Intravenous Thrombolysis in Patients With Cervical Artery Dissection: A Secondary Analysis of the STOP-CAD Study.

OBJECTIVES: Cervical artery dissection (CeAD) accounts for 25% of ischemic strokes in young adults. This study evaluated the benefits and harms of intravenous thrombolysis (IVT) in patients presenting with spontaneous CeAD and acute ischemic stroke symptoms. METHODS: This analysis used data from the retrospective STOP-CAD study and included patients with spontaneous CeAD who presented within 1 day of acute ischemic stroke symptoms. Patients were dichotomized into those who received IVT and those managed without IVT. We assessed the association between IVT and 90-day functional independence (modified Rankin Scale scores 0-2) and the incidence of symptomatic intracranial hemorrhage (ICH, defined as ICH causing new or worsening neurologic symptoms within 72 hours after CeAD diagnosis). RESULTS: This study included 1,653 patients from the original STOP-CAD cohort of 4,023. The median age was 49 years, and 35.1% were women; 512 (31.0%) received IVT. IVT was associated with 90-day functional independence (adjusted odds ratio [aOR] = 1.67, 95% CI 1.23-2.28, p = 0.001), but not with symptomatic ICH (aOR = 1.52, 95% CI 0.79-2.92, p = 0.215). DISCUSSION: In patients with spontaneous CeAD and suspected ischemic stroke, IVT improved functional outcomes, without increasing symptomatic ICH risk. These findings support current guideline recommendations to consider thrombolysis for otherwise eligible patients with CeAD. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that IVT significantly increases the probability of 90-day functional independence in patients with CeAD.

Censoring the Floor Effect in Long-Term Stargardt Disease Microperimetry Data Produces a Faster Rate of Decline.

Purpose: To evaluate progression rate estimation in long-term Stargardt disease microperimetry data by accounting for floor effect. Design: Cohort study. Subjects: Thirty-seven subjects (23 females, 14 males) with biallelic ABCA4 pathogenic or likely pathogenic variants and more than >2 years of longitudinal microperimetry data. Methods: Cross-sectional and longitudinal microperimetry data (Grid A: 18° diameter, Grid B: 6° diameter; Macular Integrity Assessment microperimeter, dynamic range 0-36 decibels [dB]) was extracted from patients with biallelic mutation in the adenosine triphosphate-binding cassette subfamily A member 4 (ABCA4) gene. For each eye, mean sensitivity (MS) and responding point sensitivity (RPS) rates were extracted. Floor censored sensitivity (FCS) progression rate, which accounts for the floor effect at each locus by terminating calculation when scotoma was observed in 2 consecutive visits, was also calculated. In a subset of eyes with ≥1 scotomatous locus at baseline (Grid A), sensitivity progression of loci around the scotoma (edge of scotoma sensitivity [ESS]) was examined against other progression parameters. Paired t test compared progression rate parameters across the same eyes. Main Outcome Measures: Microperimetry grid parameters at baseline and progression rates. Results: A total of 37 subjects with biallelic ABCA4 mutations and >2 years of longitudinal microperimetry data were included in the study. In Grid A, at baseline, the average MS and RPS were 16.5 ± 7.9 and 19.1 ± 5.7 dB, respectively. Similar MS (18.4 ± 7.6 dB) and RPS (20.0 ± 5.5 dB) values were found at baseline for Grid B. In Grid A, overall, MS, RPS, and FCS progression rates were -0.57 ± 1.05, -0.74 ± 1.24, and -1.26 ± 1.65 (all dB/year), respectively. Floor censored sensitivity progression rate was significantly greater than the MS or RPS progression rates. Similar findings were observed in Grid B (MS -1.22 ± 1.42, RPS -1.44 ± 1.44, FCS -2.16 ± 2.24, all dB/year), with paired t test again demonstrated that FCS had a significantly faster rate of decline than MS or RPS. In patients with progression data in both grids, MS, RPS, and FCS progression rates were significantly faster in the smaller Grid B. In 24 eyes with scotoma at baseline, fastest rate of decline was ESS combined with FCS compared with other progression parameters. Conclusions: Incorporation of FCS can reduce confound of floor effect in perimetry analysis and can in turn detect a faster rate of decline. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Imaging with an inverse-designed 50 mm-diameter f/1 MWIR flat lens with enhanced field of view and depth of focus.

