Search

Abstract Purpose To determine the acute effects of a mitochondrial targeting antioxidant (MitoQ) on the metabolic response during exercise. Methods Nine (n = 9) physically inactive females (age 47 ± 22 years) performed two trials (Placebo and MitoQ) in a double‐blind randomized cross‐over design. In both trials, participants performed an exercise protocol consisting of 3‐min stages at submaximal workloads followed by a ramp protocol to volitional exhaustion. Participants received either Placebo or MitoQ (80 mg) 1 h prior to exercise. Indirect calorimetry and cardiovascular measurements were collected throughout the duration of the exercise bout. Results Submaximal metabolic and cardiovascular variables were not different between trials (p > 0.05). VO2max was higher (p = 0.03) during Placebo (23.5 ± 5.7 mL kg min−1) compared to MitoQ (21.0 ± 6.6 mL kg min−1). Maximal ventilation was also higher (p = 0.02) in Placebo (82.4 ± 17.7 L/min) compared to MitoQ (75.0 ± 16.8 L/min). Maximal cardiovascular variables and blood lactate were not different between trials (p > 0.05). Conclusion An acute dose of MitoQ blunted VO2max, which was primarily mediated by impairment of ventilatory function. These data suggest that the acute accumulation of exercise‐induced mitochondrial reactive oxygen species (mtROS) are necessary for maximal aerobic capacity. Further research is warranted on mtROS‐antioxidant cell signaling cascades, and how they relate to mitochondrial function during exercise.

Adolescence is a conserved developmental period associated with low alcohol responsivity, which can contribute to heavy drinking and development of an alcohol use disorder (AUD) later in life. To investigate ethanol responsivity between adolescent and adult rats, we developed an ethanol response battery (ERB) to assess acute ethanol responses across cumulative doses of ethanol during the rising phase of the blood ethanol curve. We tested the hypothesis that adolescent male and female rats would exhibit lower ethanol responsivity to a cumulative ethanol challenge relative to adults. Male and female adolescent (postnatal day [P]40) and adult (P85) Wistar rats underwent ERB assessment following consecutive doses of ethanol (i.e., 1.0, 1.0, and 1.0 g/kg) to produce cumulative ethanol doses of 0.0, 1.0, 2.0, and 3.0 g/kg. The ERB consisted of (1) the 6-point behavioral intoxication rating scale, (2) body temperature assessment, (3) tail blood collection, (4) accelerating rotarod assessment, (5) tilting plane assessment, and (6) loss of righting reflex (LORR) assessment. Across cumulative ethanol doses, adolescent and adult rats evidenced progressive changes in ERB measures. On the ERB, adolescent rats of both sexes evidenced (1) lower intoxication rating, (2) blunted hypothermic responses, particularly in females, (3) longer latencies to fall from the accelerating rotarod, and (4) less tilting plane impairment relative to adults despite comparable BECs. All adult rats, regardless of sex, displayed a LORR at the 3.0 g/kg cumulative ethanol dose while among the adolescent rats, only one male rat and no females showed the LORR. These data reveal decreased adolescent ethanol responsivity across body temperature, intoxication, balance, and coordination responses to a cumulative ethanol challenge as assessed using the novel ERB relative to adults. The results of this study suggest that adolescent-specific low ethanol responsivity may contribute to adolescent binge drinking and increased risk for development of an AUD.

Abstract Background The high-quality evidence on managing COVID-19 patients requiring extracorporeal membrane oxygenation (ECMO) support is insufficient. Furthermore, there is little consensus on allocating ECMO resources when scarce. The paucity of evidence and the need for guidance on controversial topics required an international expert consensus statement to understand the role of ECMO in COVID-19 better. Twenty-two international ECMO experts worldwide work together to interpret the most recent findings of the evolving published research, statement formulation, and voting to achieve consensus. Objectives To guide the next generation of ECMO practitioners during future pandemics on tackling controversial topics pertaining to using ECMO for patients with COVID-19-related severe ARDS. Methods The scientific committee was assembled of five chairpersons with more than 5 years of ECMO experience and a critical care background. Their roles were modifying and restructuring the panel’s questions and, assisting with statement formulation in addition to expert composition and literature review. Experts are identified based on their clinical experience with ECMO (minimum of 5 years) and previous academic activity on a global scale, with a focus on diversity in gender, geography, area of expertise, and level of seniority. We used the modified Delphi technique rounds and the nominal group technique (NGT) through three face-to-face meetings and the voting on the statement was conducted anonymously. The entire process was planned to be carried out in five phases: identifying the gap of knowledge, validation, statement formulation, voting, and drafting, respectively. Results In phase I, the scientific committee obtained 52 questions on controversial topics in ECMO for COVID-19, further reviewed for duplication and redundancy in phase II, resulting in nine domains with 32 questions with a validation rate exceeding 75% (Fig. 1). In phase III, 25 questions were used to formulate 14 statements, and six questions achieved no consensus on the statements. In phase IV, two voting rounds resulted in 14 statements that reached a consensus are included in four domains which are: patient selection, ECMO clinical management, operational and logistics management, and ethics. Conclusion Three years after the onset of COVID-19, our understanding of the role of ECMO has evolved. However, it is incomplete. Tota14 statements achieved consensus; included in four domains discussing patient selection, clinical ECMO management, operational and logistic ECMO management and ethics to guide next-generation ECMO providers during future pandemic situations.

