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Abstract Hypoxia tolerance and its variation with temperature, activity, and body mass, are critical ecophysiological traits through which climate impacts marine ectotherms. To date, experimental determination of these traits is limited to a small subset of modern species. We leverage the close coupling of carbon and oxygen in animal metabolism to mechanistically relate these traits to the carbon isotopes in fish otoliths (δ13Coto). The model reproduces the major empirical patterns in δ13Coto at individual to global scales. The weak dependence on body size and strong, non-linear, dependence on temperature reflect the same balance between metabolism and ventilatory gas exchange that underlies organisms’ hypoxia tolerance. The global relationship between temperature and δ13Coto records both the fractionation by aragonite precipitation and the variation in hypoxia traits across ocean biomes. Because hypoxia tolerance is imprinted on both otolith geochemistry and species biogeography, the model allows the aerobic limits of species geographic ranges to be predicted from fish δ13Coto. This physiologically grounded model provides a foundation for the use of otolith chemistry to reconstruct modern spatial patterns and paleoceanographic changes in key traits that shape aerobic habitat of aquatic species.

Background: Partial-thickness rotator cuff tears (PTRCTs), often considered less severe than full-thickness rotator cuff tears (FTRCTs), can be equally symptomatic. Despite the prevalence of PTRCTs, scholarly attention has predominantly focused on FTRCTs, resulting in a relative neglect of PTRCTs. This study aimed to assess the incidence of surgical repairs for PTRCTs in the United States (U.S.) using the Nationwide Ambulatory Surgery Sample (NASS) database and delineate practice patterns among a group of American Shoulder and Elbow Surgeons (ASES) members. Methods: The NASS database, representing approximately 67% of U.S. ambulatory surgical encounters, was queried to obtain the incidence of PTRCT and FTRCT repairs for the year 2019. Data on patient sex, hospital location, setting, teaching affiliation and size, and primary payor were also obtained. Separately, a retrospective chart review was conducted by 13 ASES research group members, collecting data on rotator cuff repairs performed from July 2021 to June 2022 at their individual institutions. Collected data included age, sex, extent and type of rotator cuff tears, duration of symptoms prior to surgical repair, and type and duration of nonoperative treatment. Results: The NASS database showed that PTRCT repairs accounted for at least 23% of the 187,787 rotator cuff repairs performed in 2019, with potential underestimation due to unspecified tear categorization. The retrospective chart review of the ASES research group revealed that PTRCT repairs constituted 27.8% of all rotator cuff repairs with substantial variability among institutions (8.6%-67.1%), that nonoperative measures were commonly employed, with a mean 12-month duration before surgical repair, and that the most common type of nonoperative treatment was supervised physical therapy combined with corticosteroid injection (37.7%). Discussion: This study revealed approximately one-fourth of all rotator cuff repairs conducted in the U.S. were attributed to PTRCTs with substantial variability in proportion of PTRCT repairs across individual orthopedic practices. The overall duration of nonoperative treatment was consistent with the existing literature. This study provides insights into the landscape of PTRCT repairs and associated practice patterns. Further investigation into factors influencing treatment decisions is warranted.

Abstract There have been frequent reports of more than one strain of the nitrogen-fixing symbiont, Frankia, in the same root nodule of plants in the genus Alnus, but quantitative assessments of their relative contributions have not been made to date. Neither has the diversity of other microbes, having potential functional roles in symbiosis, been systematically evaluated. Alnus rubra root nodule microbiota were studied using Illumina short read sequencing and kmer-based read classification. Single end 76 bp sequencing was done to a median depth of 96 million reads per sample. Reads were assigned to taxa using KrakenUniq, with taxon abundances being estimated using its companion program Bracken. This was the first high resolution study of Alnus root nodules using next generation sequencing (NGS), quantifying multiple Cluster 1 A Frankia strains in single nodules, and in some cases, a Cluster 4 strain. Root nodules were found to contain diverse bacteria, including several genera containing species known to have growth-promoting effects. Evidence was found for partitioning of some bacterial strains in older versus younger lobes.

The present investigation aims to examine the role of α-synuclein seed amplification assays for screening Parkinson’s disease. Parkinson’s disease (PD) is a debilitating neurodegenerative disorder caused by the loss of dopaminergic neurons in the midbrain, leading to symptoms such as tremors, bradykinesia, postural instability, dementia, and depression. It is classified as an α-synucleinopathy related to the role of α-synuclein aggregates in neuron degeneration. Diagnosis relies on clinical assessment without premortem diagnostic tests or imaging, often resulting in delayed detection and impaired symptom management. In this regard, our study explores a screening technique using an amplification assay to measure α-synuclein levels in cerebrospinal fluid, which could potentially identify early pathological changes and improve diagnostic accuracy and patient outcomes. While preliminary results are promising, further studies are needed to evaluate this approach’s accuracy and clinical feasibility. A review of numerous trials demonstrates that α-synuclein seeding amplification assays (SAA) are a highly reliable, sensitive, and specific diagnostic tool for PD. This assay offers a promising opportunity to improve early diagnosis and quantify severity, especially for asymptomatic individuals or those with a family history of PD, allowing for earlier intervention and more effective disease management. In summary, the emerging body of evidence supporting α-synuclein as a biomarker should allow patients with PD to be detected and treated sooner, enhancing patients’ quality of life and potentially changing the disease trajectory.

IntroductionThis ecologic study explores the relationship between the Social Vulnerability Index (SVI) and probable asthma-related emergency medical service (EMS) rates before and during the COVID-19 pandemic at the county level in Illinois.MethodsThe number of asthma-related EMS visits was obtained in all 102 counties for adults aged 18 years or more, and for 82 of these counties for children aged less than 18 from 2018 to 2021. They were converted into rates and examined in relation to SVI rankings. Pearson’s correlation coefficients and negative binomial regression were used to examine associations, adjusting for the level of rurality.ResultsThe rate of asthma-related EMS visits increased in adults from 23.1 to 28.9 per 1,000 between 2018 and 2021 but decreased in children from 5.9 to 5 per 1,000. Every 1% increase in the overall SVI was associated with a nearly two-fold increase in the rate of EMS visits in adults (pre-COVID-19: IRR = 1.94, p

The Deep Brain Stimulation (DBS) Think Tank XII was held on August 21st to 23rd. This year we showcased groundbreaking advancements in neuromodulation technology, focusing heavily on the novel uses of existing technology as well as next-generation technology. Our keynote speaker shared the vision of using neuro artificial intelligence to predict depression using brain electrophysiology. Innovative applications are currently being explored in stroke, disorders of consciousness, and sleep, while established treatments for movement disorders like Parkinson’s disease are being refined with adaptive stimulation. Neuromodulation is solidifying its role in treating psychiatric disorders such as depression and obsessive-compulsive disorder, particularly for patients with treatment-resistant symptoms. We estimate that 300,000 leads have been implanted to date for neurologic and neuropsychiatric indications. Magnetoencephalography has provided insights into the post-DBS physiological changes. The field is also critically examining the ethical implications of implants, considering the long-term impacts on clinicians, patients, and manufacturers.

BackgroundThere is no neoadjuvant immunotherapy for early-stage oral cancer patients. We report a single-arm, open-label, pilot clinical trial assessing the efficacy and safety of topical toll-like receptor-7 (TLR-7) agonist, imiquimod, utilized in a neoadjuvant setting in early-stage oral squamous cell carcinoma (OSCC).MethodsThe primary endpoint is reduction in tumor cell counts assessed by quantitative multiplex immunofluorescence and the immune-related pathologic response. The secondary endpoint is safety.Results60% of patients experienced a 50% reduction or greater in tumor cell count post-treatment (95% CI = 32% to 84%). Similarly, 60% of patients had immune-related major pathologic response (irMPR) with two complete pathologic responses, and 40% had partial response (PR) with the percent residual viable tumor ranging from 25% to 65%. An increase in functional helper and cytotoxic T-cells significantly contributed to a reduction in tumor (R=0.54 and 0.55, respectively). The treatment was well tolerated with the application site mucositis being the most common adverse event (grades 1-3), and no grade 4 life-threatening event. The median follow-up time was 17 months (95% CI = 16 months - not reached), and one-year recurrence-free survival was 93% of evaluable patients.ConclusionNeoadjuvant imiquimod immunotherapy could be safe and promising regimen for early-stage oral cancer.Trial registrationClinicalTrials.gov, Identifier NCT04883645.

