic markers were analysed. Furthermore, brain acetylcholinesterase (AChE) activity and levels of dopamine (DA), gamma-aminobutyric acid GABA, and serotonin 5-HT were assessed. RESULTS: Van prolonged seizure manifestations and improved electroencephalogram (EEG)criteriain conjunction with 100 mg/kg PTZ once daily. Van administration increased Nrf2/HO-1/NQO1 levels, with subsequent attenuation of malondialdehyde (MDA) and nitric oxide (NO) levels with elevated glutathione (GSH) levels and intensified superoxide dismutase (SOD) and catalase activities. Van reduced the gene and protein expression of HMGB1/RAGE/TLR4/NFκB and decreased the levels of inflammatory and apoptotic markers. In addition, Van reduced AChE activity, and elevated glial fibrillary acidic proteins (GFAP) increased neurotransmitter and brain-derived neurotrophic factors (BDNF). CONCLUSION: By increasing Nrf2/HO-1/NQO1 levels and downregulating the HMGB1/RAGE/TLR4/ NFκB pathway, Van offered protection in PTZ-kindled mice with subsequent attenuation in lipid peroxidation, upregulation in antioxidant enzyme activities, and reduction in inflammation and apoptosis.

Discovery and Characterization of Selective, First-in-Class Inhibitors of Citron Kinase.

Citron kinase (CITK) is an AGC-family serine/threonine kinase that regulates cytokinesis. Despite knockdown experiments implicating CITK as an anticancer target, no selective CITK inhibitors exist. We transformed a previously reported kinase inhibitor with weak off-target CITK activity into a first-in-class CITK chemical probe, C3TD879. C3TD879 is a Type I kinase inhibitor which potently inhibits CITK catalytic activity (biochemical IC50 = 12 nM), binds directly to full-length human CITK in cells (NanoBRET Kd < 10 nM), and demonstrates favorable DMPK properties for in vivo evaluation. We engineered exquisite selectivity for CITK (>17-fold versus 373 other human kinases), making C3TD879 the first chemical probe suitable for interrogating the complex biology of CITK. Our small-molecule CITK inhibitors could not phenocopy the effects of CITK knockdown in cell proliferation, cell cycle progression, or cytokinesis assays, providing preliminary evidence that the structural roles of CITK may be more important than its kinase activity.