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Abstract Aims New tools are needed to identify heart failure (HF) risk earlier in its course. We evaluated the association of multidimensional cardiopulmonary exercise testing (CPET) phenotypes with subclinical risk markers and predicted long‐term HF risk in a large community‐based cohort. Methods and results We studied 2532 Framingham Heart Study participants [age 53 ± 9 years, 52% women, body mass index (BMI) 28.0 ± 5.3 kg/m2, peak oxygen uptake (VO2) 21.1 ± 5.9 kg/m2 in women, 26.4 ± 6.7 kg/m2 in men] who underwent maximum effort CPET and were not taking atrioventricular nodal blocking agents. Higher peak VO2 was associated with a lower estimated HF risk score (Spearman correlation r: −0.60 in men and −0.55 in women, P

Introduction: The prevalence of depression and anxiety in cancer patients is approximately 15% and 20%. Unfortunately, depression has been demonstrated to negatively impact patients after spinal fusion surgeries and is associated with worse overall survival in cancer patients. The rates of depression and anxiety have yet to be reported in patients with metastatic spine disease. The objective of this study was to determine the rate of depression and anxiety in patients with metastatic spine disease. MATERIALS AND METHODS: Patients >18 years of age at our institution who presented with metastatic spinal disease between 2017 and 2022 were identified through query search and verified by chart review of operative and biopsy notes. Patients who carried a depression and anxiety diagnosis were identified through a review of documentation in the electronic medical record. Demographic and surgical characteristics were recorded. Results: One hundred and fifty patients were identified. The average age and Charlson Comorbidity Index were 63.5 ± 13.0 and 8.34 ± 2.76, respectively. There were 84 (56.0%) males, 28 (18.7%) patients carrying a diagnosis of diabetes, and 40 (26.7%) current smokers. There were 127 (84.7%) surgeries performed for spinal metastases. The most common operative location was the thoracic spine (42.5%), while the sacrum was the least common (2.36%). Overall, 20.00% of our cohort carried a diagnosis of depression, 17.3% carried a diagnosis of anxiety, and 28.7% carried a diagnosis of either depression or anxiety. The most common primary cancers were lung (20.67%), breast (17.33%), and prostate cancers (15.33%). Conclusion: Our study demonstrates elevated rates of depression and anxiety in patients with spinal metastatic disease relative to the general population. When evaluating patients with spinal metastases, spine surgeons have an opportunity to screen for symptoms and place an early referral to a mental health professional.

Abstract Background Mobile Integrated Health-Community Paramedicine (MIH-CP) is a novel approach that may reduce the rural-urban disparity in vaccination uptake in the United States. MIH-CP providers, as physician extenders, offer clinical follow-up and wrap-around services in homes and communities, uniquely positioning them as trusted messengers and vaccine providers. This study explores stakeholder perspectives on feasibility and acceptability of community paramedicine vaccination programs. Methods We conducted semi-structured qualitative interviews with leaders of paramedicine agencies with MIH-CP, without MIH-CP, and state/regional leaders in Indiana. Interviews were audio recorded, transcribed verbatim, and analyzed using content analysis. Results We interviewed 24 individuals who represented EMS organizations with MIH-CP programs (MIH-CP; n = 10), EMS organizations without MIH-CP programs (non-MIH-CP; n = 9), and state/regional administrators (SRA; n = 5). Overall, the sample included professionals with an average of 19.6 years in the field (range: 1–42 years). Approximately 75% (n = 14) were male, and all identified as non-Hispanic white. MIH-CPs reported they initiated a vaccine program to reach underserved areas, operating as a health department extension. Some MIH-CPs integrated existing services, such as food banks, with vaccine clinics, while other MIH-CPs focused on providing vaccinations as standalone initiatives. Key barriers to vaccination program initiation included funding and vaccinations being a low priority for MIH-CP programs. However, participants reported support for vaccine programs, particularly as they provided an opportunity to alleviate health disparities and improve community health. MIH-CPs reported low vaccine hesitancy in the community when community paramedics administered vaccines. Non-CP agencies expressed interest in launching vaccine programs if there is clear guidance, sustainable funding, and adequate personnel. Conclusions Our study provides important context on the feasibility and acceptability of implementing an MIH-CP program. Findings offer valuable insights into reducing health disparities seen in vaccine uptake through community paramedics, a novel and innovative approach to reduce health disparities in rural communities.

Abstract Background Compliant pneumatic actuators possess many characteristics that are desirable for wearable robotic systems. These actuators can be lightweight, integrated with clothing, and accommodate uncontrolled degrees of freedom. These attributes are especially desirable for hand exoskeletons, where the soft actuator can conform to the highly variable digit shape. In particular, locating the pneumatic actuator on the palmar side of the digit may have benefits for assisting finger extension and resisting unwanted finger flexion, but this configuration requires suppleness to allow digit flexion while retaining sufficient stiffness to assist extension. Methods To meet these needs, we designed an actuator consisting of a hollow chamber long enough to span the joints of each digit while sufficiently narrow not to inhibit finger adduction. We explored the geometrical design parameter space for this chamber in terms of shape, dimensions, and wall thickness. After fabricating an elastomer-based prototype for each actuator design, we measured active extension force and passive resistance to bending for each chamber using a mechanical jig. We also created a finite element model for each chamber to enable estimation of the impact of chamber deformation, caused by joint rotation, on airflow through the chamber. Finally, we created a prototype hand exoskeleton with the chamber parameters yielding the best outcomes. Results A rectangular cross-sectional area was preferable to a semi-obround shape for the chamber; wall thickness also impacted performance. Extension joint torque reached 0.33 N-m at a low chamber pressure of 48.3 kPa. The finite element model confirmed that airflow for the rectangular chamber remained high despite deformation resulting from joint rotation. The hand exoskeleton created with the rectangular chambers enabled rapid movement, with a cycle time of 1.1 s for voluntary flexion followed by actuated extension. Conclusions The developed soft actuators are feasible for use in promoting finger extension from the palmar side of the hand. This placement utilizes pushing rather than pulling for digit extension, which is more comfortable and safer. The small chamber volumes allow rapid filling and evacuation to facilitate relatively high frequency finger movements.

Abstract To explore complex biological questions, it is often necessary to access various data types from public data repositories. As the volume and complexity of biological sequence data grow, public repositories face significant challenges in ensuring that the data is easily discoverable and usable by the biological research community. To address these challenges, the National Center for Biotechnology Information (NCBI) has created NCBI Datasets. This resource provides straightforward, comprehensive, and scalable access to biological sequences, annotations, and metadata for a wide range of taxa. Following the FAIR (Findable, Accessible, Interoperable, and Reusable) data management principles, NCBI Datasets offers user-friendly web interfaces, command-line tools, and documented APIs, empowering researchers to access NCBI data seamlessly. The data is delivered as packages of sequences and metadata, thus facilitating improved data retrieval, sharing, and usability in research. Moreover, this data delivery method fosters effective data attribution and promotes its further reuse. This paper outlines the current scope of data accessible through NCBI Datasets and explains various options for exploring and downloading the data.

