Substance use moderates relationships between apolipoprotein E genotype, hepatitis C, cognition, and depression in Miami Adult Studies on HIV (MASH) participants.

The impact of APOE on HIV and HCV disease course, cognition, and memory has been understudied in minoritized populations. This study examined whether scores on cognition and depression measures differed by APOE ε4 carrier status while considering HCV and HIV seropositivity and whether these measures were moderated by substance use. A retrospective analysis examined cognitive and psychological data from participants (n = 493) in the Miami Adult Studies on HIV (MASH) cohort. APOE genotyping was performed on banked blood samples. Multiple linear regression was employed to examine differences across participants living with and without HIV and/or HCV and by APOE ε4 genotype. APOE ε4 carriers living with HCV who used cannabis had higher depression scores than non-ε4 carriers, while nonusers had fewer depressive symptoms. APOE ε4 carriers living with HCV had better cognition scores after adjusting for cocaine, opiate, and cannabis use than non-ε4 carriers. Scores on cognitive and depression measures did not differ between APOE ε4 carriers and non-ε4 carriers in participants living with HIV, and substance use did not moderate this relationship. This study was the first of its kind to examine substance use as a moderator for cognition and depression among individuals with HIV and/or HCV stratified by APOE genotype. Findings support further research evaluating the frequency and duration of 1) domains of cognitive functioning impacted by APOE genotype relevant to substance use and 2) the influence of substance use on cognitive and depressive outcomes among adults living with HIV and HCV, HIV, or HCV.

Capturing the Value of Vaccination within Health Technology Assessment and Health Economics-Practical Considerations for Expanding Valuation by Including Key Concepts.

Following the development of a value of vaccination (VoV) framework for health technology assessment/cost-effectiveness analysis (HTA/CEA), and identification of three vaccination benefits for near-term inclusion in HTA/CEA, this final paper provides decision makers with methods and examples to consider benefits of health systems strengthening (HSS), equity, and macroeconomic gains. Expert working groups, targeted literature reviews, and case studies were used. Opportunity cost methods were applied for HSS benefits of rotavirus vaccination. Vaccination, with HSS benefits included, reduced the incremental cost-effectiveness ratio (ICER) by 1.4-50.5% (to GBP 11,552-GBP 23,016) depending on alternative conditions considered. Distributional CEA was applied for health equity benefits of meningococcal vaccination. Nearly 80% of prevented cases were among the three most deprived groups. Vaccination, with equity benefits included, reduced the ICER by 22-56% (to GBP 7014-GBP 12,460), depending on equity parameters. Macroeconomic models may inform HTA deliberative processes (e.g., disease impact on the labour force and the wider economy), or macroeconomic outcomes may be assessed for individuals in CEAs (e.g., impact on non-health consumption, leisure time, and income). These case studies show how to assess broader vaccination benefits in current HTA/CEA, providing decision makers with more accurate and complete VoV assessments. More work is needed to refine inputs and methods, especially for macroeconomic gains.

Enhanced HONO Formation from Aqueous Nitrate Photochemistry in the Presence of Marine Relevant Organics: Impact of Marine-Dissolved Organic Matter (m-DOM) Concentration on HONO Yields and Potential Synergistic Effects of Compounds within m-DOM.

Nitrous acid (HONO) is a key molecule in the reactive nitrogen cycle. However, sources and sinks for HONO are not fully understood. Particulate nitrate photochemistry has been suggested to play a role in the formation of HONO in the marine boundary layer (MBL). Here we investigate the impact of marine relevant organic compounds on HONO formation from aqueous nitrate photochemistry. In particular, steady-state, gas-phase HONO yields were measured from irradiated nitrate solutions at low pH containing marine-dissolved organic matter (m-DOM). m-DOM induces a nonlinear increase in HONO yield across all concentrations compared to that for pure nitrate solutions, with rates of HONO formation increasing by up to 3-fold when m-DOM is present. Furthermore, to understand the potential synergistic effects that may occur within complex samples such as m-DOM, mixtures of chromophoric (light-absorbing) and aliphatic (non-light-absorbing) molecular proxies were utilized. In particular, mixtures of 4-benzoylbenzoic acid (4-BBA) and ethylene glycol (EG) in acidic aqueous solutions containing nitrate showed more HONO upon irradiation compared to solutions containing only one of the molecular proxies. This suggests that synergistic effects in the HONO formation can occur in complex organic samples. Atmospheric implications of the results presented here are discussed.