Abstract Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix®. Here, we dissect disease mechanisms and interactions with environmental triggers in a multi-ethnic sample of 6,073 cases and 84,856 controls. We fine-mapped GWAS signals within HLA (DQ0602, DQB1*03:01 and DPB1*04:02) and discovered seven novel associations (CD207, NAB1, IKZF4-ERBB3, CTSC, DENND1B, SIRPG, PRF1). Significant signals at TRA and DQB1*06:02 loci were found in 245 vaccination-related cases, who also shared polygenic risk. T cell receptor associations in NT1 modulated TRAJ*24, TRAJ*28 and TRBV*4-2 chain-usage. Partitioned heritability and immune cell enrichment analyses found genetic signals to be driven by dendritic and helper T cells. Lastly comorbidity analysis using data from FinnGen, suggests shared effects between NT1 and other autoimmune diseases. NT1 genetic variants shape autoimmunity and response to environmental triggers, including influenza A infection and immunization with Pandemrix®.

Abstract Background Although depressive and anxious symptoms negatively impact musculoskeletal health and orthopedic outcomes, a gap remains in identifying modalities through which mental health intervention can realistically be delivered during orthopedic care. The purpose of this study was to understand orthopedic stakeholders’ perceptions regarding the feasibility, acceptability, and usability of digital, printed, and in-person intervention modalities to address mental health as part of orthopedic care. Methods This single-center, qualitative study was conducted within a tertiary care orthopedic department. Semi-structured interviews were conducted between January and May 2022. Two stakeholder groups were interviewed using a purposive sampling approach until thematic saturation was reached. The first group included adult orthopedic patients who presented for management of ≥ 3 months of neck or back pain. The second group included early, mid, and late career orthopedic clinicians and support staff members. Stakeholders’ interview responses were analyzed using deductive and inductive coding approaches followed by thematic analysis. Patients also performed usability testing of one digital and one printed mental health intervention. Results Patients included 30 adults out of 85 approached (mean (SD) age 59 [14] years, 21 (70%) women, 12 (40%) non-White). Clinical team stakeholders included 22 orthopedic clinicians and support staff members out of 25 approached (11 (50%) women, 6 (27%) non-White). Clinical team members perceived a digital mental health intervention to be feasible and scalable to implement, and many patients appreciated that the digital modality offered privacy, immediate access to resources, and the ability to engage during non-business hours. However, stakeholders also expressed that a printed mental health resource is still necessary to meet the needs of patients who prefer and/or can only engage with tangible, rather than digital, mental health resources. Many clinical team members expressed skepticism regarding the current feasibility of scalably incorporating in-person support from a mental health specialist into orthopedic care. Conclusions Although digital intervention offers implementation-related advantages over printed and in-person mental health interventions, a subset of often underserved patients will not currently be reached using exclusively digital intervention. Future research should work to identify combinations of effective mental health interventions that provide equitable access for orthopedic patients. Trial registration Not applicable.

ABSTRACTCLIGEN is a stochastic weather generator that creates statistically representative timeseries of daily and sub-daily point-scale weather variables from observed monthly statistics and other parameters. CLIGEN precipitation timeseries are used as climate input for various risk-assessment modelling applications as an alternative to observe long-term, high temporal resolution records. Here, we queried gridded global climate datasets (TerraClimate, ERA5, GPM-IMERG, and GLDAS) to estimate various 20-year climate statistics and obtain complete CLIGEN input parameter sets with coverage of the African and South American continents at 0.25 arc degree resolution. The estimation of CLIGEN precipitation parameters was informed by a ground-based dataset of >10,000 locations worldwide. The ground observations provided target values to fit regression models that downscale CLIGEN precipitation input parameters. Aside from precipitation parameters, CLIGEN’s parameters for temperature, solar radiation, etc. were in most cases directly calculated according to the original global datasets. Cross-validation for estimated precipitation parameters quantified errors that resulted from applying the estimation approach in a predictive fashion. Based on all training data, the RMSE was 2.23 mm for the estimated monthly average single-event accumulation and 4.70 mm/hr for monthly maximum 30-min intensity. This dataset facilitates exploration of hydrological and soil erosional hypotheses across Africa and South America.

Glioblastoma multiforme (GBM) is among the most difficult cancers to treat with a 5-year survival rate less than 5%. An immunotherapeutic vaccine approach targeting GBM-specific antigen, EGFRvIII, previously demonstrated important clinical impact. However, immune escape variants were reported in the trial, suggesting that multivalent approaches targeting GBM-associated antigens may be of importance. Here we focused on multivalent in vivo delivery of synthetic DNA-encoded bispecific T cell engagers (DBTEs) targeting two GBM-associated antigens, EGFRvIII and HER2. We designed and optimized an EGFRvIII-DBTE that induced T cell-mediated cytotoxicity against EGFRvIII-expressing tumor cells. In vivo delivery in a single administration of EGFRvIII-DBTE resulted in durable expression over several months in NSG mice and potent tumor control and clearance in both peripheral and orthotopic animal models of GBM. Next, we combined delivery of EGFRvIII-DBTEs with an HER2-targeting DBTE to treat heterogeneous GBM tumors. In vivo delivery of dual DBTEs targeting these two GBM-associated antigens exhibited enhanced tumor control and clearance in a heterogeneous orthotopic GBM challenge, while treatment with single-target DBTE ultimately allowed for tumor escape. These studies support that combined delivery of DBTEs, targeting both EGFRvIII and HER2, can potentially improve outcomes of GBM immunotherapy, and such multivalent approaches deserve additional study.