Objectives: The purpose of this study is to identify if construct length affects the rate of surgical complications and instrumentation revision following surgical fixation of subaxial and thoracolumbar Type B and C fractures. This study evaluates the effect of ankylosing spondylitis/diffuse idiopathic skeletal hyperostosis (AS/DISH) within this population on outcomes. Methods: Retrospective review of 91 cervical and 89 thoracolumbar Type B and C fractures. Groups were divided by construct length for analysis: short-segment (constructs spanning two or less segments adjacent to the fracture) and long-segment (constructs spanning more than two segments adjacent to the vertebral fracture). Results: For cervical fractures, construct length did not impact surgical complications (P = 0.641), surgical hardware revision (P = 0.167), or kyphotic change (P = 0.994). For thoracolumbar fractures, construct length did not impact surgical complications (P = 0.508), surgical hardware revision (P = 0.224), and kyphotic change (P = 0.278). Cervical Type B fractures were nonsignificantly more likely to have worsened kyphosis (P = 0.058) than Type C fractures. Assessing all regions of the spine, a diagnosis of AS/DISH was associated with an increase in kyphosis (P = 0.030) and a diagnosis of osteoporosis was associated with surgical hardware failure (P = 0.006). Conclusion: Patients with short-segment instrumentation have similar surgical outcomes and changes in kyphosis compared to those with long-segment instrumentation. A diagnosis of AS/DISH or osteoporosis was associated with worse surgical outcomes.

Abstract This pragmatic review synthesises the current understanding of prodromal dementia with Lewy bodies (pDLB) and prodromal Alzheimer’s disease (pAD), including clinical presentations, neuropsychological profiles, neuropsychiatric symptoms, biomarkers, and indications for disease management. The core clinical features of dementia with Lewy bodies (DLB)—parkinsonism, complex visual hallucinations, cognitive fluctuations, and REM sleep behaviour disorder are common prodromal symptoms. Supportive clinical features of pDLB include severe neuroleptic sensitivity, as well as autonomic and neuropsychiatric symptoms. The neuropsychological profile in mild cognitive impairment attributable to Lewy body pathology (MCI-LB) tends to include impairment in visuospatial skills and executive functioning, distinguishing it from MCI due to AD, which typically presents with impairment in memory. pDLB may present with cognitive impairment, psychiatric symptoms, and/or recurrent episodes of delirium, indicating that it is not necessarily synonymous with MCI-LB. Imaging, fluid and other biomarkers may play a crucial role in differentiating pDLB from pAD. The current MCI-LB criteria recognise low dopamine transporter uptake using positron emission tomography or single photon emission computed tomography (SPECT), loss of REM atonia on polysomnography, and sympathetic cardiac denervation using meta-iodobenzylguanidine SPECT as indicative biomarkers with slowing of dominant frequency on EEG among others as supportive biomarkers. This review also highlights the emergence of fluid and skin-based biomarkers. There is little research evidence for the treatment of pDLB, but pharmacological and non-pharmacological treatments for DLB may be discussed with patients. Non-pharmacological interventions such as diet, exercise, and cognitive stimulation may provide benefit, while evaluation and management of contributing factors like medications and sleep disturbances are vital. There is a need to expand research across diverse patient populations to address existing disparities in clinical trial participation. In conclusion, an early and accurate diagnosis of pDLB or pAD presents an opportunity for tailored interventions, improved healthcare outcomes, and enhanced quality of life for patients and care partners.

Abstract Background Substance use disorder treatment and recovery support services are critical for achieving and maintaining recovery. There are limited data on how structural and social changes due to the COVID-19 pandemic impacted individual-level experiences with substance use disorder treatment-related services among community-based samples of people who inject drugs. Methods People with a recent history of injection drug use who were enrolled in the community-based AIDS Linked to the IntraVenous Experience study in Baltimore, Maryland participated in a one-time, semi-structured interview between July 2021 and February 2022 about their experiences living through the COVID-19 pandemic (n = 28). An iterative inductive coding process was used to identify themes describing how structural and social changes due to the COVID-19 pandemic affected participants’ experiences with substance use disorder treatment-related services. Results The median age of participants was 54 years (range = 24–73); 10 (36%) participants were female, 16 (57%) were non-Hispanic Black, and 8 (29%) were living with HIV. We identified several structural and social changes due the pandemic that acted as barriers and facilitators to individual-level engagement in treatment with medications for opioid use disorder (MOUD) and recovery support services (e.g., support group meetings). New take-home methadone flexibility policies temporarily facilitated engagement in MOUD treatment, but other pre-existing rigid policies and practices (e.g., zero-tolerance) were counteracting barriers. Changes in the illicit drug market were both a facilitator and barrier to MOUD treatment. Decreased availability and pandemic-related adaptations to in-person services were a barrier to recovery support services. While telehealth expansion facilitated engagement in recovery support group meetings for some participants, other participants faced digital and technological barriers. These changes in service provision also led to diminished perceived quality of both virtual and in-person recovery support group meetings. However, a facilitator of recovery support was increased accessibility of individual service providers (e.g., counselors and Sponsors). Conclusions Structural and social changes across several socioecological levels created new barriers and facilitators of individual-level engagement in substance use disorder treatment-related services. Multilevel interventions are needed to improve access to and engagement in high-quality substance use disorder treatment and recovery support services among people who inject drugs.

Summary: The rapid emergence of SARS-CoV-2 variants of concern (VoC) and the threat of future zoonotic sarbecovirus spillover emphasizes the need for broadly protective next-generation vaccines and therapeutics. We utilized SARS-CoV-2 spike ferritin nanoparticle (SpFN), and SARS-CoV-2 receptor binding domain ferritin nanoparticle (RFN) immunogens, in an equine model to elicit hyperimmune sera and evaluated its sarbecovirus neutralization and protection capacity. Immunized animals rapidly elicited sera with the potent neutralization of SARS-CoV-2 VoC, and SARS-CoV-1 pseudoviruses, and potent binding against receptor binding domains from sarbecovirus clades 1b, 1a, 2, 3, and 4. Purified equine polyclonal IgG provided protection against Omicron XBB.1.5 virus in the K18-hACE2 transgenic mouse model. These results suggest that SARS-CoV-2-based nanoparticle vaccines can rapidly produce a broad and protective sarbecovirus response in the equine model and that equine serum has therapeutic potential against emerging SARS-CoV-2 VoC and diverse sarbecoviruses, presenting a possible alternative or supplement to monoclonal antibody immunotherapies.

T1ρ and Quantitative Susceptibility Mapping (QSM) are evolving as substrates for quantifying the progressive nature of knee osteoarthritis. Objective: To evaluate the effects of spin lock time combinations on depth-dependent T1ρ estimation, in adjunct to QSM, and characterize the degree of shared variance in QSM and T1ρ for the quantitative measurement of articular cartilage. Design: Twenty healthy participants (10 ​M/10F, 22.2 ​± ​3.4 years) underwent bilateral knee MRI using T1ρ MAPPS sequences with varying TSLs ([0–120] ms), along with a 3D spoiled gradient echo for QSM. Five total TSL combinations were used for T1ρ computation, and direct depth-based comparison. Depth-wide variance was assessed in comparison to QSM as a basis to assess for depth-specific variation in T1ρ computations across healthy cartilage. Results: Longer T1ρ relaxation times were observed for TSL combinations with higher spin lock times. Depth-specific differences were documented for both QSM and T1ρ, with most change found at ∼60% depth of the cartilage, relative to the surface. Direct squared linear correlation revealed that most T1ρ TSL combinations can explain over 30% of the variability in QSM, suggesting inherent shared sensitivity to cartilage microstructure. Conclusions: T1ρ mapping is subjective to the spin lock time combinations used for computation of relaxation times. When paired with QSM, both similarities and differences in signal sensitivity may be complementary to capture depth-wide changes in articular cartilage.