Summary: Antibodies that target the gp120-gp41 interface of the HIV-1 envelope (Env) trimer comprise a commonly elicited category of broadly neutralizing antibodies (bNAbs). Here, we isolate and characterize VRC44, a bNAb lineage with up to 52% neutralization breadth. The cryoelectron microscopy (cryo-EM) structure of antibody VRC44.01 in complex with the Env trimer reveals binding to the same gp120-gp41 interface site of vulnerability as antibody 35O22 from a different HIV-1-infected donor. In addition to having similar angles of approach and extensive contacts with glycans N88 and N625, VRC44 and 35O22 derive from the same IGHV1-18 gene and share convergent mutations, indicating these two antibodies to be members of the only known highly glycan-dependent multidonor class. Strikingly, both lineages achieved almost 100% neutralization breadth against virus strains displaying high-mannose glycans. The high breadth and reproducible elicitation of VRC44 and 35O22 lineages validate germline-based methods of immunogen design for targeting the HIV-1 gp120-gp41 interface.

Purpose: To determine the relationship between cam morphology of the hip and ipsilateral sacroiliac motion compared to the native hip in a cadaveric model. Methods: A simulated cam state was created using a 3-dimensional printed cam secured to the head-neck junction of 5 cadaveric hips. Hips were studied using a computed tomography–based optic metrology system and a 6 degree-of-freedom robot to exert an internal rotation torque at 3 different torque levels (6 N-m, 12 N-m, 18 N-m). Outcomes included translational and rotational movement about 3 axes and composite (total) translational motion at the ipsilateral sacroiliac (SI) joint. Statistical analysis included a linear mixed model regression with repeated measures. Results: The presence of a simulated cam was associated with medial motion in the coronal plane (P = .03) and posterior motion in the sagittal plane (P < .01) but not composite motion (P = .37). Motion in the axial plane was in an inferior direction (P = .08). Cam morphology significantly changed rotation in the sagittal plane (P < .01) but not in the coronal (P = .63) or axial plane (P = .18). Composite motion was related to the amount of torque applied to the hip (P < .01). The amount of torque applied to the hip was related to rotation in the coronal plane (P < .01), axial plane (P < .01), and sagittal plane (P < .01) with increased effects as torque increased. Torque was not associated with translation movement in any of the anatomic planes. Conclusions: The presence of simulated cam morphology is associated with motion in a more medial, inferior, and posterior direction at the ipsilateral SI joint relative to a native state. Increasing torque affects the magnitude of translation, but not its direction, which in this study is primarily influenced by cam morphology. Clinical Relevance: This biomechanical connection between cam-type femoroacetabular impingement syndrome and the ipsilateral SI joint provides insight into SI joint dysfunction in patients with femoroacetabular impingement syndrome.

Abstract Access to broad genomic resources and closely linked marker‐trait associations for common beans (Phaseolus vulgaris L.) can facilitate development of improved varieties with increased yield, improved market quality traits, and enhanced disease resistance. The emergence of virulent races of anthracnose (caused by Colletotrichum lindemuthianum) and bean common mosaic virus (BCMV) highlight the need for improved methods to identify and incorporate pan‐genomic variation in breeding for disease resistance. We sequenced the P. vulgaris Andean Diversity Panel (ADP) and performed a genome‐wide association study (GWAS) to identify associations for resistance to BCMV and eight races of anthracnose. Historical single nucleotide polymorphism (SNP)‐chip and phenotypic data enabled a three‐way comparison between SNP‐chip, reference‐based whole genome shotgun sequence (WGS)‐SNP, and reference‐free k‐mer (short nucleotide subsequence) GWAS. Across all traits, there was excellent concordance between SNP‐chip, WGS‐SNP, and k‐mer GWAS results—albeit at a much higher marker resolution for the WGS data sets. Significant k‐mer haplotype variation revealed selection of the linked I‐gene and Co‐u traits in North American breeding lines and cultivars. Due to structural variation, only 9.1 to 47.3% of the significantly associated k‐mers could be mapped to the reference genome. Thus, to determine the genetic context of cis‐associated k‐mers, we generated draft whole genome assemblies of four ADP accessions and identified an expanded local repertoire of disease resistance genes associated with resistance to anthracnose and BCMV. With access to variant data in the context of a pan‐genome, high resolution mapping of agronomic traits for common bean is now feasible.

Extensive evidence demonstrates that prenatal nutrition is crucial for adequate fetal development. Specifically, maternal choline intake plays a significant role in gene expression, epigenetics, and cell membrane formation. Preclinical models have shown that maternal dietary intake improves the development of the cerebral cortex and hippocampus. This review focuses on the role of prenatal choline intake and discusses its potential role in neurodevelopmental disorders especially since choline has emerged as a promising coadjutant to mitigate cognitive and developmental disorders. However, more evidence regarding timing, dosage, and molecular mechanisms is needed. In this review, we discuss the impact of prenatal choline availability, evidence from current models, and gaps to address in how choline may impact the symptomology and manifestation of Rett syndrome, fragile X syndrome, and Down syndrome. Our ultimate goal is to highlight the importance of choline for maternal health and its potential beneficial impact on neurodevelopmental disorders.

IntroductionGlobal climate change and associated stressors threaten forest ecosystems due to the rapid pace of climate change, which could exceed the natural migration rate of some tree species. In response, there is growing interest to research and implement forest assisted migration (FAM). Here, we used a species-independent indicator based on climate analogy, according to the sigma (dis)similarity (σd) index, to match planting sites across the eastern US with (future) climatically-compatible seedlots (CCS).MethodsWe developed CCS for a grid composed of 1 × 1° of latitude and longitude. CCS were based on future climate analogs with ≤2σd analogy to ensure CCS were representative of future climate change. CCS were located for three time periods, 2030's, 2050's, and 2090's and three emissions scenarios (SSP2-4.5, SSP3-7.0, and SSP5-8.5) from the Coupled Model Intercomparison Project phase 6 database, using 12 climate variables.ResultsCCS were identified for the majority of 1 × 1° grids based on the SSP3-7.0 scenario. Approximately 28% of 1 × 1° grid's 2090's projections included future climate novelty. The 2030's, 2050's, and 2090's CCS were located on average 222, 358, and 662 km or 1, 2, and 3 eastern seed zones away from the 1 × 1° grids, respectively. CCS were also located further south-southwest (188–197°). In addition, the average forest cover of CCS was approximately 2%, 5%, and 10% less than that of the 1 × 1° grids.DiscussionOur development and synthesis of CCS emphasized four key results: (i) average distances to 2030's and 2050's CCS were similar to seed-transfer guidelines for some tree species, but 2090's CCS exceeded current recommendations; (ii) south-southwesterly locations of CCS aligned with tree species habitat distribution dynamics; (iii) future climate novelty potentially challenges the conceptual basis of FAM if tree species are not adapted to climate change; and (iv) variation in forest cover among CCS presents potential opportunities and challenges due the presence or absence of forestland to source seed. Ultimately, our goal was to locate and synthesize CCS that could enable FAM decision support.

Recently, the diagnosis of autism spectrum disorder (ASD) has increased from 1 in 150 to every 1 in 36 children in the United States, warranting a need for novel prevention and therapeutic strategies. Broad-spectrum cannabidiol oil, free from delta-9-tetrahydrocannabinol, the psychoactive component of cannabis, may be one such therapeutic. It has a high safety profile and is frequently used as a complementary and integrative intervention by persons experiencing symptoms of anxiety, stress, and inflammation. Using a neurodevelopmental rat model of ASD (based on neuroinflammation induced by stress and terbutaline exposure during pre- and postnatal development), we sought to prevent the development of ASD-like behaviors in male offspring by administering broad-spectrum cannabidiol oil to dams throughout pregnancy (10 mg/kg, i.p., daily, embryonic days 3–16). To assess an ASD-like phenotype in the offspring, we used three behavioral measures relevant to three core ASD symptoms: 1) social communication (time spent vocalizing when alone); 2) repetitive behavior (marbles buried during a marble burying test); and 3) social interaction (time spent interacting with a novel conspecific during the three-chamber social interaction test). Broad-spectrum cannabidiol oil given during pregnancy decreased scores for all three ASD-related behavioral responses, resulting in an overall significant prevention of the ASD-like phenotype. These findings highlight the potential of broad-spectrum cannabidiol oil as a complementary and integrative approach for prevention of stressor-induced sequelae relevant to development of an ASD-like phenotype.