We utilize inverse design and grayscale optical lithography to create a flat lens with a diameter and focal length of 50 mm, operating in the mid-wavelength infrared (MWIR) band. This lens demonstrates an extended depth of focus (DOF ≥±100µm), a field of view (FOV ≥20°), and an angular resolution of 300µrad. We characterize the lens's performance and use it as the primary optic in a hybrid refractive-diffractive telescope, which increases the angular resolution to 160µrad. Using this telescope, we perform video imaging of aircraft and vehicles. Our experiments were constrained by the higher f-number of the focal plane array. Nonetheless, through rigorous simulations, we demonstrate that the inverse-designed flat lens surpasses the performance of a conventional Fresnel zone plate (FZP) in DOF and in FOV, even under these limitations. The flat lens, weighing approximately 20g, is significantly lighter than its refractive counterparts, confirming the feasibility of high-resolution, lightweight MWIR imaging systems.

Exploitation of Pore Structure for Increased CO2 Selectivity in Type 3 Porous Liquids.

CO2 capture requires materials with high adsorption selectivity and an industrial ease of implementation. To address these needs, a new class of porous materials was recently developed that combines the fluidity of solvents with the porosity of solids. Type 3 porous liquids (PLs) composed of solvents and metal-organic frameworks (MOFs) offer a promising alternative to current liquid carbon capture methods due to the inherent tunability of the nanoporous MOFs. However, the effects of MOF structural features and solvent properties on CO2-MOF interactions within PLs are not well understood. Herein experimental and computational data of CO2 gas adsorption isotherms were used to elucidate both solvent and pore structure influences on ZIF-based PLs. The roles of the pore structure including solvent size exclusion, structural environment, and MOF porosity on PL CO2 uptake were examined. A comparison of the pore structure and pore aperture was performed using ZIF-8, ZIF-L, and amorphous-ZIF-8. Adsorption experiments here have verified our previously proposed solvent size design principle for ZIF-based PLs (1.8× ZIF pore aperture). Furthermore, the CO2 adsorption isotherms of the ZIF-based PLs indicated that judicious selection of the pore environment allows for an increase in CO2 selectivity greater than expected from the individual PL components or their combination. This nonlinear increase in the CO2 selectivity is an emergent behavior resulting from the complex mixture of components specific to the ZIF-L + 2'-hydroxyacetophenone-based PL.

A National Simulation-Based Study of Pediatric Critical Care Transport Teams Performance.

OBJECTIVES: To assess pediatric critical care transport (CCT) teams' performance in a simulated environment and to explore the impact of team and center characteristics on performance. STUDY DESIGN: This observational, multi-center, simulation-based study enlisted a national cohort of pediatric transport centers. Teams participated in three scenarios: non-accidental abusive head injury (NAT), sepsis, and cardiac arrest. The primary outcome was teams' simulation performance score. Secondary outcomes were associations between performance, center and team characteristics. RESULTS: We recruited 78 transport teams with 196 members from 12 CCT centers. Scores on performance measures that were developed were 89% (IQR 78-100) for NAT, 63.3% (IQR 45.5-81.8) for sepsis, and 86.6% (IQR 66.6-93.3) for cardiac arrest. In multivariable analysis, overall performance was higher for teams including a respiratory therapist (RT; (0.5 points [95% CI: 0.13, 0.86]) or paramedic (0.49 points [95% CI: 0.1, 0.88]) and dedicated pediatric teams (0.37 points [95% 0.06, 0.68]). Each year increase in program age was associated with an increase of 0.04 points (95% CI: 0.02, 0.06). CONCLUSIONS: Dedicated pediatric teams, inclusion of RTs and paramedics, and center age were associated with higher simulation scores for pediatric CCT teams. These insights can guide efforts to enhance the quality of care for children during interfacility transports.

SARS-CoV-2 Rapidly Infects Peripheral Sensory and Autonomic Neurons, Contributing to Central Nervous System Neuroinvasion before Viremia.

