RREACT: A mobile multidisciplinary response to overdose.

Opioid overdose is a leading cause of death in the United States, and engaging with patients following overdose to provide harm reduction and recovery resources can prove difficult. Quick response models use mobile, multidisciplinary teams to establish a time-sensitive connection between individuals who overdosed and harm reduction and recovery resources that improve outcomes. These quick response models are consistent with the broader field of mobile-integrated health programs that are growing in number and acceptability, though the literature base is sparse and programs vary. We describe the 5-year reach, effectiveness, adoption, implementation and maintenance (RE-AIM) framework of the Rapid Response Emergency Addiction and Crisis Team (RREACT), a fire/emergency medical services-led, multidisciplinary (firefighter/paramedic, law enforcement officer, social worker) mobile outreach team. RREACT provides harm reduction, linkage/transportation to care and wrap-around services to individuals following a nonfatal opioid overdose that resulted in an emergency response in Columbus, Franklin County, Ohio, United States. Between 2018 and 2022, RREACT made 22,157 outreach attempts to 11,739 unique patients. RREACT recorded 3,194 direct patient contacts during this time, resulting in 1,200 linkages to care: 799 direct transports to opioid use disorder treatment and 401 warm handoffs to community treatment agencies. Furthermore, RREACT's staffing increased from 4 full-time equivalent staff in 2018 to 15.5 in 2022 and was supported by the surrounding community through 287 community outreach events and the development of an alumni program. These preliminary results further support the deployment of multidisciplinary mobile outreach teams to increase access to harm reduction and recovery resources following opioid overdose.

Effect of the Communities That HEAL Intervention on Overdose Education and Naloxone Distribution: A Cluster-Randomized, Wait-List Controlled Trial.

Objectives. To determine whether the Communities That HEAL (CTH) intervention is effective in increasing naloxone distribution compared with usual care. Methods. The HEALing (Helping to End Addiction Long-Term) Communities Study (HCS) is a cluster-randomized, parallel-arm, wait-list controlled implementation science trial testing the impact of the CTH intervention on increasing the use of evidence-based practices to lower opioid-related overdose deaths. Communities (n = 67) highly impacted by opioid overdose in Kentucky, Massachusetts, New York, and Ohio were allocated to CTH intervention (n = 34) or wait-list comparison (usual care; n = 33) arms. The primary outcome for this study was the number of naloxone units distributed in HCS communities during the comparison period (July 1, 2021‒June 30, 2022), examined using an intent-to-treat negative binomial regression model. Results. Naloxone distribution was 79% higher in the CTH intervention versus usual care arm (adjusted relative rate = 1.79; 95% confidence interval = 1.28, 2.51; P = .001; adjusted rates of naloxone distribution 3378 vs 1884 naloxone units per 100 000 residents), when controlling for urban‒rural status, state, baseline opioid-related overdose death rate, and baseline naloxone distribution rate. Conclusions. The CTH intervention increased naloxone distribution compared with usual care in communities highly impacted by the opioid crisis. Trial Registration. ClinicalTrials.gov identifier: NCT04111939. (Am J Public Health. Published online ahead of print October 10, 2024:e1-e12. https://doi.org/10.2105/AJPH.2024.307845).

Cortical surface area profile mediates effects of childhood disadvantage on later-life general cognitive ability.

OBJECTIVES: Childhood disadvantage is associated with lower general cognitive ability (GCA) and brain structural differences in midlife and older adulthood. However, the neuroanatomical mechanisms underlying childhood disadvantage effects on later-life GCA remain poorly understood. Although total surface area (SA) has been linked to lifespan GCA differences, total SA does not capture the non-uniform nature of childhood disadvantage effects on neuroanatomy, which varies across unimodal and transmodal cortices. Here, we examined whether cortical SA profile-the extent to which the spatial patterning of SA deviates from the normative unimodal-transmodal cortical organization-is a mediator of childhood disadvantage effects on later-life GCA. METHOD: In 477 community-dwelling men aged 56-72 years old, childhood disadvantage index (CDI) was derived from four indicators of disadvantages and GCA was assessed using a standardized test. Cortical SA was obtained from structural magnetic resonance imaging. For cortical SA profile, we calculated the spatial similarity between maps of individual cortical SA and MRI-derived principal gradient (i.e., unimodal-transmodal organization). Mediation analyses were conducted to examine the indirect effects of CDI through cortical SA profile on GCA. RESULTS: Around 1.31% of CDI effects on later-life GCA were mediated by cortical SA profile, whereas total SA did not. Higher CDI was associated with more deviation of the cortical SA spatial patterning from the principal gradient, which in turn related to lower later-life GCA. DISCUSSION: Childhood disadvantage may contribute to later-life GCA differences partly by influencing the spatial patterning of cortical SA in a way that deviates from the normative cortical organizational principle.