Background: Climate change has been associated with adverse cardiovascular health, prompting interest in climate mitigation strategies while improving access for cardiovascular patients. We estimated greenhouse gas and air pollution savings from telehealth use in cardiology. Methods: Using cardiology telehealth visits at a large academic medical center from July 2020 to March 2024, carbon dioxide (CO2), nitrogen oxides (NOx), carbon monoxide (CO), and particulate matter (PM2.5) emissions saved were calculated using U.S. Environmental Protection Agency modeling software. Savings were converted into real-world comparators and differences were assessed by cardiology subspecialty and patient insurance status. Results: Over 45 months, 14,828 telehealth visits among 9942 patients resulted in savings of 484,152 kg of CO2, 5225 kg of CO, 243,491 g of NOx, and 9091 g of PM2.5 with the total carbon saved equivalent to planting 9070 tree saplings over ten years. CO2 emissions saved per visit (kg) differed significantly by payor (Self-pay 24.99, Medicare 19.67, Medicaid 19.54, Private 17.85, Other 17.37, p = 0.004) and by subspecialty (Interventional 23.79, General 19.08, Heart Failure 18.86, Electrophysiology 17.81, Adult Congenital 16.59, p

IntroductionWhen Coronavirus Disease-19 (COVID-19) struck the world in December 2019, initiatives started to investigate the efficacy of convalescent plasma, a readily available source of passive antibodies, collected from recovered patients as a therapeutic option. This was based on historical observational data from previous virus outbreaks.MethodsA scoping review was conducted on the efficacy and safety of convalescent plasma and hyperimmune immunoglobulins for COVID-19 treatment. This review included the latest Cochrane systematic review update on 30-day mortality and safety. We also covered use in pediatric and immunocompromised patients, as well as the logistic challenges faced in donor recruitment and plasma collection in general. Challenges for low resource countries were specifically highlighted.ResultsA major challenge is the high donation frequency required from first-time donors to ensure a safe product, which minimizes the risk of transfusion-transmitted infectious. This is particularly difficult in low- and middle- income countries due to inadequate infrastructure and insufficient blood product supplies. High-certainty evidence indicates that convalescent plasma does not reduce mortality or significantly improve clinical outcomes in patients with moderate to severe COVID-19 infection. However, CCP may provide a viable treatment for patients unable to mount an endogenous immune response to SARS-CoV-2, based on mostly observational studies and subgroup data of published and ongoing randomized trials. Convalescent plasma has been shown to be safe in adults and children with COVID-19 infection. However, the efficacy in pediatric patients remains unclear.DiscussionData on efficacy and safety of CCP are still underway in ongoing (randomized) studies and by reporting the challenges, limitations and successes encountered to-date, research gaps were identified to be addressed for the future.ConclusionThis experience serves as a valuable example for future pandemic preparedness, particularly when therapeutic options are limited, and vaccines are either being developed or ineffective due to underlying immunosuppression.

Objective: Emotion recognition, reactivity, and regulation are important in the development and maintenance of anxiety disorders. Whether and how these processes differentiate between different trajectories in anxiety remain unclear. The current study examined emotional processes as prospective predictors of anxiety symptom trajectories in psychiatrically hospitalized youth. Method: Participants were 180 adolescents (Mage = 14.89; SD = 1.35) from a psychiatric inpatient unit. At index hospitalization, participants completed a behavioral task assessing facial emotion recognition, and self-report measures of emotion dysregulation and reactivity. They completed a self-report measure on anxiety symptoms at baseline and 3, 6, 12, and 18 months post-discharge. Latent growth curve analysis was conducted to identify subgroups of individuals based upon their trajectory of anxiety symptoms across 18-months. ANOVAs were used to examine subgroup differences in emotional processing variables. Results: Three distinct trajectories were identified, a stable moderate-to-high anxiety group, a group with moderate-to-high anxiety at baseline with symptom improvement over time, and a group characterized by relatively stable low-to-moderate anxiety throughout the study. The two initially moderate-to-high anxiety groups scored higher for emotion dysregulation and emotion reactivity at baseline compared to the low-to-moderate anxiety group. Emotion regulation difficulties relating to emotional non-acceptance were higher for the stable moderate-to-high anxiety group than for the moderate-to-high anxiety group that experience symptom improvement over time. Conclusions: These findings may have clinical implications for discharge planning. Future studies should explore emotion regulation with a focus on non-acceptance of one’s emotional experiences as a potential target of intervention in individuals with elevated anxiety.

Abstract When making choices, individuals differ from one another, as well as from normativity, in how they weigh different types of information. One explanation for this relates to idiosyncratic preferences in what information individuals represent when evaluating choice options. Here, we test this explanation with a simple risky-decision making task, combined with magnetoencephalography (MEG). We examine the relationship between individual differences in behavioral markers of information weighting and neural representation of stimuli pertinent to incorporating that information. We find that the extent to which individuals (N = 19) behaviorally weight probability versus reward information is related to how preferentially they neurally represent stimuli most informative for making probability and reward comparisons. These results are further validated in an additional behavioral experiment (N = 88) that measures stimulus representation as the latency of perceptual detection following priming. Overall, the results suggest that differences in the information individuals consider during choice relate to their risk-taking tendencies.

Abstract The field of hybrid engineered living materials seeks to pair living organisms with synthetic materials to generate biocomposite materials with augmented function since living systems can provide highly-programmable and complex behavior. Engineered living materials have typically been fabricated using techniques in benign aqueous environments, limiting their application. In this work, biocomposite fabrication is demonstrated in which spores from polymer-degrading bacteria are incorporated into a thermoplastic polyurethane using high-temperature melt extrusion. Bacteria are engineered using adaptive laboratory evolution to improve their heat tolerance to ensure nearly complete cell survivability during manufacturing at 135 °C. Furthermore, the overall tensile properties of spore-filled thermoplastic polyurethanes are substantially improved, resulting in a significant improvement in toughness. The biocomposites facilitate disintegration in compost in the absence of a microbe-rich environment. Finally, embedded spores demonstrate a rationally programmed function, expressing green fluorescent protein. This research provides a scalable method to fabricate advanced biocomposite materials in industrially-compatible processes.

Commonly used adenine-induced chronic kidney disease (CKD) murine models often employ C57BL/6 mice; however, this strain has inherent limitations due to its natural resistance to developing key pathological features of CKD, such as tubulointerstitial fibrosis and inflammation. There have been attempts to overcome these barriers by using multiple concentrations of adenine-supplemented diets or by performing prolonged experiments up to 20 weeks. Here, we demonstrate that SKH1 Elite mice develop clinically relevant CKD phenotypes (e.g., polyuria, proteinuria, inflammation, and renal fibrosis) over the course of only 6 weeks of low-dose (0.15%) adenine supplementation. As a docile, immunocompetent, and hairless strain, SKH1 Elite mice offer several logistical advantages over C57BL/6 mice, including ease of handling and the ability to study dermal conditions, which are often secondary to CKD.

ObjectivesBlood transfusion is an important mode of infectious disease transmission in low- and middle-income countries (LMICs). This study describes a model to determine the prevalence of transfusion-transmitted infections (TTIs) and the associated burden of disease.MethodsA five-step model was developed to determine the TTI-related burden of disease measured by disability-adjusted life years (DALYs). Uganda was selected as the study country.ResultsApproximately 298,266 units of blood were transfused in Uganda in 2019, yielding an estimated TTI incidence of 6,858 new TTIs (2.3% of transfused units) and prevalence of 19,141 TTIs (6.4% of transfused units). The total burden of disease is 2,903 DALYs, consisting of approximately 2,590 years of life lost (YLLs), and 313 years lived with disability (YLDs).ConclusionThe incidence and prevalence of TTIs and the associated burden of disease can be calculated on a local and national level. The model can be applied by health ministries to estimate the impact of TTIs in order to develop blood safety strategies to reduce the burden of disease.

