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Background: Large Vessel Occlusion (LVO) stroke patients with tandem lesions (TLs) have been observed to have worse outcomes when compared to patients with simple isolated intracranial occlusions., Objective: To examine the difference in post-operative functional status at discharge for patients treated with mechanical thrombectomy for an acute LVO stroke based on the presence of a tandem carotid lesion., Methods: This is a retrospective cohort study of 589 patients presenting within the first 24 hours of stroke onset who underwent mechanical thrombectomy. The primary outcome was functional status quantified by modified Rankin Score (mRS) at time of discharge. The secondary outcomes were presence of hemorrhagic conversion, midline shift >5 cm, malignant cerebral edema, reocclusion, Thrombolysis in Cerebral Infarction Scale (TICI), and discharge location., Results: Patients with tandem occlusions and those with isolated intracranial lesions had similar baseline demographics. However, in patients with TLs, there was a significantly higher NIH stroke scale at admission and a longer time to recanalization. Modified Rankin Score prior to admission was similar for both groups, but was significantly higher in patients with TLs at discharge. The secondary outcomes were similar for hemorrhagic conversion, discharge to hospice, and a TICI scale of 0, but were significantly worse for patients with TLs for in-hospital mortality, midline shift >5 mm, and malignant cerebral edema. The presence of a tandem lesion predicted a higher modified Rankin Score at discharge in univariate regression modeling (β = .45; P -value = .006)., Conclusion: The two groups were similar in baseline characteristics and cardiovascular risk factors, yet patients with tandem carotid lesions experienced more complications during their hospitalization and had greater functional disability at discharge. Patients with a TL had a longer mean time to recanalization, representing a potential explanation for these differences in outcomes., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: Our Health Counts (OHC) Toronto, an Indigenous population database which addresses gaps in urban health information, was used to measure Thistle's (2017) 12 dimensions of Indigenous homelessness. Using this framework, we examine the sociodemographic characteristics of First Nations, Inuit, and Metis (FNIM) adults living in Toronto, the 12 dimensions as experienced by this population, and the distinctions between FNIM adults who were and those who were not experiencing physical homelessness., Methods: Respondent-driven sampling (RDS)-II proportions and 95% confidence intervals were produced from the database (n = 915 FNIM adults) to describe key sociodemographic characteristics of the population and to estimate the proportion and number of dimensions of Indigenous homelessness experienced by FNIM adults. Results were compared between those who were and those who were not living physically homeless., Results: This study shows that 27.3% of FNIM adults in Toronto were living physically homeless. The proportion of homelessness was significantly higher among males, adults aged 26 to 54, and unemployed individuals. Using the OHC database, 7 of the 12 dimensions were measurable. Almost all FNIM adults had experienced one or more of the 7 measurable dimensions. The most common were cultural disintegration and loss, mental disruption and balance, contemporary geographic separation, and relocation and mobility. These dimensions were significantly more common among FNIM adults experiencing physical homelessness., Conclusion: Results show that FNIM adults living physically homeless are more likely to experience other dimensions of homelessness. Using existing data, 5 of the 12 dimensions were not measurable. This points to a critical need to develop new survey tools to fully understand the historical, environmental, social, political, spiritual, and emotional factors that influence pathways into homelessness among FNIM populations., Competing Interests: Declarations. Ethics approval: Seventh Generation Midwives Toronto, the OHC Toronto data owners, and community partners have reviewed and approved this manuscript. This research project has been approved by St. Michael’s Hospital Research Ethics Board (OHC Toronto REB no. 14–083). Consent to participate: Informed consent was obtained from all individual participants in the study. Consent for publication: N/A. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s).)

Objectives: Our Health Counts (OHC) methods are designed to address gaps in urban-based Indigenous health information. In partnership with local Indigenous health service providers, we have successfully implemented OHC in six Ontario cities. The aim of this study is to summarize findings regarding Indigenous population undercount, health inequities, and health service access barriers across study sites., Methods: We estimated Indigenous population size using OHC census participation survey responses and a multiplier approach. Health inequities between Indigenous populations and overall populations in each city were examined using respondent-driven sampling (RDS), adjusted OHC survey results, and existing public data. Measures included health status outcomes; determinants of health; barriers to health service access, including discrimination by health service providers; and unmet health needs., Results: Indigenous social networks were strong and extensive, and the urban populations demonstrate resilience and cultural continuity across multiple measures. Self-reported rates of census participation for Indigenous populations were markedly lower than those for the general population in each city, and OHC Indigenous population size estimates were consistently 2‒4 times higher than reported in the census. Indigenous to general population health inequities cut across measures of chronic disease, determinants of health, and unmet health needs. Indigenous populations experienced multiple barriers to health services access, including racial discrimination by health service providers., Conclusion: The Canadian census appears to markedly underestimate Indigenous population size in urban areas. Indigenous health inequities and service access barriers are striking and cross-cutting. Timely adaptation of health policies, services, and funding allocations in response to these findings is recommended., Competing Interests: Declarations. Ethics approval: Ethics approval for the Our Health Counts (OHC) projects was provided by the Well Living House Counsel of Grandparents and community research partners. The OHC studies also received ethics clearance from the St. Michael’s Hospital Research Ethics Board at Unity Health Toronto (REB# 09–108, OHC Hamilton and OHC Inuit Ottawa; REB# 14–083, OHC Toronto; REB#14–390 OHC London; REB# 18–25, OHC Kenora and OHC Thunder Bay). Consent to participate: All participants provided informed consent as approved by the ethics board. Consent for publication: N/A. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s).)

Objectives: Methods for enumeration and population-based health assessment for First Nations, Inuit, and Metis (FNIM) living in Canadian cities are underdeveloped, with resultant gaps in essential demographic, health, and health service access information. Our Health Counts (OHC) was designed to engage FNIM peoples in urban centres in "by community, for community" population health assessment and response., Methods: The OHC methodology was designed to advance Indigenous self-determination and FNIM data sovereignty in urban contexts through deliberate application of Indigenous principles and linked implementation strategies. Three interwoven principles (good relationships are foundational; research as gift exchange; and research as a vehicle for Indigenous community resurgence) provide the framework for linked implementation strategies which include actively building and maintaining relationships; meaningful Indigenous community guidance, leadership, and participation in all aspects of the project; transparent and equitable sharing of project resources and benefits; and technical innovations, including respondent-driven sampling, customized comprehensive health assessment surveys, and linkage to ICES data holdings to generate measures of health service use., Results: OHC has succeeded across six urban areas in Ontario to advance Indigenous data sovereignty and health assessment capacity; recruit and engage large population-representative cohorts of FNIM living in urban and related homelands; customize comprehensive health surveys and data linkages; generate previously unavailable population-based FNIM demographic, health, and social information; and translate results into enhanced policy, programming, and practice., Conclusion: The OHC methodology has been demonstrated as effective, culturally relevant, and scalable across diverse Ontario cities., Competing Interests: Declarations. Ethics approval: Ethics approval for the Our Health Counts (OHC) projects was provided by the Well Living House Counsel of Grandparents and community research partners. The OHC studies also received ethics clearance from the St. Michael’s Hospital Research Ethics Board at Unity Health Toronto (REB# 09-108, OHC Hamilton and OHC Inuit Ottawa; REB# 14-083, OHC Toronto; REB#14-390, OHC London; REB# 18-25, OHC Kenora and OHC Thunder Bay). Consent to participate: All participants provided informed consent as approved by the ethics board. Consent for publication: N/A Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Blastomycosis is an environmentally acquired fungal infection that can result in severe pulmonary illness and high hospitalization rates. In 2023, a blastomycosis outbreak was detected among workers at a paper mill in Delta County, Michigan., Methods: We included patients with clinical and laboratory evidence of blastomycosis who had spent ≥40 hours in Delta County since September 1, 2022 and had illness onset December 1, 2022-July 1, 2023. We assessed epidemiological and clinical features of patients and evaluated factors associated with hospitalization. We performed whole-genome sequencing to characterize genetic relatedness of clinical isolates from eight patients., Results: In total, 131 patients were identified; all had worked at or visited the mill. Sixteen patients (12%) were hospitalized; one died. Compared with non-hospitalized patients, more hospitalized patients had diabetes (p=0.03) and urine antigen titers above the lower limit of quantification (p<0.001). Hospitalized patients were also more likely to have had ≥1 healthcare visits before receiving a blastomycosis diagnostic test (p=0.02) and to have been treated with antibiotics prior to antifungal prescription (p=0.001). All sequenced isolates were identified as Blastomyces gilchristii and clustered into a distinct outbreak cluster., Conclusions: This was the largest documented blastomycosis outbreak in the United States. Epidemiologic evidence indicated exposures occurred at or near the mill, and genomic findings suggested a common exposure source. Patients with diabetes may have increased risk for hospitalization, and elevated urine antigen titers could indicate greater disease severity. Early suspicion of blastomycosis may prompt earlier diagnosis and treatment, potentially reducing unnecessary antibiotic prescriptions and improving patient outcomes., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2024.)