Postmortem Digital Image Correlation and Finite Element Modeling Demonstrate Posterior Scleral Deformations during Optic Nerve Adduction Tethering.

Postmortem human eyes were subjected to optic nerve (ON) traction in adduction and elevated intraocular pressure (IOP) to investigate scleral surface deformations. We incrementally adducted 11 eyes (age 74.1 ± 9.3 years, standard deviation) from 26° to 32° under normal IOP, during imaging of the posterior globe, for analysis by three-dimensional digital image correlation (3D-DIC). In the same eyes, we performed uniaxial tensile testing in multiple regions of the sclera, ON, and ON sheath. Based on individual measurements, we analyzed eye-specific finite element models (FEMs) simulating adduction and IOP loading. Analysis of 3D-DIC showed that the nasal sclera up to 1 mm from the sheath border was significantly compressed during adduction. IOP elevation from 15 to 30 mmHg induced strains less than did adduction. Tensile testing demonstrated ON sheath stiffening above 3.4% strain, which was incorporated in FEMs of adduction tethering that was quantitatively consistent with changes in scleral deformation from 3D-DIC. Simulated IOP elevation to 30 mmHg did not induce scleral surface strains outside the ON sheath. ON tethering in incremental adduction from 26° to 32° compressed the nasal and stretched the temporal sclera adjacent to the ON sheath, more so than IOP elevation. The effect of ON tethering is influenced by strain stiffening of the ON sheath.

Emerging Adults With Type 2 Diabetes: Understanding Illness Experience and Transition to Adult Care.

PURPOSE: Youth-onset type 2 diabetes (T2D) is increasingly common and is often diagnosed shortly before transition from pediatric to adult care. Little is known about the experience of emerging adults (EAs) with T2D and the readiness, barriers, and facilitators to transition. This study sought to describe the illness experience of EAs with T2D and perceptions about transition, and explore themes by "transition readiness," measured by the Transition Readiness Assessment Questionnaire (TRAQ). METHODS: In this mixed-methods study, we conducted semi-structured interviews with EAs with T2D using a guide grounded in the health belief model, administered the TRAQ, and collected disease metrics from the electronic medical record. We developed a coding scheme using a directed content-analysis approach and triangulated qualitative and quantitative data to compare themes stratified by mean TRAQ score. RESULTS: Participants described modifying factors like adjusting to life with a chronic illness and coping with mental health issues as critical elements of the illness experience that influence transition. Individual beliefs emerged including the perceived risk of disease complications being informed by experience of family members, self-efficacy in diabetes care hinging on the ability to be highly organized, and transition as a daunting obstacle with numerous emotional and logistical barriers. Participants emphasized the need for support from caregivers and providers throughout transition. Themes did not vary significantly by TRAQ score. DISCUSSION: Experiences of EAs with T2D suggest more assistance is needed in the transition period to address factors such as mental health, organizational skills, and identifying support people to facilitate care.

Adolescent Preferences for a Pediatric Primary Care-based Sexually Transmitted Infection and HIV Prevention Intervention.

PURPOSE: We sought to elicit perspectives on HIV and sexually transmitted infection (STI) prevention among adolescents with recent STIs in primary care to optimize acceptability and effectiveness in designing a novel HIV/STI prevention intervention. METHODS: We enrolled 13-19 year-olds with recent gonorrhea, chlamydia, trichomonas, and/or syphilis in a multimethods cross-sectional study at two primary care clinics. Participants completed surveys and interviews. We used an integrated analytic approach deductively coding data using the Integrated Behavioral Model, then inductively coding to identify themes not represented in the Integrated Behavioral Model. RESULTS: Participants (n = 35) were 85% cisgender female, 14% cisgender male, 1% transgender female; 25% identified as lesbian, bisexual, or queer. Most (97%) identified as non-Latinx Black. None used condoms consistently, 26% were aware of pre-exposure prophylaxis (PrEP), and 31% were never HIV tested. Five key themes emerged. 1) Mental health was central to HIV prevention behavior uptake and coping with STI diagnosis. 2) Youth desired prevention counseling that allowed decisional autonomy and individualized goal setting. 3) Negative social norms around condoms and absent norms around HIV testing and PrEP limited method uptake. 4) Both confidence and concrete skills were needed to initiate prevention methods. 5) Youth desired education at the time of STI diagnosis to improve subsequent prevention decision making. DISCUSSION: Key intervention design considerations included 1) integrating mental health assessment and referral to services, 2) promoting individualized goal setting, 4) building communication skills, 4) providing navigation and material support for PrEP uptake and HIV testing, and 5) augmenting comprehensive STI and HIV prevention education.