Introduction: Engagement in self-harm is common among youth in psychiatric inpatient units, however the nature of self-harm may be different in psychiatric care due to the increased supervision and theoretically decreased access to typical means of self-harm. This study aims to describe daily reports of self-harm experienced during psychiatric inpatient stays among adolescents and compare these inpatient self-harm experiences based on neurodevelopmental diagnoses (NDDs, including autism) given that self-harm methods differ across NDD diagnostic groups outside of the inpatient unit. Methods: Data were derived from a larger study of risk factors among a sample of 119 suicidal adolescent inpatients, recruited from a large, urban adolescent inpatient psychiatric unit. Participants answered a daily series of self-report questions, including items about self-harm engagement, frequency, and methods used since the last survey. Results: There was no difference in the number of participants who reported any engagement in self-harm based on diagnostic group (χ2 = 0.08, p = .96). There were also no differences in the frequency of self-harm across diagnostic groups (F = 2.40, p = .12). There were no differences in the use of any method across diagnostic groups (ps > 0.05). Conclusions: Findings revealed that in an inpatient unit where patients are presenting for self-harm risk, there are no significant differences in engagement, frequency, or methods used for self-harm based on autism and NDD status. These analyses provide valuable clinical information regarding a lack of differences in self-harm by these diagnostic subgroups. Future research should seek to further explore functional purposes of self-harm on inpatient unit and how this differs by diagnoses.

ABSTRACT Infectious diseases are emerging and re-emerging far more frequently than many appreciate. In the past two decades alone, there have been numerous outbreaks (e.g., Ebola, chikungunya, Zika, and Mpox) and pandemics (i.e., swine flu and coronavirus disease 2019) with profound effects to public health, the economy, and society at large. Rather than view these in isolation, there are important lessons pertaining to how best to contend with future outbreaks of emerging infectious diseases. Those lessons span definition (i.e., what constitutes a pandemic), through deficiencies in surveillance, data collection and reporting, the execution of research in a rapidly changing environment, the nuances of study design and hierarchy of clinical evidence, triage according to clinical need as supply chains become overwhelmed, and the challenges surrounding forecasting of outbreaks. Understanding those lessons and drawing on both the successes and failures of the past are imperative if we are to overcome the challenges of outbreak/pandemic responsiveness.

Abstract Background Healthcare restrictions during the COVID-19 pandemic, particularly in ophthalmology, led to a differential underutilization of care. An analytic approach is needed to characterize pandemic health services usage across many conditions. Methods A common analytical framework identified pandemic care utilization patterns across 261 ophthalmic diagnoses. Using a United States eye care registry, predictions of utilization expected without the pandemic were established for each diagnosis via models trained on pre-pandemic data. Pandemic effects on utilization were estimated by calculating deviations between observed and expected patient volumes from January 2020 to December 2021, with two sub-periods of focus: the hiatus (March-May 2020) and post-hiatus (June 2020–December 2021). Deviation patterns were analyzed using cluster analyses, data visualizations, and hypothesis testing. Results Records from 44.62 million patients and 2455 practices show lasting reductions in ophthalmic care utilization, including visits for leading causes of visual impairment (age-related macular degeneration, diabetic retinopathy, cataract, glaucoma). Mean deviations among all diagnoses are 67% below expectation during the hiatus peak, and 13% post-hiatus. Less severe conditions experience greater utilization reductions, with heterogeneities across diagnosis categories and pandemic phases. Intense post-hiatus reductions occur among non-vision-threatening conditions or asymptomatic precursors of vision-threatening diseases. Many conditions with above-average post-hiatus utilization pose a risk for irreversible morbidity, such as emergent pediatric, retinal, or uveitic diseases. Conclusions We derive high-resolution insights on pandemic care utilization in the US from high-dimensional data using an analytical framework that can be applied to study healthcare disruptions in other settings and inform efforts to pinpoint unmet clinical needs.

Objective High body mass index is a well-established modifiable comorbidity that is known to increase postoperative complications in all types of surgery, including spine surgery. Obesity is increasing in prevalence amongst the general population. As this growing population of obese patients ages, understanding how they faire undergoing cervical disc arthroplasty (CDA) is important for providing safe and effective evidence-based care for cervical degenerative pathology. Methods Our study used the Healthcare Cost and Utilization Project’s National Inpatient Sample to assess patients undergoing CDA comparing patient characteristics and outcomes in nonobese patients to obese patients from 2004 to 2014. Results Our study found a significant increase in the overall utilization of CDA as a treatment modality (p = 0.012) and a statistically significant increase in obese patients undergoing CDA (p < 0.0001) from 2004 to 2014. Obesity was identified as an independent risk factor associated with increased rates of inpatient neurologic complications (odds ratio [OR], 6.99; p = 0.03), pulmonary embolus (OR, 5.41; p = 0.05), and wound infection (OR, 6.97; p < 0.001) in patients undergoing CDA from 2004 to 2014. Conclusion In patients undergoing CDA, from 2004 to 2014, obesity was identified as an independent risk factor with significantly increased rates of inpatient neurologic complications, pulmonary embolus and wound infection. Large prospective trials are needed to validate these findings.

Myokines, bioactive peptides released by skeletal muscle, have emerged as crucial regulators of metabolic and protective pathways in peripheral tissues, particularly in combating oxidative stress and inflammation. Their plasma concentration significantly increases following exercise, offering valuable insights into the role of physical activity in preventing sarcopenia and mitigating metabolic diseases, including obesity, diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD). This review focuses on discussing the roles of specific myokines in activating intracellular signaling pathways within the liver, which confer protection against steatosis and lipid peroxidation. We detail the mechanism underlying lipid peroxidation and highlight the liver’s antioxidant defenses, such as glutathione (GSH) and glutathione peroxidase 4 (GPX4), which are pivotal in reducing ferroptosis. Furthermore, we provide an in-depth analysis of key myokines, including myostatin, brain-derived neurotrophic factor (BDNF), and irisin, among others, and their potential impact on liver function. Finally, we discuss the molecular mechanisms through which these myokines influence oxidate stress and lipid metabolism, emphasizing their capacity to modulate antioxidant responses in the liver. Finally, we underscore the therapeutic potential of exercise as a non-pharmacological intervention to enhance myokine release, thereby preventing the progression of MASD through improved hepatic antioxidant defenses. This review represents a comprehensive perspective on the intersection of exercise, myokine biology, and liver health.

Objective: To examine the association of COVID-19 convalescent plasma transfusion with mortality and the differences between subgroups in hospitalized patients with COVID-19. Patients and Methods: On October 26, 2022, a systematic search was performed for clinical studies of COVID-19 convalescent plasma in the literature from January 1, 2020, to October 26, 2022. Randomized clinical trials and matched cohort studies investigating COVID-19 convalescent plasma transfusion compared with standard of care treatment or placebo among hospitalized patients with confirmed COVID-19 were included. The electronic search yielded 3841 unique records, of which 744 were considered for full-text screening. The selection process was performed independently by a panel of 5 reviewers. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data were extracted by 5 independent reviewers in duplicate and pooled using an inverse-variance random effects model. The prespecified end point was all-cause mortality during hospitalization. Results: Thirty-nine randomized clinical trials enrolling 21,529 participants and 70 matched cohort studies enrolling 50,160 participants were included in the systematic review. Separate meta-analyses reported that transfusion of COVID-19 convalescent plasma was associated with a decrease in mortality compared with the control cohort for both randomized clinical trials (odds ratio [OR], 0.87; 95% CI, 0.76-1.00) and matched cohort studies (OR, 0.76; 95% CI, 0.66-0.88). The meta-analysis of subgroups revealed 2 important findings. First, treatment with convalescent plasma containing high antibody levels was associated with a decrease in mortality compared with convalescent plasma containing low antibody levels (OR, 0.85; 95% CI, 0.73 to 0.99). Second, earlier treatment with COVID-19 convalescent plasma was associated with a decrease in mortality compared with the later treatment cohort (OR, 0.63; 95% CI, 0.48 to 0.82). Conclusion: During COVID-19 convalescent plasma use was associated with a 13% reduced risk of mortality, implying a mortality benefit for hospitalized patients with COVID-19, particularly those treated with convalescent plasma containing high antibody levels treated earlier in the disease course.

