Estimating the potential value of MSM-focused evidence-based implementation interventions in three Ending the HIV Epidemic jurisdictions in the United States: a model-based analysis.

INTRODUCTION: Improving the delivery of existing evidence-based interventions to prevent and diagnose HIV is key to Ending the HIV Epidemic in the United States. Structural barriers in the access and delivery of related health services require municipal or state-level policy changes; however, suboptimal implementation can be addressed directly through interventions designed to improve the reach, effectiveness, adoption or maintenance of available interventions. Our objective was to estimate the cost-effectiveness and potential epidemiological impact of six real-world implementation interventions designed to address these barriers and increase the scale of delivery of interventions for HIV testing and pre-exposure prophylaxis (PrEP) in three US metropolitan areas. METHODS: We used a dynamic HIV transmission model calibrated to replicate HIV microepidemics in Atlanta, Los Angeles (LA) and Miami. We identified six implementation interventions designed to improve HIV testing uptake ("Academic detailing for HIV testing," "CyBER/testing," "All About Me") and PrEP uptake/persistence ("Project SLIP," "PrEPmate," "PrEP patient navigation"). Our comparator scenario reflected a scale-up of interventions with no additional efforts to mitigate implementation and structural barriers. We accounted for potential heterogeneity in population-level effectiveness across jurisdictions. We sustained implementation interventions over a 10-year period and evaluated HIV acquisitions averted, costs, quality-adjusted life years and incremental cost-effectiveness ratios over a 20-year time horizon (2023-2042). RESULTS: Across jurisdictions, implementation interventions to improve the scale of HIV testing were most cost-effective in Atlanta and LA (CyBER/testing cost-saving and All About Me cost-effective), while interventions for PrEP were most cost-effective in Miami (two of three were cost-saving). We estimated that the most impactful HIV testing intervention, CyBER/testing, was projected to avert 111 (95% credible interval: 110-111), 230 (228-233) and 101 (101-103) acquisitions over 20 years in Atlanta, LA and Miami, respectively. The most impactful implementation intervention to improve PrEP engagement, PrEPmate, averted an estimated 936 (929-943), 860 (853-867) and 2152 (2127-2178) acquisitions over 20 years, in Atlanta, LA and Miami, respectively. CONCLUSIONS: Our results highlight the potential impact of interventions to enhance the implementation of existing evidence-based interventions for the prevention and diagnosis of HIV.

Ending the HIV Epidemic in Metropolitan Atlanta: a mixed-methods study to support the local HIV/AIDS response.

INTRODUCTION: Four counties within the Atlanta, Georgia 20-county eligible metropolitan area (EMA) are currently prioritized by the US "Ending the HIV Epidemic" (EHE) initiative which aims for a 90% reduction in HIV incidence by 2030. Disparities driving Atlanta's HIV epidemic warrant an examination of local service availability, unmet needs and organizational capacity to reach EHE targets. We conducted a mixed-methods evaluation of the Atlanta EMA to examine geographic HIV epidemiology and distribution of services, service needs and organization infrastructure for each pillar of the EHE initiative. METHODS: We collected 2021 county-level data (during June 2022), from multiple sources including: AIDSVu (HIV prevalence and new diagnoses), the Centers for Disease Control and Prevention web-based tools (HIV testing and pre-exposure prophylaxis [PrEP] locations) and the Georgia Department of Public Health (HIV testing, PrEP screenings, viral suppression and partner service interviews). We additionally distributed an online survey to key local stakeholders working at major HIV care agencies across the EMA to assess the availability of services, unmet needs and organization infrastructure (June-December 2022). The Organizational Readiness for Implementing Change questionnaire assessed the organization climate for services in need of scale-up or implementation. RESULTS: We found racial/ethnic and geographic disparities in HIV disease burden and service availability across the EMA-particularly for HIV testing and PrEP in the EMA's southern counties. Five counties not currently prioritized by EHE (Clayton, Douglas, Henry, Newton and Rockdale) accounted for 16% of the EMA's new diagnoses, but <9% of its 177 testing sites and <7% of its 130 PrEP sites. Survey respondents (N = 48; 42% health agency managers/directors) reported high unmet need for HIV self-testing kits, mobile clinic testing, HIV case management, peer outreach and navigation, integrated care, housing support and transportation services. Respondents highlighted insufficient existing staffing and infrastructure to facilitate the necessary expansion of services, and the need to reduce inequities and address intersectional stigma. CONCLUSIONS: Service delivery across all EHE pillars must substantially expand to reach national goals and address HIV disparities in metro Atlanta. High-resolution geographic data on HIV epidemiology and service delivery with community input can provide targeted guidance to support local EHE efforts.