Layperson-Administered Naloxone Trends Reported in Emergency Medical Service Activations, 2020-2022.

Importance: Layperson-administered naloxone (LAN) is a powerful but incompletely characterized intervention to prevent opioid-related overdose mortality. LAN trends are relevant to policy and strategic planning in naloxone distribution initiatives. Objective: To assess the 2-year LAN trend for persons in the United States receiving naloxone during emergency medical services (EMS) activations. Design, Setting, and Participants: This retrospective cross-sectional study was conducted in the United States from June 2020 to June 2022 among 65 621 195 EMS activations from 911 responses, EMS standbys, or when EMS crews functioned in an ambulance intercept role or during mutual aid to another ambulance response. Activations within health care settings and interfacility or medical transports were excluded. Data are from the National Emergency Medical Services Information System (NEMSIS), the national EMS patient care record database. From June 2020 to June 2022, NEMSIS included more than 96 million EMS activations from nearly 14 000 agencies across 54 states and territories. Exposures: EMS clinician-reported LAN. Main Outcome and Measures: The primary outcome was the trend of receiving LAN, measured by EMS clinician documentation. Results: From June 2020 to June 2022, EMS reported 744 078 patients receiving naloxone, with 24 990 (3.4%) involving LAN. Patients were predominantly male (17 331 [69.4%]) and had a median (IQR) age of 42 (31-56) years, with the majority treated in urban homes or residences (21 692 [86.8%] urban; 13 223 [52.9%] in-home or residence). Of the total naloxone recipients, 243 985 patients (32.8%) had suspected drug overdose documentation as either the primary or secondary impression. Overall, the percentage change in naloxone administration rates decreased 6.1% over the study period (from 1140.1 [95% CI, 1135.1-1145.1] per 100 000 EMS activations to 1070.1 [95% CI, 1064.9-1075.3] per 100 000 EMS activations), while the percentage change of persons receiving LAN increased 43.5% (from 30.0 [95% CI, 29.2-30.8] per 100 000 EMS activations to 43.1 [95% CI, 42.0-44.1] per 100 000 EMS activations). Conclusions and Relevance: In this cross-sectional study, the LAN rate increased from June 2020 to June 2022 as reported in the national EMS database. These findings help inform policies and practices aimed at mitigating the devastating impacts of the opioid epidemic and saving lives. Novel public health strategies are needed to measure the effects of this intervention nationally, evaluate approaches to expand naloxone distribution, and address naloxone usage barriers.

Spectinamide MBX-4888A exhibits favorable lesion and tissue distribution and promotes treatment shortening in advanced murine models of tuberculosis.

The spectinamides are novel, narrow-spectrum semisynthetic analogs of spectinomycin, modified to avoid intrinsic efflux by Mycobacterium tuberculosis. Spectinamides, including lead MBX-4888A (Lee-1810), exhibit promising therapeutic profiles in mice, as single drugs and as partner agents with other anti-tuberculosis antibiotics including rifampin and/or pyrazinamide. Here, we show that MBX-4888A, given by injection with the front-line standard of care regimen, is treatment shortening in multiple murine tuberculosis infection models. The positive treatment responses to MBX-4888A combination therapy in multiple mouse models, including mice exhibiting advanced pulmonary disease, can be attributed to favorable distribution in tissues and lesions, retention in caseum, along with favorable effects with rifampin and pyrazinamide under conditions achieved in necrotic lesions. This study also provides an additional data point regarding the safety and tolerability of spectinamide MBX-4888A in long-term murine efficacy studies.