Tmc1 and Tmc2 are essential pore-forming subunits of mechanosensory transduction channels localized to the tips of stereovilli in auditory and vestibular hair cells of the inner ear. To investigate expression and function of Tmc1 and Tmc2 in vestibular organs, we used quantitative polymerase chain reaction (qPCR), fluorescence in situ hybridization – hairpin chain reaction (FISH-HCR), immunostaining, FM1-43 uptake and we measured vestibular evoked potentials (VsEPs) and vestibular ocular reflexes (VORs). We found that Tmc1 and Tmc2 showed dynamic developmental changes, differences in regional expression patterns, and overall expression levels which differed between the utricle and saccule. These underlying changes contributed to unanticipated phenotypic loss of VsEPs and VORs in Tmc1 KO mice. In contrast, Tmc2 KO mice retained VsEPs despite the loss of the calcium buffering protein calretinin, a characteristic biomarker of mature striolar calyx-only afferents. Lastly, we found that neonatal Tmc1 gene replacement therapy is sufficient to restore VsEP in Tmc1 KO mice for up to six months post-injection.

ABSTRACTTwo growth modes have been described for the filamentous Streptomyces bacteria. Their classic developmental life cycle culminates in the formation of dormant spores, where movement to new environments is mediated through spore dispersal. In contrast, exploratory growth proceeds as a rapidly expanding vegetative mycelium that leads to extensive surface colonization and is associated with the release of volatile compounds that promote alkalinization (and reduced iron bioavailability) of its surrounding environment. Here, we report that exploratory growth in Streptomyces venezuelae can proceed in tandem with classic sporulating development in response to specific nutritional cues. Sporulating exploration is not accompanied by a rise in environmental pH but has the same iron acquisition requirements as conventional exploration. We found that mutants that were defective in their ability to sporulate were unaffected in exploration, but mutants undergoing precocious sporulation were compromised in their exploratory growth and this appeared to be mediated through premature activation of the developmental regulator WhiI. Cell envelope integrity was also found to be critical for exploration, as mutations in the cell envelope stress-responsive extracytoplasmic function sigma factor SigE led to a failure to explore robustly under all exploration-promoting conditions. Finally, in expanding the known exploration-promoting conditions, we discovered that the model species Streptomyces lividans exhibited exploration capabilities, supporting the proposal that exploration is conserved across diverse streptomycetes.IMPORTANCEStreptomyces bacteria have evolved diverse developmental and metabolic strategies to thrive in dynamic environmental niches. Here, we report the amalgamation of previously disparate developmental pathways, showing that colony expansion via exploration can proceed in tandem with colony sporulation. This developmental integration extends beyond phenotype to include shared genetic elements, with sporulation-specific repressors being required for successful exploration. Comparing this new exploration mode with previously identified strategies has revealed key differences (e.g., no need for environmental alkalinization), and simultaneously allowed us to define unifying requirements for Streptomyces exploration. The “reproductive exploration” phenomenon reported here represents a unique bet-hedging strategy, with the Streptomyces colony engaging in an aggressive colonization strategy while transporting a protected genetic repository.

Purpose: To compare functional outcomes and failure rates between medial patellofemoral ligament (MPFL) reconstructions with and without lateral retinacular release (LRR) at minimum 1-year follow up. Methods: A retrospective review identified consecutive patients from 2013 to 2019 at a single center who met all of the following inclusion criteria: at least 1 confirmed patellar dislocation, patellar tilt (evidenced by tight retinaculum on operative examination or patellar tilt on radiographs), underwent either MPFL reconstruction alone or combined with LRR, had available preoperative documentation and imaging, and were at least 1 year out of surgery. Patients were excluded if they had previous surgery to the ipsilateral limb or had any concomitant procedure performed. Demographics and preoperative imaging were evaluated. Failure rates and functional outcome scores were obtained including Kujala, Patient-Reported Outcomes Measurement Information System, International Knee Documentation Committee, Single Assessment Numeric Evaluation, and Knee injury and Osteoarthritis Outcome Scores. Clinical failure was defined as revision MPFL reconstruction on the affected knee or at least 1 instance of postoperative patellar dislocation. Results: A total of 18 patients underwent isolated MPFL reconstruction (mean follow-up = 29.3 ± 8.3 months, range = 15.1-42.8 months), and 31 underwent MPFL reconstruction combined with LRR (mean follow up = 36.0 ± 11.3 months, range = 14.0-51.9 months). At final follow-up, there were no statistical differences between the isolated MPFL and MPFL combined with LRR cohorts for any of the functional outcome scores (P > .05 for all). At the time of final follow-up, no patients who underwent isolated MPFL and 19.3% (n = 6) or patients undergoing MPFL combined with LRR experienced clinical failure (P = .073), as defined by subsequent patellar dislocation or revision MPFL reconstruction. Of these, 2 patients underwent revision MPFL reconstructions with distal tubercle transfer for borderline abnormal TT:TG (i.e., >15 mm). Conclusions: MPFL reconstruction surgery combined with LRR failed to demonstrate significantly different functional outcome scores and failure rates compared with isolated MPFL reconstruction at minimum 1-year follow up. In addition, there were no differences in rates of achieving MCID between both groups Level of Evidence: Level III, retrospective cohort study.

Introduction: Craniospinal irradiation (CSI) is indicated for adult patients diagnosed with leptomeningeal disease (LMD). Proton-based vertebral body sparing (VBS) CSI has been explored with pediatric patients to minimize hematologic toxicity; however, utilization of VBS in an adult population is limited. A recent phase II trial has shown efficacy of proton-based CSI to treat non-small cell lung and breast cancer with LMD. We hypothesize that VBS CSI using volumetric modulated arc therapy (VMAT) could also effectively reduce dose to vertebral bodies and surrounding organs at risk, minimizing toxicity for adult patients with LMD and comparing favorably to proton-based CSI. Methods and Materials: Consecutive patients with LMD received VMAT VBS CSI, 30 Gy in 10 fractions, as a part of a prospective registry. Full VMAT arcs for the brain fields matched to 2 spine isocenters for the upper and lower spine were created using limited posterior arcs. To further decrease the vertebral body dose, an avoid entry and exit contour was created. Acute toxicity data were collected using Common Terminology Criteria for Adverse Events v5. Results: Ten adult patients were treated in this cohort. One patient experienced grade 2 neutropenia with the remaining 9 experiencing grade 1 hematologic toxicity. Three patients experienced grade 2 gastrointestinal toxicity with the remaining 7 experiencing grade 1 nausea. No patient experienced grade 3+ toxicities in this cohort. One patient experienced a 5-day delay in systemic therapy initiation due to neutropenia; otherwise, all patients planned for systemic therapy started without delay. Conclusions: In this study, VMAT VBS CSI led to acceptable toxicity compared with patients treated with proton CSI on a phase 2 clinical trial. Given its promising early results, future prospective evaluation of the technique is warranted.

Abstract SARS-CoV-2 variants have continuously emerged in the face of effective vaccines. Reduced neutralization against variants raises questions as to whether other antibody functions are similarly compromised, or if they might compensate for lost neutralization activity. Here, the breadth and potency of antibody recognition and effector function is surveyed following either infection or vaccination. Considering pregnant women as a model cohort with higher risk of severe illness and death, we observe similar binding and functional breadth for healthy and immunologically vulnerable populations, but considerably greater functional antibody breadth and potency across variants associated with vaccination. In contrast, greater antibody functional activity targeting the endemic coronavirus OC43 is noted among convalescent individuals, illustrating a dichotomy in recognition between close and distant human coronavirus strains associated with exposure history. This analysis of antibody functions suggests the differential potential for antibody effector functions to contribute to protecting vaccinated and convalescent subjects as novel variants continue to evolve.