Background: Hyponatremia is a common complication following endoscopic endonasal resection (EER) of pituitary adenomas. We report a single-center, multisurgeon study detailing baseline clinical data, outcomes, and factors associated with postoperative hyponatremia., Methods: This was a retrospective cohort study of patients undergoing EER for pituitary adenoma at Tufts Medical Center. Most procedures were performed by the senior author (C.B.H.). Cases were included if at least 1 postoperative sodium value was available and pathology confirmed pituitary adenoma. Hyponatremia was defined as a postoperative sodium level <135 mEq/L., Results: A total of 272 patients underwent 310 EER procedures that met the study inclusion criteria. The mean patient age was 53.3 years, and mean tumor size was 18.8 mm. Postoperative hyponatremia occurred in 12.6% of cases, with 3.6% developing hyponatremia prior to discharge. Lower preoperative sodium level was associated with an increased risk of developing any postoperative hyponatremia. Older age, prolactinoma pathology, and use of selective serotonin reuptake inhibitors were associated with moderate to severe hyponatremia (≤129 mEq/L), and lower preoperative sodium was associated with mild hyponatremia (130-134 mEq/L). Hyponatremia-related readmissions within 30 days occurred in 3.9% of patients. Both African-American race and postoperative hyponatremia were associated with an increased risk of 30-day readmission. The mean nadir sodium for hyponatremic patients was 129.9 mEq/L. Growth hormone-secreting pathology was associated with lower postoperative nadir sodium, whereas higher preoperative sodium was associated with higher postoperative nadir sodium., Conclusions: Hyponatremia is a common postoperative complication of EER for pituitary lesions that can cause significant morbidity, increased readmissions, and increased healthcare costs., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Thermogenic brown adipocytes (BAs) catabolize lipids to generate heat, representing powerful agents against the growing global obesity epidemic. We and others reported recently that LETMD1 is a BA-specific protein essential for mitochondrial structure and function, but the mechanisms of action remain unclear. We performed sequential digestion to demonstrate that LETMD1 is a trans-inner mitochondrial membrane protein. We then generated UCP1Cre-driven BA-specific Letmd1 knockout ( Letmd1 UKO ) mice to show that Letmd1 UKO leads to protein aggregation, reactive oxidative stress, hyperpolarization, and mitophagy in BAs. We further employed TurboID proximity labeling to identify LETMD1-interacting proteins. Many candidate proteins are associated with mitochondrial ribosomes, protein import machinery, and electron transport chain complexes (ETC-I and ETC-IV). Using quantitative proteomics, we confirmed the elevated aggregations of ETC and mitochondrial ribosomal proteins, impairing mitochondrial protein synthesis in the Letmd1 UKO BAs. Therefore, LETMD1 may function to maintain mitochondrial proteostasis through regulating import of nuclear-encoded proteins and local protein translation in brown fat mitochondria., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Type 2 diabetes (T2D) and prediabetes are classically defined by the level of fasting glucose or surrogates such as hemoglobin HbA1c. This classification does not take into account the heterogeneity in the pathophysiology of glucose dysregulation, the identification of which could inform targeted approaches to diabetes treatment and prevention and/or predict clinical outcomes. We performed gold-standard metabolic tests in a cohort of individuals with early glucose dysregulation and quantified four distinct metabolic subphenotypes known to contribute to glucose dysregulation and T2D: muscle insulin resistance, β-cell dysfunction, impaired incretin action, and hepatic insulin resistance. We revealed substantial inter-individual heterogeneity, with 34% of individuals exhibiting dominance or co-dominance in muscle and/or liver IR, and 40% exhibiting dominance or co-dominance in β-cell and/or incretin deficiency. Further, with a frequently-sampled oral glucose tolerance test (OGTT), we developed a novel machine learning framework to predict metabolic subphenotypes using features from the dynamic patterns of the glucose time-series ("shape of the glucose curve"). The glucose time-series features identified insulin resistance, β-cell deficiency, and incretin defect with auROCs of 95%, 89%, and 88%, respectively. These figures are superior to currently-used estimates. The prediction of muscle insulin resistance and β-cell deficiency were validated using an independent cohort. We then tested the ability of glucose curves generated by a continuous glucose monitor (CGM) worn during at-home OGTTs to predict insulin resistance and β-cell deficiency, yielding auROC of 88% and 84%, respectively. We thus demonstrate that the prediabetic state is characterized by metabolic heterogeneity, which can be defined by the shape of the glucose curve during standardized OGTT, performed in a clinical research unit or at-home setting using CGM. The use of at-home CGM to identify muscle insulin resistance and β-cell deficiency constitutes a practical and scalable method by which to risk stratify individuals with early glucose dysregulation and inform targeted treatment to prevent T2D.

Gastrulation is the highly coordinated process by which the early embryo breaks symmetry, establishes germ layers and a body plan, and sets the stage for organogenesis. As early mammalian development is challenging to study in vivo, stem cell-derived models have emerged as powerful surrogates, e.g. human and mouse gastruloids. However, although single cell RNA-seq (scRNA-seq) and high-resolution imaging have been extensively applied to characterize such in vitro embryo models, a paucity of measurements of protein dynamics and regulation leaves a major gap in our understanding. Here, we sought to address this by applying quantitative proteomics to human and mouse gastruloids at four key stages of their differentiation (naïve ESCs, primed ESCs, early gastruloids, late gastruloids). To the resulting data, we perform network analysis to map the dynamics of expression of macromolecular protein complexes and biochemical pathways, including identifying cooperative proteins that associate with them. With matched RNA-seq and phosphosite data from these same stages, we investigate pathway-, stage- and species-specific aspects of translational and post-translational regulation, e.g. finding peri-gastrulation stages of human and mice to be discordant with respect to the mitochondrial transcriptome vs. proteome, and nominating novel kinase-substrate relationships based on phosphosite dynamics. Finally, we leverage correlated dynamics to identify conserved protein networks centered around congenital disease genes. Altogether, our data (https://gastruloid.brotmanbaty.org/) and analyses showcase the potential of intersecting in vitro embryo models and proteomics to advance our understanding of early mammalian development in ways not possible through transcriptomics alone.