State program enables the identification of factors associated with naloxone awareness, self-efficacy, and use for overdose reversal: A cross-sectional, observational study in an urban emergency department population.

INTRODUCTION: To assist the state of Ohio in addressing the opioid epidemic, the Ohio Attorney General appointed experts in a variety of academic disciplines to the Scientific Committee on Opioid Prevention and Education (SCOPE). The focus of SCOPE is the application of scientific principles to the development of prevention and educational strategies for reducing substance use disorder and related harms (e.g., promoting naloxone awareness). Naloxone awareness is a step in the naloxone cascade, which is a useful model for understanding the sequential steps laypeople must take to prepare themselves to intervene using naloxone; other steps include training and previous administration experience. Prior work has explored correlates of these steps among individuals with risky substance use, but fewer studies have focused on broader populations containing potential bystanders (e.g., family and community members). METHODS: This study was a secondary data analysis of patients from three urban emergency departments. Subsamples differed across five models (n = 479-1208) and included opioid-exposed and -naïve participants. Logistic regression characterized clinically useful sociodemographic predictors (e.g., race, ethnicity, education, employment, housing status) of naloxone awareness, self-efficacy (which relates to training), and previous-overdose administration. Two additional logistic regressions tested associations between risk factors for witnessing an opioid overdose and two cascade steps (awareness and self-efficacy). RESULTS: Non-White race, Hispanic ethnicity, and lower education predicted not being aware of naloxone; non-White race also predicted lower naloxone self-efficacy, and older age predicted lack of previous-overdose administration. Having family members with risky opioid use was heavily associated with awareness, while personal substance-use behaviors and previous overdose witnessing were associated with both awareness and higher naloxone self-efficacy. CONCLUSIONS: Characteristics associated with lower likelihood of completing each cascade step highlight opportunities for targeted interventions. Specifically, findings indicated the importance of expanding naloxone education and training programs to more diverse populations and to family members of individuals with risky opioid use. Further, these findings demonstrate how a state-funded program such as SCOPE can have a positive impact on identifying strategies that may assist in reducing mortality associated with opioid overdose.

Genome-wide association study meta-analysis of neurofilament light (NfL) levels in blood reveals novel loci related to neurodegeneration.

Neurofilament light chain (NfL) levels in circulation have been established as a sensitive biomarker of neuro-axonal damage across a range of neurodegenerative disorders. Elucidation of the genetic architecture of blood NfL levels could provide new insights into molecular mechanisms underlying neurodegenerative disorders. In this meta-analysis of genome-wide association studies (GWAS) of blood NfL levels from eleven cohorts of European ancestry, we identify two genome-wide significant loci at 16p12 (UMOD) and 17q24 (SLC39A11). We observe association of three loci at 1q43 (FMN2), 12q14, and 12q21 with blood NfL levels in the meta-analysis of African-American ancestry. In the trans-ethnic meta-analysis, we identify three additional genome-wide significant loci at 1p32 (FGGY), 6q14 (TBX18), and 4q21. In the post-GWAS analyses, we observe the association of higher NfL polygenic risk score with increased plasma levels of total-tau, Aß-40, Aß-42, and higher incidence of Alzheimer's disease in the Rotterdam Study. Furthermore, Mendelian randomization analysis results suggest that a lower kidney function could cause higher blood NfL levels. This study uncovers multiple genetic loci of blood NfL levels, highlighting the genes related to molecular mechanism of neurodegeneration.

Association of genetic variants in CYP3A5, DRD2 and NK1R with opioid overdose.