Abstract Optimization of water pumping systems has been studied using various techniques which include classical, mathematical, and heuristics. Few studies have explored use of optimal controllers in agricultural water pumping applications. Some studies also ignore the interconnection between the water demand and energy used. Introduction of renewable energy sources such as photovoltaic (PV) necessitates different geographical studies as the intensity of the renewable energy varies widely with location. In this paper, an optimal controller for a batteryless grid-connected photovoltaic system to power water supply system for irrigation purposes was developed. The aim was to minimize the operational cost of grid energy by maximizing utilization of photovoltaic power and minimizing the utilization of grid power. A case study was done at a farm in Kajiado (−1.6033257 $$^{\circ }$$ ∘ latitude and 36.7863352 $$^{\circ }$$ ∘ longitude). The farm photovoltaic, grid power, water pumps (underground and booster pump), and storage tanks were modelled into a binary linear programming optimization problem and solved using intlinprog solver on MATLAB. Energy demand data was collected using a three-phase power logger, while water demand data was collected using onsite water meter and stopwatch timer. Photovoltaic power produced was estimated using Photovoltaic Geographical Information System (PVGIS). Simulation results obtained show that the use of an optimal controller results in reduced cost of energy by 44.4%. Better utilization of renewable photovoltaic energy by 24% was observed, and 3.6% more water was pumped.

DZNep (3-deazaneplanocin A) is commonly used to reduce lysine methylation. DZNep inhibits S-adenosyl-l-homocysteine hydrolase (AHCY), preventing the conversion of S-adenosyl-l-homocysteine (SAH) into L-homocysteine. As a result, the SAM-to-SAH ratio decreases, an indicator of the methylation potential within a cell. Many studies have characterized the impact of DZNep on histone lysine methylation or in specific cell or disease contexts, but there has yet to be a study looking at the potential downstream impact of DZNep treatment on proteins other than histones. Recently, protein thermal stability has provided a new dimension for studying the mechanism of action of small-molecule inhibitors. In addition to ligand binding, post-translational modifications and protein–protein interactions impact thermal stability. Here, we sought to characterize the protein thermal stability changes induced by DZNep treatment in HEK293T cells using the Protein Integral Solubility Alteration (PISA) assay. DZNep treatment altered the thermal stability of 135 proteins, with over half previously reported to be methylated at lysine residues. In addition to thermal stability, we identify changes in transcript and protein abundance after DZNep treatment to distinguish between direct and indirect impacts on thermal stability. Nearly one-third of the proteins with altered thermal stability had no changes at the transcript or protein level. Of these thermally altered proteins, CDK6 had a stabilized methylated peptide, while its unmethylated counterpart was unaltered. Multiple methyltransferases were among the proteins with thermal stability alteration, including DNMT1, potentially due to changes in the SAM/SAH levels. This study systematically evaluates DZNep’s impact on the transcriptome, the proteome, and the thermal stability of proteins.

The Deep Brain Stimulation (DBS) Think Tank XI was held on August 9–11, 2023 in Gainesville, Florida with the theme of “Pushing the Forefront of Neuromodulation”. The keynote speaker was Dr. Nico Dosenbach from Washington University in St. Louis, Missouri. He presented his research recently published in Nature inn a collaboration with Dr. Evan Gordon to identify and characterize the somato-cognitive action network (SCAN), which has redefined the motor homunculus and has led to new hypotheses about the integrative networks underpinning therapeutic DBS. The DBS Think Tank was founded in 2012 and provides an open platform where clinicians, engineers, and researchers (from industry and academia) can freely discuss current and emerging DBS technologies, as well as logistical and ethical issues facing the field. The group estimated that globally more than 263,000 DBS devices have been implanted for neurological and neuropsychiatric disorders. This year's meeting was focused on advances in the following areas: cutting-edge translational neuromodulation, cutting-edge physiology, advances in neuromodulation from Europe and Asia, neuroethical dilemmas, artificial intelligence and computational modeling, time scales in DBS for mood disorders, and advances in future neuromodulation devices.

Substantial effort has been made in manually tracking plant maturity and to measure early-stage plant density and crop height in experimental fields. In this study, RGB drone imagery and deep learning (DL) approaches are explored to measure relative maturity (RM), stand count (SC), and plant height (PH), potentially offering higher throughput, accuracy, and cost-effectiveness than traditional methods. A time series of drone images was utilized to estimate dry bean RM employing a hybrid convolutional neural network (CNN) and long short-term memory (LSTM) model. For early-stage SC assessment, Faster RCNN object detection algorithm was evaluated. Flight frequencies, image resolution, and data augmentation techniques were investigated to enhance DL model performance. PH was obtained using a quantile method from digital surface model (DSM) and point cloud (PC) data sources. The CNN-LSTM model showed high accuracy in RM prediction across various conditions, outperforming traditional image preprocessing approaches. The inclusion of growing degree days (GDD) data improved the model’s performance under specific environmental stresses. The Faster R-CNN model effectively identified early-stage bean plants, demonstrating superior accuracy over traditional methods and consistency across different flight altitudes. For PH estimation, moderate correlations with ground-truth data were observed across both datasets analyzed. The choice between PC and DSM source data may depend on specific environmental and flight conditions. Overall, the CNN-LSTM and Faster R-CNN models proved more effective than conventional techniques in quantifying RM and SC. The subtraction method proposed for estimating PH without accurate ground elevation data yielded results comparable to the difference-based method. Additionally, the pipeline and open-source software developed hold potential to significantly benefit the phenotyping community.

ABSTRACT Early COVID-19 convalescent plasma (CCP) transfusion to outpatients with COVID-19 decreases progression to hospitalization, but the mechanism of how CCP reduces severity is unknown. Among 882 COVID-19 participants transfused with CCP or control plasma in a randomized controlled trial, 21 cytokines and chemokines were measured using electrochemiluminescence assays. Wilcoxon rank sum tests were used to evaluate the difference between early (transfused within 5 days of symptom onset) CCP vs early control plasma and late (transfused 6–9 days after symptom onset) CCP vs late control plasma at each visit. Linear mixed-effect models were used to assess the difference in the slope of cytokine change. Median cytokine and chemokine levels were similar between the early CCP and early control groups pre-transfusion. At the day 14 visit, only the median IL-6 (P = 0.014) and IL-16 (P = 0.036) levels were lower in the early CCP group compared to the early control group, but these differences were not statistically significant after correcting for multiple comparisons (requiring P < 0.0024). IL-6 levels decreased significantly faster in the early CCP group from screening to the day 14 visit compared to the early control group (P < 0.001). No difference was observed in the slope of cytokine change from screening to day 90 between early CCP and early control groups. Late control and late CCP arms showed similar cytokine and chemokine levels through study follow-up. One mechanism by which early CCP transfusion reduces hospitalization may be by decreasing IL-6 levels, as the reduction is associated with better recovery from COVID-19. IMPORTANCE This study examined the role that cytokines may have played in the beneficial outcomes found when outpatient individuals infected with SARS-CoV-2 were transfused with COVID-19 convalescent plasma (CCP) early in their infection. We found that the pro-inflammatory cytokine IL-6 decreased significantly faster in patients treated early with CCP. Participants with COVID-19 treated with CCP later in the infection did not have the same effect. This decrease in IL-6 levels after early CCP treatment suggests a possible role of inflammation in COVID-19 progression. The evidence of IL-6 involvement brings insight into the possible mechanisms involved in CCP treatment mitigating SARS-CoV-2 severity.

Abstract Introduction: In response to the COVID-19 pandemic, we rapidly implemented a plasma coordination center, within two months, to support transfusion for two outpatient randomized controlled trials. The center design was based on an investigational drug services model and a Food and Drug Administration-compliant database to manage blood product inventory and trial safety. Methods: A core investigational team adapted a cloud-based platform to randomize patient assignments and track inventory distribution of control plasma and high-titer COVID-19 convalescent plasma of different blood groups from 29 donor collection centers directly to blood banks serving 26 transfusion sites. Results: We performed 1,351 transfusions in 16 months. The transparency of the digital inventory at each site was critical to facilitate qualification, randomization, and overnight shipments of blood group-compatible plasma for transfusions into trial participants. While inventory challenges were heightened with COVID-19 convalescent plasma, the cloud-based system, and the flexible approach of the plasma coordination center staff across the blood bank network enabled decentralized procurement and distribution of investigational products to maintain inventory thresholds and overcome local supply chain restraints at the sites. Conclusion: The rapid creation of a plasma coordination center for outpatient transfusions is infrequent in the academic setting. Distributing more than 3,100 plasma units to blood banks charged with managing investigational inventory across the U.S. in a decentralized manner posed operational and regulatory challenges while providing opportunities for the plasma coordination center to contribute to research of global importance. This program can serve as a template in subsequent public health emergencies.

