Endovascular Therapy for Patients With Low NIHSS Scores and Large Vessel Occlusion in the 6- to 24-Hour Window: Analysis of the CLEAR Study

Background and objectives: There is uncertainty about whether patients with an anterior circulation large vessel occlusion (LVO) and a low NIH Stroke Scale (NIHSS) score (≤5) benefit from endovascular therapy (EVT) in the late time window (6-24 hours). We compared the clinical outcomes of these patients receiving EVT with those receiving medical management (MM). Methods: The CT for Late Endovascular Reperfusion multinational cohort study was conducted at 66 sites across 10 countries from January 2014 to May 2022. This subanalysis included consecutive patients with late-window stroke due to an anterior circulation LVO, defined as occlusion of the internal carotid artery or proximal middle cerebral artery (M1/M2 segments), and a baseline NIHSS score ≤5 who received EVT or MM alone. The primary end point was a 90-day ordinal shift in the modified Rankin Scale (mRS) score. Secondary outcomes were 90-day excellent outcome (defined as mRS scores 0-1 or return to baseline mRS score in patients with a prestroke mRS score >1) and favorable outcome (defined as mRS scores 0-2 or return to baseline mRS score in patients with prestroke mRS score >2). Safety outcomes were symptomatic intracranial hemorrhage and 90-day mortality. We used ordinal and binary logistic regression models to test for outcome differences. Results: Among 5,098 patients, 318 patients were included (median [interquartile range] age 67 [56-76] years; 149 [46.9%] were female; baseline NIHSS score was 4 [2-5]). A total of 202 patients (63.5%) received EVT and 116 MM (36.5%). There was no difference in favorable 90-day ordinal mRS score shift (adjusted common odds ratio [OR] 0.77, 95% CI 0.45-1.32), excellent outcome (adjusted OR 0.86, 95% CI 0.49-1.50), or favorable outcome (adjusted OR 0.72, 95% CI 0.35-1.50) in the EVT group compared with MM. Symptomatic intracranial hemorrhage risk (adjusted OR 3.40, 95% CI 0.84-13.73) and mortality at 90 days (adjusted OR 2.44, 95% CI 0.60-10.02) were not statistically different between treatment groups. Discussion: In patients with an anterior LVO and low NIHSS score in the 6-24-hour time window, there was no statistical difference in disability outcomes or intracranial bleeding risk between patients treated with EVT compared with MM. The retrospective and observational design limits our findings. Ongoing randomized controlled trials will provide further insight. Classification of evidence: This study provides Class III evidence that in adult patients with anterior circulation LVO and low NIHSS score (≤5) presenting in the late time window (6-24 hours), EVT does not improve clinical outcome vs MM. Trial registration: This study was registered at clinicaltrials.gov under NCT04096248.No embarg

Examining Race-Based and Gender-Based Discrimination, Trust in Providers, and Mental Well-Being Among Black Women

Objectives: To examine experiences of discrimination among Black women, and to determine if experiencing race- and gender-based discrimination is associated with mental well-being and trust. Methods: Data from the TRUST study were used to examine experiences of discrimination among 559 Black women with hypertension receiving healthcare at a safety-net hospital in Birmingham, Alabama. A three-level variable was constructed to combine the race-based and gender-based measures of the Experiences of Discrimination scale. Linear regression was used to examine the association between experiences of discrimination with mental well-being and trust. Results: Women who reported no experiences of race- or gender-based discrimination were older and reported higher mental well-being scores and greater trust. Fifty-three percent of study participants reported experiencing discrimination. Compared to participants who did not experience race- or gender-based discrimination, participants reporting experiences of race- or gender-based discrimination and those reporting experiencing both race- and gender-based discrimination were more likely to report poorer mental health. Conclusion: Reported experiences of gender- and/or race-based discrimination in this study were associated with lower mental health scores and less trust in health care providers. Our findings highlight the importance of examining experiences of discrimination among Black women, and the role of discrimination as a stressor and in reducing trust for providers. Incorporating an understanding and acknowledgement of experiences of discrimination into interventions, programs, and during clinical encounters may foster more trusting relationships between providers and patients

Navigating the uncertainty of precision cancer screening: The role of shared decision-making

Objective: Describe how applying a shared decision making (SDM) lens to the implementation of new technologies can improve patient-centeredness. Methods: This paper argues that the emergence of polygenic risk scores (PRS) for cancer screening presents an illustrative opportunity to include SDM when novel technologies enter clinical care. Results: PRS are novel tools that indicate an individual's genetic risk of a given disease relative to the population. PRS are anticipated to help identify individuals most and least likely to benefit from screening. However, PRS have several types of uncertainty, including validity across populations, disparate computational methods, and inclusion of different genomic data across laboratories. Conclusion: Implementing SDM alongside new technologies could prove useful for their ethical and patient-centered utilization. SDM's importance as an approach to decision-making will not diminish, as evidence, uncertainty, and patient values will remain intrinsic to the art and science of clinical care. Innovation: SDM can help providers and patients navigate the considerable uncertainty inherent in implementing new technologies, enabling decision-making based on existing evidence and patient values