This study examined the relationship between lifestyles (diet, sleep, and physical activity) and glucose responses at a personal level. 36 healthy adults in the Bay Area were monitored for their lifestyles and glucose levels using wearables and continuous glucose monitoring (NCT03919877). Gold-standard metabolic tests were conducted to phenotype metabolic characteristics. Through the lifestyle data (2,307 meals, 1,809 nights, and 2,447 days) and 231,206 CGM readings from metabolically-phenotyped individuals with normoglycemia or prediabetes, we found: 1) eating timing was associated with hyperglycemia, muscle insulin resistance (IR), and incretin dysfunction, whereas nutrient intakes were not; 2) timing of increased activity in muscle IS and IR participants was associated with differential benefits of glucose control; 3) Integrated ML models using lifestyle factors predicted distinct metabolic characteristics (muscle, adipose IR or incretin dysfunction). Our data indicate the differential impact of lifestyles on glucose regulation among individuals with different metabolic phenotypes, highlighting the value of personalized lifestyle modifications., Competing Interests: Competing Interests. A.A.M. is currently an employee of Google, and A.D. is an employee of Calico Life Sciences. D.P. and T.M. are members of the scientific advisory board of January AI. M.P.S. is a co-founder and a member of the scientific advisory board of Personalis, Qbio, January AI, SensOmics, Protos, Mirvie, RTHM and Iollo. He is on the scientific advisory board of Danaher, Neuvivo and Jupiter. All other authors declare no financial or non-financial competing interests.

The objective of this study was to determine the model fit of a standardized hypnotizability measure in a targeted clinical sample. The Stanford Hypnotic Susceptibility Scale, Form C (SHSS:C) was administered to 168 post-menopausal women aged 39 to 75 years. Confirmatory factor analysis was conducted, and comparative fit index (CFI) and root mean square error of approximation (RMSEA) were used to determine goodness of fit. Results indicated that the single-factor structure modeled with twelve indicators based on the individual items on the SHSS:C provided the best description of fit. Results of the present study demonstrate that the SHSS:C has a single-factor structure. These findings suggest that new scales of hypnotizability can be optimized by focusing on the use of items that correlate highly with the overall score representing the unidimensional construct of hypnotizability. The findings should be interpreted with caution due to the small sample size, and further research is needed with other populations to clarify generalizability.

Physical activity, including structured exercise, is associated with favorable health-related chronic disease outcomes. Although there is evidence of various molecular pathways that affect these responses, a comprehensive molecular map of these molecular responses to exercise has not been developed. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) is a multicenter study designed to isolate the effects of structured exercise training on the molecular mechanisms underlying the health benefits of exercise and physical activity. MoTrPAC contains both a preclinical and human component. The details of the human studies component of MoTrPAC that include the design and methods are presented here. The human studies contain both an adult and pediatric component. In the adult component, sedentary participants are randomized to 12 wk of Control, Endurance Exercise Training, or Resistance Exercise Training with outcomes measures completed before and following the 12 wk. The adult component also includes recruitment of highly active endurance-trained or resistance-trained participants who only complete measures once. A similar design is used for the pediatric component; however, only endurance exercise is examined. Phenotyping measures include weight, body composition, vital signs, cardiorespiratory fitness, muscular strength, physical activity and diet, and other questionnaires. Participants also complete an acute rest period (adults only) or exercise session (adults, pediatrics) with collection of biospecimens (blood only for pediatrics) to allow for examination of the molecular responses. The design and methods of MoTrPAC may inform other studies. Moreover, MoTrPAC will provide a repository of data that can be used broadly across the scientific community. NEW & NOTEWORTHY The Molecular Transducers of Physical Activity Consortium (MoTrPAC) will be the first large trial to isolate the effects of structured exercise training on the molecular mechanisms underlying the health benefits of exercise and physical activity. By generating a compendium of the molecular responses to exercise, MoTrPAC will lay the foundation for a new era of biomedical research on Precision Exercise Medicine. Presented here is the design, protocols, and procedures for the MoTrPAC human studies.

While immunotherapy has shown efficacy in lung adenocarcinoma (LUAD) patients, many respond only partially or not at all. One limitation in improving outcomes is the lack of a complete understanding of immune checkpoint regulation. Here, we investigated a possible link between an environmental chemical receptor implicated in lung cancer and immune regulation, (the aryl hydrocarbon receptor/AhR), a known but counterintuitive mediator of immunosuppression (IFNγ), and regulation of two immune checkpoints (PD-L1 and IDO). AhR gene-edited LUAD cell lines, a syngeneic LUAD mouse model, bulk- and scRNA sequencing of LUADs and tumor-infiltrating leukocytes were used to map out a signaling pathway leading from IFNγ through the AhR to JAK/STAT, PD-L1, IDO, and tumor-mediated immunosuppression. The data demonstrate that: 1) IFNγ activation of the JAK/STAT pathway leading to PD-L1 and IDO1 upregulation is mediated by the AhR in murine and human LUAD cells, 2) AhR-driven IDO1 induction results in the production of Kynurenine (Kyn), an AhR ligand, which likely mediates an AhR→IDO1→Kyn→AhR amplification loop, 3) transplantation of AhR-knockout LUAD cells results in long-term tumor immunity in most recipients. 4) The 23% of AhR-knockout tumors that do grow do so at a much slower pace than controls and exhibit higher densities of CD8 + T cells expressing markers of immunocompetence, increased activity, and increased cell-cell communication. The data definitively link the AhR to IFNγ-induced JAK/STAT pathway and immune checkpoint-mediated immunosuppression and support the targeting of the AhR in the context of LUAD.

Precision medicine promises significant health benefits but faces challenges such as the need for complex data management and analytics, interdisciplinary collaboration, and education of researchers, healthcare professionals, and participants. Addressing these needs requires the integration of computational experts, engineers, designers, and healthcare professionals to develop user-friendly systems and shared terminologies. The widespread adoption of large language models (LLMs) like GPT-4 and Claude 3 highlights the importance of making complex data accessible to non-specialists. The Stanford Data Ocean (SDO) strives to mitigate these challenges through a scalable, cloud-based platform that supports data management for various data types, advanced research, and personalized learning in precision medicine. SDO provides AI tutors and AI-powered data visualization tools to enhance educational and research outcomes and make data analysis accessible for users from diverse educational backgrounds. By extending engagement and cutting-edge research capabilities globally, SDO particularly benefits economically disadvantaged and historically marginalized communities, fostering interdisciplinary biomedical research and bridging the gap between education and practical application in the biomedical field.

Objective: This study aimed to fill a gap in the literature regarding the role of resilience in the relationship between symptoms of Attention-Deficit/Hyperactivity Disorder (ADHD) and loss of control (LOC) eating in a nonclinical sample of emerging adults. Resilience was examined as a potential moderator and as a potential mediator of ADHD symptoms and engagement in LOC eating behaviors. Improved understanding of this relationship may inform clinical intervention and risk screening methodologies for disordered eating behaviors in college students., Methods: Participants were undergraduate students (N = 386) from a private university in the northeastern United States. Linear regression analysis examined whether greater ADHD symptoms related to greater LOC eating. Pathway analyses examined resilience as either a moderator or mediator of the relationship between ADHD symptoms and LOC eating., Results: A direct positive relationship was found between ADHD symptoms and LOC eating (p < .05). Resilience partially mediated this relationship, such that increased ADHD symptoms indirectly related to increased LOC eating through low resilience (p < .05)., Conclusion: Findings indicate that undergraduate students with greater ADHD symptoms engaged in more frequent LOC eating, and that low resilience was a partial mediator of this positive relationship., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Clot based assays used for lupus anticoagulant (LAC) detection are typically interpreted in a qualitative fashion and may not reflect LAC potency. In this cross-sectional study, we describe a method for quantifying the LAC titer using serial (dependent) two-fold dilutions in normal pooled plasma., Methods: Serial dilutions of 51 residual plasma samples from 50 patients were tested using the Russell's viper venom screening time (DRVVT) and activated partial thromboplastin screening time (APTT) methodologies. The measured clotting times and the corresponding dilution factors were then used to derive a four-parameter logistic model. The LAC titer for each patient was interpolated as the sample dilution that corresponds to the upper reference interval limit of the corresponding assay., Results: Calculated APTT and DRVVT LAC titers displayed a strong linear correlation (R 2  = 0.84) between each other, but not with the degree of prolongation of the APTT/DRVVT screening time in the neat undiluted samples. Using data driven partitioning, patients could be grouped into low (<10) or high (≥10) DRVVT LAC titer. There were no significant differences in anticardiolipin (aCL) or anti-beta 2 glycoprotein 1 (aB2GPI) antibody levels or prevalence of thromboembolic events between low and high LAC titer groups. In contrast, antiphosphatidylserine/prothrombin (aPS/PT) IgM antibody levels, but not IgG, were significantly higher in the high LAC titer group., Conclusions: The degree of prolongation of the APTT/DRVVT screening time is not correlated with the LAC titer. Only aPS/PT IgM antibodies levels were strongly correlated with the LAC titers. Additional studies are warranted to determine clinical implications of high LAC titers., (© 2024 John Wiley & Sons Ltd.)

