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Abstract Restoring motor function after stroke necessitates involvement of numerous cognitive systems. However, the impact of damage to motor and cognitive network organization on recovery is not well understood. To discover correlates of successful recovery, we explored imaging characteristics in chronic stroke subjects by combining noninvasive brain stimulation and fMRI. Twenty stroke survivors (6 months or more after stroke) were randomly assigned to a single session of transcranial direct current stimulation (tDCS) or sham during image acquisition. Twenty healthy subjects were included as controls. tDCS was limited to 10 min at 2 mA to serve as a mode of network modulation rather than therapeutic delivery. Fugl-Meyer Assessments (FMA) revealed significant motor improvement in the chronic stroke group receiving active stimulation (p = 0.0005). Motor changes in this group were correlated in a data-driven fashion with imaging features, including functional connectivity (FC), surface-based morphometry, electric field modeling and network topology, focusing on relevant regions of interest. We observed stimulation-related changes in FC in supplementary motor (p = 0.0029), inferior frontal gyrus (p = 0.0058), and temporo-occipital (p = 0.0095) areas, though these were not directly related to motor improvement. The feature most strongly associated with FMA improvement in the chronic stroke cohort was graph topology of the dorsal attention network (DAN), one of the regions surveyed and one with direct connections to each of the areas with FC changes. Chronic stroke subjects with a greater degree of motor improvement had lower signal transmission cost through the DAN (p = 0.029). While the study was limited by a small stroke cohort with moderate severity and variable lesion location, these results nevertheless suggest a top-down role for higher order areas such as attention in helping to orchestrate the stroke recovery process.

Abstract Presbycusis, or age-related hearing loss, affects both elderly humans and dogs, significantly impairing their social interactions and cognition. In humans, presbycusis involves changes in peripheral and central auditory systems, with central changes potentially occurring independently. While peripheral presbycusis in dogs is well-documented, research on central changes remains limited. Diffusion tensor imaging (DTI) is a useful tool for detecting and quantifying cerebral white matter abnormalities. This study used DTI to explore the central auditory pathway of senior dogs, aiming to enhance our understanding of canine presbycusis. Dogs beyond 75% of their expected lifespan were recruited and screened with brainstem auditory evoked response testing to select dogs without severe peripheral hearing loss. Sixteen dogs meeting the criteria were scanned using a 3 T magnetic resonance scanner. Tract-based spatial statistics was used to analyze the central auditory pathways. A significant negative correlation between fractional lifespan and fractional anisotropy was found in the acoustic radiation, suggesting age-related white matter changes in the central auditory system. These changes, observed in dogs without severe peripheral hearing loss, may contribute to central presbycusis development.

Histoplasmosis is a fungal disease associated with substantial mortality rates among persons with advanced HIV disease. Our systematic review synthesized data on the global prevalence of Histoplasma­-caused antigenuria in persons with HIV. We searched PubMed/Medline, Embase, and Scopus databases on January 3, 2023, to identify cross-sectional and cohort studies evaluating Histoplasma antigenuria prevalence among adults with HIV infection. We calculated point estimates and 95% CIs to summarize prevalence. Of 1,294 studies screened, we included 15. We found Histoplasma antigenuria among 581/5,096 (11%; 95% CI 11%–12%) persons with HIV and 483/3,789 persons with advanced HIV disease (13%; 95% CI 12%–14%). Among persons with HIV and symptoms consistent with histoplasmosis, Histoplasma antigenuria prevalence was 14% (95% CI 13%–15%; 502/3,631 participants). We determined that persons with advanced HIV disease, inpatients, and symptomatic persons might benefit from a systematic approach to early detection of histoplasmosis using urine antigen testing.

Abstract The Bacillus Calmette-Guérin (BCG) vaccine, which has been used for > 100 years to prevent tuberculosis, is well-established for bladder cancer treatment, and under study for neurological and autoimmune diseases. In patients with type 1 diabetes (T1D), BCG vaccinations have been shown in randomized clinical trials to gradually lower blood sugar to near normal levels. This effect appears to be driven by a BCG-induced shift in lymphoid cells’ glucose metabolism from oxidative phosphorylation to aerobic glycolysis. The latter is a state of high glucose utilization that draws more glucose from the blood. Apart from blood, it is unknown whether BCG establishes residence in any organs and alters their glucose metabolism. In this two-year-long clinical trial in type 1 diabetics, we use positron emission tomography (PET) and x-ray computed tomography (CT) to map organs that increase their uptake of the glucose analogue 18F-fluorodeoxyglucose (18F-FDG) before versus after BCG vaccinations. We also injected BALB/c mice with BCG to test for the presence of BCG in various organs. Results from both studies point to the spleen as the dominant site for glucose uptake and BCG residence. The human spleen is significant because its 47% increase in 18F-FDG uptake by a large population of lymphocytes and monocytes might help to explain BCG’s systemic lowering of blood glucose to near normal levels. Findings suggest that the spleen, triggered by BCG, assumes a critical role in systemic glucose regulation in the absence of a functional pancreas.