Background Aficamten, a novel cardiac myosin inhibitor, reversibly reduces cardiac hypercontractility in obstructive hypertrophic cardiomyopathy. We present a prespecified analysis of the pharmacokinetics, pharmacodynamics, and safety of aficamten in SEQUOIA‐HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM). Methods and Results A total of 282 patients with obstructive hypertrophic cardiomyopathy were randomized 1:1 to daily aficamten (5–20 mg) or placebo between February 1, 2022, and May 15, 2023. Aficamten dosing targeted the lowest effective dose for achieving site‐interpreted Valsalva left ventricular outflow tract gradient

Atrial fibrillation (AF) represents the most common cardiac arrhythmia with significant morbidity and mortality implications. It is a common cause of hospital admissions, significantly impacts quality of life, increases morbidity and decreases life expectancy. Despite advancements in treatment options, prevalence of AF remains exceptionally high. AF is a challenging disease to manage, not just clinically but also financially. Evidence suggests lifestyle modification, including dietary changes, plays a significant role in the treatment of AF. This review aims to analyze the existing literature on the effects of dietary modifications on the incidence, progression, and outcomes of atrial fibrillation. It examines various dietary components, including alcohol, caffeine, omega-3 polyunsaturated fatty acids and minerals, and their impact on AF incidence, progression, and outcomes. The evidence surrounding the effects of dietary patterns, such as the Mediterranean and low carbohydrate diets, on AF is also evaluated. Overall, this review underscores the importance of dietary interventions as part of a comprehensive approach to AF management and highlights the need for further research in this emerging field.

Background: Peak oxygen consumption and oxygen pulse along with their respective percent predicted measures are gold standards of exercise capacity. To date, no studies have investigated the relationship between percent predicted peak oxygen pulse (%PredO2P) and ventricular-vascular response (VVR) and the association of %PredO2P with all-cause mortality in heart failure with preserved ejection fraction (HFpEF) patients. Objectives: The authors investigated the association between: 1) CPET measures of %PredO2P and VVR; and 2) %PredO2P and all-cause mortality in HFpEF patients. Methods: Our cohort of 154 HFpEF patients underwent invasive CPET and were grouped into %PredO2P tertiles. The association between percent predicted Fick components and markers of VVR (ie, proportionate pulse pressure, effective arterial elastance) was determined with correlation analysis. The Cox proportional hazards model was used to identify predictors of mortality. Results: The participants’ mean age was 57 ± 15 years. Higher %PredO2P correlated with higher exercise capacity. In terms of VVR, higher %PredO2P correlated with a lower pressure for a given preload (effective arterial elastance r = −0.45, P

Abstract Background Sleep is a critical component of recovery, but it can be disrupted following prolonged endurance exercise. The objective of this study was to examine the capacity of male and female professional cyclists to recover between daily race stages while competing in the 2022 Tour de France and the 2022 Tour de France Femmes, respectively. The 17 participating cyclists (8 males from a single team and 9 females from two teams) wore a fitness tracker (WHOOP 4.0) to capture recovery metrics related to night-time sleep and autonomic activity for the entirety of the events and for 7 days of baseline before the events. The primary analyses tested for a main effect of ‘stage classification’—i.e., rest, flat, hilly, mountain or time trial for males and flat, hilly or mountain for females—on the various recovery metrics. Results During baseline, total sleep time was 7.2 ± 0.3 h for male cyclists (mean ± 95% confidence interval) and 7.7 ± 0.3 h for female cyclists, sleep efficiency was 87.0 ± 4.4% for males and 88.8 ± 2.6% for females, resting HR was 41.8 ± 4.5 beats·min−1 for males and 45.8 ± 4.9 beats·min−1 for females, and heart rate variability during sleep was 108.5 ± 17.0 ms for males and 119.8 ± 26.4 ms for females. During their respective events, total sleep time was 7.2 ± 0.1 h for males and 7.5 ± 0.3 h for females, sleep efficiency was 86.4 ± 1.2% for males and 89.6 ± 1.2% for females, resting HR was 44.5 ± 1.2 beats·min−1 for males and 50.2 ± 2.0 beats·min−1 for females, and heart rate variability during sleep was 99.1 ± 4.2 ms for males and 114.3 ± 11.2 ms for females. For male cyclists, there was a main effect of ‘stage classification’ on recovery, such that heart rate variability during sleep was lowest after mountain stages. For female cyclists, there was a main effect of ‘stage classification’ on recovery, such that the percentage of light sleep (i.e., lower-quality sleep) was highest after mountain stages. Conclusions Some aspects of recovery were compromised after the most demanding days of racing, i.e., mountain stages. Overall however, the cyclists obtained a reasonable amount of good-quality sleep while competing in these physiologically demanding endurance events. This study demonstrates that it is now feasible to assess recovery in professional athletes during multiple-day endurance events using validated fitness trackers.

Abstract Background As antiretroviral therapy has become widely available and highly effective, HIV has evolved to a manageable, chronic disease. Despite this health advancement, people living with HIV (PLWH) are at an increased risk for age-related non-communicable diseases (NCDs) compared to HIV-uninfected individuals. Similarly, PLWH are at an increased risk for selected oral diseases. PLWH with a history of injecting drugs experience an even greater burden of disease than their counterparts. The overall objective of the Baltimore Oral Epidemiology, Disease Effects, and HIV Evaluation (BEEHIVE) study is to determine the combined effects of HIV infection and NCDs on oral health status. The specific aims of the study are to: (1) determine to what extent HIV status influences access to and utilization of oral health care services; (2) determine to what extent HIV status affects self-reported and clinical oral health status; (3) determine to what extent HIV status influences the progression of periodontitis; and (4) determine to what extent HIV status impacts the periodontitis-associated oral microbiome signature. Methods The BEEHIVE study uses a prospective cohort study design to collect data from participants at baseline and at a 24-month follow-up visit. Data are collected through questionnaire assessments, clinical examinations, and evaluation of oral microbiological samples to determine the drivers of oral disease among a high-risk population of PLWH with a history of injection drug use and prevalent comorbid NCDs. The established AIDS Linked to the Intravenous Experience (ALIVE) cohort serves as the source of participants for the BEEHIVE Study. Discussion Upon completion of the BEEHIVE study, the knowledge gained will be important in informing future clinical and preventive interventions that can be implemented into medical and dental practice to ultimately help eliminate long-standing oral health inequities that PLWH experience.

Abstract Background Injection drug use (IDU) can increase mortality and morbidity. Therefore, identifying IDU early and initiating harm reduction interventions can benefit individuals at risk. However, extracting IDU behaviors from patients’ electronic health records (EHR) is difficult because there is no other structured data available, such as International Classification of Disease (ICD) codes, and IDU is most often documented in unstructured free-text clinical notes. Although natural language processing can efficiently extract this information from unstructured data, there are no validated tools. Methods To address this gap in clinical information, we design a question-answering (QA) framework to extract information on IDU from clinical notes for use in clinical operations. Our framework involves two main steps: (1) generating a gold-standard QA dataset and (2) developing and testing the QA model. We use 2323 clinical notes of 1145 patients curated from the US Department of Veterans Affairs (VA) Corporate Data Warehouse to construct the gold-standard dataset for developing and evaluating the QA model. We also demonstrate the QA model’s ability to extract IDU-related information from temporally out-of-distribution data. Results Here, we show that for a strict match between gold-standard and predicted answers, the QA model achieves a 51.65% F1 score. For a relaxed match between the gold-standard and predicted answers, the QA model obtains a 78.03% F1 score, along with 85.38% Precision and 79.02% Recall scores. Moreover, the QA model demonstrates consistent performance when subjected to temporally out-of-distribution data. Conclusions Our study introduces a QA framework designed to extract IDU information from clinical notes, aiming to enhance the accurate and efficient detection of people who inject drugs, extract relevant information, and ultimately facilitate informed patient care.