Background: Recent advances in data-driven computational approaches have been helpful in devising tools to objectively diagnose psychiatric disorders. However, current machine learning studies limited to small homogeneous samples, different methodologies, and different imaging collection protocols, limit the ability to directly compare and generalize their results. Here we aimed to classify individuals with PTSD versus controls and assess the generalizability using a large heterogeneous brain datasets from the ENIGMA-PGC PTSD Working group. Methods: We analyzed brain MRI data from 3,477 structural-MRI; 2,495 resting state-fMRI; and 1,952 diffusion-MRI. First, we identified the brain features that best distinguish individuals with PTSD from controls using traditional machine learning methods. Second, we assessed the utility of the denoising variational autoencoder (DVAE) and evaluated its classification performance. Third, we assessed the generalizability and reproducibility of both models using leave-one-site-out cross-validation procedure for each modality. Results: We found lower performance in classifying PTSD vs. controls with data from over 20 sites (60 % test AUC for s-MRI, 59 % for rs-fMRI and 56 % for d-MRI), as compared to other studies run on single-site data. The performance increased when classifying PTSD from HC without trauma history in each modality (75 % AUC). The classification performance remained intact when applying the DVAE framework, which reduced the number of features. Finally, we found that the DVAE framework achieved better generalization to unseen datasets compared with the traditional machine learning frameworks, albeit performance was slightly above chance. Conclusion: These results have the potential to provide a baseline classification performance for PTSD when using large scale neuroimaging datasets. Our findings show that the control group used can heavily affect classification performance. The DVAE framework provided better generalizability for the multi-site data. This may be more significant in clinical practice since the neuroimaging-based diagnostic DVAE classification models are much less site-specific, rendering them more generalizable.

Abstract Lysine methylation modulates the function of histone and non-histone proteins, and the enzymes that add or remove lysine methylation—lysine methyltransferases (KMTs) and lysine demethylases (KDMs), respectively—are frequently mutated and dysregulated in human diseases. Identification of lysine methylation sites proteome-wide has been a critical barrier to identifying the non-histone substrates of KMTs and KDMs and for studying functions of non-histone lysine methylation. Detection of lysine methylation by mass spectrometry (MS) typically relies on the enrichment of methylated peptides by pan-methyllysine antibodies. In this study, we use peptide microarrays to show that pan-methyllysine antibodies have sequence bias, and we evaluate how the differential selectivity of these reagents impacts the detection of methylated peptides in MS-based workflows. We discovered that most commercially available pan-Kme antibodies have an in vitro sequence bias, and multiple enrichment approaches provide the most comprehensive coverage of the lysine methylome. Overall, global lysine methylation proteomics with multiple characterized pan-methyllysine antibodies resulted in the detection of 5089 lysine methylation sites on 2751 proteins from two human cell lines, nearly doubling the number of reported lysine methylation sites in the human proteome.

Objectives Prevention programs that can help adults improve the quality of their diets to reduce cancer risk are needed. This Phase IIa study prospectively tested a mHealth intervention designed to improve adherence to dietary quality guidelines for cancer prevention. Methods All participants (N = 62) received nutrition education and a self-regulation skills curriculum, with a primary target of changing grocery shopping behavior. Using a randomized, factorial design, the study varied whether each of the following 4 components were added to the 20-week intervention: (1) location-triggered app messaging, delivered when individuals arrived at grocery stores, (2) reflections on benefits of change, delivered with extra coaching time and tailored app messages, (3) coach monitoring, in which food purchases were digitally monitored by a coach, and (4) involvement of a household member in the intervention. Results Benchmarks were successfully met for recruitment, retention, and treatment acceptability. Across conditions, there were significant reductions in highly processed food intake ( P < .001, η 2 = .48), red and processed meat intake ( P < .001, η 2 = .20), and sugar-sweetened beverage intake ( P = .008, η 2 = .13) from pre-to post-treatment. Analyses examining whether each intervention component influenced change across time found that participants who received coach monitoring increased their intake of fruits, vegetables, and fiber, whereas those with no coach monitoring had less improvement ( P = .01, η 2 = .14). The improvement in red and processed meat was stronger among participants with household support ON, at a marginally significant level, than those with household support OFF ( P = .056, η 2 = .07). Conclusion This study showed feasibility, acceptability, and preliminary signals of efficacy of a remotely delivered intervention to facilitate adherence to dietary guidelines for cancer prevention and that coach monitoring and household support may be especially effective strategies. A fully powered clinical trial is warranted to test an optimized version of the intervention that includes nutrition education, self-regulation skills training, coach monitoring, and household member involvement. Trial Registration ClinicalTrials.gov NCT04947150.

Introduction Carotid stump syndrome (CSS) is a paradoxical phenomenon that occurs when there are repeated ischemic events in the carotid vascular territory despite demonstrated occlusion of the ipsilateral internal carotid artery (ICA). It is thought to be caused by turbulent blood flow in the patent stump of the occluded ICA creating microemboli which reach the brain through anastomotic channels and retrograde flow. We present a case of recurrent infarctions in setting of known ipsilateral ICA occlusion, who was diagnosed with carotid stump syndrome. Methods A male veteran in his 60s with a medical history of DVTs on apixaban, PVD, and ischemic stroke with residual right‐sided weakness, presented with worsening right‐sided weakness and difficulty with ambulation. Two months prior to the presentation he was diagnosed with acute infarcts in left frontal, parietal, and temporal lobes due to thromboembolism from left ICA occlusion. On presentation his neurological exam revealed right‐sided hemiparesis. MRI brain showed multiple acute and chronic cortical and subcortical infarcts in the left frontotemporoparietal lobes and lack of flow void in the left distal ICA. To further evaluate the dynamics of blood flow patient underwent a cerebral angiogram which confirmed the diagnosis of complete occlusion of left ICA and demonstrated reconstitution of the intracranial ICA through retrograde filling via the ophthalmic artery and anastomotic branches with the internal maxillary artery (IMax). For secondary prevention he was started on statin and aspirin while his home Apixaban was continued. Surgical and endovascular treatment approaches were discussed but the patient declined any intervention. In his four months follow up clinic visit he had no further concerns of recurrent strokes or new symptoms. Results Carotid stump syndrome is a rare cause of cerebral and retinal ischemia; however, it must be considered in patients with recurrent ischemic strokes and chronic ipsilateral ICA occlusion. Due to the patent proximal, or perhaps in some cases distal, carotid stump, there’s turbulent flow and hence the thrombus formation can occur. Hemodynamic and embolic factors attribute towards the microembolization from the proximal carotid stump through the external carotid artery (ECA), into the facial artery and IMax and their distal branches which anastomose with the ophthalmic artery, causing the emboli to end up in the major branches of the carotid terminus. If a distal stump is symptomatic, then the microemboli can readily end up in the distal ICA branches. In addition to medical management with DAPT or anticoagulation and high intensity statin, our literature review supports endovascular or surgical interventions due to reportedly good outcomes. Interventional approaches may include ECA‐ICA stenting with a covered stent or stent‐assisted coil embolization of the proximal stump. Surgical procedures include an endarterectomy on the ipsilateral ECA or contralateral ICA to increase collateral circulation. ECA‐ICA bypass is another option. Conclusion Carotid stump syndrome is a rare and underrecognized cause of recurrent ischemic strokes, though it is a potentially treatable entity. The therapeutic goals include medical management along with endovascular or surgical treatment whenever possible.