Although single-cell and spatial sequencing methods enable simultaneous measurement of more than one biological modality, no technology can capture all modalities within the same cell. For current data integration methods, the feasibility of cross-modal integration relies on the existence of highly correlated, a priori 'linked' features. We describe matching X-modality via fuzzy smoothed embedding (MaxFuse), a cross-modal data integration method that, through iterative coembedding, data smoothing and cell matching, uses all information in each modality to obtain high-quality integration even when features are weakly linked. MaxFuse is modality-agnostic and demonstrates high robustness and accuracy in the weak linkage scenario, achieving 20~70% relative improvement over existing methods under key evaluation metrics on benchmarking datasets. A prototypical example of weak linkage is the integration of spatial proteomic data with single-cell sequencing data. On two example analyses of this type, MaxFuse enabled the spatial consolidation of proteomic, transcriptomic and epigenomic information at single-cell resolution on the same tissue section., (© 2023. The Author(s).)

Improving health and achieving health equity includes access to sexual and reproductive health care for all populations, especially those most in need. However, access to life-saving and life-affirming contraception with an individual's chosen perinatal provider can be impeded by restrictive regulations that limit scope and practice authority. This is especially true for the majority of community and direct entry midwives in the United States who have historically been unable to legally provide effective contraceptive methods. Recently, licensed midwives in Washington state were the first in the nation to achieve prescriptive authority, enabling their clients to directly obtain contraception and access to medications for common prenatal and postpartum conditions. Sustained advocacy efforts in the state's capitol enabled the Midwives' Association of Washington State to build relationships over time with legislators and government agencies to achieve this long-term goal. We present a successful midwifery-led innovation that achieved scope expansion for licensed midwives whose practice authority was limited by restrictive laws. Lessons learned are described and strategies offered to aid midwives and their advocates in other locales who want to improve health equity and access to contraception. Midwives are well positioned to provide this essential care to individuals living in underserved rural and urban areas and those from historically marginalized communities, but their ability to do so is limited by restrictive legislation., (© 2024 by the American College of Nurse‐Midwives.)

Understanding cellular architectures and their connectivity is essential for interrogating system function and dysfunction. However, we lack technologies for mapping the multiscale details of individual cells and their connectivity in the human organ-scale system. We developed a platform that simultaneously extracts spatial, molecular, morphological, and connectivity information of individual cells from the same human brain. The platform includes three core elements: a vibrating microtome for ultraprecision slicing of large-scale tissues without losing cellular connectivity (MEGAtome), a polymer hydrogel-based tissue processing technology for multiplexed multiscale imaging of human organ-scale tissues (mELAST), and a computational pipeline for reconstructing three-dimensional connectivity across multiple brain slabs (UNSLICE). We applied this platform for analyzing human Alzheimer's disease pathology at multiple scales and demonstrating scalable neural connectivity mapping in the human brain.

Introduction: Mobile mental health applications are a novel treatment method with unique qualities and capabilities for enhancing existing psychiatric treatments. Outpatient settings such as Mile Square Health Clinic have identified a need to leverage this new technology into their routine care., Background: In the U.S., over 40 million people suffer from an anxiety disorder, however, only 1 in 4 responds to pharmacological treatment. Preliminary research indicates mental health apps are acceptable, feasible, and can improve patient outcomes for those with anxiety., Methods: Participants from two different outpatient psychiatric clinics locations with generalized anxiety disorder were identified and recruited by participating nurse practitioners. Participants were instructed on how to download and use IntelliCare by the Project Lead. The Project Lead administered a semi-structured interview to collect qualitative data at three weeks and six weeks follow-up., Results and Conclusions: Survey responses at three and six weeks showed relevant themes of increased journaling, increased feelings of connectedness, positive associations with gamification, and IntelliCare being most useful for a moderate to severe level of anxiety., Recommendations: The results of this QI project demonstrate the clinical utility of incorporating the IntelliCare app into regular outpatient practice. IntelliCare should be used with those with moderate to severe anxiety and journaling features should follow research developments to incorporate best-practice guidelines., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Psychological factors are amongst the most robust predictors of healthspan and longevity, yet are rarely incorporated into scientific and medical frameworks of aging. The prospect of characterizing and integrating the psychological influences of aging is therefore an unmet step for the advancement of geroscience. Psychogenic Aging research is an emerging branch of biogerontology that aims to address this gap by investigating the impact of psychological factors on human longevity. It is an interdisciplinary field that integrates complex psychological, neurological, and molecular relationships that can be best understood with precision medicine methodologies. This perspective argues that psychogenic aging should be considered an integral component of the Hallmarks of Aging framework, opening the doors for future biopsychosocial integration in longevity research. By providing a unique perspective on frequently overlooked aspects of organismal aging, psychogenic aging offers new insights and targets for anti-aging therapeutics on individual and societal levels that can significantly benefit the scientific and medical communities., (© 2024. The Author(s).)

Aims/hypothesis: Infection with coxsackie B viruses (CVBs) can cause diseases ranging from mild common cold-type symptoms to severe life-threatening conditions. CVB infections are considered to be prime candidates for environmental triggers of type 1 diabetes. This, together with the significant disease burden of acute CVB infections and their association with chronic diseases other than diabetes, has prompted the development of human CVB vaccines. The current study evaluated the safety and immunogenicity of the first human vaccine designed against CVBs associated with type 1 diabetes in a double-blind randomised placebo-controlled Phase I trial., Methods: The main eligibility criteria for participants were good general health, age between 18 and 45 years, provision of written informed consent and willingness to comply with all trial procedures. Treatment allocation (PRV-101 or placebo) was based on a computer-generated randomisation schedule and people assessing the outcomes were masked to group assignment. In total, 32 participants (17 men, 15 women) aged 18-44 years were randomised to receive a low (n=12) or high (n=12) dose of a multivalent, formalin-inactivated vaccine including CVB serotypes 1-5 (PRV-101), or placebo (n=8), given by intramuscular injections at weeks 0, 4 and 8 at a single study site in Finland. The participants were followed for another 24 weeks. Safety and tolerability were the primary endpoints. Anti-CVB IgG and virus-neutralising titres were analysed using an ELISA and neutralising plaque reduction assays, respectively., Results: Among the 32 participants (low dose, n=12; high dose, n=12; placebo, n=8) no serious adverse events or adverse events leading to study treatment discontinuation were observed. Treatment-emergent adverse events considered to be related to the study drug occurred in 37.5% of the participants in the placebo group and 62.5% in the PRV-101 group (injection site pain, headache, injection site discomfort and injection site pruritus being most common). PRV-101 induced dose-dependent neutralising antibody responses against all five CVB serotypes included in the vaccine in both the high- and low-dose groups. Protective titres ≥8 against all five serotypes were seen in >90% of participants over the entire follow-up period., Conclusions/interpretation: The results indicate that the tested multivalent CVB vaccine is well tolerated and immunogenic, supporting its further clinical development., Trial Registration: ClinicalTrials.gov NCT04690426., Funding: This trial was funded by Provention Bio, a Sanofi company., (© 2024. The Author(s).)