Objective To evaluate preoperative disability’s influence on patient-reported outcomes (PROs) following surgery for degenerative spondylolisthesis (DS). Methods DS patients who underwent surgical intervention were retrospectively identified from a single-surgeon spine registry. Cohorts based on Oswestry Disability Index (ODI) < 41 (milder disability) and ≥ 41 (severe disability) were created. Demographic differences were accounted for with 1:1 propensity score matching. For the matched sample, perioperative and PRO data were additionally collected. PROs assessed included mental health, physical function, pain, and disability. Pre- and up to 2-year postoperative PROs were utilized. Average time to final follow-up was 15.7 ± 8.8 months. Improvements in PROs and minimal clinically important difference (MCID) rates were calculated. Continuous variables were compared through Student t-test and categorical variables were compared through chi-square tests. Results Altogether, 214 patients were included with 77 in the milder disability group. The severe disability group had worse postoperative day (POD) 1 pain scores and longer hospital stays (p ≤ 0.038, both). The severe disability group reported worse outcomes pre- and postoperatively (p < 0.011, all), but had greater average improvement in 12-item Short Form health survey mental composite score (SF-12 MCS), 9-Item Patient Health Questionnaire (PHQ-9), visual analogue scale (VAS)-back, and ODI by 6 weeks (p ≤ 0.037, all) and PHQ-9, VAS-back and ODI by final follow-up (p ≤ 0.015, all). The severe disability cohort was more likely to achieve MCID for SF-12 MCS, PHQ-9, and ODI (p ≤ 0.003, all). Conclusion Patients with greater baseline disability report higher POD 1 pain and discharge later than patients with milder disability. While these patients report inferior physical/mental health before and after surgery, they report greater improvements in mental health and disability postoperatively.

Objective To evaluate the effect of Veterans RAND 12-item health survey mental composite score (VR-12 MCS) on postoperative patient-reported outcome measures (PROMs) after undergoing lateral lumbar interbody fusion. Methods Retrospective data from a single-surgeon database created 2 cohorts: patients with VR-12 MCS ≥ 50 or VR-12 MCS < 50. Preoperative, 6-week, and final follow-up (FF)- PROMs including VR-12 MCS/physical composite score (PCS), 12-item Short Form health survey (SF-12) MCS/PCS, Patient-Reported Outcomes Measurement Information System Physical Function (PROMIS-PF), Patient Health Questionnaire-9 (PHQ-9), visual analogue scale (VAS)-back/leg pain (VAS-BP/LP), and Oswestry Disability Index (ODI) were collected. ∆6-week and ∆FF-PROMs were calculated. Minimal clinically important difference (MCID) achievement rates were determined from established cutoffs from the literature. For intercohort comparison, chi-square analysis was used for categorical variables, and Student t-test for continuous variables. Results Seventy-nine patients were included; 25 were in VR-12 MCS < 50. Mean postoperative follow-up time was 17.12 ± 8.43 months. The VR-12 MCS < 50 cohort had worse VR-12 PCS, SF-12 MCS, PROMIS-PF, PHQ-9, VAS-BP, and ODI scores preoperatively (p ≤ 0.014, all), worse VR-12 MCS/PCS, SF-12 MCS, PROMIS-PF, PHQ-9, and ODI scores at 6-week postoperatively (p ≤ 0.039, all), and worse VR-12 MCS, SF-12 MCS, PROMIS-PF, PHQ-9, VAS-BP, VAS-LP, and ODI scores at FF (p ≤ 0.046, all). The VR-12 MCS < 50 cohort showed greater improvement in VR-12 MCS and SF-12 MCS scores at 6 weeks and FF (p ≤ 0.005, all). The VR-12 MCS < 50 cohort experienced greater MCID achievement for VR-12 MCS, SF-12 MCS, and PHQ-9 (p ≤ 0.006, all). Conclusion VR-12 MCS < 50 yielded worse mental health, physical function, pain and disability postoperatively, yet reported greater improvements in magnitude and MCID achievement for mental health.

Analysis of purple dyestuff from a tin labeled “1 oz. Cudbear, No. 1 N. F. Powdered”, marketed by the American business S. B. Penick & Company, “Manufacturers of fine drugs and chemicals”, confirmed that the material was indeed a lichen dyestuff. It contains the same major orcein components identified in several other lichen dyes and dyed samples dating from the mid-19th century to today. These dyestuffs were analyzed using several analytical techniques. Fluorescence and fiber optic reflectance spectroscopic data for all the samples were similar. High performance liquid chromatography with diode array detection coupled to mass spectrometry confirmed that this commercial American cudbear was very similar to the samples from the United Kingdom but rather different from the archil-dyed reference yarns from Europe. The significance of the observations is discussed, and chemical structures are proposed for several of the unknown dye components detected in this study.

This paper describes the identification of dyes on fifty yarn samples from a tapestry created by the well-known 17th-century Flemish workshop of the Mattens family. The design of the tapestry is based on the first of ten drawings known as the Acts of the Apostles by the famed 16th-century Italian painter Raphael. The drawings were commissioned by Pope Leo X and translated into tapestries by Pieter van Aelst; these original tapestries are still in the collection of the Vatican Museums. The present work was reproduced over a century later from the original drawing and is one in a possible set of nearly fifty known copies of the original tapestry cycle. Most of the Mattens yarn samples were found to be dyed by weld, indigo, and madder, as well as a few using brazilwood and lichen, but no insect dyes were detected. A significant finding in the present study was the detection of the dye component pseudoindirubin 1, alongside indigotin and indirubin, as well as yarns that only yielded the latter two dyes. The implication of using this new marker as objective evidence of the use of both woad and most likely Asian indigo is explored. The historical and conservation significance of the dyestuffs identified is also discussed.

Abstract Nucleobase editors represent an emerging technology that enables precise single-base edits to the genomes of eukaryotic cells. Most nucleobase editors use deaminase domains that act upon single-stranded DNA and require RNA-guided proteins such as Cas9 to unwind the DNA prior to editing. However, the most recent class of base editors utilizes a deaminase domain, DddAtox, that can act upon double-stranded DNA. Here, we target DddAtox fragments and a FokI-based nickase to the human CIITA gene by fusing these domains to arrays of engineered zinc fingers (ZFs). We also identify a broad variety of Toxin-Derived Deaminases (TDDs) orthologous to DddAtox that allow us to fine-tune properties such as targeting density and specificity. TDD-derived ZF base editors enable up to 73% base editing in T cells with good cell viability and favorable specificity.

Study Design Retrospective cohort study. Purpose To correlate cervical facet fluid characteristics to radiographic spondylolisthesis, determine if facet fluid is associated with instability in cervical degenerative spondylolisthesis, and examine whether vertebral levels with certain facet fluid characteristics and spondylolisthesis are more likely to be operated on. Overview of Literature The relationship between facet fluid and lumbar spondylolisthesis is well-documented; however, there is a paucity of literature investigating facet fluid in degenerative cervical spondylolisthesis. Methods Patients diagnosed with cervical degenerative spondylolisthesis were identified from a hospital’s medical records. Demographic and surgical characteristics were collected through a structured query language search and manual chart review. Radiographic measurements were made on preoperative MRIs for all vertebral levels diagnosed with spondylolisthesis and adjacent undiagnosed levels between C3 and C6. The facet fluid index was calculated by dividing the facet fluid measurement by the width of the facet. Bivariate analysis was conducted to compare facet characteristics based on radiographic spondylolisthesis and spondylolisthesis stability. Results We included 154 patients, for whom 149 levels were classified as having spondylolisthesis and 206 levels did not. The average facet fluid index was significantly higher in patients with spondylolisthesis (0.26±0.07 vs. 0.23±0.08, p

Statistical analysis of low latitude spread F is presented for three different longitudinal sectors from Jicamarca (12°S, 76.8°W, −2.5° declination angle) from 2001 to 2016, Ascension Island (7.9°S, 14.4°W, −15.09° declination angle) from 2000 to 2014, Kwajalein (8.71°N, 167.7°E, 7.5° declination angle) from 2004 to 2012. Digisonde data from these stations have been processed and analyzed to study statistical variations of equatorial spread F, a diagnostic of irregular plasma structure in the ionosphere. A new automated method of spread F detection using pattern recognition and edge detection for low latitude regions is used to determine solar and seasonal variation over these three sites. An algorithm has been developed to detect the foF2 and hpF2 parameters and this has been validated by comparisons with manually scaled data as well as with SAMI2 and International Reference Ionosphere models showing good correlation. While significant variation is not observed over the solar cycle, the different longitudes and declination angles contribute to the variations over the seasonal cycle.