Sustainable chitosan-based materials as heterogeneous catalyst for application in wastewater treatment and water purification: An up-to-date review.

Water pollution is one of serious environmental issues due to the rapid development of industrial and agricultural sectors, and clean water resources have been receiving increasing attention. Recently, more and more studies have witnessed significant development of catalysts (metal oxides, metal sulfides, metal-organic frameworks, zero-valent metal, etc.) for wastewater treatment and water purification. Sustainable and clean catalysts immobilized into chitosan-based materials (Cat@CSbMs) are considered one of the most appealing subclasses of functional materials due to their high catalytic activity, high adsorption capacities, non-toxicity and relative stability. This review provides a summary of various upgrading renewable Cat@CSbMs (such as cocatalyst, photocatalyst, and Fenton-like reagent, etc.). As for engineering applications, further researches of Cat@CSbMs should focus on treating complex wastewater containing both heavy metals and organic pollutants, as well as developing continuous flow treatment methods for industrial wastewater using Cat@CSbMs. In conclusion, this review abridges the gap between different approaches for upgrading renewable and clean Cat@CSbMs and their future applications. This will contribute to the development of cleaner and sustainable Cat@CSbMs for wastewater treatment and water purification.

Missouri's Overdose Field Report: descriptive analysis, survival trends, and naloxone dosing patterns from a community-based survey tool, 2018-2022.

Background: Missouri's Overdose Field Report (ODFR) is a community-based reporting system which intends to capture overdoses which may not be otherwise recorded.Objectives: Describe the factors related to non-fatal overdoses reported to Missouri's ODFR.Methods: This study used a descriptive epidemiological approach to examine the demographics and circumstances of overdoses reported to the ODFR. We used binary logistic regression to evaluate factors associated with survival and ordinal logistic regression to evaluate factors associated with number of doses used. Factors were chosen based on their relevance to overdose education and survival, and naloxone distribution.Results: Between 2018 and 2022, 12,225 overdoses (67% male; 78% White) were reported through the ODFR, with a 96% (n = 11,225) survival rate. Overdose survival (ps < .02) was associated with younger age (OR = .58), no opioid and stimulant co-involvement (OR = .61), and private location (OR = .48). Intramuscular naloxone in particular was associated with a significantly higher odds of survival compared to nasal naloxone (OR = 2.11). An average of 1.6 doses of naloxone per incident were administered. Additional doses were associated (ps < .02) with being older (OR = .45), female (OR = .90), nasal naloxone (versus intravenous) (OR = .65), and the belief fentanyl was present (OR = 1.49).Conclusion: Our reporting form provides a comprehensive picture of the events surrounding reported overdoses, including factors associated with survival, how much naloxone was used, and the effects of respondents believing fentanyl was involved. Missouri's report can provide support for current naloxone dosing, contextualize refusing post-overdose transport, and can be used to improve overdose response by community and first responders.

Etiological Mechanisms and Genetic/Biological Modulation Related to PTH1R in Primary Failure of Tooth Eruption.