Background: Thymic atrophy is characterized by loss of thymocytes, destruction of thymic architecture, and a subsequent decrease in naïve T cells with compromised immunity. Thymic atrophy occurs during aging. Environmental factors including alcohol misuse also induce thymic atrophy. Despite the link between alcohol misuse and thymic atrophy, the underlying mechanism is understudied. We aimed to identify molecules and signaling pathways that underly alcohol-induced thymic atrophy during aging., Methods: F344 rats were given 3-day binge-ethanol (4.8 g/kg/day; 52% w/v; i.g.) and the thymus was collected and weighed. Molecular mechanisms underlying ethanol-induced thymic atrophy were investigated by network meta-analysis using the QIAGEN Ingenuity Pathway Analysis (IPA). The molecules associated with ethanol were identified from the QIAGEN Knowledge Base (QKB) and those associated with thymic atrophy were identified from QKB and Mouse Genome Informatics (MGI). Aging-mediated Differential Expression Genes (DEGs) from mouse thymocytes were obtained from the Gene Expression Omnibus (GEO) database (GSE132136). The relationship between the molecules and associated signaling pathways were studied using IPA., Results: Binge-ethanol decreased thymic weight in F344 rats. Our meta-analysis using IPA identified molecules commonly shared by ethanol and thymic atrophy through which simulation with ethanol increased thymic atrophy. We then obtained aging-mediated DEGs from the atrophied thymocytes. We found that ethanol contributed to thymic atrophy through modulation of the aging-mediated DEGs. Our network meta-analysis suggests that ethanol may augment thymic atrophy through increased expression of cytokines (e.g., IL-6, IL-17A and IL-33) along with their regulators (e.g., STAT1 and STAT3)., Conclusions: Exposure to alcohol may augment thymic atrophy by altering the activity of key inflammatory mediators, such as STAT family members and inflammatory cytokines. These findings provide insights into the signaling pathways and upstream regulators that underly alcohol-induced thymic atrophy during aging, suggesting that alcohol consumption could prepone thymic atrophy., (© 2024 Research Society on Alcohol.)

The vaginal microbiome's composition varies among ethnicities. However, the evolutionary landscape of the vaginal microbiome in the multi-ethnic context remains understudied. We perform a systematic evolutionary analysis of 351 vaginal microbiome samples from 35 multi-ethnic pregnant women, in addition to two validation cohorts, totaling 462 samples from 90 women. Microbiome alpha diversity and community state dynamics show strong ethnic signatures. Lactobacillaceae have a higher ratio of non-synonymous to synonymous polymorphism and lower nucleotide diversity than non-Lactobacillaceae in all ethnicities, with a large repertoire of positively selected genes, including the mucin-binding and cell wall anchor genes. These evolutionary dynamics are driven by the long-term evolutionary process unique to the human vaginal niche. Finally, we propose an evolutionary model reflecting the environmental niches of microbes. Our study reveals the extensive ethnic signatures in vaginal microbial ecology and evolution, highlighting the importance of studying the host-microbiome ecosystem from an evolutionary perspective., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

There has been an increase in the use of commercially available multi-ingredient preworkout supplements (MIPS); however, there are inconsistencies regarding the efficacy of MIPS in resistance-trained women., Purpose: To determine the effect of varying doses of MIPS compared with caffeine only (C) and a placebo (PL) on resistance-training performance in trained women., Methods: Ten women (21.5 [2.3] y) completed 1-repetition-maximum tests at baseline for leg press and bench press. A within-group, double-blind, and randomized design was used to assign supplement drinks (ie, PL, C, MIPS half scoop [MIPS-H], and MIPS full scoop [MIPS-F]). Repetitions to failure were assessed at 75% and 80% to 85% of 1-repetition maximum for bench and leg press, respectively. Total performance volume was calculated as load × sets × repetitions for each session. Data were analyzed using a 1-way repeated-measures analysis of variance and reported as means and SDs., Results: There were no differences in repetitions to failure for bench press (PL: 14.4 [3.2] repetitions, C: 14.4 [2.9] repetitions, MIPS-H: 14.2 [2.6] repetitions, MIPS-F: 15.1 [3.1] repetitions; P = .54) or leg press (PL: 13.9 [7.8] repetitions, C: 10.8 [5.9] repetitions, MIPS-H: 13.1 [7.1] repetitions, MIPS-F: 12.4 [10.7] repetitions; P = .44). Furthermore, there were no differences in total performance volume across supplements for bench press (PL: 911.2 [212.8] kg, C: 910.7 [205.5] kg, MIPS-H: 913.6 [249.3] kg, MIPS-F: 951.6 [289.6] kg; P = .39) or leg press (PL: 4318.4 [1633.6] kg, C: 3730.0 [1032.5] kg, MIPS-H: 4223.0 [1630.0] kg, MIPS-F: 4085.5 [2098.3] kg; P = .34)., Conclusions: Overall, our findings suggest that caffeine and MIPS do not provide ergogenic benefits for resistance-trained women in delaying muscular failure.

About two-thirds of college students rate their sleep as suboptimal which is associated with a variety of additional issues. Poor sleep is shown to follow certain pre-sleep cognitive activity that inhibits sleep onset and reduces sleep quality. Preliminary evidence suggests that a self-administered hypnosis intervention is feasible in improving sleep within a college student population, and the current study explores potential correlating variables to inform future mechanistic research. Twenty-two college students who self-reported poor sleep quality utilized a three-week self-administered hypnosis intervention while completing baseline and endpoint measures of sleep quality, insomnia symptoms, and psychological factors. Results indicated that participants experienced significant improvement with large effects in sleep quality ( d  = -1.21) and significant decreases in insomnia symptoms ( d  = 1.05) from pre- to post-intervention. Significant improvements were also observed on measures of pre-sleep arousal and worry. The results suggest that a self-administered hypnosis intervention may modulate pre-sleep cognitive activity associated with poor sleep quality.

Background: Arteriovenous malformations (AVMs) are vascular malformations that are more commonly found intracranially, followed by the head, neck, limbs, and trunk. Extracranially, AVMs can mimic peripheral nerve tumors, leading to misdiagnosis., Observations: A 19-year-old female, who presented with left lateral lower leg pain, was preoperatively thought to have a peripheral nerve tumor; at surgery, however, she was found to have an extracranial AVM. The distinct margins of the tumor on preoperative magnetic resonance imaging suggested that the patient might have a peripheral nerve tumor; however, the clinical symptoms of focal pain at rest and the absence of Tinel's sign should have raised questions about this diagnosis., Lessons: This case highlights the difficulty in differentiating a peripheral nerve tumor from an extracranial AVM in certain clinical scenarios. It is important to use a multifaceted diagnostic approach to get a correct preoperative diagnosis and plan treatment appropriately.

Background: Hot flashes are associated with a lower quality of life and sleep disturbances. Given the many consequences of hot flashes, it is important to find treatments to reduce them. Hypnotherapy, the use of hypnosis for a medical disorder or concern, has been shown in clinical trials to be effective in reducing hot flashes, but it is not routinely used in clinical practice. One solution to close this implementation gap is to administer hypnotherapy for hot flashes via a smartphone app. Evia is a smartphone app that delivers hypnotherapy for hot flashes. Evia has made hypnotherapy more widely accessible for women who are experiencing hot flashes; however, the app has yet to undergo empirical testing. Additionally, research on user characteristics is lacking., Objective: This study aims to (1) determine the average age, stage of menopause, and length of menopause symptoms for users of the Evia app; (2) determine the characteristics of hot flashes and night sweats for users of the Evia app; (3) determine the self-reported sleep quality of users of the Evia app; (4) determine the self-reported mental health of users of the Evia app; and (5) determine the relationship between hot flash frequency and anxiety and depression for users of the Evia app., Methods: This study analyzed data collected from participants who have downloaded the Evia app. Data were collected at 1 time point from a self-report questionnaire that assessed the demographic and clinical characteristics of users. The questionnaire was given to users when they downloaded the Evia app. Users of the Evia app fill out a questionnaire upon enrolling in the program and prior to beginning the intervention. This included 9764 users., Results: Results showed that the mean age of users was 49.31 years. A total of 41.6% (1942/4665) of users reported experiencing 5 or more hot flashes per day, while 51.2% (1473/2877) of users reported having difficulty falling asleep each night and 47.7% (1253/2626) of users reported their sleep quality to be terrible. In addition, 38.4% (1104/2877) of users reported that they often feel anxious or depressed. There was a small, significant, and negative correlation between hot flash frequency and self-report frequency of anxiety and depression (r=-0.09)., Conclusions: This study showed that the average age of app users is in line with the median age of natural menopause. A large percentage of users reported experiencing 5 or more hot flashes per day, reported difficulties with sleep, and reported experiencing depression and anxiety. These findings are in line with previous studies that assessed hot flash frequency and the consequences of hot flashes. This was the first study to report on the characteristics of users of the Evia app. Results will be used to optimize the hypnotherapy program delivered via the Evia app., (©Morgan Snyder, Gary R Elkins. Originally published in JMIR Formative Research (https://formative.jmir.org), 14.03.2024.)