In 2023, 3651 Ohioans died because of an opioid overdose. Of those opioid overdoses, 3579 (98%) of which were attributed to fentanyl. We evaluated the association between 180 candidate single nucleotide polymorphisms (SNPs) and self-reported, nonfatal opioid overdose history from a prospective sample of 1301 adult patients (≥18 years of age) seen in three urban emergency departments in Ohio. Candidate SNPs included 120 related to the dopamine reward pathway and 60 related to pharmacokinetics. Of the 821 patients who reported having been exposed to opioids in their lifetime, 95 (11.6%) also reported having experienced an opioid-related overdose. Logistic regression, adjusting for age and biologic sex, was used to characterize the association between each SNP and opioid overdose, correcting for multiple comparisons. Three SNPs, located in three different genes were associated with opioid overdose: increased odds with CYP3A5 (rs776746) and DRD2 (rs4436578), and decreased odds with NKIR (rs6715729). Homozygotic CYP3A5 (rs776746) had the highest adjusted odds ratio (OR) of 6.96 (95% CI [2.45, 29.23]) and homozygotic NK1R (rs6715729) had the lowest OR of 0.28 (95% CI [0.14, 0.54). Given that CYP3A5 (rs776746) has been associated with increased plasma concentrations of fentanyl, rs776746 could potentially be utilized as a prognostic risk indicator for the potential of an opioid overdose. NK1R regulates the expression of the neurokinin-1 receptor, a regulator of respiration and NK1R (rs6715729) represents a novel genetic marker for a decreased risk of opioid overdose risk.

Elevated C-Reactive Protein in Older Men With Chronic Pain: Association With Plasma Amyloid Levels and Hippocampal Volume.

BACKGROUND: Chronic pain leads to tau accumulation and hippocampal atrophy, which may be moderated through inflammation. In older men, we examined associations of chronic pain with Alzheimer's disease (AD)-related plasma biomarkers and hippocampal volume as moderated by systemic inflammation. METHODS: Participants were men without dementia. Chronic pain was defined as moderate-to-severe pain in 2+ study waves at average ages 56, 62, and 68. At age 68, we measured plasma amyloid-beta (Aß42, n = 871), Aß40 (n = 887), total tau (t-tau, n = 841), and neurofilament light chain (NfL, n = 915), and serum high-sensitivity C-reactive protein (hs-CRP, n = 968), a marker of systemic inflammation. A subgroup underwent structural MRI to measure hippocampal volume (n = 385). Analyses adjusted for medical morbidities, depressive symptoms, and opioid use. RESULTS: Chronic pain was related to higher Aß40 (ß = 0.25, p = .009), but hs-CRP was unrelated to AD-related biomarkers (ps > .05). There was a significant interaction such that older men with both chronic pain and higher levels of hs-CRP had higher levels of Aß42 (ß = 0.36, p = .001) and Aß40 (ß = 0.29, p = .003). Chronic pain and hs-CRP did not interact to predict levels of Aß42/Aß40, t-tau, or NfL. Furthermore, there were significant interactions such that Aß42 and Aß40 were associated with lower hippocampal volume, particularly when levels of hs-CRP were elevated (hs-CRP × Aß42: ß = -0.19, p = .002; hs-CRP × Aß40: ß = -0.21, p = .001), regardless of chronic pain status. CONCLUSIONS: Chronic pain was associated with higher plasma Aß, especially when hs-CRP was also elevated. Higher hs-CRP and Aß levels were both related to smaller hippocampal volumes. Chronic pain, when accompanied by systemic inflammation, may elevate the risk of neurodegeneration in AD-vulnerable regions.

Opioid use disorder risk alleles in self-reported assigned African American/Afro-Caribbean and European biogeographical genetic ancestry groups and in males and females.

The influence of genetic variants related to opioid use disorder (OUD) was evaluated using multiple logistic regression analysis in self-reported assigned African American/Afro-Caribbean and European biogeographical ancestry groups (BGAGs) and by sex. From a sample size of 1301 adult patients (>18 years of age) seen in emergency departments of three medical centers in Ohio, six variants were found to be associated with OUD. Two of the variants, rs2740574 (CYP3A4) and rs324029 (DRD3), were included in the analysis having met criteria of at least five subjects for each BGAG, variant carrier status, and OUD status combinations. Variant carriers in the African/Afro-Caribbean BGAG had slightly lower predicted probabilities of OUD. Variant carriers in the European BGAG had slightly higher predicted probabilities of OUD. Relative to sex, all the six variants met evaluation criteria (five subjects for all sex, variant, and OUD status combinations). No statistically significant interactions were found between a given variant, BGAGs and sex. Findings suggest variant testing relative to OUD risk can be applied across BGAGs and sex, however, studies in larger populations are needed.

Buprenorphine Prescribing Characteristics Following Relaxation of X-Waiver Training Requirements.