Primary failure of eruption (PFE) is a rare disorder that is characterized by the inability of a molar tooth/teeth to erupt to the occlusal plane or to normally react to orthodontic force. This condition is related to hereditary factors and has been extensively researched over many years. However, the etiological mechanisms of pathogenesis are still not fully understood. Evidence from studies on PFE cases has shown that PFE patients may carry parathyroid hormone 1 receptor (PTH1R) gene mutations, and genetic detection can be used to diagnose PFE at an early stage. PTH1R variants can lead to altered protein structure, impaired protein function, and abnormal biological activities of the cells, which may ultimately impact the behavior of teeth, as observed in PFE. Dental follicle cells play a critical role in tooth eruption and root development and are regulated by parathyroid hormone-related peptide (PTHrP)-PTH1R signaling in their differentiation and other activities. PTHrP-PTH1R signaling also regulates the activity of osteoblasts, osteoclasts and odontoclasts during tooth development and eruption. When interference occurs in the PTHrP-PTH1R signaling pathway, the normal function of dental follicles and bone remodeling are impaired. This review provides an overview of PTH1R variants and their correlation with PFE, and highlights that a disruption of PTHrP-PTH1R signaling impairs the normal process of tooth development and eruption, thus providing insight into the underlying mechanisms related to PTH1R and its role in driving PFE.

Inclisiran administration potently and durably lowers LDL-C over an extended-term follow-up: the ORION-8 trial.

BACKGROUND AND AIMS: Data describing the long-term efficacy, safety, and tolerability of inclisiran are limited. This was explored in ORION-8, an open-label extension study of preceding Phase 2 and Phase 3 placebo-controlled and open-label extension trials. METHODS: Adults with ASCVD, ASCVD risk equivalent, or HeFH received open-label inclisiran every 180 days (after completion of the parent trial) until Day 990, followed by an end-of-study (EOS) visit at Day 1080 or ≥90 days after last dose. Study endpoints included proportion of patients achieving pre-specified LDL-C goals (ASCVD: <1.8 mmol/L [<70 mg/dL]; ASCVD risk equivalent: <2.6 mmol/L [<100 mg/dL]), percentage and absolute changes in LDL-C at EOS, and safety of inclisiran. RESULTS: Of 3274 patients included in the analysis, 2446 (74.7%) were followed until EOS. Mean age was 64.9±9.9 years, 82.7% (n=2709) had ASCVD, and mean baseline LDL-C was 2.9±1.2 mmol/L. Mean cumulative exposure to inclisiran (including parent trials) was 3.7 years; maximum exposure was 6.8 years. With inclisiran, 78.4% (95% CI: 76.8, 80.0) of patients achieved pre-specified LDL-C goals and mean percentage LDL-C reduction was -49.4% (95% CI: -50.4, -48.3). No attenuation of LDL-C lowering over time was observed. Treatment-emergent adverse events at the injection site (all mild or moderate) occurred in 5.9% of inclisiran-treated patients. Inclisiran-associated anti-drug antibodies were infrequent (5.5%) and had no impact on the efficacy or safety of inclisiran. No new safety signals were identified. CONCLUSIONS: In the largest and longest follow-up to date, inclisiran demonstrated sustained and substantial LDL-C lowering with a favourable long-term safety and tolerability profile. ClinicalTrials.gov identifier: NCT03814187.

Evaluation of Strategies to Enhance Community-Based Naloxone Distribution Supported by an Opioid Settlement.