Abstract The development of treatments targeting the vascular endothelial growth factor (VEGF) signaling pathways have traditionally been firstly investigated in oncology and then advanced into retinal disease indications. Members of the VEGF family of endogenous ligands and their respective receptors play a central role in vasculogenesis and angiogenesis during both development and physiological homeostasis. They can also play a pathogenic role in cancer and retinal diseases. Therapeutic approaches have mostly focused on targeting VEGF-A signaling; however, research has shown that VEGF-C and VEGF-D signaling pathways are also important to the disease pathogenesis of tumors and retinal diseases. This review highlights the important therapeutic advances and the remaining unmet need for improved therapies targeting additional mechanisms beyond VEGF-A. Additionally, it provides an overview of alternative VEGF-C and VEGF-D signaling involvement in both health and disease, highlighting their key contributions in the multifactorial pathophysiology of retinal disease including neovascular age-related macular degeneration (nAMD). Strategies for targeting VEGF-C/-D signaling pathways will also be reviewed, with an emphasis on agents currently being developed for the treatment of nAMD.

Abstract Background A lack of safety data on postpartum medication use presents a potential barrier to breastfeeding and may result in infant exposure to medications in breastmilk. The type and extent of medication use by lactating women requires investigation. Methods Data were collected from the CHILD Cohort Study which enrolled pregnant women across Canada between 2008 and 2012. Participants completed questionnaires regarding medications and non-prescription medications used and breastfeeding status at 3, 6 and 12 months postpartum. Medications, along with self-reported reasons for medication use, were categorized by ontologies [hierarchical controlled vocabulary] as part of a large-scale curation effort to enable more robust investigations of reasons for medication use. Results A total of 3542 mother-infant dyads were recruited to the CHILD study. Breastfeeding rates were 87.4%, 75.3%, 45.5% at 3, 6 and 12 months respectively. About 40% of women who were breastfeeding at 3 months used at least one prescription medication during the first three months postpartum; this proportion decreased over time to 29.5% % at 6 months and 32.8% at 12 months. The most commonly used prescription medication by breastfeeding women was domperidone at 3 months (9.0%, n = 229/2540) and 6 months (5.6%, n = 109/1948), and norethisterone at 12 months (4.1%, n = 48/1180). The vast majority of domperidone use by breastfeeding women (97.3%) was for lactation purposes which is off-label (signifying unapproved use of an approved medication). Non-prescription medications were more often used among breastfeeding than non-breastfeeding women (67.6% versus 48.9% at 3 months, p

Abstract Background Clinician teachers (physicians who teach in clinical settings) experience considerable psychological challenges in providing both educational training and patient care. This study aimed to determine the prevalence of physician burnout and professional fulfillment, and to identify internal and external factors associated with mental health outcomes among Thai clinician teachers working in non-university teaching hospitals. Method A one-time online questionnaire was completed by physicians at 37 governmental, non-university teaching hospitals in Thailand, with 227 respondents being assessed in the main analyses. Four outcomes were evaluated including burnout, professional fulfillment, quality of life, and intentions to quit. Results The observed prevalence of professional fulfillment was 20%, and burnout was 30.7%. Hierarchical regression analysis showed a significant internal, psychological predictor (clinical teaching self-efficacy) and external, structural predictors (multiple roles at work, teaching support), controlling for the background variables of gender, years of teaching experience, family roles, and active chronic disease, with clinical teaching self-efficacy positively predicting professional fulfillment (b = 0.29, p ≤.001) and negatively predicting burnout (b = − 0.21, p =.003). Conclusions Results highlight the importance of faculty development initiatives to enhance clinical teaching self-efficacy and promote mental health among Thai physicians.

Objectives We developed a machine-learning model-based algorithm (MBA) for smoking in Administrative Health Data (AHD). The validity of this MBA was compared to a rule-based algorithm (RBA). Approaches The study included adults (≥18 years) from a clinical registry containing self-reported current smoking from 2017 to 2020 in Manitoba, Canada. Clinical data were linked to up to five years of hospitalization, physician billing claims, and prescription medication records. The RBA was based on diagnosis codes for tobacco use and nicotine dependence medication. MBAs, constructed using random forest (RF) models, included these indicators in addition to comorbid condition diagnoses and sociodemographic factors. Sensitivity, specificity, positive and negative predictive values (PPV, NPV), and 95% confidence intervals (CIs) were estimated. Results The cohort comprised 24,718 individuals (88.6% female); prevalence of current smokers was 10.0%. The RBA had sensitivity of 27.3% (95% CI: 24.2-30.7), specificity of 96.6% (95% CI: 96.1-97.0), and PPV of 47.2% (95% CI: 42.9-51.5). The MBA had sensitivity of 68.6% (95% CI: 65.1-71.9), specificity of 76.3% (95% CI: 75.2-77.3), and PPV of 24.3% (95% CI: 23.2-25.6). NPV was high irrespective of algorithms. Stratified analyses revealed similar estimates for males and females, and the number of years of AHD did not affect the MBA results. Conclusions An RF-based MBA for smoking ascertainment in linked AHD sources improved sensitivity compared to the RBA. However, the RBA excelled in specificity and PPV. Implication Balancing accurate smoker identification with the risk of false positives is crucial when choosing an algorithm to ascertain current smokers using AHD.