Objective: Regionalization of surgery for non–small cell lung cancer (NSCLC) to high-volume centers (HVCs) improves perioperative outcomes but frequently increases patient travel distance. Travel might decrease rates of adjuvant chemotherapy (AC) use, however, the relationship of distance, volume, and receipt of AC with outcomes is unknown. Our objective was to evaluate the association of distance, volume, and receipt of AC with overall survival among patients with NSCLC. Methods: Patients with stage I to IIIA (N0-N1) NSCLC were identified between 2004 and 2018 using the National Cancer Database. Distance to surgical facility was categorized into quartiles (

Enzymatic catalysis requires cofactors such as NAD(P)H, whose regeneration is currently accomplished via secondary enzymes or electrolytic cell. Here, the authors report an electrochemical method of cofactors regeneration without supporting enzymes or mediators, nor formation of NAD2 dimers.

Abstract Background A primary goal in transoral robotic surgery (TORS) for oropharyngeal squamous cell cancer (OPSCC) survivors is to optimize swallowing function. However, the uncertainty in the outcomes of TORS including postoperative residual positive margin (PM) and extranodal extension (ENE), may necessitate adjuvant therapy, which may cause significant swallowing toxicity to survivors. Methods A secondary analysis was performed on a prospective registry data with low‐ to intermediate‐risk human papillomavirus–related OPSCC possibly resectable by TORS. Decision trees were developed to model the uncertainties in TORS compared with definitive radiation therapy (RT) and chemoradiation therapy (CRT). Swallowing toxicities were measured by Dynamic Imaging Grade of Swallowing Toxicity (DIGEST), MD Anderson Dysphagia Inventory (MDADI), and the MD Anderson Symptom Inventory–Head and Neck (MDASI‐HN) instruments. The likelihoods of PM/ENE were varied to determine the thresholds within which each therapy remains optimal. Results Compared with RT, TORS resulted in inferior swallowing function for moderate likelihoods of PM/ENE (>60% in short term for all instruments, >75% in long term for DIGEST and MDASI) leaving RT as the optimal treatment. Compared with CRT, TORS remained the optimal therapy based on MDADI and MDASI but showed inferior swallowing outcomes based on DIGEST for moderate‐to‐high likelihoods of PM/ENE (>75% for short‐term and >40% for long‐term outcomes). Conclusion In the absence of reliable estimation of postoperative PM/ENE concurrent with significant postoperative PM, the overall toxicity level in OPSCC patients undergoing TORS with adjuvant therapy may become more severe compared with patients receiving nonsurgical treatments thus advocating definitive (C)RT protocols.

Abstract Background Congenital heart disease (CHD) is a common and significant birth defect, frequently requiring surgical intervention. For beneficiaries of the Department of Defense, a new diagnosis of CHD may occur while living at rural duty stations. Choice of tertiary care center becomes a function of geography, referring provider recommendations, and patient preference. Methods Using billing data from the Military Health System over a 5-year period, outcomes for beneficiaries age 50 high complexity cases annually) demonstrated decreased one year mortality, but increased cost and length of stay. Conclusions Together, these findings contribute to the national conversation of rural community medicine versus regionalized subspecialty care; separation of patients between rural areas and more urban locations for initial CHD surgical care does not increase their mortality risk. In fact, traveling to high volume centers may have an associated mortality benefit.

Purpose: Varicocele is a common problem among infertile men. Varicocele repair (VR) is frequently performed to improve semen parameters and the chances of pregnancy. However, there is a lack of consensus about the diagnosis, indications for VR and its outcomes. The aim of this study was to explore global practice patterns on the management of varicocele in the context of male infertility. Materials and Methods: Sixty practicing urologists/andrologists from 23 countries contributed 382 multiple-choice-questions pertaining to varicocele management. These were condensed into an online questionnaire that was forwarded to clinicians involved in male infertility management through direct invitation. The results were analyzed for disagreement and agreement in practice patterns and, compared with the latest guidelines of international professional societies (American Urological Association [AUA], American Society for Reproductive Medicine [ASRM], and European Association of Urology [EAU]), and with evidence emerging from recent systematic reviews and meta-analyses. Additionally, an expert opinion on each topic was provided based on the consensus of 16 experts in the field. Results: The questionnaire was answered by 574 clinicians from 59 countries. The majority of respondents were urologists/ uro-andrologists. A wide diversity of opinion was seen in every aspect of varicocele diagnosis, indications for repair, choice of technique, management of sub-clinical varicocele and the role of VR in azoospermia. A significant proportion of the responses were at odds with the recommendations of AUA, ASRM, and EAU. A large number of clinical situations were identified where no guidelines are available. Conclusions: This study is the largest global survey performed to date on the clinical management of varicocele for male infertility. It demonstrates: 1) a wide disagreement in the approach to varicocele management, 2) large gaps in the clinical practice guidelines from professional societies, and 3) the need for further studies on several aspects of varicocele management in infertile men.