Gene silencing without gene editing holds great potential for the development of safe therapeutic applications. Here, we describe a novel strategy to concomitantly repress multiple genes using zinc finger proteins fused to Krüppel-Associated Box repression domains (ZF-Rs). This was achieved via the optimization of a lentiviral system tailored for the delivery of ZF-Rs in hematopoietic cells. We showed that an optimal design of the lentiviral backbone is crucial to multiplex up to three ZF-Rs or two ZF-Rs and a chimeric antigen receptor. ZF-R expression had no impact on the integrity and functionality of transduced cells. Furthermore, gene repression in ZF-R-expressing T cells was highly efficient in vitro and in vivo during the entire monitoring period (up to 10 weeks), and it was accompanied by epigenetic remodeling events. Finally, we described an approach to improve ZF-R specificity to illustrate the path toward the generation of ZF-Rs with a safe clinical profile. In conclusion, we successfully developed an epigenetic-based cell engineering approach for concomitant modulation of multiple gene expressions that bypass the risks associated with DNA editing.

We demonstrate indirect electric-field control of ferromagnetic resonance (FMR) in devices that integrate the low-loss, molecule-based, room-temperature ferrimagnet vanadium tetracyanoethylene (V[TCNE]x∼2) mechanically coupled to PMN-PT piezoelectric transducers. Upon straining the V[TCNE]x films, the FMR frequency is tuned by more than 6 times the resonant linewidth with no change in Gilbert damping for samples with α = 6.5 × 10−5. We show this tuning effect is due to a strain-dependent magnetic anisotropy in the films and find the magnetoelastic coefficient |λs| ∼ (1–4.4) ppm, backed by theoretical predictions from density-functional theory calculations and magnetoelastic theory. Noting the rapidly expanding application space for strain-tuned FMR, we define a new metric for magnetostrictive materials, magnetostrictive agility, given by the ratio of the magnetoelastic coefficient to the FMR linewidth. This agility allows for a direct comparison between magnetostrictive materials in terms of their comparative efficacy for magnetoelectric applications requiring ultra-low loss magnetic resonance modulated by strain. With this metric, we show V[TCNE]x is competitive with other magnetostrictive materials, including YIG and Terfenol-D. This combination of ultra-narrow linewidth and magnetostriction, in a system that can be directly integrated into functional devices without requiring heterogeneous integration in a thin film geometry, promises unprecedented functionality for electric-field tuned microwave devices ranging from low-power, compact filters and circulators to emerging applications in quantum information science and technology.

Introduction/Objectives: Despite U.S. Preventive Services Task Force and American Cancer Society endorsement of primary HPV screening, limited published data shows low uptake. Primary Aim: Assess cervical cancer screening rates over time, particularly primary HPV test uptake, among patients in a midwestern practice. Secondary Aim: Evaluate associations between sociodemographics and screening adherence. Methods: Cross-sectional study. Qualifying subjects and type of screening test used were identified by applying ICD-9, ICD-10, lab test, and CPT codes to the Unified Data Platform. Sociodemographics were found through the electronic health record. Results: Primary HPV uptake represented

Background The relation of cardiorespiratory fitness (CRF) to lifestyle behaviors and factors linked with cardiovascular health remains unclear. We aimed to understand how the American Heart Association's Life's Essential 8 (LE8) score (and its changes over time) relate to CRF and complementary exercise measures in community‐dwelling adults. Methods and Results Framingham Heart Study (FHS) participants underwent maximum effort cardiopulmonary exercise testing for direct quantification of peak oxygen uptake (V̇O2). A 100‐point LE8 score was constructed as the average across 8 factors: diet, physical activity, nicotine exposure, sleep, body mass index, lipids, blood glucose, and blood pressure. We related total LE8 score, score components, and change in LE8 score over 8 years with peak V̇O2 (log‐transformed) and complementary CRF measures. In age‐ and sex‐adjusted linear models (N=1838, age 54±9 years, 54% women, LE8 score 76±12), a higher LE8 score was associated favorably with peak V̇O2, ventilatory efficiency, resting heart rate, and blood pressure response to exercise (all P

Abstract The repeat emergence of SARS-CoV-2 variants of concern (VoC) with decreased susceptibility to vaccine-elicited antibodies highlights the need to develop next-generation vaccine candidates that confer broad protection. Here we describe the antibody response induced by the SARS-CoV-2 Spike Ferritin Nanoparticle (SpFN) vaccine candidate adjuvanted with the Army Liposomal Formulation including QS21 (ALFQ) in non-human primates. By isolating and characterizing several monoclonal antibodies directed against the Spike Receptor Binding Domain (RBD), N-Terminal Domain (NTD), or the S2 Domain, we define the molecular recognition of vaccine-elicited cross-reactive monoclonal antibodies (mAbs) elicited by SpFN. We identify six neutralizing antibodies with broad sarbecovirus cross-reactivity that recapitulate serum polyclonal antibody responses. In particular, RBD mAb WRAIR-5001 binds to the conserved cryptic region with high affinity to sarbecovirus clades 1 and 2, including Omicron variants, while mAb WRAIR-5021 offers complete protection from B.1.617.2 (Delta) in a murine challenge study. Our data further highlight the ability of SpFN vaccination to stimulate cross-reactive B cells targeting conserved regions of the Spike with activity against SARS CoV-1 and SARS-CoV-2 variants.

Abstract The relationships between place (e.g., neighborhood) and HIV are commonly investigated. As measurements of place are multivariate, most studies apply some dimension reduction, resulting in one variable (or a small number of variables), which is then used to characterize place. Typical dimension reduction methods seek to capture the most variance of the raw items, resulting in a type of summary variable we call “disadvantage score”. We propose to add a different type of summary variable, the “vulnerability score,” to the toolbox of the researchers doing place and HIV research. The vulnerability score measures how place, as known through the raw measurements, is predictive of an outcome. It captures variation in place characteristics that matters most for the particular outcome. We demonstrate the estimation and utility of place-based vulnerability scores for HIV viral non-suppression, using data with complicated clustering from a cohort of people with histories of injecting drugs.