Importance: Local-level data are needed to understand whether the relaxation of X-waiver training requirements for prescribing buprenorphine in April 2021 translated to increased buprenorphine treatment. Objective: To assess whether relaxation of X-waiver training requirements was associated with changes in the number of clinicians waivered to and who prescribe buprenorphine for opioid use disorder and the number of patients receiving treatment. Design, Setting, and Participants: This serial cross-sectional study uses an interrupted time series analysis of 2020-2022 data from the HEALing Communities Study (HCS), a cluster-randomized, wait-list-controlled trial. Urban and rural communities in 4 states (Kentucky, Massachusetts, New York, and Ohio) with a high burden of opioid overdoses that had not yet received the HCS intervention were included. Exposure: Relaxation of X-waiver training requirements (ie, allowing training-exempt X-waivers) on April 28, 2021. Main Outcomes and Measures: The monthly number of X-waivered clinicians, X-waivered buprenorphine prescribers, and patients receiving buprenorphine were each summed across communities within a state. Segmented linear regression models to estimate pre- and post-policy change by state were used. Results: The number of individuals in 33 participating HCS communities included 347 863 in Massachusetts, 815 794 in Kentucky, 971 490 in New York, and 1 623 958 in Ohio. The distribution of age (18-35 years: range, 29.4%-32.4%; 35-54 years: range, 29.9%-32.5%; ≥55 years: range, 35.7%-39.3%) and sex (female: range, 51.1%-52.6%) was similar across communities. There was a temporal increase in the number of X-waivered clinicians in the pre-policy change period in all states, which further increased in the post-policy change period in each state except Ohio, ranging from 5.2% (95% CI, 3.1%-7.3%) in Massachusetts communities to 8.4% (95% CI, 6.5%-10.3%) in Kentucky communities. Only communities in Kentucky showed an increase in the number of X-waivered clinicians prescribing buprenorphine associated with the policy change (relative increase, 3.2%; 95% CI, 1.5%-4.9%), while communities in other states showed no change or a decrease. Similarly, only communities in Massachusetts experienced an increase in patients receiving buprenorphine associated with the policy change (relative increase, 1.7%; 95% CI, 0.8%-2.6%), while communities in other states showed no change. Conclusions and Relevance: In this serial cross-sectional study, relaxation of X-waiver training requirements was associated with an increase in the number of X-waivered clinicians but was not consistently associated with an increase in the number of buprenorphine prescribers or patients receiving buprenorphine. These findings suggest that training requirements may not be the primary barrier to expanding buprenorphine treatment.

A twin analysis to estimate genetic and environmental factors contributing to variation in weighted gene co-expression network module eigengenes.

Multivariate network-based analytic methods such as weighted gene co-expression network analysis are frequently applied to human and animal gene-expression data to estimate the first principal component of a module, or module eigengene (ME). MEs are interpreted as multivariate summaries of correlated gene-expression patterns and network connectivity across genes within a module. As such, they have the potential to elucidate the mechanisms by which molecular genomic variation contributes to individual differences in complex traits. Although increasingly used to test for associations between modules and complex traits, the genetic and environmental etiology of MEs has not been empirically established. It is unclear if, and to what degree, individual differences in blood-derived MEs reflect random variation versus familial aggregation arising from heritable or shared environmental influences. We used biometrical genetic analyses to estimate the contribution of genetic and environmental influences on MEs derived from blood lymphocytes collected on a sample of N = 661 older male twins from the Vietnam Era Twin Study of Aging (VETSA) whose mean age at assessment was 67.7 years (SD = 2.6 years, range = 62-74 years). Of the 26 detected MEs, 14 (56%) had statistically significant additive genetic variation with an average heritability of 44% (SD = 0.08, range = 35%-64%). Despite the relatively small sample size, this demonstration of significant family aggregation including estimates of heritability in 14 of the 26 MEs suggests that blood-based MEs are reliable and merit further exploration in terms of their associations with complex traits and diseases.

Testing the causal impact of amyloidosis on total Tau using a genetically informative sample of adult male twins.