Importance: Many US states are substantially increasing community-based naloxone distribution, supported in part through settlements from opioid manufacturers and distributors. Objectives: To evaluate the potential impact of increased naloxone availability on opioid overdose deaths (OODs) and explore strategies to enhance this impact by integrating interventions to address solitary drug use. Design, Setting, and Participants: This decision analytical modeling study used PROFOUND (Prevention and Rescue of Fentanyl and Other Opioid Overdoses Using Optimized Naloxone Distribution Strategies), a previously published simulation model, to forecast annual OODs between January 2023 and December 2025. The simulated study population included individuals from Rhode Island who misused opioids and stimulants and were at risk for opioid overdose. Exposures: The study modeled expanded naloxone distribution supported by the state's opioid settlement (50 000 naloxone nasal spray kits each year). Two approaches to expanding naloxone distribution were evaluated: one based on historical spatial patterns of naloxone distribution (supply-based approach) and one based on the spatial distribution of individuals at risk (demand-based approach). In addition, hypothetical interventions to enhance the likelihood of witnessed overdoses in private or semiprivate settings were considered. Main Outcomes and Measures: Annual number of OODs and ratio of fatal to nonfatal opioid overdoses. Results: Modeling results indicated that distributing more naloxone supported by the state's opioid settlement could reduce OODs by 6.3% (95% simulation interval [SI], 0.3%-13.7%) and 8.8% (95% SI, 1.8%-17.5%) in 2025 with the supply-based and demand-based approaches, respectively. However, increasing witnessed overdoses by 20% to 60% demonstrated greater potential for reducing OODs, ranging from 8.5% (95% SI, 0.0%-20.3%) to 24.1% (95% SI, 8.6%-39.3%). Notably, synergistic associations were observed when combining both interventions: increased naloxone distribution with the 2 approaches and a 60% increase in witnessed overdoses could reduce OODs in 2025 by 33.5% (95% SI, 17.1%-50.4%) and 37.4% (95% SI, 19.6%-56.3%), respectively. Conclusions and Relevance: These findings suggest that interventions to address solitary drug use are needed to maximize the impact of continued efforts to increase community-based naloxone distribution, which may be particularly important for jurisdictions that have strong community-based naloxone distribution programs.

The association between naloxone claims and proportion of independent vs. chain pharmacies: A longitudinal analysis of naloxone claims in the US.

BACKGROUND: Expanding access to naloxone through pharmacies is an important policy goal. Our objective was to characterize national county-level naloxone dispensing of chain versus independent pharmacies. METHODS: The primary exposure in our longitudinal analysis was the proportion of chain pharmacies in a county, identified through the US Department of Homeland Security 2010 Infrastructure Foundation-Level Data. We defined counties as having "higher proportion" of chain pharmacies if at least 50% of pharmacies were large national chains. The primary outcome was quarter-year (2016Q1-2019Q2) rate of pharmacy naloxone claims per 100,000 persons from Symphony Health at the county-level. We compared the naloxone dispensing rate between county types using two-sample t-tests. We estimated the association between county-level chain pharmacy proportion and rate of naloxone claims using a linear model with year-quarter fixed effects. RESULTS: Nearly one third of counties (n=946) were higher proportion. Higher proportion counties had a significantly higher rate of naloxone claims across the study period, in 4 of 6 urban-rural classifications, and in counties with and without naloxone access laws. The linear model confirmed that higher proportion counties had a significantly higher rate of naloxone claims, adjusting for urban/rural designation, income, population characteristics, opioid mortality rate, co-prescribing laws and naloxone access laws. CONCLUSION: In this national study, we found an association between naloxone dispensing rates and the county-level proportion of chain (versus independent) pharmacies. Incentivizing naloxone dispensing through educational, regulatory, or legal efforts may improve naloxone availability and dispensing rates - particularly in counties with proportionately high numbers of independent pharmacies.

Cell-excreted proteins mediate the interactions of differently sized silica nanoparticles during cellular uptake.

Exposure to different types of nanoparticles (NPs) results in their deposition in human bodies. While most studies have examined the cellular uptake of only one type of NP at a time, how the dynamics of NP uptake may change in the presence of other types of NPs remains unclear. We therefore investigated the interplay of two differently sized SiO2 NPs during their uptake by A549 human lung carcinoma cells. Both NPs contained a CdSeTe core, which was labeled with different Cd isotopes to differentiate between them. Our study showed that the uptake of one size of SiO2 NPs either increased or decreased with the concentration of the other size of SiO2 NPs. This variation in uptake was attributable to the concentration-dependent aggregation of SiO2 NPs, as determined by the amount of cell-excreted proteins adsorbed on the NP surface. Further, the effects of the protein corona on the attachment of SiO2 NPs to the cell surface and uptake competition between differently sized SiO2 NPs also played important roles. Cell-excreted proteins were then analyzed by proteomics. Overall, the complex interactions between coexisting NPs of different physicochemical properties and cell-excreted proteins should be considered during bio-applications and bio-safety evaluations of NPs.