Neurological symptoms associated with COVID-19, acute and long term, suggest SARS-CoV-2 affects both the peripheral and central nervous systems (PNS/CNS). Although studies have shown olfactory and hematogenous invasion into the CNS, coinciding with neuroinflammation, little attention has been paid to susceptibility of the PNS to infection or to its contribution to CNS invasion. Here we show that sensory and autonomic neurons in the PNS are susceptible to productive infection with SARS-CoV-2 and outline physiological and molecular mechanisms mediating neuroinvasion. Our infection of K18-hACE2 mice, wild-type mice, and golden Syrian hamsters, as well as primary peripheral sensory and autonomic neuronal cultures, show viral RNA, proteins, and infectious virus in PNS neurons, satellite glial cells, and functionally connected CNS tissues. Additionally, we demonstrate, in vitro, that neuropilin-1 facilitates SARS-CoV-2 neuronal entry. SARS-CoV-2 rapidly invades the PNS prior to viremia, establishes a productive infection in peripheral neurons, and results in sensory symptoms often reported by COVID-19 patients.

Comparing development-matched and age-matched play targets: A replication and extension.

Previous research has supported selecting development-matched targets rather than age-matched targets to teach play skills to children with autism spectrum disorder. However, few studies have been conducted, and replications and extensions of this research are needed. The current study replicated Pane et al. (2022) by comparing the acquisition of development-matched and age-matched play targets when teaching play skills to four children with autism. No contrived prompts or consequences were used to teach play skills in either condition. Extensions included identifying targets via a newer version of the Developmental Play Assessment, targeting different play categories, assessing additional imitation skills, and conducting a caregiver assessment to identify socially valid toys, play actions, and vocalizations based on each participant's common experiences and preferences as well as their caregiver's values and preferences. As in Pane et al., participants demonstrated a higher level of scripted play actions in the development-matched condition.

Toward once-monthly insulin therapy via synergy in two pharmacokinetic protractors: Fc-conjugation and fatty acid acylation.

Pharmacokinetic properties and duration of therapeutic action of a pharmaceutical agent can be significantly extended through the combination of two distinct strategies aimed at increasing plasma half-life: fatty acid acylation and Fc-conjugation. Using insulin as a case study, we demonstrate that a doubly protracted insulin analog produces a substantial prolongation of pharmacodynamic effect to lower blood glucose in STZ-treated mice when compared to the Fc-only counterparts. This enhancement is further corroborated by direct pharmacokinetic measurements in rat and dog models, demonstrating the potential for once-monthly insulin therapy. The results suggest that this approach might have broad application across a diverse spectrum of peptide- and protein-based therapeutics.

Comprehensive Evaluation of Cocaine and its Hydroxy Metabolites in Seized Cocaine and a Large Cohort of Hair Samples.

As cocaine is not only incorporated into hair via blood following ingestion but also by external contamination, hair samples are commonly tested for cocaine metabolites to prove ingestion. However, cocaine metabolites can also be present as degradation products in typical street cocaine samples. The present study investigates minor hydroxycocaine metabolites para- and meta-hydroxycocaine together with para- and meta-hydroxybenzoylecgonine in seized cocaine (n=200) and hair samples from routine casework (n=2,389). Analytical results of hair samples were interpreted using an established decision model for the differentiation between actual use and external contamination using metabolic ratios (metabolite to cocaine). They were further examined concerning background of request, hair color, body site of sample collection, sex, and metabolic ratios of the main metabolites (benzoylecgonine, norcocaine, and cocaethylene). All seized cocaine samples were positive for para- and meta-hydroxycocaine with a maximum percentage of 0.025 and 0.052 %, respectively; para- and meta-hydroxybenzoylecgonine were detected in 55 and 56 % of samples with a maximum percentage of 0.044 and 0.024 %, respectively. Analytical results of 424 hair samples (17.7 %) were interpreted as being predominantly from contamination; the majority of these samples were from traffic medicine cases (83.7 %). Metabolic ratios of minor hydroxycocaine metabolites were significantly higher in hair samples interpreted as originating from use than in samples interpreted as caused by contamination. Metabolic ratios for hydroxycocaines were significantly higher in forensic cases compared to abstinence controls and also in black hair compared to blond/gray hair. However, this was not the case for hydroxybenzoylecgonine metabolic ratios. No statistical difference was observed with regard to the donor's sex. Hydroxycocaine metabolic ratios increased significantly with increasing ratios of norcocaine and cocaethylene to cocaine, respectively. The study demonstrates that hydroxycocaine metabolites (including thresholds for their metabolic ratios) must be used for a reliable interpretation of positive cocaine results in hair samples.