Background and Aims: Placebo response impedes the development of novel irritable bowel syndrome (IBS) therapies and the interpretability of randomized clinical trials. This study sought to characterize the magnitude, timing, and durability of IBS symptom relief in patients undergoing a non-drug placebo-like control. Methods: One hundred forty-five Rome III-diagnosed patients (80% F, M age = 42 years) were assigned to education/nondirective support delivered over a 10-week acute phase. Treatment response was based on the IBS version of the Clinical Global Improvement Scale completed 2 weeks after treatment ended. Candidate predictors were assessed at baseline (eg, emotion regulation, pain catastrophizing, distress, neuroticism, stress, somatization, gastrointestinal-specific anxiety) or clinically relevant points during treatment (patient-provider relationship, treatment expectancy/credibility). Results: Midtreatment response was associated with lower levels of stress and somatization at baseline and greater patient-provider agreement on treatment tasks (P < .001). Treatment response was associated with baseline gastroenterologist-rated IBS severity, anxiety, ability to reappraise emotions to reduce their impact [cognitive reappraisal], and agreement that provider and patient shared goals from provider perspective (P < .001). The day-to-day ability to reappraise emotions at baseline distinguished rapid from delayed placebo responders (P = .011). Conclusion: Patient beliefs (eg, perceived stress, cognitive reappraisal) impacted the magnitude, timing, and persistence of placebo response measured at midway point of acute phase and 2 weeks after treatment discontinuation. Baseline beliefs that patients could alter the impact of stressful events by rethinking their unpleasantness distinguished rapid vs delayed placebo responders. Collaborative agreement between doctor and patient around shared tasks/goals from the clinician perspective predicted placebo response.

Study Design This study is a retrospective cohort study. Purpose This study aims to determine whether preoperative neuroforaminal stenosis (FS) severity is associated with motor function patient-reported outcome measures (PROMs) following anterior cervical discectomy and fusion (ACDF). Overview of Literature Cervical FS can significantly contribute to patient symptoms. While magnetic resonance imaging (MRI) has been used to classify FS, there has been limited research into the impact of FS severity on patient outcomes. Methods Patients undergoing primary, elective 1–3 level ACDF for radiculopathy at a single academic center between 2015 and 2021 were identified retrospectively. Cervical FS was evaluated using axial T2-weighted MRI images via a validated grading scale. The maximum degree of stenosis was used for multilevel disease. Motor symptoms were classified using encounters at their final preoperative and first postoperative visits, with examinations ≤3/5 indicating weakness. PROMs were obtained preoperatively and at 1-year follow-up. Bivariate analysis was used to compare outcomes based on stenosis severity, followed by multivariable analysis. Results This study included 354 patients, 157 with moderate stenosis and 197 with severe stenosis. Overall, 58 patients (16.4%) presented with upper extremity weakness ≤3/5. A similar number of patients in both groups presented with baseline motor weakness (13.5% vs. 16.55, p=0.431). Postoperatively, 97.1% and 87.0% of patients with severe and moderate FS, respectively, experienced full motor recovery (p=0.134). At 1-year, patients with severe neuroforaminal stenosis presented with significantly worse 12-item Short Form Survey Physical Component Score (PCS-12) (33.3 vs. 37.3, p=0.049) but demonstrated a greater magnitude of improvement (ΔPCS-12: 5.43 vs. 0.87, p=0.048). Worse stenosis was independently associated with greater ΔPCS-12 at 1-year (β=5.59, p=0.022). Conclusions Patients with severe FS presented with worse preoperative physical health. While ACDF improved outcomes and conferred similar motor recovery in all patients, those with severe FS reported much better improvement in physical function.

Study Design Retrospective cohort study. Purpose This study aimed to determine whether the initiation of anti-calcitonin gene-related peptide (CGRP inhibitor) medication therapy for migraines was also associated with improvements in back/neck pain, mobility, and function in a patient population with comorbid degenerative spinal disease and migraine. Overview of Literature CGRP upregulates pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin-6, brain-derived neurotrophic factor, and nerve growth factor in spinal spondylotic disease, which results in disc degeneration and sensitization of nociceptive neurons. Although CGRP inhibitors can quell neurogenic inflammation in migraines, their off-site efficacy as a therapeutic target for discogenic back/neck pain conditions remains unknown. Methods All adult patients diagnosed with spinal spondylosis and migraine treated with CGRP inhibitors at a single academic institution between 2017 and 2020 were retrospectively identified. Patient demographic and medical data, follow-up duration, migraine severity and frequency, spinal pain, functional status, and mobility before and after the administration of CGRP inhibitors were collected. Paired univariate analysis was conducted to determine significant changes in spinal pain, headache severity, and headache frequency before and after the administration of CGRP inhibitors. The correlation between changes in the spinal pain score and functional or mobility improvement was assessed with Spearman’s rho. Results In total, 56 patients were included. The mean follow-up time after the administration of CGRP inhibitors was 123 days for spinal pain visits and 129 days for migraine visits. Back/neck pain decreased significantly (p

ABSTRACTPrion diseases are fatal neurologic disorders that can be transmitted by blood transfusion. The route for neuroinvasion following exposure to infected blood is not known. Carotid bodies (CBs) are specialized chemosensitive structures that detect the concentration of blood gasses and provide feedback for the neural control of respiration. Sensory cells of the CB are highly perfused and densely innervated by nerves that are synaptically connected to the brainstem and thoracic spinal cord, known to be areas of early prion deposition following oral infection. Given their direct exposure to blood and neural connections to central nervous system (CNS) areas involved in prion neuroinvasion, we sought to determine if there were cells in the human CB that express the cellular prion protein (PrPC), a characteristic that would support CBs serving as a route for prion neuroinvasion. We collected CBs from cadaver donor bodies and determined that mast cells located in the carotid bodies express PrPC and that these cells are in close proximity to blood vessels, nerves, and nerve terminals that are synaptically connected to the brainstem and spinal cord.

Abstract Background Joint hypermobility is a common clinical finding amongst hereditary connective tissue disorders that is observed in pediatric rheumatological settings, and often associated with chronic pain. Joint hypermobility may also contribute to deficits in physical functioning and physical activity, but previous findings have been inconsistent. It is possible that physical activity impairment in joint hypermobility may be due to chronic aberrant movement patterns subsequent to increased joint laxity. Method As part of a larger randomized pilot trial of juvenile onset fibromyalgia (JFM), a secondary analysis was conducted to explore whether adolescents with JFM and joint hypermobility differed from non-joint hypermobility peers in terms of pain, daily functioning, and biomechanics (i.e., kinetics and kinematics) during a moderately vigorous functional task. Results From the larger sample of adolescents with JFM (N = 36), 13 adolescents (36.1%) met criteria for joint hypermobility and 23 did not have joint hypermobility. Those with joint hypermobility exhibited poorer overall functioning (Md = 20, Q 1 ,Q 3 [5.8, 7.6] vs. Md = 29, Q 1 ,Q 3 [5.1, 7.6]) but there were no differences in pain (Md = 6.9, Q 1 ,Q 3 [22, 33] , vs. Md = 6.45, Q 1 ,Q 3 [15, 29.5]). Inspection of time-series plots suggests those with joint hypermobility exhibited decreased hip flexion and frontal plane hip moment (e.g., resistance to dynamic valgus) during the landing phase (early stance) and greater hip and knee transverse plane moments during the propulsion phase (late stance) of the drop vertical jump task (DVJ). No other differences in lower extremity biomechanics were observed between study groups. Conclusions In this exploratory study, there were small but notable differences in biomechanics between patients with JFM who also had joint hypermobility versus those without joint hypermobility during a landing and jumping task (e.g., DVJ). These differences may indicate decreased joint stiffness during landing, associated with increased joint laxity and decreased joint stability, which may put them at greater risk for injury. Further study with a larger sample size is warranted to examine whether these biomechanical differences in patients with JFM and joint hypermobility affect their response to typical physical therapy or exercise recommendations.