Low-dose venetoclax combined with azacitidine for blastic plasmacytoid dendritic cell neoplasm: a case report and literature review.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy that is highly aggressive with a poor prognosis. There is no standard treatment for BPDCN. Although conventional chemotherapies are usually sensitive in the initial therapy, relapse and drug resistance are inevitable within a short duration. Targeted therapies have enlightened new prospects for the treatment of BPDCN, especially for those in a frail state and intolerable to standard chemotherapies or hematopoietic stem cell transplantation. Here, we report an 82-year-old man diagnosed with cutaneous-limited BPDCN. Considering the old age and limited involvement of the tumor, we reduced the dosage of venetoclax. His skin lesions subsided significantly after 1 cycle of azacytidine (100 mg d1-7) combined with reduced doses of venetoclax (200 mg d1-14). The reduction in the dose of venetoclax avoided severe myelosuppression while achieving satisfactory outcomes. The patient received 2 cycles of therapy with no skin lesions re-occurred for 7 months before relapsing.

A review on chitosan/metal oxide nanocomposites for applications in environmental remediation.

A cleaner and safer environment is one of the most important requirements in the future. It has become increasingly urgent and important to fabricate novel environmentally-friendly materials to remove various hazardous pollutants. Compared with traditional materials, chitosan is a more environmentally friendly material due to its abundance, biocompatibility, biodegradability, film-forming ability and hydrophilicity. As an abundant of -NH2 and -OH groups on chitosan molecular chain could chelate with all kinds of metal ions efficiently, chitosan-based materials hold great potential as a versatile supporting matrix for metal oxide nanomaterials (MONMs) (TiO2, ZnO, SnO2, Fe3O4, etc.). Recently, many chitosan/metal oxide nanomaterials (CS/MONMs) have been reported as adsorbents, photocatalysts, heterogeneous Fenton-like agents, and sensors for potential and practical applications in environmental remediation and monitoring. This review analyzed and summarized the recent advances in CS/MONMs composites, which will provide plentiful and meaningful information on the preparation and application of CS/MONMs composites for wastewater treatment and help researchers to better understand the potential of CS/MONMs composites for environmental remediation and monitoring. In addition, the challenges of CS/MONM have been proposed.

Safety and Tolerability of Inclisiran for Treatment of Hypercholesterolemia in 7 Clinical Trials.

BACKGROUND: Inclisiran is a small interfering RNA agent to lower low-density lipoprotein cholesterol. OBJECTIVES: The purpose of this study was to provide reliable evidence to date on the long-term safety profile of inclisiran. METHODS: This post hoc analysis comprised patients treated with 300 mg inclisiran sodium or placebo in the completed (ORION-1, -3, -5, -9, -10, and -11) and ongoing (ORION-8) trials. Exposure-adjusted incidence rates and Kaplan-Meier estimates of cumulative incidence of reported treatment-emergent adverse events (TEAE), abnormal laboratory measurements, and incidence of antidrug antibodies were analyzed. RESULTS: This analysis included 3,576 patients treated with inclisiran for up to 6 years and 1,968 patients treated with placebo for up to 1.5 years, with 9,982.1 and 2,647.7 patient-years of exposure, respectively. Baseline characteristics were balanced between groups. Kaplan-Meier analyses showed that TEAEs that were serious or led to discontinuation; hepatic, muscle, and kidney events; incident diabetes; and elevations of creatine kinase or creatinine accrued at a comparable rate between groups for up to 1.5 years, with similar trends continuing for inclisiran beyond this period. Numerically fewer major cardiovascular events reported as TEAEs occurred with inclisiran during this period. Treatment-induced antidrug antibodies were uncommon with inclisiran (4.6%), with few of these persistent (1.4%) and not associated with greater incidence of TEAEs leading to study drug discontinuation or serious TEAEs. CONCLUSIONS: Long-term treatment with inclisiran was well tolerated in a diverse population, without new safety signals, supporting the safety of inclisiran in patients with dyslipidemia.

Dermatophagoides farinae microRNAs released to external environments via exosomes regulate inflammation-related gene expression in human bronchial epithelial cells.