The Clinical Nurse Specialist: Maximizing Return on Investment.

The United States health care system is facing an unprecedented nursing shortage, increasing complexity of care, and fewer experienced nurse mentors. These factors contribute to a cycle of burnout, turnover, decreased quality and safety, and a worsening financial bottom line. Improving these contributing factors depends on our ability to mitigate the structural causes of burnout and turnover. The clinical nurse specialist role is essential to improving the work environment, advancing evidence-based nursing practice, reducing turnover, and stabilizing the bottom line.

Non-syndromic OTX2-associated pattern dystrophy: a 10-year multimodal imaging study.

PURPOSE: To report novel multimodal imaging features and long-term follow-up of Orthodenticle Homeobox 2 (OTX2)-associated pattern Gdystrophy. METHODS: A 14-year-old boy referred with glaucoma suspect and macular pigmentation underwent fundus autofluorescence imaging, optical coherence tomography, fluorescein and indocyanine green angiography, visual field test, microperimetry and electrophysiology over a ten-year period. Next-generation sequencing panel identified a de novo heterozygous likely pathogenic OTX2 variant, c.259G>A, [p.(Glu87Lys)]. RESULTS: Visual acuity was 20/40 OD and 20/30 OS. Examination showed bilateral enlarged optic nerve heads and increased disc cupping, multiple cilioretinal arteries, a pigmentary maculopathy with stellate-shaped region of hypoautofluorescence, shallow serous macular detachment, subretinal deposits and temporal avascular retina. Angiography showed no source of leakage and absence of retinal neovascularisation despite extensive peripheral non perfusion. Electrophysiological assessments demonstrated mild progressive rod and cone pathway abnormalities, reduced light-adapted b:a ratio, and reduced Arden ratio on electro-oculogram. Ten-year follow-up confirmed a stable disease course despite persistent submacular fluid. There was no associated pituitary structural abnormality or dysfunction. CONCLUSIONS: This case study contributes to further understanding of OTX2-associated pattern dystrophy, highlighting its stability over 10 years. Further investigation into inter-individual and intrafamilial variability is warranted.

Bettering Sleep Hygiene to Decrease Delirium and Improve Patient Satisfaction on an Inpatient Oncology Unit.

Poor sleep during hospitalization can negatively affect patient health, well-being, and satisfaction. This nurse-led quality improvement project aimed to promote quality sleep on an inpatient telemetry medical-surgical onco.

In silico fragment-based discovery of CIB1-directed anti-tumor agents by FRASE-bot.

Chemical probes are an indispensable tool for translating biological discoveries into new therapies, though are increasingly difficult to identify since novel therapeutic targets are often hard-to-drug proteins. We introduce FRASE-based hit-finding robot (FRASE-bot), to expedite drug discovery for unconventional therapeutic targets. FRASE-bot mines available 3D structures of ligand-protein complexes to create a database of FRAgments in Structural Environments (FRASE). The FRASE database can be screened to identify structural environments similar to those in the target protein and seed the target structure with relevant ligand fragments. A neural network model is used to retain fragments with the highest likelihood of being native binders. The seeded fragments then inform ultra-large-scale virtual screening of commercially available compounds. We apply FRASE-bot to identify ligands for Calcium and Integrin Binding protein 1 (CIB1), a promising drug target implicated in triple negative breast cancer. FRASE-based virtual screening identifies a small-molecule CIB1 ligand (with binding confirmed in a TR-FRET assay) showing specific cell-killing activity in CIB1-dependent cancer cells, but not in CIB1-depletion-insensitive cells.

Generation of two induced pluripotent stem cell lines from an Usher syndrome type 1B patient with the homozygous c.496del MYO7A variant.