Abstract Background This study investigated the association of hearing loss and tinnitus with overall health‐related quality of life (HRQoL) among long‐term oropharyngeal cancer (OPC) survivors. Methods This study included OPC survivors treated between 2000 and 2013 and surveyed from September 2015 to July 2016. Hearing loss and tinnitus were measured by asking survivors to rate their “difficulty with hearing loss and/or ringing in the ears” from 0 (not present) to 10 (as bad as you can imagine). Hearing loss and tinnitus scores were categorized as follows: 0 for none, 1–4 for mild, and 5–10 for moderate to severe. The primary outcome was the mean score of MD nderson Symptom Inventory Head & Neck module interference component as a HRQoL surrogate dichotomized as follows: 0 to 4 for none to mild and 5 to 10 for moderate to severe interference. Results Among 880 OPC survivors, 35.6% (314), reported none, 39.3% (347) reported mild, and 25.1% (221) reported moderate to severe hearing loss and tinnitus. On multivariable analysis, mild (OR, 5.83; 95% CI; 1.48–22.88; p = 0.012) and moderate (OR, 30.01; 95% CI; 7.96–113.10; p

Abstract Background Seizures, strokes, and intracranial hemorrhage are common and feared complications in children receiving extracorporeal membrane oxygenation (ECMO) support. Researchers and clinicians have proposed and deployed methods for monitoring and detecting neurologic injury, but best practices are unknown. We sought to characterize clinicians’ approach to electroencephalography (EEG) and brain imaging modalities in children supported by ECMO. Methods We performed a retrospective observational cohort study among US Children’s Hospitals participating in the Pediatric Health Information System (PHIS) from 2016 to 2021. We identified hospitalizations containing ECMO support. We stratified these admissions by pediatric, neonatal, cardiac surgery, and non-cardiac surgery. We characterized the frequency of EEG, cranial ultrasound, brain computed tomography (CT), magnetic resonance imaging (MRI), and transcranial Doppler during ECMO hospitalizations. We reported key diagnoses (stroke and seizures) and the prescription of antiseizure medication. To assess hospital variation, we created multilevel logistic regression models. Results We identified 8746 ECMO hospitalizations. Nearly all children under 1 year of age (5389/5582) received a cranial ultrasound. Sixty-two percent of the cohort received an EEG, and use increased from 2016 to 2021 (52–72% of hospitalizations). There was marked variation between hospitals in rates of EEG use. Rates of antiseizure medication use (37% of hospitalizations) and seizure diagnoses (20% of hospitalizations) were similar across hospitals, including high and low EEG utilization hospitals. Overall, 37% of the cohort received a CT and 36% received an MRI (46% of neonatal patients). Stroke diagnoses (16% of hospitalizations) were similar between high- and low-MRI utilization hospitals (15% vs 17%, respectively). Transcranial Doppler (TCD) was performed in just 8% of hospitalizations, and 77% of the patients who received a TCD were cared for at one of five centers. Conclusions In this cohort of children at high risk of neurologic injury, there was significant variation in the approach to EEG and neuroimaging in children on ECMO. Despite the variation in monitoring and imaging, diagnoses of seizures and strokes were similar across hospitals. Future work needs to identify a management strategy that appropriately screens and monitors this high-risk population without overuse of resource-intensive modalities.

CD102 is an enriched biomarker for long-lived plasma cells in non-human primates (NHPs) and is conserved across NHPs, humans, and mice.

Aroma profiles of blueberries contain a heterogeneous mixture of volatile organic compounds (VOCs), and headspace sampling is the most efficient approach to VOC extraction from berries. Typically, headspace solid-phase microextraction (HS-SPME) has been applied to blueberry VOCs. Though HS-SPME has been the most common choice for headspace sampling, the fiber chemistry introduces selectivity to the extraction: preferential sorption may skew aroma profiles. Dynamic headspace (DHS) is an attractive substitute for HS-SPME, given its improved sensitivity and lessened bias imparted due to extraction phase selectivity. DHS extractions tend to yield a larger number of compounds and require even less sample than HS-SPME. These two extraction techniques were applied to homogenized blueberries and extracts were subjected to analysis by comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry (GC×GC-TOFMS). Major chemical classes were identified with filtering scripts for GC×GC-TOFMS data. The HS-SPME and DHS methods were assessed for reproducibility and chemical diversity (i.e., recovered chemical classes).

As consumer adoption of immersive technologies grows, virtual avatars will play a prominent role in the future of social computing. However, as people begin to interact more frequently through virtual avatars, it is important to ensure that the research community has validated tools to evaluate the effects and consequences of such technologies. We present the first iteration of a new, freely available 3D avatar library called the Virtual Avatar Library for Inclusion and Diversity (VALID), which includes 210 fully rigged avatars with a focus on advancing racial diversity and inclusion. We also provide a detailed process for creating, iterating, and validating avatars of diversity. Through a large online study (n = 132) with participants from 33 countries, we provide statistically validated labels for each avatar’s perceived race and gender. Through our validation study, we also advance knowledge pertaining to the perception of an avatar’s race. In particular, we found that avatars of some races were more accurately identified by participants of the same race.