A2Ar-dependent PD-1+ and TIGIT+ Treg cells have distinct homing requirements to suppress autoimmune uveitis in mice

The proper function of regulatory T cells (Tregs) to suppress inflammation requires homing to the correct tissue site. Resolution of autoimmune uveitis generates distinct programmed death receptor 1 (PD-1) and T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) Tregs in an adenosine 2A receptor (A2Ar)-dependent manner found in the spleen. Where and how these Tregs migrate from the spleen to prevent uveitis is not known. In this work, we show that A2Ar-dependent Tregs migrated to the eye and secondary lymphoid tissue and expressed chemokine receptor (CCR)6 and CCR7. Suppression of autoimmune uveitis required CCR6 and CCR7 expression for TIGIT Tregs but not PD-1 Tregs. Moreover, stimulation of A2Ar on T cells from patients showed a decreased capacity to induce TIGIT Tregs that expressed CCR6 or CCR7, and PD-1 Treg that expressed CCR6. This work provides a mechanistic understanding of the homing requirements of each of these Treg populations. Importantly, this work is clinically relevant because patients with chronic autoimmune uveitis are unable to induce the Treg populations identified in mice that home to the target tissue.No embarg

Molecular imaging of inflammation with PET in acute and ventilator-induced lung injury

This review focuses on methods to image acute lung inflammation with Positron Emission Tomography (PET). Four approaches are discussed that differ for biologic function of the PET reporter probe, radiotracer employed, and the specific aspect of the inflammatory response that is targeted. 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) is an enzyme substrate whose uptake is used to measure the metabolic activation of inflammatory cells during acute lung injury in the noncancerous lung. H2 15O and radiolabeled plasma proteins are inert molecules with the same physical characteristics as their nonradioactive counterparts and are used to measure edema and vascular permeability. Tagged enzyme or receptor inhibitors are used to probe expression of these targets induced by inflammatory stimuli. Lastly, cell-specific tracers are being developed to differentiate the cell types that contribute to the inflammatory response. Taken together, these methods cast PET imaging as a versatile and quantitative tool to measure inflammation in vivo noninvasively during acute and ventilator-induced lung injury

Serologic Screening for Genital Herpes Infection: US Preventive Services Task Force Reaffirmation Recommendation Statement

Importance: Genital herpes is a common sexually transmitted infection caused by 2 related viruses, herpes simplex type 1 (HSV-1) and herpes simplex type 2 (HSV-2). Infection is lifelong; currently, there is no cure for HSV infection. Antiviral medications may provide clinical benefits to symptomatic persons. Transmission of HSV from a pregnant person to their infant can occur, most commonly during delivery; when genital lesions or prodromal symptoms are present, cesarean delivery can reduce the risk of transmission. Neonatal herpes infection is uncommon yet can result in substantial morbidity and mortality. Objective: To reaffirm its 2016 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a reaffirmation evidence update on targeted key questions to systematically evaluate the evidence on accuracy, benefits, and harms of routine serologic screening for HSV-2 infection in asymptomatic adolescents, adults, and pregnant persons. Population: Adolescents and adults, including pregnant persons, without known history, signs, or symptoms of genital HSV infection. Evidence assessment: The USPSTF concludes with moderate certainty that the harms outweigh the benefits for population-based screening for genital HSV infection in asymptomatic adolescents and adults, including pregnant persons. Recommendation: The USPSTF recommends against routine serologic screening for genital HSV infection in asymptomatic adolescents and adults, including pregnant persons. (D recommendation)

Defining the substrate envelope of SARS-CoV-2 main protease to predict and avoid drug resistance

Coronaviruses can evolve and spread rapidly to cause severe disease morbidity and mortality, as exemplified by SARS-CoV-2 variants of the COVID-19 pandemic. Although currently available vaccines remain mostly effective against SARS-CoV-2 variants, additional treatment strategies are needed. Inhibitors that target essential viral enzymes, such as proteases and polymerases, represent key classes of antivirals. However, clinical use of antiviral therapies inevitably leads to emergence of drug resistance. In this study we implemented a strategy to pre-emptively address drug resistance to protease inhibitors targeting the main protease (M(pro)) of SARS-CoV-2, an essential enzyme that promotes viral maturation. We solved nine high-resolution cocrystal structures of SARS-CoV-2 M(pro) bound to substrate peptides and six structures with cleavage products. These structures enabled us to define the substrate envelope of M(pro), map the critical recognition elements, and identify evolutionarily vulnerable sites that may be susceptible to resistance mutations that would compromise binding of the newly developed M(pro) inhibitors. Our results suggest strategies for developing robust inhibitors against SARS-CoV-2 that will retain longer-lasting efficacy against this evolving viral pathogen

Reproducibility of Neuroretinal Rim Measurements Obtained from High-Density Spectral Domain Optical Coherence Tomography Volume Scans