Post-COVID conditions (PCCs) are common and have significant morbidity. Risk factors for PCC include advancing age, female sex, obesity, and diabetes mellitus. Little is known about treatment, inflammation, and PCC. Among 882 individuals with confirmed SARS-CoV-2 infection participating in a randomized trial of COVID-19 convalescent plasma (CCP) vs control plasma with available biospecimens and symptom data, the association between early CCP treatment, cytokine levels, and PCC was evaluated. Cytokine and chemokine levels were assessed at baseline, day 14, and day 90 using a multiplexed sandwich immunoassay (Meso Scale Discovery). Presence of any self-reported PCC symptoms was assessed at day 90. Associations between CCP treatment, cytokine levels, and PCC were examined using multivariate logistic regression models. One third of the 882 participants had day 90 PCC symptoms, with fatigue (14.5%) and anosmia (14.5%) being most common. Cytokine levels decreased from baseline to day 90. In a multivariable analysis, female sex (adjusted odds ratio [AOR] = 2.69 [1.93–3.81]), older age (AOR = 1.32 [1.17–1.50]), and elevated baseline levels of IL-6 (AOR = 1.59 [1.02–2.47]) were independently associated with development of PCC. Those who received early CCP treatment (≤5 days after symptom onset) compared to late CCP treatment had statistically significant lower odds of PCC. IMPORTANCE Approximately 20% of individuals infected with SARS-CoV-2 experienced long-term health effects, as defined PCC. However, it is unknown if there are any early biomarkers associated with PCC or whether early intervention treatments may decrease the risk of PCC. In a secondary analysis of a randomized clinical trial, this study demonstrates that among outpatients with SARS-CoV-2, increased IL-6 at time of infection is associated with increased odds of PCC. In addition, among individuals treated early, within 5 days of symptom onset, with COVID-19 convalescent plasma, there was a trend for decreased odds of PCC after adjusting for other demographic and clinical characteristics. Future treatment studies should be considered to evaluate the effect of early treatment and anti-IL-6 therapies on PCC development.

Abstract While a definitive mechanism‐of‐action remains to be identified, recent findings indicate that ghrelin, particularly the unacylated form (UnAG), stimulates skeletal muscle fatty acid oxidation. The biological importance of UnAG‐mediated increases in fat oxidation remains unclear, as UnAG peaks in the circulation before mealtimes, and decreases rapidly during the postprandial situation before increases in postabsorptive circulating lipids. Therefore, we aimed to determine if the UnAG‐mediated stimulation of fat oxidation would persist long enough to affect the oxidation of meal‐derived fatty acids, and if UnAG stimulated the translocation of fatty acid transporters to the sarcolemma as a mechanism‐of‐action. In isolated soleus muscle strips from male rats, short‐term pre‐treatment with UnAG elicited a persisting stimulus on fatty acid oxidation 2 h after the removal of UnAG. UnAG also caused an immediate phosphorylation of AMPK, but not an increase in plasma membrane FAT/CD36 or FABPpm. There was also no increase in AMPK signaling or increased FAT/CD36 or FABPpm content at the plasma membrane at 2 h which might explain the sustained increase in fatty acid oxidation. These findings confirm UnAG as a stimulator of fatty acid oxidation and provide evidence that UnAG may influence the handling of postprandial lipids. The underlying mechanisms are not known.

Connector ‘hubs’ are brain regions with links to multiple networks. These regions are hypothesized to play a critical role in brain function. While hubs are often identified based on group-average functional magnetic resonance imaging (fMRI) data, there is considerable inter-subject variation in the functional connectivity profiles of the brain, especially in association regions where hubs tend to be located. Here we investigated how group hubs are related to locations of inter-individual variability. To answer this question, we examined inter-individual variation at group-level hubs in both the Midnight Scan Club and Human Connectome Project datasets. The top group hubs defined based on the participation coefficient did not overlap strongly with the most prominent regions of inter-individual variation (termed ‘variants’ in prior work). These hubs have relatively strong similarity across participants and consistent cross-network profiles, similar to what was seen for many other areas of cortex. Consistency across participants was further improved when these hubs were allowed to shift slightly in local position. Thus, our results demonstrate that the top group hubs defined with the participation coefficient are generally consistent across people, suggesting they may represent conserved cross-network bridges. More caution is warranted with alternative hub measures, such as community density (which are based on spatial proximity to network borders) and intermediate hub regions which show higher correspondence to locations of individual variability.

ObjectivePost-translational protein modifications with malondialdehyde-acetaldehyde (MAA) and citrulline (CIT) are implicated in the pathogenesis of rheumatoid arthritis (RA). Although precise mechanisms have not been elucidated, macrophage-fibroblast interactions have been proposed to play a central role in the development and progression of RA. The purpose of our study was to evaluate the downstream effects of macrophage released soluble mediators, following stimulation with fibrinogen (FIB) modified antigens, on human fibroblast-like synoviocytes (HFLS).MethodsPMA-treated U-937 monocytes (Mϕ) and macrophage-differentiated peripheral blood mononuclear cells (MP) were stimulated with FIB, FIB-MAA, FIB-CIT, or FIB-MAA-CIT. HFLS-RA cells were stimulated directly with FIB antigens or with supernatants (SN) from macrophages (Mϕ-SN or MP-SN) stimulated with FIB antigens. Genes associated with an aggressive HFLS phenotype, extracellular matrix proteins, and activated signaling pathways were evaluated.ResultsHFLS-RA cells treated with Mϕ-SNFIB-CIT and Mϕ-SNFIB-MAA-CIT demonstrated significant increases in mRNA expression of genes associated with an aggressive phenotype at 24-h as compared to direct stimulation with the same antigens. Similar results were obtained using MP-SN. Cellular morphology was altered and protein expression of vimentin (p

Background and objectives: Carotid-cavernous fistulas (CCFs) represent a group of rare, abnormal arteriovenous communications between the carotid arterial system and the cavernous sinuses (CS). CCFs often produce ophthalmologic symptoms related to increased CS pressures and retrograde venous drainage of the eye. Although endovascular occlusion remains the preferred treatment for symptomatic or high-risk CCFs, most of the data for these lesions is limited to small, single-center series. As such, we performed a systematic review and meta-analysis evaluating endovascular occlusions of CCFs to determine any differences in clinical outcomes based on presentation, fistula type, and treatment paradigm. Method: A retrospective review of all studies discussing the endovascular treatment of CCFs published through March 2023 was conducted using PubMed, Scopus, Web of Science, and Embase databases. A total of 36 studies were included in the meta-analysis. Data from the selected articles were extracted and analyzed using Stata software version 14. Results: 1494 patients were included. 55.08% were female and the mean age of the cohort was 48.10 years. A total number of 1516 fistulas underwent endovascular treatment, 48.05% of which were direct and 51.95% of which were indirect. 87.17% of CCFs were secondary to a known trauma while 10.18% were spontaneous. The most common presenting symptoms were 89% exophthalmos (95% CI: 78.0–100.0; I2 = 75.7%), 84% chemosis (95% CI: 79.0–88.0; I2 = 91.6%), 79% proptosis (95% CI: 72.0–86.0; I2 = 91.8%), 75.0% bruits (95% CI: 67.0–82.0; I2 = 90.7%), 56% diplopia (95% CI: 42.0–71.0; I2 = 92.3%), 49% cranial nerve palsy (95% CI: 32.0–66.0; I2 = 95.1%), 39% visual decline (95% CI: 32.0–45.0; I2 = 71.4%), 32% tinnitus (95% CI: 6.0–58.0; I2 = 96.7%), 29% elevated intraocular pain (95% CI: 22.0–36.0; I2 = 0.0%), 31% orbital or pre-orbital pain (95% CI: 14.0–48.0; I2 = 89.9%) and 24% headache (95% CI: 13.0–34.0; I2 = 74.98%). Coils, balloons, and stents were the three most used embolization methods respectively. Immediate complete occlusion of the fistula was seen in 68% of cases and complete remission was seen in 82%. Recurrence of CCF occurred in only 35% of the patients. Cranial nerve paralysis after treatment was observed in 7% of the cases. Conclusions: Exophthalmos, Chemosis, proptosis, bruits, cranial nerve palsy, diplopia, orbital and periorbital pain, tinnitus, elevated intraocular pressure, visual decline and headache are the most common clinical manifestations of CCFs. The majority of endovascular treatments involved coiling, balloons and onyx and a high percentage of CCF patients experienced complete remission with the improvement of their clinical symptoms.