Summary: The reduced effectiveness of COVID-19 vaccines due to the emergence of variants of concern (VOCs) necessitated the use of vaccine boosters to bolster protection against disease. However, it remains unclear how boosting expands protective breadth when primary vaccine platforms are distinct and how boosters containing VOC spike(s) broaden humoral responses. Here, we report that boosters composed of recombinant spike antigens of ancestral (prototype) and Beta VOCs elicit a robust, pan-VOC, and multi-functional humoral response in non-human primates largely independent of the primary vaccine series platform. Interestingly, Beta-spike-containing boosters stimulate immunoglobulin A (IgA) with a greater breadth of recognition in protein-primed recipients when administered with adjuvant system 03 (AS03). Our results highlight the utility of a component-based booster strategy for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for broad humoral recognition, independent of primary vaccine series. This is of high global health importance given the heterogeneity of primary vaccination platforms distributed.

Background Considerable resources are spent to track fish movement in marine environments, often with the intent of estimating behavior, distribution, and abundance. Resulting data from these monitoring efforts, including tagging studies and genetic sampling, often can be siloed. For Pacific salmon in the Northeast Pacific Ocean, predominant data sources for fish monitoring are coded wire tags (CWTs) and genetic stock identification (GSI). Despite their complementary strengths and weaknesses in coverage and information content, the two data streams rarely have been integrated to inform Pacific salmon biology and management. Joint, or integrated, models can combine and contextualize multiple data sources in a single statistical framework to produce more robust estimates of fish populations. Methods We introduce and fit a comprehensive joint model that integrates data from CWT recoveries and GSI sampling to inform the marine life history of Chinook salmon stocks at spatial and temporal scales relevant to ongoing fisheries management efforts. In a departure from similar models based primarily on CWT recoveries, modeled stocks in the new framework encompass both hatchery- and natural-origin fish. We specifically model the spatial distribution and marine abundance of four distinct stocks with spawning locations in California and southern Oregon, one of which is listed under the U.S. Endangered Species Act. Results Using the joint model, we generated the most comprehensive estimates of marine distribution to date for all modeled Chinook salmon stocks, including historically data poor and low abundance stocks. Estimated marine distributions from the joint model were broadly similar to estimates from a simpler, CWT-only model but did suggest some differences in distribution in select seasons. Model output also included novel stock-, year-, and season-specific estimates of marine abundance. We observed and partially addressed several challenges in model convergence with the use of supplemental data sources and model constraints; similar difficulties are not unexpected with integrated modeling. We identify several options for improved data collection that could address issues in convergence and increase confidence in model estimates of abundance. We expect these model advances and results provide management-relevant biological insights, with the potential to inform future mixed-stock fisheries management efforts, as well as a foundation for more expansive and comprehensive analyses to follow.

A solvent-free post-treatment process known as vapor phase infiltration (VPI) is used to engineer the organic solvent reverse osmosis (OSRO) performance of polymer of intrinsic microporosity 1 (PIM-1) membranes via infiltration of trimethylaluminum (TMA) metal-organic vapor. The infiltration of inorganic aluminum constituents hybridizes the pure polymer PIM-1 into an organic-inorganic material (AlOxHy/PIM-1) with enhanced chemical stability. A homogenous distribution of inorganic loading in PIM-1 is achieved due to the reaction-limited infiltration mechanism, and the OSRO performance is enhanced as a result. OSRO separations of ethanol/isooctane mixtures using these membranes are shown to be capable of breaking the azeotropic composition with a separation factor for ethanol over isooctane greater than 5 and an ethanol permeance of 0.1 Lm–2h–1bar–1. Thus, these organic-inorganic hybrid membranes created via VPI show promise as an alternative method for separating azeotropic liquid mixtures.

Introduction Endoscopic endonasal approach(EEA) techniques have been increasingly utilized and have been associated with development of cerebrospinal fluid(CSF) leak, meningitis, diabetes insipidus post‐operatively. Cerebral vasospasm following EEA has rarely been described. Here, we describe the clinical course and management of a patient who underwent EEA for encephalocele repair whose course was complicated by postoperative subarachnoid hemorrhage(SAH) and cerebral vasospasm. Methods n/a Results Case Presentation: 40 year old female with past medical history significant for cerebral venous sinus stent on aspirin, CSF rhinorrhea secondary to right nasal encephalocele s/p endoscopic transnasal transethmoidal repair with nasoseptal flap reconstruction and lumbar drain placement eleven days prior presented with speech difficulties and right sided weakness. On exam, patient was noted to have mild right hemiparesis and expressive aphasia. MRI brain showed subacute infarcts in left greater than right frontal lobes, corpus collosum and right anterior perforated substance. MRA head demonstrated multifocal arterial stenosis. In light of postoperative CT head showing SAH in the basilar, perimesencephalic, prepontine cisterns, interhemispheric fissure and right frontal sulci as well as intraventricular hemorrhage in fourth ventricle, her presentation was thought to be secondary to cerebral vasospasm in the setting of postoperative SAH. She was treated with intravenous hydration, permissive hypertension with head of bed in flat position and transferred for further evaluation. On arrival, she continued have mild right hemiparesis and aphasia. Repeat CTA head/neck and CT perfusion showed severe stenosis of bilateral M1 segments and left greater than right A1 segments as well as ischemic penumbra in left ACA/MCA watershed territory. Diagnostic cerebral angiogram showed bilateral severe A1 stenosis and mild to moderate bilateral M1 and supraclinoid ICA stenosis which improved with intra‐arterial verapamil. She was started on nimodipine. Systolic blood pressure was augmented with vasopressors for goal of 150‐180mmHg. Daily TCDs were followed. She developed worsening right leg weakness following day, thus she was taken for repeat diagnostic cerebral angiogram during which time she was re‐administered intra‐arterial verapamil with improvement in vasospasm. After the second treatment, she had improvement in speech and motor strength. Systolic blood pressure goal was gradually normalized. She was noted to have incidental left internal jugular (IJ) vein thrombosis for which anticoagulation was held in the setting of recent neurosurgical procedure and SAH. Workup for vasculitis and hypercoagulability was unrevealing. Lumbar puncture demonstrated 13 WBC/cu mm with lymphocytic predominance(90%), 23 RBC/cu mm, glucose 89mg/dl, protein 30mg/dl. CSF cultures were negative. Pleocytosis in CSF was attributed to recent neurosurgical procedure. Her neurological exam improved to baseline on hospital day(HD) 9.On HD12, she was found to have left common femoral deep venous thrombus in addition to the left IJ thrombus. Anticoagulation with low dose heparin infusion was started which was transitioned to apixaban on discharge. She was discharged home on HD20. Conclusion We report a case of EEA associated with severe multifocal cerebral vasospasm secondary to postoperative SAH that was successfully treated with induced hypertension, oral nimodipine and intra‐arterial verapamil as an adjunct therapy with an excellent outcome.