A Social Network Analysis of a Multi-sector Service System for Intimate Partner Violence in a Large US City.

About one in four women in the US report having experienced some form of intimate partner violence (IPV) during their lifetime and an estimated 15.5 million children live in families in which IPV occurred in the past year. Families of young children with IPV experiences often face complex needs and require well-coordinated efforts among service providers across social and health sectors. One promising partnership aims to support pregnant and parenting IPV survivors through coordination between IPV agencies and community-based maternal and early childhood home visiting programs. This study used social network analysis (SNA) to understand the interconnectedness of the system of IPV prevention and intervention for families with young children in a large US city. The SNA included 43 agencies serving this population across various service domains spanning IPV, legal, maternal and child health, and public benefit programs. An SNA survey collected data on four forms of collaboration between agencies, including formal administrative relationship, referral reciprocity, case consultation, and shared activities in community committees/organizing bodies. Density and centrality were the primary outcomes of interest. A community detection analysis was performed as a secondary analysis. The overall level of interconnectedness between the 43 responding agencies was low. Making referrals to each other was the most common form of collaboration, with a network density of 30%. IPV agencies had the highest average number of connections in the networks. There was a high level of variation in external collaborations among home visiting agencies, with several home visiting agencies having very few connections in the community but one home visiting program endorsing collaborative relationships with upwards of 38 partner agencies in the network. In serving families at risk for IPV, home visiting agencies were most likely to have referral relationships with mental health provider agencies and substance use disorder service agencies. A community detection analysis identified distinct communities within the network and demonstrated that certain agency types were more connected to one another while others were typically siloed within the network. Notably, the IPV and home visiting communities infrequently overlapped. Sensitivity analyses showed that survey participants' knowledge of their agencies' external collaborations varied by their work roles and agencies overall had low levels of consensus about their connectedness to one another. We identified a heterogeneous service system available to families of young children at-risk for or experiencing IPV. Overall inter-agency connectedness was low, with many siloed agencies and a lack of shared knowledge of community resources. Understanding current collaborations, silos, and centrality of agencies is an effective public health tool for allocating scarce resources across diverse service sectors to efficiently improve the system serving families experiencing IPV.

Years of Life Lost to Firearm Suicide Among Young People in the US.

This cross-sectional study examines years of life lost among the top 3 causes of death and compares firearm suicide with other methods of suicide among individuals aged 10 to 24 years in the US.

Importance of self-weighing to avoid post-cessation weight gain: A secondary analysis of the fit and quit randomized trial.

Background: Smoking cessation is associated with weight gain, and the risk of weight gain is a common deterrent to quitting smoking. Thus, the identification of strategies for reducing post-smoking cessation weight gain is critical. Objective: Conduct secondary analysis of data from the Fit & Quit trial to determine if greater frequency of self-weighing is associated with less weight gain in the context of smoking cessation. Methods: Participants (N = 305) were randomized to one of three 2-month weight interventions (i.e., Stability, Loss, Bibliotherapy), followed by a smoking cessation intervention. Stability and Loss conditions received different types of self-weighing feedback. All participants received e-scales at baseline, to capture daily self-weighing data over 12 months. General linear models were applied to test the main objective. Results: Frequency of self-weighing was (mean ± SD) 2.67 ± 1.84 days/week. The Stability condition had significantly higher self-weighing frequency (3.18 ± 1.72 days/week) compared to the Loss (2.51 ± 1.99 days/week) and the Bibliotherapy conditions (2.22 ± 1.63 days/week). Adjusting for baseline weight and treatment condition, self-weighing 3-4 days/week was associated with weight stability (-0.77 kg, 95% CI: -2.2946, 0.7474, p = 0.3175), and self-weighing 5 or more days/week was associated with 2.26 kg weight loss (95% CI: -3.9249, -0.5953, p = 0.0080). Conclusions: Self-weighing may serve as a useful tool for weight gain prevention after smoking cessation. Feedback received about self-weighing behaviors and weight trajectory (similar to the feedback Stability participants received) might enhance adherence.