INTRODUCTION: The amyloid cascade hypothesis predicts that amyloid-beta (Aß) aggregation drives tau tangle accumulation. We tested competing causal and non-causal hypotheses regarding the direction of causation between Aß40 and Aß42 and total Tau (t-Tau) plasma biomarkers. METHODS: Plasma Aß40, Aß42, t-Tau, and neurofilament light chain (NFL) were measured in 1,035 men (mean = 67.0 years) using Simoa immunoassays. Genetically informative twin modeling tested the direction of causation between Aßs and t-Tau. RESULTS: No clear evidence that Aß40 or Aß42 directly causes changes in t-Tau was observed; the alternative causal hypotheses also fit the data well. In contrast, exploratory analyses suggested a causal impact of the Aß biomarkers on NFL. Separately, reciprocal causation was observed between t-Tau and NFL. DISCUSSION: Plasma Aß40 or Aß42 do not appear to have a direct causal impact on t-Tau. In contrast, Aß aggregation may causally impact NFL in cognitively unimpaired men in their late 60s.

Early Cortical Microstructural Changes in Aging Are Linked to Vulnerability to Alzheimer's Disease Pathology.

BACKGROUND: Early identification of Alzheimer's disease (AD) risk is critical for improving treatment success. Cortical thickness is a macrostructural measure used to assess neurodegeneration in AD. However, cortical microstructural changes appear to precede macrostructural atrophy and may improve early risk identification. Currently, whether cortical microstructural changes in aging are linked to vulnerability to AD pathophysiology remains unclear in nonclinical populations, who are precisely the target for early risk identification. METHODS: In 194 adults, we calculated magnetic resonance imaging-derived maps of changes in cortical mean diffusivity (microstructure) and cortical thickness (macrostructure) over 5 to 6 years (mean age: time 1 = 61.82 years; time 2 = 67.48 years). Episodic memory was assessed using 3 well-established tests. We obtained positron emission tomography-derived maps of AD pathology deposition (amyloid-ß, tau) and neurotransmitter receptors (cholinergic, glutamatergic) implicated in AD pathophysiology. Spatial correlational analyses were used to compare pattern similarity among maps. RESULTS: Spatial patterns of cortical macrostructural changes resembled patterns of cortical organization sensitive to age-related processes (r = -0.31, p < .05), whereas microstructural changes resembled the patterns of tau deposition in AD (r = 0.39, p = .038). Individuals with patterns of microstructural changes that more closely resembled stereotypical tau deposition exhibited greater memory decline (ß = 0.22, p = .029). Microstructural changes and AD pathology deposition were enriched in areas with greater densities of cholinergic and glutamatergic receptors (ps < .05). CONCLUSIONS: Patterns of cortical microstructural changes were more AD-like than patterns of macrostructural changes, which appeared to reflect more general aging processes. Microstructural changes may better inform early risk prediction efforts as a sensitive measure of vulnerability to pathological processes prior to overt atrophy and cognitive decline.

Practical Synthesis of 7-Bromo-4-chloro-1H-indazol-3-amine: An Important Intermediate to Lenacapavir.

7-Bromo-4-chloro-1H-indazol-3-amine is a heterocyclic fragment used in the synthesis of Lenacapavir, a potent capsid inhibitor for the treatment of HIV-1 infections. In this manuscript, we describe a new approach to synthesizing 7-bromo-4-chloro-1H-indazol-3-amine from inexpensive 2,6-dichlorobenzonitrile. This synthetic method utilizes a two-step sequence including regioselective bromination and heterocycle formation with hydrazine to give the desired product in an overall isolated yield of 38-45%. The new protocol has been successfully demonstrated on hundred-gram scales without the need for column chromatography purification. This new synthesis provides a potential economical route to the large-scale production of this heterocyclic fragment of Lenacapavir.

Brain reserve in midlife is associated with executive function changes across 12 years.

We examined how brain reserve in midlife, measured by brain-predicted age difference scores (Brain-PADs), predicted executive function concurrently and longitudinally into early old age, and whether these associations were moderated by young adult cognitive reserve or APOE genotype. 508 men in the Vietnam Era Twin Study of Aging (VETSA) completed neuroimaging assessments at mean age 56 and six executive function tasks at mean ages 56, 62, and 68 years. Results indicated that greater brain reserve at age 56 was associated with better concurrent executive function (r=.10, p=.040) and less decline in executive function over 12 years (r=.34, p=.001). These associations were not moderated by cognitive reserve or APOE genotype. Twin analysis suggested associations with executive function slopes were driven by genetic influences. Our findings suggest that greater brain reserve allowed for better cognitive maintenance from middle- to old age, driven by a genetic association. The results are consistent with differential preservation of executive function based on brain reserve that is independent of young adult cognitive reserve or APOE genotype.