BackgroundCancer-related cognitive decline (CRCD) is one of the most reported and debilitating symptoms associated with breast cancer treatment with no currently accepted treatment. Physical activity has emerged as a promising solution for maintaining cognitive health after cancer, with research suggesting that earlier intervention may be important for preventing or mitigating CRCD. There is a clear need to pilot the feasibility and efficacy of pragmatic physical activity interventions to promote cognitive health during active breast cancer treatment. The purpose of this study is to pilot test a home-based prehabilitation physical activity intervention aimed at preventing cognitive decline during chemotherapy, as well as assess the feasibility, acceptability and appropriateness of the intervention among patients.MethodsThis study is a two-arm, pilot randomized controlled trial in 40 adult patients newly diagnosed with breast cancer stages I-III who are scheduled to receive curative intent neo-adjuvant chemotherapy. Participants will be randomized 1:1 to a usual care waitlist control group or a home-based prehabilitation physical activity intervention delivered by a licensed physical therapist. The exercise group will receive an individualized, tapered exercise program comprised of home exercise sessions and virtual coaching calls. Both groups will receive activity monitors and be encouraged to maintain a healthy lifestyle during treatment. Participant adherence and adverse events will be assessed throughout the study.ResultsThis research was supported by the Alvin J. Siteman Cancer Center through The Foundation for Barnes-Jewish Hospital (award No. 6257). The protocol was approved by Washington University's Protocol Review and Monitoring Committee and Institutional Review Board. Enrollment began in May 2023 and is anticipated to continue through July 2024.ConclusionsThis study will provide the necessary preliminary data to support larger trials investigating if and how physical activity can be incorporated into early rehabilitation strategies to prevent chemotherapy-related sequelae.Trial registrationClinicalTrials.gov, NCT05716542.

Summary: Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection. Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7–15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures. Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05–0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01–0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease. Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection. Funding: National Institutes of Health.

Negative regulation of exocytosis from secretory cells is accomplished through inhibitory signals from Gi/o GPCRs by Gβγ subunit inhibition of 2 mechanisms: decreased calcium entry and direct interaction of Gβγ with soluble N-ethylmaleimide–sensitive factor attachment protein (SNAP) receptor (SNARE) plasma membrane fusion machinery. Previously, we disabled the second mechanism with a SNAP25 truncation (SNAP25Δ3) that decreased Gβγ affinity for the SNARE complex, leaving exocytotic fusion and modulation of calcium entry intact and removing GPCR-Gβγ inhibition of SNARE-mediated exocytosis. Here, we report substantial metabolic benefit in mice carrying this mutation. Snap25Δ3/Δ3 mice exhibited enhanced insulin sensitivity and beiging of white fat. Metabolic protection was amplified in Snap25Δ3/Δ3 mice challenged with a high-fat diet. Glucose homeostasis, whole-body insulin action, and insulin-mediated glucose uptake into white adipose tissue were improved along with resistance to diet-induced obesity. Metabolic protection in Snap25Δ3/Δ3 mice occurred without compromising the physiological response to fasting or cold. All metabolic phenotypes were reversed at thermoneutrality, suggesting that basal autonomic activity was required. Direct electrode stimulation of sympathetic neuron exocytosis from Snap25Δ3/Δ3 inguinal adipose depots resulted in enhanced and prolonged norepinephrine release. Thus, the Gβγ-SNARE interaction represents a cellular mechanism that deserves further exploration as an additional avenue for combating metabolic disease.