Years of life lost due to deaths of despair and COVID-19 in the United States in 2020: patterns of excess mortality by gender, race and ethnicity.

BACKGROUND: In 2020 COVID-19 was the third leading cause of death in the United States. Increases in suicides, overdoses, and alcohol related deaths were seen-which make up deaths of despair. How deaths of despair compare to COVID-19 across racial, ethnic, and gender subpopulations is relatively unknown. Preliminary studies showed inequalities in COVID-19 mortality for Black and Hispanic Americans in the pandemic's onset. This study analyzes the racial, ethnic and gender disparities in years of life lost due to COVID-19 and deaths of despair (suicide, overdose, and alcohol deaths) in 2020. METHODS: This cross-sectional study calculated and compared years of life lost (YLL) due to Deaths of Despair and COVID-19 by gender, race, and ethnicity. YLL was calculated using the CDC WONDER database to pull death records based on ICD-10 codes and the Social Security Administration Period Life Table was used to get estimated life expectancy for each subpopulation. RESULTS: In 2020, COVID-19 caused 350,831 deaths and 4,405,699 YLL. By contrast, deaths of despair contributed to 178,598 deaths and 6,045,819 YLL. Men had more deaths and YLL than women due to COVID-19 and deaths of despair. Among White Americans and more than one race identification both had greater burden of deaths of despair YLL than COVID-19 YLL. However, for all other racial categories (Native American/Alaskan Native, Asian, Black/African American, Native Hawaiian/Pacific Islander) COVID-19 caused more YLL than deaths of despair. Also, Hispanic or Latino persons had disproportionately higher mortality across all causes: COVID-19 and all deaths of despair causes. CONCLUSIONS: This study found greater deaths of despair mortality burden and differences in burden across gender, race, and ethnicity in 2020. The results indicate the need to bolster behavioral health research, support mental health workforce development and education, increase access to evidence-based substance use treatment, and address systemic inequities and social determinants of deaths of despair and COVID-19.

Therapeutic activity of lipoxin A4 in TiO2-induced arthritis in mice: NF-κB and Nrf2 in synovial fluid leukocytes and neuronal TRPV1 mechanisms.

Background: Lipoxin A4 (LXA4) has anti-inflammatory and pro-resolutive roles in inflammation. We evaluated the effects and mechanisms of action of LXA4 in titanium dioxide (TiO2) arthritis, a model of prosthesis-induced joint inflammation and pain. Methods: Mice were stimulated with TiO2 (3mg) in the knee joint followed by LXA4 (0.1, 1, or 10ng/animal) or vehicle (ethanol 3.2% in saline) administration. Pain-like behavior, inflammation, and dosages were performed to assess the effects of LXA4 in vivo. Results: LXA4 reduced mechanical and thermal hyperalgesia, histopathological damage, edema, and recruitment of leukocytes without liver, kidney, or stomach toxicity. LXA4 reduced leukocyte migration and modulated cytokine production. These effects were explained by reduced nuclear factor kappa B (NFκB) activation in recruited macrophages. LXA4 improved antioxidant parameters [reduced glutathione (GSH) and 2,2-azino-bis 3-ethylbenzothiazoline-6-sulfonate (ABTS) levels, nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA and Nrf2 protein expression], reducing reactive oxygen species (ROS) fluorescent detection induced by TiO2 in synovial fluid leukocytes. We observed an increase of lipoxin receptor (ALX/FPR2) in transient receptor potential cation channel subfamily V member 1 (TRPV1)+ DRG nociceptive neurons upon TiO2 inflammation. LXA4 reduced TiO2-induced TRPV1 mRNA expression and protein detection, as well TRPV1 co-staining with p-NFκB, indicating reduction of neuronal activation. LXA4 down-modulated neuronal activation and response to capsaicin (a TRPV1 agonist) and AITC [a transient receptor potential ankyrin 1 (TRPA1) agonist] of DRG neurons. Conclusion: LXA4 might target recruited leukocytes and primary afferent nociceptive neurons to exert analgesic and anti-inflammatory activities in a model resembling what is observed in patients with prosthesis inflammation.

pH Dependence of the speciation and optical properties of 4-benzoylbenzoic acid.