Spectinamide MBX-4888A exhibits favorable lesion and tissue distribution and promotes treatment shortening in advanced murine models of tuberculosis.

The spectinamides are novel, narrow-spectrum semisynthetic analogs of spectinomycin, modified to avoid intrinsic efflux by Mycobacterium tuberculosis . Spectinamides, including lead MBX-4888A (Lee-1810), exhibit promising therapeutic profiles in mice, as single drugs and as partner agents with other anti-tuberculosis antibiotics including rifampin and/or pyrazinamide. To demonstrate that this translates to more effective cure, we first confirmed the role of rifampin, with or without pyrazinamide, as essential to achieve effective bactericidal responses and sterilizing cure in the current standard of care regimen in chronically infected C3HeB/FeJ mice compared to BALB/c mice. Thus, demonstrating added value in testing clinically relevant regimens in murine models of increasing pathologic complexity. Next we show that MBX-4888A, given by injection with the front-line standard of care regimen, is treatment shortening in multiple murine tuberculosis infection models. The positive treatment responses to MBX-4888A combination therapy in multiple mouse models including mice exhibiting advanced pulmonary disease can be attributed to favorable distribution in tissues and lesions, retention in caseum, along with favorable effects with rifampin and pyrazinamide under conditions achieved in necrotic lesions. This study also provides an additional data point regarding the safety and tolerability of spectinamide MBX-4888A in long-term murine efficacy studies.

Variant-specific pathophysiological mechanisms of AFF3 differently influence transcriptome profiles.

BACKGROUND: We previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with intellectual disability (ID), mesomelic dysplasia and horseshoe kidney, caused by de novo variants in the degron of AFF3. Mouse knock-ins and overexpression in zebrafish provided evidence for a dominant-negative mode of action, wherein an increased level of AFF3 resulted in pathological effects. METHODS: Evolutionary constraints suggest that other modes-of-inheritance could be at play. We challenged this hypothesis by screening ID cohorts for individuals with predicted-to-be damaging variants in AFF3. We used both animal and cellular models to assess the deleteriousness of the identified variants. RESULTS: We identified an individual with a KINSSHIP-like phenotype carrying a de novo partial duplication of AFF3 further strengthening the hypothesis that an increased level of AFF3 is pathological. We also detected seventeen individuals displaying a milder syndrome with either heterozygous Loss-of-Function (LoF) or biallelic missense variants in AFF3. Consistent with semi-dominance, we discovered three patients with homozygous LoF and one compound heterozygote for a LoF and a missense variant, who presented more severe phenotypes than their heterozygous parents. Matching zebrafish knockdowns exhibit neurological defects that could be rescued by expressing human AFF3 mRNA, confirming their association with the ablation of aff3. Conversely, some of the human AFF3 mRNAs carrying missense variants identified in affected individuals did not rescue these phenotypes. Overexpression of mutated AFF3 mRNAs in zebrafish embryos produced a significant increase of abnormal larvae compared to wild-type overexpression further demonstrating deleteriousness. To further assess the effect of AFF3 variation, we profiled the transcriptome of fibroblasts from affected individuals and engineered isogenic cells harboring + / + , KINSSHIP/KINSSHIP, LoF/ + , LoF/LoF or KINSSHIP/LoF AFF3 genotypes. The expression of more than a third of the AFF3 bound loci is modified in either the KINSSHIP/KINSSHIP or the LoF/LoF lines. While the same pathways are affected, only about one third of the differentially expressed genes are common to the homozygote datasets, indicating that AFF3 LoF and KINSSHIP variants largely modulate transcriptomes differently, e.g. the DNA repair pathway displayed opposite modulation. CONCLUSIONS: Our results and the high pleiotropy shown by variation at this locus suggest that minute changes in AFF3 function are deleterious.