Background: Dermatophagoides farinae (DFA) is an important species of house dust mites (HDMs) that causes allergic diseases. Previous studies have focused on allergens with protein components to explain the allergic effect of HDMs; however, there is little knowledge on the role of microRNAs (miRNAs) in the allergic effect of HDMs. This study aimed to unravel the new mechanism of dust mite sensitization from the perspective of cross-species transport of extracellular vesicles-encapsulated miRNAs from HDMs. Methods: Small RNA (sRNA) sequencing was performed to detect miRNAs expression profiles from DFA, DFA-derived exosomes and DFA culture supernatants. A quantitative fluorescent real-time PCR (qPCR) assay was used to detect miRNAs expression in dust specimens. BEAS-2B cells endocytosed exosomes were modeled in vitro to detect miRNAs from DFA and the expression of related inflammatory factors. Representative dfa-miR-276-3p and dfa-novel-miR2 were transfected into BEAS-2B cells, and then differentially expressed genes (DEGs) were analyzed by RNA sequencing. Protein-protein interaction (PPI) network analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) terms enrichment analyses were performed on the first 300 nodes of DEGs. Results: sRNA sequencing identified 42 conserved miRNAs and 66 novel miRNAs in DFA, DFA-derived exosomes, and DFA culture supernatants. A homology analysis was performed on the top 18 conserved miRNAs with high expression levels. The presence of dust mites and miRNAs from HDMs in living environment were also validated. Following uptake of DFA-derived exosomes by BEAS-2B cells, exosomes transported miRNAs from DFA to target cells and produced pro-inflammatory effects in corresponding cells. RNA sequencing identified DEGs in dfa-miR-276-3p and dfa-novel-miR2 transfected BEAS-2B cells. GO and KEGG enrichment analyses revealed the role of exosomes with cross-species transporting of DFA miRNAs in inflammatory signaling pathways, such as JAK-STAT signaling pathway, PI3K/AKT signaling pathway and IL-6-mediated signaling pathway. Conclusion: Our findings demonstrate the miRNAs expression profiles in DFA for the first time. The DFA miRNAs are delivered into living environments via exosomes, and engulfed by human bronchial epithelial cells, and cross-species regulation may contribute to inflammation-related processes.

Estimating the epidemiological impact of reaching the objectives of the Florida integrated HIV prevention and care plan in Miami-Dade County.

Background: The US Ending the HIV Epidemic (EHE) initiative aims to reduce national HIV incidence 90% by 2030 and to address the disproportionate burden of HIV among different racial/ethnic populations. Florida's state-wide 2022-2026 Integrated HIV Prevention and Care Plan outlines objectives for reaching EHE goals. In Miami-Dade County, we determined the epidemiological impact of achieving the integrated plan's objectives individually and jointly. Methods: We adapted an HIV transmission model calibrated to Miami-Dade County adjusting access to HIV testing, pre-exposure prophylaxis (PrEP) and antiretroviral treatment to model the effects of each objective between 2022 and 2030. We compared two service scale-up approaches: (a) scale-up proportionally to existing racial/ethnic group access levels, and (b) scale-up according to new diagnoses across racial/ethnic groups (equity-oriented). We estimated reductions in new HIV infections by each objective and approach, compared to the EHE's incidence reduction target. Findings: The single most influential strategy was reducing new HIV diagnoses in Hispanic/Latinx men who have sex with men through increased PrEP uptake, resulting in 907/2444 (37.1%) fewer annual new HIV infections in 2030. Achieving all objectives jointly would result in 1537/2444 (62.9%) and 1553/2444 (63.5%) fewer annual new HIV infections with the proportional and equity-oriented approaches, respectively. Interpretation: Achieving the goals of Florida's integrated care plan would significantly reduce HIV incidence in Miami-Dade County; however, further efforts are required to achieve EHE targets. Structural changes in service delivery and a focus on effective implementation of available interventions to address racial/ethnic disparities will be crucial to ending the HIV epidemic. Funding: This work was supported by the National Institutes of Health/National Institute on Drug Abuse grant no. R01-DA041747.