Abstract Small nucleotide variants in non-coding regions of the genome can alter transcriptional regulation, leading to changes in gene expression which can activate oncogenic gene regulatory networks. Melanoma is heavily burdened by non-coding variants, representing over 99% of total genetic variation, including the well-characterized TERT promoter mutation. However, the compendium of regulatory non-coding variants is likely still functionally under-characterized. We developed a pipeline to identify hotspots, i.e. recurrently mutated regions, in melanoma containing putatively functional non-coding somatic variants that are located within predicted melanoma-specific regulatory regions. We identified hundreds of statistically significant hotspots, including the hotspot containing the TERT promoter variants, and focused on a hotspot in the promoter of CDC20. We found that variants in the promoter of CDC20, which putatively disrupt an ETS motif, lead to lower transcriptional activity in reporter assays. Using CRISPR/Cas9, we generated an indel in the CDC20 promoter in human A375 melanoma cell lines and observed decreased expression of CDC20, changes in migration capabilities, increased growth of xenografts, and an altered transcriptional state previously associated with a more proliferative and less migratory state. Overall, our analysis prioritized several recurrent functional non-coding variants that, through downregulation of CDC20, led to perturbation of key melanoma phenotypes.

Abstract Systemic inflammation has been implicated in the pathobiology of heart failure with preserved ejection fraction (HFpEF). Here, we examine the association of upstream mediators of inflammation as ascertained by fatty-acid derived eicosanoid and eicosanoid-related metabolites with HFpEF status and exercise manifestations of HFpEF. Among 510 participants with chronic dyspnea and preserved LVEF who underwent invasive cardiopulmonary exercise testing, we find that 70 of 890 eicosanoid and related metabolites are associated with HFpEF status, including 17 named and 53 putative eicosanoids (FDR q-value

Background: Surgeon visual estimation of shoulder range of motion (ROM) is commonplace in the outpatient office setting and routinely reported in clinical research, but the reliability and accuracy of this practice remain unclear. The purpose of this study is to establish the reliability and accuracy of remote visual estimation of shoulder ROM in healthy volunteers and symptomatic patients among a large group of shoulder surgeons. Our hypothesis is that remote visual estimation would be reliable and accurate compared with the digital goniometer method. Methods: Fifty shoulder surgeon members of the PacWest Shoulder and Elbow Society independently determined the active shoulder forward flexion (FF), internal rotation at 90° abduction (IR90), external rotation at 90° abduction, external rotation at the side , and maximal spinal level reached with internal rotation (IRspine) through visual estimation of video recordings taken from 10 healthy volunteers and 10 symptomatic patients. Variations in measurements were quantified using the interobserver reliability through calculation of the intraclass correlation coefficient. Accuracy was determined through comparison with digital goniometer measurements obtained with an on-screen protractor application using Bland–Altman mean differences and 95% limits of agreement. Results: The interobserver reliability among examiners showed moderate to excellent correlation, with intraclass correlation coefficient ranging from 0.768 to 0.928 for the healthy volunteers and 0.739 to 0.878 for the symptomatic patients. Accuracy was limited, with upper limits of agreement exceeding the established minimal clinically important differences (MCIDs) for FF (20° vs. MCID of 14°) and IR90 (25° vs. 18°) in the healthy volunteers and for FF (33° vs. 16°), external rotation at 90° abduction (21° vs. 18°), and IR90 (31° vs. 20°) in the symptomatic patients. Conclusion: Despite generally high intersurgeon reliability in the visual estimation of shoulder ROM, there was questionable accuracy when compared to digital goniometer measurements,with measurement errors often exceeding established MCID values. Given the potential implications for the clinical response to treatment and the significance of research findings, the adoption of validated instruments to measure ROM and the standardization of examination procedures should be considered.

This paper concerns the analysis of large quantum states. It is a notoriously difficult problem to quantify separability of quantum states, and for large quantum states, it is unfeasible. Here we posit that when quantum states are large, we can deduce reasonable expectations for the complex structure of non-classical multipartite correlations with surprisingly little information about the state. We show, with pegagogical examples, how known results from combinatorics can be used to reveal the expected structure of various correlations hidden in the ensemble described by a state.

Abstract A cavity‐magnonic system composed of a superconducting microwave resonator coupled to a magnon mode hosted by the organic‐based ferrimagnet vanadium tetracyanoethylene (V[TCNE]x) is demonstrated. This work is motivated by the challenge of scalably integrating a low‐damping magnetic system with planar superconducting circuits. V[TCNE]x has ultra‐low intrinsic damping, can be grown at low processing temperatures on arbitrary substrates, and can be patterned via electron beam lithography. The devices operate in the strong coupling regime, with a cooperativity exceeding 1000 for coupling between the Kittel mode and the resonator mode at T≈0.4 K, suitable for scalable quantum circuit integration. Higher‐order magnon modes are also observed with much narrower linewidths than the Kittel mode. This work paves the way for high‐cooperativity hybrid quantum devices in which magnonic circuits can be designed and fabricated as easily as electrical wires.

Atherosclerosis results from the deposition and oxidation of LDL and immune cell infiltration in the sub-arterial space leading to arterial occlusion. Studies have shown that transcytosis transports circulating LDL across endothelial cells lining blood vessels. LDL transcytosis is initiated by binding to either scavenger receptor B1 (SR-B1) or activin A receptor-like kinase 1 on the apical side of endothelial cells leading to its transit and release on the basolateral side. HDL is thought to partly protect individuals from atherosclerosis due to its ability to remove excess cholesterol and act as an antioxidant. Apolipoprotein A1 (APOA1), an HDL constituent, can bind to SR-B1, raising the possibility that APOA1/HDL can compete with LDL for SR-B1 binding, thereby limiting LDL deposition in the sub-arterial space. To examine this possibility, we used in vitro approaches to quantify the internalization and transcytosis of fluorescent LDL in coronary endothelial cells. Using microscale thermophoresis and affinity capture, we find that SR-B1 and APOA1 interact and that binding is enhanced when using the cardioprotective variant of APOA1 termed Milano (APOA1-Milano). In male mice, transiently increasing the levels of HDL reduced the acute deposition of fluorescently labeled LDL in the atheroprone inner curvature of the aorta. Reduced LDL deposition was also observed when increasing circulating wild-type APOA1 or the APOA1-Milano variant, with a more robust inhibition from the APOA1-Milano. The results suggest that HDL may limit SR-B1-mediated LDL transcytosis and deposition, adding to the mechanisms by which it can act as an atheroprotective particle.

Ischemic stroke is the leading cause of serious long-term disability and the 5th leading cause of death in the United States. Revascularization of the occluded cerebral artery, either by thrombolysis or endovascular thrombectomy, is the only effective, clinically-approved stroke therapy. Several potentially neuroprotective agents, including glutamate antagonists, anti-inflammatory compounds and free radical scavenging agents were shown to be effective neuroprotectants in preclinical animal models of brain ischemia. However, these compounds did not demonstrate efficacy in clinical trials with human patients following stroke. Proposed reasons for the translational failure include an insufficient understanding on the cellular and molecular pathophysiology of ischemic stroke, lack of alignment between preclinical and clinical studies and inappropriate design of clinical trials based on the preclinical findings. Therefore, novel neuroprotective treatments must be developed based on a clearer understanding of the complex spatiotemporal mechanisms of ischemic stroke and with proper clinical trial design based on the preclinical findings from specific animal models of stroke. We and others have demonstrated the clinical potential for neuregulin-1 (NRG-1) in preclinical stroke studies. NRG-1 significantly reduced ischemia-induced neuronal death, neuroinflammation and oxidative stress in rodent stroke models with a therapeutic window of >13 h. Clinically, NRG-1 was shown to be safe in human patients and improved cardiac function in multisite phase II studies for heart failure. This review summarizes previous stroke clinical candidates and provides evidence that NRG-1 represents a novel, safe, neuroprotective strategy that has potential therapeutic value in treating individuals after acute ischemic stroke.