Organic chromophores initiate much of daytime aqueous phase chemistry in the environment. Thus, studying the absorption spectra of commonly used organic photosensitizers is paramount to fully understand their relevance in environmental processes. In this work, we combined UV-Vis spectroscopy, 1H-NMR spectroscopy, quantum chemical calculations, and molecular dynamics simulations to investigate the absorption spectra of 4-benzoyl benzoic acid (4BBA), a widely used photosensitizer and a common proxy of environmentally relevant chromophores. Solutions of 4BBA at different pH values show that protonated and deprotonated species have an effect on its absorbance spectra. Theoretical calculations of these species in water clusters provide physical and chemical insights into the spectra. Quantum chemical calculations were conducted to analyze the UV-Vis absorbance spectra of 4BBA species using various cluster sizes, such as C6H5COC6H4COOH·(H2O)n, where n = 8 for relatively small clusters and n = 30 for larger clusters. While relatively small clusters have been successfully used for smaller chromophores, our results indicate that simulations of protonated species of 4BBA require relatively larger clusters of n = 30. A comparison between the experimental and theoretical results shows good agreement in the pH-dependent spectral shift between the hydrated cluster model and the experimental data. Overall, the theoretical and empirical results indicate that the experimental optical spectra of aqueous phase 4BBA can be represented by the acid-base equilibrium of the keto-forms, with a spectroscopically measured pKa of 3.41 ± 0.04. The results summarized here contribute to a molecular-level understanding of solvated organic molecules through calculations restricted to cluster models, and thereby, broader insight into environmentally relevant chromophores.

Implementation of a heart failure educational intervention for patients with recent admissions for acute decompensated heart failure.

Purpose: This study examined whether implementation of a heart failure (HF) education class targeted at patients and their caregivers decreased worsening HF, emergency department (ED) visits and hospital admissions, and improved patient quality of life and confidence in disease state management. Methods: Patients with HF and a recent hospital admission for acute decompensated heart failure (ADHF) were offered an educational course covering HF pathophysiology, medications, diet, and lifestyle modifications. Patients completed surveys before and 30 days after completion of the educational course. Outcomes of participants at 30 and 90 days after class completion were compared against outcomes for the same patients at 30 and 90 days prior to course attendance. Data was collected using electronic medical records, in-person during the class, and during a phone follow-up. Results: The primary outcome was a composite of hospital admission, ED visit, and/or outpatient visit for HF at 90 days. A total of twenty-six patients attended classes between September 2018 and February 2019 and were included in the analysis. Median age was 70 years, and most patients were white. All patients were American College of Cardiology/American Heart Association (ACC/AHA) Stage C and a majority had New York Heart Association (NYHA) Class II or III symptoms. Median left ventricular ejection fraction (LVEF) was 40%. The primary composite outcome occurred significantly more frequently in the 90 days prior to class attendance than in the 90 days following attendance (96% vs. 35%, p < 0.01). Likewise, the secondary composite outcome occurred significantly more frequently in the 30 days before class attendance than in the 30 days following (54% vs. 19%, p = 0.02). These results were driven by a decrease in admissions and ED visits for HF symptoms. Survey scores related to patient HF self-management practices and patient confidence in ability to self-manage HF increased numerically from baseline to 30 days after class attendance. Conclusion: Implementation of an educational class for HF patients improved patient outcomes, confidence, and ability to self-manage HF. Hospital admissions and ED visits also decreased. Adoption of such a course might help to decrease overall health care costs and improve patient quality of life.

Years of life lost due to unintentional drug overdose among perinatal individuals in the United States.