Purpose: To compare the reproducibility of two-dimensional (2D) peripapillary retinal nerve fiber layer (RNFL) thickness and three-dimensional (3D) neuroretinal rim measurements using spectral domain optical coherence tomography (SDOCT) in normal and glaucoma subjects. Methods: One eye per subject for 27 normal and 40 glaucoma subjects underwent repeat SDOCT RNFL thickness scans and optic nerve volume scans on the same day. From the volume scan, custom software calculated five neuroretinal rim parameters: 3D minimum distance band (MDB) thickness, 3D MDB area, 3D rim volume, 2D rim area, and 2D rim thickness. Within-subject variance (Sw), coefficient of variation (CV), and intraclass correlation coefficient (ICC) were analyzed. Results: MDB thickness and RNFL thickness have similar reproducibility among normal and glaucoma subjects (eg, global MDB thickness CVs of 2.4% and 3.6%, and global RNFL thickness CVs of 1.3% and 2.2%; P > 0.05 for both comparisons). Reproducibility of MDB thickness was lower in glaucoma patients for the superior and inferior quadrants compared to normal subjects (CVs of 9.6% versus 3.4% and 6.9% versus 2.7%; P < 0.05, respectively). There were no statistically significant differences between both groups for RNFL thickness in the four quadrants. For both patient groups and for all regions, MDB thickness had the lowest CVs among all five neuroretinal rim parameters (eg, global MDB thickness CVs of 2.4% and 3.6% versus 3.0% and 18.9% for the other four neuroretinal rim parameters). Conclusion: Global MDB and global RNFL thickness are similarly reproducible among normal and glaucoma subjects, though MDB thickness for the superior and inferior quadrants is less reproducible among glaucoma subjects

Cumulative exposure to state-level structural sexism and risk of disordered eating: Results from a 20-year prospective cohort study

Background: Gendered inequities in disordered eating are well-documented, yet few studies have examined their structural drivers. To help fill this gap, we investigated whether cumulative exposure to state-level structural sexism from childhood through young adulthood potentiates differences in disordered eating risk between cisgender girls/women and boys/men. Methods: Participants came from the Growing Up Today Study (N = 16,875), a cohort of children aged 9-14 years in 1996 who we followed through 2016. Using a composite index of relevant state policies and social inequalities from the Institute for Women's Policy Research, we categorized states as having high or low levels of structural sexism and summed the number of years participants had lived in a high structural sexism state during the study period to quantify their cumulative exposure. We fit sequential conditional mean models to estimate the effect of cumulative exposure on risk of four outcomes (chronic dieting, purging, binge eating, and overeating), controlling for individual- and state-level confounders via propensity scores. We then tested whether effects differed between girls/women and boys/men by including cumulative-exposure-by-gender-identity interaction terms and calculating the relative excess risk due to interaction (RERI). Results: In the full sample, each additional year of living in a high structural sexism state was associated with a 5% increased risk of purging (95% confidence interval (CI): 3%, 7%), an 8% increased risk of binge eating (95% CI: 6%, 10%), and a 9% increased risk of overeating (95% CI: 8%, 11%). Risk increases were larger on average for girls/women than for boys/men, and girls/women who had lived in a high structural sexism state for four or more years had excess risk of chronic dieting (RERI: 0.64, 95% CI: 0.18, 1.10), purging (RERI: 2.64, 95% CI: 1.24, 4.30), and binge eating (RERI: 2.21, 95% CI: 0.93, 3.50). Conclusions: Structural sexism may contribute to inequities in disordered eating between cisgender girls/women and boys/men. Future research should include transgender and gender diverse participants, explore intersectional effects, and identify underlying mechanisms to inform policy-oriented interventions

Structure-based design of selective, orally available salt-inducible kinase inhibitors that stimulate bone formation in mice

Osteoporosis is a major public health problem. Currently, there are no orally available therapies that increase bone formation. Intermittent parathyroid hormone (PTH) stimulates bone formation through a signal transduction pathway that involves inhibition of salt-inducible kinase isoforms 2 and 3 (SIK2 and SIK3). Here, we further validate SIK2/SIK3 as osteoporosis drug targets by demonstrating that ubiquitous deletion of these genes in adult mice increases bone formation without extraskeletal toxicities. Previous efforts to target these kinases to stimulate bone formation have been limited by lack of pharmacologically acceptable, specific, orally available SIK2/SIK3 inhibitors. Here, we used structure-based drug design followed by iterative medicinal chemistry to identify SK-124 as a lead compound that potently inhibits SIK2 and SIK3. SK-124 inhibits SIK2 and SIK3 with single-digit nanomolar potency in vitro and in cell-based target engagement assays and shows acceptable kinome selectivity and oral bioavailability. SK-124 reduces SIK2/SIK3 substrate phosphorylation levels in human and mouse cultured bone cells and regulates gene expression patterns in a PTH-like manner. Once-daily oral SK-124 treatment for 3 wk in mice led to PTH-like effects on mineral metabolism including increased blood levels of calcium and 1,25-vitamin D and suppressed endogenous PTH levels. Furthermore, SK-124 treatment increased bone formation by osteoblasts and boosted trabecular bone mass without evidence of short-term toxicity. Taken together, these findings demonstrate PTH-like effects in bone and mineral metabolism upon in vivo treatment with orally available SIK2/SIK3 inhibitor SK-124