Cost-Effectiveness of HIV Screening in Emergency Departments: Results From the Pragmatic Randomized HIV Testing Using Enhanced Screening Techniques in Emergency Departments Trial.

STUDY OBJECTIVE: Identification of HIV remains a critical health priority for which emergency departments (EDs) are a central focus. The comparative cost-effectiveness of various HIV screening strategies in EDs remains largely unknown. The goal of this study was to compare programmatic costs and cost-effectiveness of nontargeted and 2 forms of targeted opt-out HIV screening in EDs using results from a multicenter, pragmatic randomized clinical trial. METHODS: This economic evaluation was nested in the HIV Testing Using Enhanced Screening Techniques in Emergency Departments (TESTED) trial, a multicenter pragmatic clinical trial of different ED-based HIV screening strategies conducted from April 2014 through January 2016. Patients aged 16 years or older, with normal mental status and not critically ill, or not known to be living with HIV were randomized to 1 of 3 HIV opt-out screening approaches, including nontargeted, enhanced targeted, or traditional targeted, across 4 urban EDs in the United States. Each screening method was fully integrated into routine emergency care. Direct programmatic costs were determined using actual trial results, and time-motion assessment was used to estimate personnel activity costs. The primary outcome was newly diagnosed HIV. Total annualized ED programmatic costs by screening approach were calculated using dollars adjusted to 2023 as were costs per patient newly diagnosed with HIV. One-way and multiway sensitivity analyses were performed. RESULTS: The trial randomized 76,561 patient visits, resulting in 14,405 completed HIV tests, and 24 (0.2%) new diagnoses. Total annualized new diagnoses were 12.9, and total annualized costs for nontargeted, enhanced targeted, and traditional targeted screening were $111,861, $88,629, and $70,599, respectively. Within screening methods, costs per new HIV diagnoses were $20,809, $23,554, and $18,762, respectively. Enhanced targeted screening incurred higher costs but with similar annualized new cases detected compared with traditional targeted screening. Nontargeted screening yielded an incremental cost-effectiveness ratio of $25,586 when compared with traditional targeted screening. Results were most sensitive to HIV prevalence and costs of HIV tests. CONCLUSION: Nontargeted HIV screening was more costly than targeted screening largely due to an increased number of HIV tests performed. Each HIV screening strategy had similar within-strategy costs per new HIV diagnosis with traditional targeted screening yielding the lowest cost per new diagnosis. For settings with budget constraints or very low HIV prevalences, the traditional targeted approach may be preferred; however, given only a slightly higher cost per new HIV diagnosis, ED settings looking to detect the most new cases may prefer nontargeted screening.

Associations of plasma neurofilament light chain with cognition and neuroimaging measures in community-dwelling early old age men.

BACKGROUND: Plasma neurofilament light chain (NfL) is a promising biomarker of neurodegeneration with potential clinical utility in monitoring the progression of neurodegenerative diseases. However, the cross-sectional associations of plasma NfL with measures of cognition and brain have been inconsistent in community-dwelling populations. METHODS: We examined these associations in a large community-dwelling sample of early old age men (N = 969, mean age = 67.57 years, range = 61-73 years), who are either cognitively unimpaired (CU) or with mild cognitive impairment (MCI). Specifically, we investigated five cognitive domains (executive function, episodic memory, verbal fluency, processing speed, visual-spatial ability), as well as neuroimaging measures of gray and white matter. RESULTS: After adjusting for age, health status, and young adult general cognitive ability, plasma NfL level was only significantly associated with processing speed and white matter hyperintensity (WMH) volume, but not with other cognitive or neuroimaging measures. The association with processing speed was driven by individuals with MCI, as it was not detected in CU individuals. CONCLUSIONS: These results suggest that in early old age men without dementia, plasma NfL does not appear to be sensitive to cross-sectional individual differences in most domains of cognition or neuroimaging measures of gray and white matter. The revealed plasma NfL associations were limited to WMH for all participants and processing speed only within the MCI cohort. Importantly, considering cognitive status in community-based samples will better inform the interpretation of the relationships of plasma NfL with cognition and brain and may help resolve mixed findings in the literature.