Usher syndrome (USH) is the most common cause of inherited deaf-blindness. Here, we produced the LEIi020-A and LEIi020-B induced pluripotent stem cell (iPSC) lines from dermal fibroblasts derived from a patient with USH1B caused by inheritance of homozygous c.496del variants in MYO7A using episomal plasmids encoding OCT4, SOX2, KLF4, L-MYC, LIN28, mir302/367 microRNA and shRNA for TP53. Both iPSC lines expressed pluripotency markers, demonstrated trilineage differentiation potential and displayed a 46,XY karyotype. These cell lines represent a valuable resource for the production of retinal and otic tissues to support research into the pathogenesis and treatment of USH1B.

Defining and Addressing Research Priorities in Cancer Cachexia through Transdisciplinary Collaboration.

For many patients, the cancer continuum includes a syndrome known as cancer-associated cachexia (CAC), which encompasses the unintended loss of body weight and muscle mass, and is often associated with fat loss, decreased appetite, lower tolerance and poorer response to treatment, poor quality of life, and reduced survival. Unfortunately, there are no effective therapeutic interventions to completely reverse cancer cachexia and no FDA-approved pharmacologic agents; hence, new approaches are urgently needed. In May of 2022, researchers and clinicians from Moffitt Cancer Center held an inaugural retreat on CAC that aimed to review the state of the science, identify knowledge gaps and research priorities, and foster transdisciplinary collaborative research projects. This review summarizes research priorities that emerged from the retreat, examples of ongoing collaborations, and opportunities to move science forward. The highest priorities identified include the need to (1) evaluate patient-reported outcome (PRO) measures obtained in clinical practice and assess their use in improving CAC-related outcomes; (2) identify biomarkers (imaging, molecular, and/or behavioral) and novel analytic approaches to accurately predict the early onset of CAC and its progression; and (3) develop and test interventions (pharmacologic, nutritional, exercise-based, and through mathematical modeling) to prevent CAC progression and improve associated symptoms and outcomes.

An Overview of Adherence-What It Is and Why It Is Important.

Asthma, allergic rhinitis, and food allergy are common allergic diseases, yet adherence to many management options remains poor, leading to worse health outcomes and financial implications for society and health systems. The underlying causes of nonadherence are numerous, ranging from patient-specific factors to broader socioeconomic and systems-based factors. In this review, we aim to discuss the definition of adherence, which can be divided into 3 components: initiation, implementation, and persistence, as well as to review various methods of measuring adherence. Subsequently, we will review the epidemiology of adherence to asthma and allergic rhinitis medications, allergen immunotherapy, and oral immunotherapy. Finally, we will discuss the multifaceted etiology of poor adherence and its subsequent impact on patients and society.

Mobile App-Based Mindfulness Intervention for Addressing Psychological Distress Among Survivors of Hospitalization for COVID-19 Infection.

BACKGROUND: Psychological distress symptoms are present and persistent among many patients who survive a critical illness like COVID-19. RESEARCH QUESTION: Could a self-directed mobile app-delivered mindfulness intervention be feasibly and rapidly implemented within a clinical trials network to reduce distress symptoms? STUDY DESIGN AND METHODS: A randomized clinical trial was conducted between January 2021 and May 2022 at 29 US sites and included survivors of hospitalization due to COVID-19-related illness with elevated symptoms of depression at discharge. Participants were randomized to intervention or usual care control. The intervention consisted of four themed weeks of daily audio, video, and text content. All study procedures were virtual. The primary outcome was depression symptoms assessed with the Patient Health Questionnaire 9 at 3 months. Secondary outcomes included anxiety (Generalized Anxiety Disorder 7-item scale), quality of life (EQ-5D), and adherence. We used general linear models to estimate treatment arm differences in outcomes over time. RESULTS: Among 56 randomized participants (mean age ± SD, 51.0 ± 13.2 years; 38 female [67.9%]; 14 Black participants [25%]), 45 (intervention: n = 23 [79%]; control: n = 22 [81%]) were retained at 6 months. There was no difference in mean improvement between intervention and control participants at 3 months in Patient Health Questionnaire 9 (-0.5 vs 0.1), Generalized Anxiety Disorder 7-item scale (-0.3 vs 0.1), or EQ-5D (-0.03 vs 0.02) scores, respectively; 6-month results were similar. Only 15 participants (51.7%) initiated the intervention, whereas the mean number ± SD of the 56 prescribed intervention activities completed was 12.0 ± 15.2. Regulatory approvals delayed trial initiation by nearly a year. INTERPRETATION: Among survivors of COVID-19 hospitalization with elevated psychological distress symptoms, a self-directed mobile app-based mindfulness intervention had poor adherence. Future psychological distress interventions mobilized at broad scale should focus efforts on patient engagement and regulatory simplification to enhance success. TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT04581200; URL: www.clinicaltrials.gov.