Alcohol misuse and, particularly adolescent drinking, is a major public health concern. While evidence suggests that adolescent alcohol use affects frontal brain regions that are important for cognitive control over behavior, little is known about how acute alcohol exposure alters large-scale brain networks and how sex and age may moderate such effects. Here, we employ a recently developed functional magnetic resonance imaging (fMRI) protocol to acquire rat brain functional connectivity data and use an established analytical pipeline to examine the effect of sex, age, and alcohol dose on connectivity within and between three major rodent brain networks: default mode, salience, and lateral cortical network. We identify the intra- and inter-network connectivity differences and establish moderation models to reveal significant influences of age on acute alcohol-induced lateral cortical network connectivity. Through this work, we make brain-wide isotropic fMRI data with acute alcohol challenge publicly available, with the hope to facilitate future discovery of brain regions/circuits that are causally relevant to the impact of acute alcohol use.

The progress of incorporating deep learning in the field of medical image interpretation has been greatly hindered due to the tremendous cost and time associated with generating ground truth for supervised machine learning, alongside concerns about the inconsistent quality of images acquired. Active learning offers a potential solution to these problems of expanding dataset ground truth by algorithmically choosing the most informative samples for ground truth labeling. Still, this effort incurs the costs of human labeling, which needs minimization. Furthermore, automatic labeling approaches employing active learning often exhibit overfitting tendencies while selecting samples closely aligned with the training set distribution and excluding out-of-distribution samples, which could potentially improve the model’s effectiveness. We propose that the majority of out-of-distribution instances can be attributed to inconsistent cross images. Since the FDA approved the first whole-slide image system for medical diagnosis in 2017, whole-slide images have provided enriched critical information to advance the field of automated histopathology. Here, we exemplify the benefits of a novel deep learning strategy that utilizes high-resolution whole-slide microscopic images. We quantitatively assess and visually highlight the inconsistencies within the whole-slide image dataset employed in this study. Accordingly, we introduce a deep learning-based preprocessing algorithm designed to normalize unknown samples to the training set distribution, effectively mitigating the overfitting issue. Consequently, our approach significantly increases the amount of automatic region-of-interest ground truth labeling on high-resolution whole-slide images using active deep learning. We accept 92% of the automatic labels generated for our unlabeled data cohort, expanding the labeled dataset by 845%. Additionally, we demonstrate expert time savings of 96% relative to manual expert ground-truth labeling.

Abstract Background An open-source, extensible medical viewing platform is described, called the TriDFusion image viewer (3DF). The 3DF addresses many broad unmet needs in nuclear medicine research; it provides a viewer with several tools not available in commercial nuclear medicine workstations, yet invaluable for imaging in research studies. Results The 3DF includes an image integration platform to register images from multiple imaging modalities together with delineated volumes of interest (VOIs), structures and dose distributions. It can process images from different vendors’ systems and is therefore vendor neutral. The 3DF also provides a convenient tool for performing multi-modality image analysis and fusion. The functional components currently being distributed is open-source code that includes: (1) a high quality viewer that can display axial, coronal, and sagittal tomographic images, maximum intensity projection images, structure contours, and isointensity contour lines or dose colorwash, (2) multi-image fusion allowing multiple images to be fused with VOI and dose distributions, (3) a suite of segmentation tools to edit and/or create tumor and organ VOIs, (4) dosimetry tools for several radioisotopes, (5) clinical tools for correcting acquisition errors, including patient orientation, and (6) the ability to save the resultant image and VOI as DICOM files or to export the numerical results as comma separated values files. Because the code is written in MATLAB™, it is highly readable and is easier for the coder to make changes compared to languages such as C or C++. In what follows, we describe the content of the new TriDFusion (3DF) image viewer software platform using examples of a number of clinical research workflows. Such examples vary in complexity but illustrate the main attributes of the software. Conclusions In summary, 3DF provides a powerful, convenient, easy-to-use suite of open-source imaging research tools for the nuclear medicine community that allows physicians, medical physicists, and academic researchers to display, manipulate, and analyze images.

Glioblastoma is an aggressive tumor with poor survival rates. Bispecific T cell engagers (BTEs) against different cancers are in various stages of clinical development. Toxicity resulting from cytokine release syndrome and the short half-life of BTEs, which necessitates continuous infusion, complicating delivery and increasing costs, are major challenges in the field. Here we describe the development of in vivo DNA-launched BTEs (dBTEs) with highly focused targeting of interleukin-13 receptor α2 (IL-13Rα2), a glioblastoma cell-surface target. We developed 4 BTEs targeting 2 epitopes of IL-13Rα2 and studied how heavy-light chain orientation affects BTE function. The dBTEs induced T cell activation, cytokine production, and tumor cytolysis in the presence of IL-13Rα2+ tumor cells, but we observed unique patterns of immune activation. We found a strong correlation between granzyme B secretion and dBTE-induced cytolysis of specific and nonspecific tumors. We down-selected dBTE PB01-forward based on lower cytokine induction profile and highest activation specificity. In vivo, dBTE PB01-forward demonstrated an improved half-life versus intravenous recombinant BTE delivery. In an orthotopic glioblastoma model, dBTE PB01-forward controlled tumor growth, improving animal survival, supporting the hypothesis that the blood-brain barrier does not affect the function of systemically delivered dBTE. Further study of PB01-forward for targeting glioblastoma and other IL-13Rα2+ cancers is warranted.