In recent years, the development of sensor and wearable technologies have led to their increased adoption in clinical and health monitoring settings. One area that is in early, but promising, stages of development is the use of biosensors for therapeutic drug monitoring (TDM). Traditionally, TDM could only be performed in certified laboratories and was used in specific scenarios to optimize drug dosage based on measurement of plasma/blood drug concentrations. Although TDM has been typically pursued in settings involving medications that are challenging to manage, the basic approach is useful for characterizing drug activity. TDM is based on the idea that there is likely a clear relationship between plasma/blood drug concentration (or concentration in other matrices) and clinical efficacy. However, these relationships may vary across individuals and may be affected by genetic factors, comorbidities, lifestyle, and diet. TDM technologies will be valuable for enabling precision medicine strategies to determine the clinical efficacy of drugs in individuals, as well as optimizing personalized dosing, especially since therapeutic windows may vary inter-individually. In this mini-review, we discuss emerging TDM technologies and their applications, and factors that influence TDM including drug interactions, polypharmacy, and supplement use. We also discuss how using TDM within single subject (N-of-1) and aggregated N-of-1 clinical trial designs provides opportunities to better capture drug response and activity at the individual level. Individualized TDM solutions have the potential to help optimize treatment selection and dosing regimens so that the right drug and right dose may be matched to the right person and in the right context., Competing Interests: Author WL was a paid consultant of Net/Bio, Inc. Authors LG, NS, and SS are founders of Net/Bio, Inc. with equity. Authors MS and BB-J are unpaid consultants., (Copyright © 2024 Liang, Beaulieu-Jones, Smalley, Snyder, Goetz and Schork.)

Borane-amines have garnered attention over the last several decades in a variety of applications, ranging from hydrogen storage materials to hypergolic fuel systems. An investigation into the synthesis of borane-amines with high-nitrogen content heterocycles was undertaken in this work. Borane-amines were formed by the reaction of BH 3 ·Me 2 S in tetrahydrofuran (THF) with the requisite nitrogen-containing heterocycle and isolated by placing the crude reaction mixture in hexanes to precipitate the product. X-ray crystallography, thermogravimetric analysis (TGA), high resolution mass spectroscopy (HRMS), 1 H NMR, 13 C NMR, and 11 B NMR were utilized for product characterization, while impact and friction sensitivity testing were conducted to identify sensitivity in the synthesized compounds. Most isolated borane-amines, except one, were found to decompose in the atmosphere and were more sensitive to mechanical stimuli than their starting materials; however, all synthesized compounds were found to be hypergolic in the presence of white fuming nitric acid (WFNA)., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

In this work, we employ a recently developed biophysical technique that uses diethylpyrocarbonate (DEPC) covalent labeling and mass spectrometry for the identification of mAb binding patches to two multimodal cation exchange resins at different pH. This approach compares the labeling results obtained in the bound and unbound states to identify residues that are sterically shielded and thus located in the mAb binding domains. The results at pH 6 for one mAb (mAb B) indicated that while the complementarity determining region (CDR) had minimal interactions with both resins, the F C domain was actively involved in binding. In contrast, DEPC/MS data with another mAb (mAb C) indicated that both the CDR and F C domains were actively involved in binding. These results corroborated chromatographic retention data with these two mAbs and their fragments and helped to explain the significantly stronger retention of both the intact mAb C and its Fab fragment. In contrast, labeling results with mAb C at pH 7, indicated that only the CDR played a significant role in resin binding, again corroborating chromatographic data. The binding domains identified from the DEPC/MS experiments were also examined using protein surface hydrophobicity maps obtained using a recently developed sparse sampling molecular dynamics (MD) approach in concert with electrostatic potential maps. These results demonstrate that the DEPC covalent labeling/mass spectrometry technique can provide important information about the domain contributions of multidomain proteins such as monoclonal antibodies when interacting with multimodal resins over a range of pH conditions., (© 2023 American Institute of Chemical Engineers.)

Objective: Various disciplines at all education levels worldwide are steeped in contradictions regarding the value of answer changing on exams. Therefore, the purpose of this scoping review was to explore the current evidence related to answer changing at the graduate and undergraduate level with a focus on nursing education., Design: The scoping review was guided by Arksey and O'Malley's scoping review framework. The team used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews guideline to report the findings., Data Sources: Using identified keywords such as answer changing, backtracking and test wiseness, researchers located forty-nine relevant studies from multiple databases. After applying the predetermined inclusion criteria including college students from all disciplines at the undergraduate or graduate level, ten remained for review., Review Method: The a priori protocol was; changing answers on tests will lower scores. Studies were randomly assigned to each researcher for a first and second review using an author designed abstraction tool. Verbal reconciliation was the third and final review of each article., Results: The scoping review revealed that answer changes produced more wrong to right answers. In addition, total score improvements with answer changes were as high as 45.15 %., Conclusion: The synthesis of findings from 10 articles refuted assumptions that answer changing would negatively impact the number of correct responses and potentially lower the overall exam score. The findings from this scoping review support permitting answer changes. However, the varied research approaches in the studies reviewed also suggest the need to conduct further research on the topic., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Background and Objectives: Several neurosurgical pathologies, ranging from glioblastoma to hemorrhagic stroke, use volume thresholds to guide treatment decisions. For chronic subdural hematoma (cSDH), with a risk of retreatment of 10%-30%, the relationship between preoperative and postoperative cSDH volume and retreatment is not well understood. We investigated the potential link between preoperative and postoperative cSDH volumes and retreatment., Methods: We performed a retrospective chart review of patients operated for unilateral cSDH from 4 level 1 trauma centers, February 2009-August 2021. We used a 3-dimensional deep learning, automated segmentation pipeline to calculate preoperative and postoperative cSDH volumes. To identify volume thresholds, we constructed a receiver operating curve with preoperative and postoperative volumes to predict cSDH retreatment rates and selected the threshold with the highest Youden index. Then, we developed a light gradient boosting machine to predict the risk of cSDH recurrence., Results: We identified 538 patients with unilateral cSDH, of whom 62 (12%) underwent surgical retreatment within 6 months of the index surgery. cSDH retreatment was associated with higher preoperative (122 vs 103 mL; P < .001) and postoperative (62 vs 35 mL; P < .001) volumes. Patients with >140 mL preoperative volume had nearly triple the risk of cSDH recurrence compared with those below 140 mL, while a postoperative volume >46 mL led to an increased risk for retreatment (22% vs 6%; P < .001). On multivariate modeling, our model had an area under the receiver operating curve of 0.76 (95% CI: 0.60-0.93) for predicting retreatment. The most important features were preoperative and postoperative volume, platelet count, and age., Conclusion: Larger preoperative and postoperative cSDH volumes increase the risk of retreatment. Volume thresholds may allow identification of patients at high risk of cSDH retreatment who would benefit from adjunct treatments. Machine learning algorithm can quickly provide accurate estimates of preoperative and postoperative volumes., (Copyright © Congress of Neurological Surgeons 2023. All rights reserved.)