BACKGROUND: The United States has one of the highest maternal mortality rates of developing countries, but the contribution of perinatal drug overdose is not known. Communities of color also have higher rates of maternal morbidity and mortality when compared to White communities, however the contribution due to overdose has not yet been examined in this population. OBJECTIVES: To quantify the years of life lost due to unintentional overdose in perinatal individuals from 2010 to 2019 and assess for disparity by race. STUDY DESIGN: This was a cross-sectional retrospective study with summary-level mortality statistics for the years 2010-2019 obtained from the Centers for Disease Control (CDC) Wide-Ranging Online Data for Epidemiologic Research (WONDER) mortality file. A total of 1,586 individuals of childbearing age (15-44 years) who died during pregnancy or six weeks postpartum (perinatal) from unintentional overdose in the United States from January 1, 2010 to December 31, 2019 were included. Total years of life lost (YLL) was calculated and summated for White, Black, Hispanic, Asian/Pacific Islander, and American Indian/Native Alaska women. Additionally, the top three overall causes of death were also identified for women in this age group for comparison. RESULTS: Unintentional drug overdose accounted for 1,586 deaths and 83,969.78 YLL in perinatal individuals from 2010 to 2019 in the United States. Perinatal American Indian/Native American individuals had a disproportionate amount of YLL when compared to other ethnic groups, with 2.39% of YLL due to overdose, while only making up 0.80% of the population. During the last two years of the study, only American Indian/Native American and Black individuals had increased rates of mortality when compared to other races. During the ten-year study period, when including the top three causes of mortality, unintentional drug overdoses made up 11.98% of the YLL overall and 46.39% of accidents. For the years 2016-2019, YLL due to unintentional overdose was the third leading cause of YLL overall for this population. CONCLUSIONS: Unintentional drug overdose is a leading cause of death for perinatal individuals in the United States, claiming nearly 84,000 years of life over a ten-year period. When examining by race, American Indian/Native American women are most disproportionately affected.

Aspirin-Triggered Resolvin D1 (AT-RvD1) Protects Mouse Skin against UVB-Induced Inflammation and Oxidative Stress.

Intense exposure to UVB radiation incites excessive production of reactive oxygen species (ROS) and inflammation. The resolution of inflammation is an active process orchestrated by a family of lipid molecules that includes AT-RvD1, a specialized proresolving lipid mediator (SPM). AT-RvD1 is derived from omega-3, which presents anti-inflammatory activity and reduces oxidative stress markers. The present work aims to investigate the protective effect of AT-RvD1 on UVB-induced inflammation and oxidative stress in hairless mice. Animals were first treated with 30, 100, and 300 pg/animal AT-RvD1 (i.v.) and then exposed to UVB (4.14 J/cm2). The results showed that 300 pg/animal of AT-RvD1 could restrict skin edema, neutrophil and mast cell infiltration, COX-2 mRNA expression, cytokine release, and MMP-9 activity and restore skin antioxidant capacity as per FRAP and ABTS assays and control O2•- production, lipoperoxidation, epidermal thickening, and sunburn cells development. AT-RvD1 could reverse the UVB-induced downregulation of Nrf2 and its downstream targets GSH, catalase, and NOQ-1. Our results suggest that by upregulating the Nrf2 pathway, AT-RvD1 promotes the expression of ARE genes, restoring the skin's natural antioxidant defense against UVB exposition to avoid oxidative stress, inflammation, and tissue damage.

Years of life lost due to unintentional drug overdose relative to the leading underlying causes of death in the United States: a comparative analysis of excess mortality 2017-2019.

The present study aims to compare Years of Life Lost for unintentional drug overdose and the leading underlying causes of death in the United States annually from 2017 to 2019. Years of Life Lost provide valuable context to incident deaths when comparing the relative mortality burden of underlying causes of death. Prior research has shown unintentional drug overdose was the third leading cause of Years of Life Lost in the state of Ohio in 2017. However, this finding has yet to be replicated at the national level in the US. Death statistics for 2017-2019 were accessed via CDC WONDER. Years of Life Lost were calculated for unintentional drug overdose and each of the top five causes of incident deaths in the US during the study period. Unintentional drug overdose caused nearly seven million Years of Life Lost in the US during the three-year period of study and was the fourth leading cause of Years of Life Lost after cancer, heart disease and other accidents. Incidence alone provides an incomplete picture of the effect of unintentional drug overdose on overall mortality burden in the US. Years of Life Lost give critical context to the overdose crisis, underscoring unintentional drug overdose as a leading cause of premature mortality.

Standard of care drugs do not modulate activity of senescent primary human lung fibroblasts.