Abstract A ureterocele is a rare congenital anomaly with cystic dilation of the terminal segment of the ureter entirely within the bladder (orthotopic) or associated with ectopic ureter (ectopic). Its aetiology has not been fully clarified; however, it may involve genetic or acquired factors. Urothelial carcinoma (UC) is the most common type of canine urinary tract neoplasm, among which over 90% of cases are invasive. The non‐papillary (flat) non‐infiltrating form accounts for a very small percentage of canine UCs and is considered carcinoma in situ (CIS). The neoplastic cells of CIS remain within the ureteral mucosa and do not breach the basement membrane. UCs originating from the canine ureter are extremely rare, and no report of a ureteral UC concurrently occurring with a ureterocele has been reported. A 7‐year‐old castrated male Maltese dog weighing 3.5 kg was referred with a 2‐week history of lethargy, anorexia, pollakiuria and intermittent panting. The dog underwent open surgery for removal of bladder calculi 2 years prior, and at the time of the surgery, no other urinary system abnormalities were identified. Ultrasonographic and computed tomographic scans revealed a severely enlarged right kidney and ureter with a ureterocele on the ipsilateral side. A diagnosis of an orthotopic ureterocele causing hydronephrosis and hydroureter was established. Complete nephroureterectomy and ureterocelectomy using the marsupialisation technique were performed. The postoperative histological examination of the excised tissues showed a multifocal carcinoma in situ (non‐papillary non‐infiltrating UC) in the proximal ureter and a fluid‐filled kidney with a thin rim of fibrotic renal tissue. No neoplastic changes were observed in the ureterocele tissue. Postoperatively, the dog recovered rapidly without complications except temporary urinary incontinence, and no evidence of tumour recurrence was detected by ultrasonography performed 6 months after surgery. This case report describes the first case of a dog with an orthotopic ureterocele and ureteral UC, which occurred concurrently at the ipsilateral side of the ureter. The condition was successfully managed with a nephroureterectomy and partial ureterocelectomy.

Abstract Loneliness is associated with mental and physical health problems and elevated suicide risk, and is increasingly widespread in modern societies. However, identifying the primary factors underlying loneliness remains a major public health challenge. Historically, loneliness was thought to result from a lack of high-quality social connections, but broader cultural factors (e.g. social norms) are increasingly recognized to also influence loneliness. Here, we used a large-scale survey (N = 4977) to assess to what degree the loneliness epidemic in Japan is associated with traditional measures of social isolation (number of close friends), cultural factors (perceptions of social rigidity, as measured by relational mobility), and socioeconomic factors (e.g. income). We confirmed that a lack of close friends is a dominant factor underlying loneliness in Japan. We also found that perceptions of the social rigidity in one’s environment was a major correlate of loneliness. Subjects who perceived lower levels of rigidity in their social environments felt significantly less lonely than those who perceived higher levels of social rigidity, though the association was weak in low income males. Thus, Japanese society and other high social rigidity cultures may need to reflect on the possibility that inflexible traditional norms of socialization are exacerbating loneliness.

Outpatient parenteral antimicrobial therapy (OPAT) has been widely used in clinical practice for many decades because of its associated cost savings, reductions in inpatient hospital days, and decreases in hospital-associated infections. Despite this long history, evolving practice patterns and new drug delivery devices continue to present challenges as well as opportunities for clinicians when designing appropriate outpatient antimicrobial regimens. One such change is the increasing use of extended and continuous infusion (CI) of antimicrobials to optimize the achievement of pharmacokinetic and pharmacodynamic targets. Elastomeric devices are also becoming increasingly popular in OPAT, including for the delivery of CI. In this article, we review the clinical evidence for CI in OPAT, as well as practical considerations of patient preferences, cost, and antimicrobial stability.

Introduction: Using a digital process that leverages electronic health records (EHRs) can ease many of the challenges presented by the traditional enrollment process for clinical trials. We tested if automated batch enrollment using a technology-enabled subject recruitment system (TESRS) enhances recruitment while preserving representation of research subjects for the study population in our study setting. Methods: An ongoing community-based prospective adult cohort study was used to randomize 600 subjects who were eligible by age and residential address to TESRS (n = 300) and standard mailing method (n = 300), respectively, for 3 months. Then, TESRS was initiated and included automatic identification of patients’ preference for being contacted (online patient portal vs postal mail) from EHRs and automatic sending out of invitation letters followed by completion of a short online survey for checking eligibility and the digital consent process if eligible. We compared (1) median time to consent from invitation sent out per subject and total subjects recruited after a 3-month recruitment period, (2) the estimated study staff’s time, and (3) representation of sociodemographic characteristics (e.g., age, sex, race, SES measured by HOUSES index, and rural residence) between subjects recruited via TESRS and those via traditional mailing methods. Results: Median age of randomized subjects (n = 600) was 63 years with 52.0% female and 89.2% non-Hispanic White. Over a 3-month period, results showed consent rate via TESRS was 13% (39/297) similar to 11% (31/295) via standard mailing. However, recruitment was significantly faster with the TESRS approach (median 7 vs 26 days) given the study staff’s effort. Study staff’s time saved by using TESRS compared to standard mailing approach was estimated at 40 min per subject (equivalent to 200 h for 300 subjects). No significant differences in characteristics of research subjects from the study population were found. Conclusion: Our study demonstrated the utility of TESRS as a subject recruitment digital technology which significantly enhanced the recruitment effort while reducing the study staff burden of recruitment while maintaining the consistency of characteristics of recruited subjects. The strategy and support for implementing and testing TESRS in other study settings should be considered.