Background: Asthma and other atopic disorders can present with varying clinical phenotypes marked by differential metabolomic manifestations and enriched biological pathways., Objective: We sought to identify these unique metabolomic profiles in atopy and asthma., Methods: We analyzed baseline nonfasted plasma samples from a large multisite pediatric population of 470 children aged <13 years from 3 different sites in the United States and France. Atopy positivity (At + ) was defined as skin prick test result of ≥3 mm and/or specific IgE ≥ 0.35 IU/mL and/or total IgE ≥ 173 IU/mL. Asthma positivity (As + ) was based on physician diagnosis. The cohort was divided into 4 groups of varying combinations of asthma and atopy, and 6 pairwise analyses were conducted to best assess the differential metabolomic profiles between groups., Results: Two hundred ten children were classified as At - As - , 42 as At + As - , 74 as At - As + , and 144 as At + As + . Untargeted global metabolomic profiles were generated through ultra-high-performance liquid chromatography-tandem mass spectroscopy. We applied 2 independent machine learning classifiers and short-listed 362 metabolites as discriminant features. Our analysis showed the most diverse metabolomic profile in the At + As + /At - As - comparison, followed by the At - As + /At - As - comparison, indicating that asthma is the most discriminant condition associated with metabolomic changes. At + As + metabolomic profiles were characterized by higher levels of bile acids, sphingolipids, and phospholipids, and lower levels of polyamine, tryptophan, and gamma-glutamyl amino acids., Conclusion: The At + As + phenotype displays a distinct metabolomic profile suggesting underlying mechanisms such as modulation of host-pathogen and gut microbiota interactions, epigenetic changes in T-cell differentiation, and lower antioxidant properties of the airway epithelium., Competing Interests: Disclosure statement Supported by the Sean N. Parker Center for Allergy and Asthma Research, the Hauts-de France region, France (VIRASTHMA study funding), Stallergènes (VIRASTHMA study funding), and AstraZeneca (personal research grant to S.L.). Disclosure of potential conflict of interest: S. Lejeune declares a personal research grant from Astra Zeneca and remunerations for symposiums by Sanofi and Novartis. K. Contrepois is currently an AstraZeneca employee. The rest of the authors declare that they have no relevant conflicts of interest., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

The objective of this study was to determine the best-fit factor structure of a standardized hypnotizability measure in a clinical population. The Elkins Hypnotizability Scale (EHS) was administered to 173 post-menopausal women, age from 39 to 75 years, with a mean age of 54.61 years. Confirmatory factor analysis was conducted, and comparative fit index (CFI) and root mean square error of approximation (RMSEA) were used to determine goodness of fit. Results indicated that the single-factor structure modeled with six indicators based on the individual items on the EHS provides the best description of fit. Results of the present study demonstrate that the EHS has a single-factor structure. Further research is required with other populations and measures.

Background and Objectives: An international, multicenter, retrospective study was conducted to evaluate the long-term clinical outcomes and tumor control rates after stereotactic radiosurgery (SRS) for trigeminal schwannoma., Methods: Patient data (N = 309) were collected from 14 international radiosurgery centers. The median patient age was 50 years (range 11-87 years). Sixty patients (19%) had prior resections. Abnormal facial sensation was the commonest complaint (49%). The anatomic locations were root (N = 40), ganglion (N = 141), or dumbbell type (N = 128). The median tumor volume was 4 cc (range, 0.2-30.1 cc), and median margin dose was 13 Gy (range, 10-20 Gy). Factors associated with tumor control, symptom improvement, and adverse radiation events were assessed., Results: The median and mean time to last follow-up was 49 and 65 months (range 6-242 months). Greater than 5-year follow-up was available for 139 patients (45%), and 50 patients (16%) had longer than 10-year follow-up. The overall tumor control rate was 94.5%. Tumors regressed in 146 patients (47.2%), remained unchanged in 128 patients (41.4%), and stabilized after initial expansion in 20 patients (6.5%). Progression-free survival rates at 3 years, 5 years, and 10 years were 91%, 86%, and 80 %. Smaller tumor volume (less than 8 cc) was associated with significantly better progression-free survival ( P = .02). Seventeen patients with sustained growth underwent further intervention at a median of 27 months (3-144 months). Symptom improvement was noted in 140 patients (45%) at a median of 7 months. In multivariate analysis primary, SRS ( P = .003) and smaller tumor volume ( P = .01) were associated with better symptom improvement. Adverse radiation events were documented in 29 patients (9%)., Conclusion: SRS was associated with long-term freedom (10 year) from additional management in 80% of patients. SRS proved to be a valuable salvage option after resection. When used as a primary management for smaller volume tumors, both clinical improvement and prevention of new deficits were optimized., (Copyright © Congress of Neurological Surgeons 2023. All rights reserved.)

Biallelic mutations in the gene that encodes the enzyme N-glycanase 1 (NGLY1) cause a rare disease with multi-symptomatic features including developmental delay, intellectual disability, neuropathy, and seizures. NGLY1's activity in human neural cells is currently not well understood. To understand how NGLY1 gene loss leads to the specific phenotypes of NGLY1 deficiency, we employed direct conversion of NGLY1 patient-derived induced pluripotent stem cells (iPSCs) to functional cortical neurons. Transcriptomic, proteomic, and functional studies of iPSC-derived neurons lacking NGLY1 function revealed several major cellular processes that were altered, including protein aggregate-clearing functionality, mitochondrial homeostasis, and synaptic dysfunctions. These phenotypes were rescued by introduction of a functional NGLY1 gene and were observed in iPSC-derived mature neurons but not astrocytes. Finally, laser capture microscopy followed by mass spectrometry provided detailed characterization of the composition of protein aggregates specific to NGLY1-deficient neurons. Future studies will harness this knowledge for therapeutic development., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Cardiometabolic risk is increasing in prevalence across the life span with disproportionate ramifications for youth at socioeconomic disadvantage. Established risk factors and associated disease progression are harder to reverse as they become entrenched over time; if current trends are unchecked, the consequences for individual and societal wellness will become untenable. Interrelated root causes of ectopic adiposity and insulin resistance are understood but identified late in the trajectory of systemic metabolic dysregulation when traditional cardiometabolic risk factors cross current diagnostic thresholds of disease. Thus, children at cardiometabolic risk are often exposed to suboptimal metabolism over years before they present with clinical symptoms, at which point life-long reliance on pharmacotherapy may only mitigate but not reverse the risk. Leading-edge indicators are needed to detect the earliest departure from healthy metabolism, so that targeted, primordial, and primary prevention of cardiometabolic risk is possible. Better understanding of biomarkers that reflect the earliest transitions to dysmetabolism, beginning in utero, ideally biomarkers that are also mechanistic/causal and modifiable, is critically needed. This scientific statement explores emerging biomarkers of cardiometabolic risk across rapidly evolving and interrelated "omic" fields of research (the epigenome, microbiome, metabolome, lipidome, and inflammasome). Connections in each domain to mitochondrial function are identified that may mediate the favorable responses of each of the omic biomarkers featured to a heart-healthy lifestyle, notably to nutritional interventions. Fuller implementation of evidence-based nutrition must address environmental and socioeconomic disparities that can either facilitate or impede response to therapy.