ACS-20/FATP4 mediates the anti-ageing effect of dietary restriction in C. elegans.

Dietary restriction is an effective anti-ageing intervention across species. However, the molecular mechanisms from the metabolic aspects of view are still underexplored. Here we show ACS-20 as a key mediator of dietary restriction on healthy ageing from a genetic screen of the C. elegans acyl-CoA synthetase family. ACS-20 functions in the epidermis during development to regulate dietary restriction-induced longevity. Functional transcriptomics studies reveal that elevated expression of PTR-8/Patched is responsible for the proteostasis and lifespan defects of acs-20. Furthermore, the conserved NHR-23 nuclear receptor serves as a transcriptional repressor of ptr-8 and a key regulator of dietary restriction-induced longevity. Mechanistically, a specific region in the ptr-8 promoter plays a key role in mediating the transcription regulation and lifespan extension under dietary restriction. Altogether, these findings identify a highly conserved lipid metabolism enzyme as a key mediator of dietary restriction-induced lifespan and healthspan extension and reveal the downstream transcriptional regulation mechanisms.

Knockdown of neuronal DAF-15/Raptor promotes healthy aging in C. elegans.

The highly conserved target of rapamycin (TOR) pathway plays an important role in aging across species. Previous studies have established that inhibition of the TOR complex 1 (TORC1) significantly extends lifespan in Caenorhabditiselegans. However, it has not been clear whether TORC1 perturbation affects aging in a spatiotemporal manner. Here, we apply the auxin-inducible degradation tool to knockdown endogenous DAF-15, the C. elegans ortholog of regulatory associated protein of TOR (Raptor), to characterize its roles in aging. Global or tissue-specific inhibition of DAF-15 during development results in various growth defects, whereas neuron-specific knockdown of DAF-15 during adulthood significantly extends lifespan and healthspan. The neuronal DAF-15 deficiency-induced longevity requires the intestinal activities of DAF-16/FOXO and PHA-4/FOXA transcription factors, as well as the AAK-2/AMP-activated protein kinase α catalytic subunit. Transcriptome profiling reveals that the neuronal DAF-15 knockdown promotes expression of genes involved in protection. These findings define the tissue-specific roles of TORC1 in healthy aging and highlight the importance of neuronal modulation of aging.

Racial/ethnic differences in receipt of naloxone distributed by opioid overdose prevention programs in New York City.

INTRODUCTION: We evaluated racial/ethnic differences in the receipt of naloxone distributed by opioid overdose prevention programs (OOPPs) in New York City (NYC). METHODS: We used naloxone recipient racial/ethnic data collected by OOPPs from April 2018 to March 2019. We aggregated quarterly neighborhood-specific rates of naloxone receipt and other covariates to 42 NYC neighborhoods. We used a multilevel negative binomial regression model to assess the relationship between neighborhood-specific naloxone receipt rates and race/ethnicity. Race/ethnicity was stratified into four mutually exclusive groups: Latino, non-Latino Black, non-Latino White, and non-Latino Other. We also conducted racial/ethnic-specific geospatial analyses to assess whether there was within-group geographic variation in naloxone receipt rates for each racial/ethnic group. RESULTS: Non-Latino Black residents had the highest median quarterly naloxone receipt rate of 41.8 per 100,000 residents, followed by Latino residents (22.0 per 100,000), non-Latino White (13.6 per 100,000) and non-Latino Other residents (13.3 per 100,000). In our multivariable analysis, compared with non-Latino White residents, non-Latino Black residents had a significantly higher receipt rate, and non-Latino Other residents had a significantly lower receipt rate. In the geospatial analyses, both Latino and non-Latino Black residents had the most within-group geographic variation in naloxone receipt rates compared to non-Latino White and Other residents. CONCLUSIONS: This study found significant racial/ethnic differences in naloxone receipt from NYC OOPPs. We observed substantial variation in naloxone receipt for non-Latino Black and Latino residents across neighborhoods, indicating relatively poorer access in some neighborhoods and opportunities for new approaches to address geographic and structural barriers in these locations.