Rare-earth ion dopants in solid-state hosts are ideal candidates for quantum communication technologies, such as quantum memories, due to the intrinsic spin–photon interface of the rare-earth ion combined with the integration methods available in the solid state. Erbium-doped cerium oxide (Er:CeO2) is a particularly promising host material platform for such a quantum memory, as it combines the telecom-wavelength (∼1.5μm) 4f–4f transition of erbium, a predicted long electron spin coherence time when embedded in CeO2, and a small lattice mismatch with silicon. In this work, we report on the epitaxial growth of Er:CeO2 thin films on silicon using molecular beam epitaxy, with controlled erbium concentration between 2 and 130 parts per million (ppm). We carry out a detailed microstructural study to verify the CeO2 host structure and characterize the spin and optical properties of the embedded Er3+ ions as a function of doping density. In as-grown Er:CeO2 in the 2–3 ppm regime, we identify an EPR linewidth of 245(1) MHz, an optical inhomogeneous linewidth of 9.5(2) GHz, an optical excited state lifetime of 3.5(1) ms, and a spectral diffusion-limited homogeneous linewidth as narrow as 4.8(3) MHz. We test the annealing of Er:CeO2 films up to 900 °C, which yields narrowing of the inhomogeneous linewidth by 20% and extension of the excited state lifetime by 40%.

Purpose: To assess preoperative Brief Resilience Scale (BRS) scores as they relate to postoperative patient outcomes following primary autograft anterior cruciate ligament reconstruction (ACLR). Methods: All patients who underwent primary autograft ACLR from 2016 to 2021 and had a patient-reported follow-up of 1 year and a clinical follow-up of 6 months were included in final data analysis. Patients completed validated PROMs pre- and postoperatively. All patients were objectively assessed with range of motion (ROM) and KT-1000 arthrometer testing. Return to sport (RTS) data were obtained for all applicable patients. Patients were divided into 3 groups based on ± ½ the standard deviation for the mean preoperative BRS score. Results: In total, 170 patients who underwent primary autograft ACLR with a mean age of 20.1 years (range, 13-57 years) and a mean final follow-up time of 2.9 years (range, 1.0-5.8 years) were included in the final analysis. The mean preoperative BRS scores for the high-resilience (HR, n = 67), average-resilience (AR, n = 42), and low-resilience (LR, n = 61) groups were 28.1 (95% CI, 27.8-28.9), 24.5 (95% CI, 24.3-24.6), and 21.1 (95% CI, 20.5-21.7), respectively (P < .001). The HR group demonstrated significantly higher preoperative and postoperative patient-reported outcome measures (PROMs) compared to the AR and LR groups, with more differences seen with the LR group. The HR group demonstrated better knee extension in postoperative month 3 compared to the LR group (0.6° [95% CI, –1.2° to 0.1°] vs –2.3° [95% CI, –3.3° to –1.3°], P = .006). The HR group demonstrated a faster RTS time compared to the LR group (6.4 months [95% CI, 6.1-6.7] vs 7.6 months [95% CI, 7.1-8.1], P = .002). No differences were seen in RTS rate, knee flexion, or KT-1000 arthrometer measurements between the 3 groups. Conclusions: Low preoperative BRS scores were associated with inferior PROMs preoperatively and in the short-term postoperative period compared to those with higher preoperative BRS scores. Additionally, patients with lower preoperative BRS scores demonstrated a higher degree of knee extension loss 3 months postoperatively as well as a slower RTS. Level of Evidence: Level III, retrospective cohort study.

A major goal of modern neuroscience is to understand the functions of the varied neuronal types that comprise the mammalian brain. Toward this end, some types of neurons can be targeted and manipulated with enhancer-bearing AAV vectors. These vectors hold great promise to advance basic and translational neuroscience, but to realize this potential, their selectivity must be characterized. In this study, we investigated the selectivity of AAV vectors carrying an enhancer of the murine Dlx5 and Dlx6 genes. Vectors were injected into the visual cortex of two macaque monkeys, the frontal cortex of two others, and the somatosensory/motor cortex of three rats. Post-mortem immunostaining revealed that parvalbumin-expressing neurons were transduced efficiently in all cases but calretinin-expressing neurons were not. We speculate that this specificity is a consequence of differential activity of this DLX5/6 enhancer in adult neurons of different developmental lineages.

Abstract We evaluated the prospective association of mitochondrial DNA copy number (mtDNA CN) with markers of kidney function among a cohort of persons who inject drugs (PWID). This is a Prospective cohort study nested in the AIDS linked to the intravenous experience cohort (community-based cohort of PWID in Baltimore, MD). mtDNA CN was measured at two time-points 5 years apart using a real-time polymerase chain reaction. Kidney function (estimated glomerular filtration rate [eGFR], serum creatinine, urine protein) was measured annually. We used linear mixed effects models to evaluate kidney function trajectories (N = 946) and Cox regression models to assess hazard of incident CKD (eGFR 200, N = 573) by level of mtDNA CN (Low [lowest quartile], vs high [other three quartiles]. Models were adjusted for demographic and behavioral characteristics, HIV and/or HCV infection, and comorbidity burden. Low mtDNA CN was independently associated with higher hazard of incident CKD (aHR: 2.33, 95% CI 1.42, 3.80) and proteinuria (aHR: 1.42, 95% CI 1.04, 1.96). Participants with low mtDNA CN had greater declines in eGFR and greater increases in serum creatinine over time. Low mtDNA CN is associated with more rapid kidney function decline and risk of incident CKD and proteinuria.

Abstract Tumors acquire alterations in oncogenes and tumor suppressor genes in an adaptive walk through the fitness landscape of tumorigenesis. However, the interactions between oncogenes and tumor suppressor genes that shape this landscape remain poorly resolved and cannot be revealed by human cancer genomics alone. Here, we use a multiplexed, autochthonous mouse platform to model and quantify the initiation and growth of more than one hundred genotypes of lung tumors across four oncogenic contexts: KRAS G12D, KRAS G12C, BRAF V600E, and EGFR L858R. We show that the fitness landscape is rugged—the effect of tumor suppressor inactivation often switches between beneficial and deleterious depending on the oncogenic context—and shows no evidence of diminishing-returns epistasis within variants of the same oncogene. These findings argue against a simple linear signaling relationship amongst these three oncogenes and imply a critical role for off-axis signaling in determining the fitness effects of inactivating tumor suppressors.

The potential immunogenicity of therapeutic human and humanized monoclonal antibodies (mAb) is a significant concern, and so preclinical testing of therapeutic mAbs routinely includes assessment of anti-drug antibody (ADA) induction. Here, we report the development of automated screening and confirmatory bridging ELISAs for the detection of rat antibodies against DH1042, an engineered human mAb for the SARS-CoV-2 receptor-binding domain. The assays were evaluated for specificity, sensitivity, selectivity, absence of a prozone effect, linearity, intra- and inter- assay precision, and robustness, and found to be suitable for purpose. The assays were then used to evaluate anti-DH1042 antibodies in the sera of rats dosed with lipid-nanoparticle (LNP)-encapsulated mRNA encoding DH1042. Rats received two doses of 0.1, 0.4 or 0.6 mg/kg/dose LNP-mRNA 8 days apart. Twenty-one days after the second dose, 50-100% of rats had developed confirmed anti-DH1042 ADA depending on dose level. No animals in the control group developed anti-DH1042 ADA. These assays reflect new applications for a non-specialized laboratory automation platform, and the methodologies and approaches reported here provide a template that can be adapted for the automated detection and confirmation of ADA in preclinical testing of other biologics.