Cellular senescence is crucial in the progression of idiopathic pulmonary fibrosis (IPF), but it is not evident whether the standard-of-care (SOC) drugs, nintedanib and pirfenidone, have senolytic properties. To address this question, we performed colorimetric and fluorimetric assays, qRT-PCR, and western blotting to evaluate the effect of SOC drugs and D + Q on senescent normal and IPF lung fibroblasts. In this study, we found that SOC drugs did not provoke apoptosis in the absence of death ligand in normal or IPF senescent lung fibroblasts. Nintedanib increased caspase-3 activity in the presence of Fas Ligand in normal but not in IPF senescent fibroblasts. Conversely, nintedanib enhanced B cell lymphoma 2 expression in senescent IPF lung fibroblasts. Moreover, in senescent IPF cells, pirfenidone induced mixed lineage kinase domain-like pseudokinase phosphorylation, provoking necroptosis. Furthermore, pirfenidone increased transcript levels of FN1 and COL1A1 in senescent IPF fibroblasts. Lastly, D + Q augmented growth differentiation factor 15 (GDF15) transcript and protein levels in both normal and IPF senescent fibroblasts. Taken together, these results establish that SOC drugs failed to trigger apoptosis in senescent primary human lung fibroblasts, possibly due to enhanced Bcl-2 levels by nintedanib and the activation of the necroptosis pathway by pirfenidone. Together, these data revealed the inefficacy of SOC drugs to target senescent cells in IPF.

Chikungunya Virus and Its Envelope Protein E2 Induce Hyperalgesia in Mice: Inhibition by Anti-E2 Monoclonal Antibodies and by Targeting TRPV1.

Chikungunya virus is an arthropod-borne infectious agent that causes Chikungunya fever disease. About 90% of the infected patients experience intense polyarthralgia, affecting mainly the extremities but also the large joints such as the knees. Chronic disease symptoms persist for months, even after clearance of the virus from the blood. Envelope proteins stimulate the immune response against the Chikungunya virus, becoming an important therapeutic target. We inactivated the Chikungunya virus (iCHIKV) and produced recombinant E2 (rE2) protein and three different types of anti-rE2 monoclonal antibodies. Using these tools, we observed that iCHIKV and rE2 protein induced mechanical hyperalgesia (electronic aesthesiometer test) and thermal hyperalgesia (Hargreaves test) in mice. These behavioral results were accompanied by the activation of dorsal root ganglia (DRG) neurons in mice, as observed by calcium influx. Treatment with three different types of anti-rE2 monoclonal antibodies and absence or blockade (AMG-9810 treatment) of transient receptor potential vanilloid 1 (TRPV1) channel diminished mechanical and thermal hyperalgesia in mice. iCHIKV and rE2 activated TRPV1+ mouse DRG neurons in vitro, demonstrating their ability to activate nociceptor sensory neurons directly. Therefore, our mouse data demonstrate that targeting E2 CHIKV protein with monoclonal antibodies and inhibiting TRPV1 channels are reasonable strategies to control CHIKV pain.

Optical Coherence Tomography Angiography Demonstrates Strain and Volume Effects on Optic Disk and Peripapillary Vasculature Caused by Horizontal Duction.

PURPOSE: The optic nerve mechanically loads the eye during ocular rotation, thus altering the configuration of the disk and peripapillary tissues. We used optical coherence tomography (OCT) angiography (OCTA) to investigate mechanical strains and volume changes in disk and peripapillary blood vessels during horizontal duction. METHODS: Structural OCT and OCTA were performed centered on optic disks; imaging was repeated in central gaze, and in 30° ab- and adduction. By an algorithm employing point-set registration of 3 D features, we developed a novel approach for measuring disk strains, and strains and volumes of the blood vessels associated with horizontal duction. Repeatability was demonstrated in each gaze position. RESULTS: 19 eyes of 10 healthy adults of average age 37 ± 15 (standard deviation, SD) years were imaged. The method was validated by demonstrating numerically consistent vascular volumes and strains for repeated imaging under identical conditions. Compared with central gaze, vascular volume increased by 5.2 ± 4.1% in adduction. Adduction and abduction caused strains of 3.0 ± 1.6% and 2.6 ± 1.8% in the optic disk, whereas blood vessels showed greater strains of 8.1 ± 1.3% and 8.2 ± 1.7%. Decomposition of strain components depending on directionality and regions demonstrated that adduction induces significant net tensile strains, suggesting traction exerted by the optic nerve. The decomposition also showed that nasotemporal compressive strains are larger in temporal hemidisks than nasal hemidisks. The Bruch's membrane opening was significantly compressed horizontally in adduction by 1.1% (p = .009). CONCLUSION: This novel analysis combining structural OCT and OCTA demonstrates that optic disk compression during adduction is associated with disk and vascular strains much larger than reported for intraocular pressure elevation and pulsatile perfusion, as well as compressing the disk and increasing peripapillary vascular volume. These changes may be relevant to the pathogenesis of optic nerve and retinal vascular disorders.