The effectiveness of lifestyle interventions in reducing caloric intake and increasing physical activity for preventing Type 2 Diabetes (T2D) has been previously demonstrated. The use of modern technologies can potentially further improve the success of these interventions, promote metabolic health, and prevent T2D at scale. To test this concept, we built a remote program that uses continuous glucose monitoring (CGM) and wearables to make lifestyle recommendations that improve health. We enrolled 2,217 participants with varying degrees of glucose levels (normal range, and prediabetes and T2D ranges), using continuous glucose monitoring (CGM) over 28 days to capture glucose patterns. Participants logged food intake, physical activity, and body weight via a smartphone app that integrated wearables data and provided daily insights, including overlaying glucose patterns with activity and food intake, macronutrient breakdown, glycemic index (GI), glycemic load (GL), and activity measures. The app furthermore provided personalized recommendations based on users' preferences, goals, and observed glycemic patterns. Users could interact with the app for an additional 2 months without CGM. Here we report significant improvements in hyperglycemia, glucose variability, and hypoglycemia, particularly in those who were not diabetic at baseline. Body weight decreased in all groups, especially those who were overweight or obese. Healthy eating habits improved significantly, with reduced daily caloric intake and carbohydrate-to-calorie ratio and increased intake of protein, fiber, and healthy fats relative to calories. These findings suggest that lifestyle recommendations, in addition to behavior logging and CGM data integration within a mobile app, can enhance the metabolic health of both nondiabetic and T2D individuals, leading to healthier lifestyle choices. This technology can be a valuable tool for T2D prevention and treatment., (© 2023. The Author(s).)

Background: The mortality benefit of VV-ECMO in ARDS has been extensively studied, but the impact on long-term functional outcomes of survivors is poorly defined. We aimed to assess the association between ECMO and functional outcomes in a contemporaneous cohort of survivors of ARDS., Methods: Multicenter retrospective cohort study of ARDS survivors who presented to follow-up clinic. The primary outcome was FVC% predicted. Univariate and multivariate regression models were used to evaluate the impact of ECMO on the primary outcome., Results: This study enrolled 110 survivors of ARDS, 34 of whom were managed using ECMO. The ECMO cohort was younger (35 [28, 50] vs. 51 [44, 61] years old, p < 0.01), less likely to have COVID-19 (58% vs. 96%, p < 0.01), more severely ill based on the Sequential Organ Failure Assessment (SOFA) score (7 [5, 9] vs. 4 [3, 6], p < 0.01), dynamic lung compliance (15 mL/cmH 2 0 [11, 20] vs. 27 mL/cmH 2 0 [23, 35], p < 0.01), oxygenation index (26 [22, 33] vs. 9 [6, 11], p < 0.01), and their need for rescue modes of ventilation. ECMO patients had significantly longer lengths of hospitalization (46 [27, 62] vs. 16 [12, 31] days, p < 0.01) ICU stay (29 [19, 43] vs. 10 [5, 17] days, p < 0.01), and duration of mechanical ventilation (24 [14, 42] vs. 10 [7, 17] days, p < 0.01). Functional outcomes were similar in ECMO and non-ECMO patients. ECMO did not predict changes in lung function when adjusting for age, SOFA, COVID-19 status, or length of hospitalization., Conclusions: There were no significant differences in the FVC% predicted, or other markers of pulmonary, neurocognitive, or psychiatric functional recovery outcomes, when comparing a contemporaneous clinic-based cohort of survivors of ARDS managed with ECMO to those without ECMO., (© 2023. The Author(s).)

A 56-year-old female presented with a symptomatic giant fusiform mid-splenic artery aneurysm (7.3 x 6.4 cm). The patient underwent hybrid management of the aneurysm with endovascular embolization of the aneurysm and inflow splenic artery followed by laparoscopic splenectomy with control and division of the outflow vessels. The patient had an uneventful post-operative course. This case demonstrates the safety and efficacy of an innovative, hybrid management of a giant splenic artery aneurysm with endovascular embolization and laparoscopic splenectomy that spares the pancreatic tail.

In the United States, approximately 27 million people have a documented penicillin allergy, but 90% of the allergies are falsely labeled. By rechallenging suspected allergies, a pharmacist can optimize patient care, fulfill antimicrobial stewardship objectives, and educate patients on true allergies. We suggest a protocol that allows pharmacists to investigate the presence of an allergy and conduct a challenge when indicated. The protocol consists of a patient interview, a risk assessment, an oral rechallenge, and the potential for a skin test. The testing and delabeling of penicillin allergies will enhance the practice of antimicrobial stewardship in the outpatient setting. In the changing landscape of pharmacy, community pharmacists can increase their services and improve patient care. Owing to limited documented experience in the outpatient pharmacy, an opportunity to set the standard and be a leader in the field is present., (Copyright © 2023 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: Metabolic syndrome (MetS) refers to a group of risk factors, which increase the risk of cardiovascular disease (CVD), type 2 diabetes (T2D), and other chronic diseases. Dietary fiber has been shown to mitigate many of the effects of various risk factors associated with MetS. Our review summarizes the recent findings on the association between dietary fiber deficiency and MetS., Recent Findings: A number of studies have shown that dietary fiber deficiency is associated with an increased risk of MetS. The main mechanisms by which dietary fiber may reduce the risk of MetS include reduction of cholesterol levels; improvement of blood sugar control; reduction of inflammation; and promotion of weight loss., Summary: Literature suggests that a deficiency in dietary fiber consumption is a risk factor for MetS. An increase in dietary fiber intake may help to reduce the risk of developing MetS and its associated chronic diseases., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: A 6FFF Monte Carlo (MC) dose calculation algorithm was commissioned for spine stereotactic radiosurgery (SRS). Model generation, validation, and ensuing model tuning are presented., Methods: The model was generated using in-air and in-water commissioning measurements of field sizes between 10 and 400 mm 2 . Commissioning measurements were compared to simulated water tank MC calculations to validate output factors, percent depth doses (PDDs), profile sizes and penumbras. Previously treated Spine SRS patients were re-optimized with the MC model to achieve clinically acceptable plans. Resulting plans were calculated on the StereoPHAN phantom and subsequently delivered to the microDiamond and SRSMapcheck to verify calculated dose accuracy. Model tuning was performed by adjusting the model's light field offset (LO) distance between physical and radiological positions of the MLCs, to improve field size and StereoPHAN calculation accuracy. Following tuning, plans were generated and delivered to an anthropomorphic 3D-printed spine phantom featuring realistic bone anatomy, to validate heterogeneity corrections. Finally, plans were validated using polymer gel (VIPAR based formulation) measurements., Results: Compared to open field measurements, MC calculated output factors and PDDs were within 2%, profile penumbra widths were within 1 mm, and field sizes were within 0.5 mm. Calculated point dose measurements in the StereoPHAN were within 0.26% ± 0.93% and -0.10% ± 1.37% for targets and spinal canals, respectively. Average SRSMapcheck per-plan pass rates using a 2%/2 mm/10% threshold relative gamma analysis was 99.1% ± 0.89%. Adjusting LOs improved open field and patient-specific dosimetric agreement. Anthropomorphic phantom measurements were within -1.29% ± 1.00% and 0.27% ± 1.36% of MC calculated for the vertebral body (target) and spinal canal, respectively. VIPAR gel measurements confirmed good dosimetric agreement near the target-spine junction., Conclusion: Validation of a MC algorithm for simple fields and complex SRS spine deliveries in homogeneous and heterogeneous phantoms has been performed. The MC algorithm has been released for clinical use., (© 2023 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)

The field of microbe-metal interactions has been gaining significant attention. While the direct impact of metal oxyanions on bacteria has been investigated, significantly less attention has been placed on the ability of certain microbes to 'collect' such metal ions via secreted proteins. Many bacteria possess low-weight molecules called siderophores, which collect Fe from the environment to be brought back to the cell. However, some appear to have additional roles, including binding other metals, termed 'metallophores'. Microbes can remove/sequester these from their surroundings, but the breadth of those that can be removed is still unknown. Using the Chromeazurol S assay, we identified eight isolates, most belonging to the genus Pseudomonas , possessing siderophore activity, mainly from sites impacted by coal mine drainage, also possessing a metallophore activity toward the rare earth elements that does not appear to be related to ionic radii or previously reported EC 50 concentrations for E. coli . We found the strength of metallophore activity towards these elements was as follows: Pr > Sc > Eu > Tm > Tb > Er > Yb > Ce > Lu > Sm > Ho > La > Nd > Dy > Gd > Y. This is the first study to investigate such activity and indicates bacteria may provide a means of removal/recovery of these critical elements.