Standardised definitions and diagnostic criteria for extranodal extension detected on histopathological examination in head and neck cancer: Head and Neck Cancer International Group consensus recommendations.

Detection of extranodal extension on histopathology in surgically treated head and neck squamous cell carcinoma indicates poor prognosis. However, there is no consensus on the diagnostic criteria, interpretation, and reporting of histology detected extranodal extension, which has contributed to conflicting evidence in the literature, and likely clinical inconsistency. The Head and Neck Cancer International Group conducted a three-round modified Delphi process with a group of 19 international pathology experts representing 15 national clinical research groups to generate consensus recommendations for histology detected extranodal extension diagnostic criteria. The expert panel strongly agreed on terminology and diagnostic features for histology detected extranodal extension and soft tissue metastasis. Moreover, the panel reached consensus on reporting of histology detected extranodal extension and on nodal sampling. These consensus recommendations, endorsed by 19 organisations representing 34 countries, are a crucial development towards standardised diagnosis and reporting of histology detected extranodal extension, and more accurate data collection and analysis.

Retinal Characteristics of Female Choroideremia Carriers: Multimodal Imaging, Microperimetry, and Genetics.

PURPOSE: To describe visual function and retinal features of female carriers of choroideremia (CHM), using multimodal imaging and microperimetry. DESIGN: Cross-sectional cohort study. PARTICIPANTS AND CONTROLS: Choroideremia carriers seen in Australia (Melbourne or Perth) or the United Kingdom (Oxford or Cambridge) between 2012 and 2023. Healthy age-matched controls seen in Melbourne, Australia, between 2022 and 2023. METHODS: Participants had visual acuity, fundus-tracked microperimetry, OCT, and fundus autofluorescence imaging performed. Choroideremia carriers were either genetically or clinically confirmed (i.e., obligate carriers). Choroideremia carriers were grouped according to their retinal phenotype and compared with healthy controls. Statistical analyses were performed on StataBE (v18.0). MAIN OUTCOME MEASURES: Best-corrected visual acuity (BCVA), low-luminance visual acuity (LLVA), average retinal sensitivity, volume of macular hill of vision (HoV), inner retinal thickness, and photoreceptor complex (PRC) thickness. RESULTS: Eighty-six eyes of 43 CHM carriers and 60 eyes of 30 healthy controls were examined using multimodal imaging and microperimetry. Median age was 54 and 48.5 years for CHM carriers and controls, respectively (P = 0.18). Most CHM carriers (86%) were genetically confirmed. Choroideremia carriers and controls had strong intereye correlation between eyes for BCVA and average retinal sensitivity (P < 0.001). Low-luminance visual acuity and macular HoV tests were sensitive tests to detect changes in CHM carriers with mild phenotypes (i.e., fine and coarse). Choroideremia carriers with geographic or male-pattern phenotypes had reduced BCVA, LLVA, retinal sensitivity, and retinal thinning, compared with healthy controls. Retinal thickening of the inner retina was observed in the central 1°, despite generalized thinning of the PRC in the central 7°, indicating retinal remodeling in CHM carriers, compared with controls. There were no genotype-phenotype correlations observed. CONCLUSIONS: Female carriers of CHM with severe retinal phenotypes (i.e., geographic or male pattern) have significantly decreased visual function and retinal structural changes when compared with age-matched controls and those carriers with milder phenotypes. Low-luminance visual acuity and volumetric measures of the macular HoV were found to be the most sensitive functional tests to detect milder retinal disease (fine and coarse phenotypes) in CHM carriers. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.