Abnormal Thalamo-Cortical Interactions in Overlapping Communities of Migraine: An Edge Functional Connectivity Study.

OBJECTIVE: Migraine has been demonstrated to exhibit abnormal functional connectivity of large-scale brain networks, which is closely associated with its pathophysiology and has not yet been explored by edge functional connectivity. We used an edge-centric approach combined with motif analysis to evaluate higher-order communication patterns of brain networks in migraine. METHODS: We investigated edge-centric metrics in 108 interictal migraine patients and 71 healthy controls. We parcellated the brain into networks using independent component analysis. We applied edge graph construction, k-means clustering, community overlap detection, graph-theory-based evaluations, and clinical correlation analysis. We conducted motif analysis to explore the interactions among regions, and a classification model to test the specificity of edge-centric results. RESULTS: The normalized entropy of lateral thalamus was significantly increased in migraine, which was positively correlated with the baseline headache duration, and negatively correlated with headache duration reduction following preventive medications at 3-month follow-up. Network-wise entropy of the sensorimotor network was significantly elevated in migraine. The community similarity between lateral thalamus and postcentral gyrus was enhanced in migraine. Migraine patients showed overrepresented L-shape and diverse motifs, and underrepresented forked motifs with lateral thalamus serving as the reference node. Furthermore, migraine patients presented with overrepresented L-shape triads, where the postcentral gyrus shared different edges with the lateral thalamus. The classification model showed that entropy of the lateral thalamus had the highest discriminative power, with an area under the curve of 0.86. INTERPRETATION: Our findings indicated an abnormal higher-order thalamo-cortical communication pattern in migraine patients. The thalamo-cortical-somatosensory disturbance of concerted working may potentially lead to aberrant information flow and deficit pain processing of migraine. ANN NEUROL 2023;94:1168-1181.

Changes to opioid overdose deaths and community naloxone access among Black, Hispanic and White people from 2016 to 2021 with the onset of the COVID-19 pandemic: An interrupted time-series analysis in Massachusetts, USA.

BACKGROUND AND AIMS: The onset of the coronavirus disease 2019 (COVID-19) pandemic was associated with a surge in opioid overdose deaths in Massachusetts, particularly affecting racial and ethnic minority communities. We aimed to compare the impact of the pandemic on opioid overdose fatalities and naloxone distribution from community-based programs across racial and ethnic groups in Massachusetts. DESIGN: Interrupted time-series. SETTING AND CASES: Opioid overdose deaths (OODs) among non-Hispanic White, non-Hispanic Black, Hispanic and non-Hispanic other race people in Massachusetts, USA (January 2016 to June 2021). MEASUREMENTS: Rate of OODs per 100 000 people, rate of naloxone kits distributed per 100 000 people and ratio of naloxone kits per opioid overdose death as a measure of naloxone availability. We applied five imputation strategies using complete data in different periods to account for missingness of race and ethnicity for naloxone data. FINDINGS: Before COVID-19 (January 2016 to February 2020), the rate of OODs declined among non-Hispanic White people [0.2% monthly reduction (95% confidence interval = 0.0-0.4%)], yet was relatively constant among all other population groups. The rate of naloxone kits increased across all groups (0.8-1.2% monthly increase) and the ratio of naloxone kits per OOD death among non-Hispanic White was 1.1% (0.8-1.4%) and among Hispanic people was 1.0% (0.2-1.8%). After the onset of the pandemic (March 2020+), non-Hispanic Black people experienced an immediate increase in the rate of OODs [63.6% (16.4-130%)], whereas rates among other groups remained similar. Trends in naloxone rescue kit distribution did not substantively change among any groups, and the ratio of naloxone kits per OOD death for non-Hispanic Black people did not compensate for the surge in OODs deaths in this group. CONCLUSIONS: With the onset of the COVID-19 pandemic, there was a surge in opioid overdose deaths among non-Hispanic Black people in Massachusetts, USA with no compensatory increase in naloxone rescue kit distribution. For non-Hispanic White and Hispanic people, opioid overdose deaths remained stable and naloxone kit distribution continued to increase.