The use of vaporizers to inhale cannabis is a technique that has risen in popularity among the American public. There is a general perception that vaporizers are “safer” when compared to more traditional cannabis smoking via combustion (i.e., cigarettes). The inherent use of heated air in vaporizers might reduce the respiratory toxicants or protein toxins by heating cannabis to a temperature where active compounds form in vapor phase. Yet this temperature is below the point of combustion where smoke and associated toxicants are produced. The elemental impurities are a general concern in all botanical products including cannabis and cannabis-derived products (CCDPs). This study aimed to investigate the potential transfer of those metallic elements from cannabis material to cannabis vapor through the vaporization process. A Volcano Digit Vaporizer (Storz & Bickel) was used as the heating device to perform the vaporization. Three cannabis plant materials were evaluated with varying contents of cannabinoids, including a cannabis placebo (

Abstract Background Intervertebral disc herniation (IVDH) is the most common spinal cord disease in dogs. Little information is available regarding the clinical presentation of nerve root signature (NRS) associated with cervical IVDH. Hypothesis/Objective To detail the clinical and magnetic resonance imaging (MRI) findings in dogs with NRS associated with cervical IVDH. Animals Forty‐seven client‐owned dogs presenting with thoracic limb NRS and MRI confirmed IVDH. Methods Medical records from 2010 to 2020 were retrospectively reviewed for dogs that met inclusion criteria. Imaging studies were evaluated by 2 individuals to characterize location and severity of neural tissue compression. Results Chondrodystrophoid dogs comprised the majority of the study cohort, with dachshund the most common breed (n = 10). Three‐quarters of dogs were ≥7 years of age. Interobserver agreement was moderate or good for all of the imaging variables evaluated. The C6‐C7 intervertebral disc space was significantly overrepresented (P = .01), comprising 32% (15/47) of the affected discs. However, 42% (20/47) of cases involved C2‐C3 though C4‐C5 disc sites. Disc material was more frequently located laterally compared to medially within the vertebral canal (P = .0005), and to be associated with compression of the nerve root at the level of the intervertebral foramen (P = .012). Conclusion/Clinical Importance NRS is most commonly associated with lateralized or foraminal cervical disc herniations. It is most prevalent with C6‐C7 intervertebral disc involvement, suggesting that there might be unique anatomic factors that contribute to development of NRS at this site, but can be a clinical manifestation of IVDH occurring anywhere along the cervical spine.

Abstract There is a public health need to understand how different frequencies of COVID-19 booster vaccines may mitigate the risk of severe COVID-19, while accounting for waning of protection and differential risk by age and immune status. By analyzing United States COVID-19 surveillance and seroprevalence data in a microsimulation model, here we show that more frequent COVID-19 booster vaccination (every 6–12 months) in older age groups and the immunocompromised population would effectively reduce the burden of severe COVID-19, while frequent boosters in the younger population may only provide modest benefit against severe disease. In persons 75+ years, the model estimated that annual boosters would reduce absolute annual risk of severe COVID-19 by 199 (uncertainty interval: 183–232) cases per 100,000 persons, compared to a one-time booster vaccination. In contrast, for persons 18–49 years, the model estimated that annual boosters would reduce this risk by 14 (10–19) cases per 100,000 persons. Those with prior infection had lower benefit of more frequent boosting, and immunocompromised persons had larger benefit. Scenarios with emerging variants with immune evasion increased the benefit of more frequent variant-targeted boosters. This study underscores the benefit of considering key risk factors to inform frequency of COVID-19 booster vaccines in public health guidance and ensuring at least annual boosters in high-risk populations.

Abstract Examination of early phases of synucleinopathy when inclusions are present, but long before neurodegeneration occurs, is critical to both understanding disease progression and the development of disease modifying therapies. The rat alpha-synuclein (α-syn) preformed fibril (PFF) model induces synchronized synucleinopathy that recapitulates the pathological features of Parkinson’s disease (PD) and can be used to study synucleinopathy progression. In this model, phosphorylated α-syn (pSyn) inclusion-containing neurons and reactive microglia (major histocompatibility complex-II immunoreactive) peak in the substantia nigra pars compacta (SNpc) months before appreciable neurodegeneration. However, it remains unclear which specific genes are driving these phenotypic changes. To identify transcriptional changes associated with early synucleinopathy, we used laser capture microdissection of the SNpc paired with RNA sequencing (RNASeq). Precision collection of the SNpc allowed for the assessment of differential transcript expression in the nigral dopamine neurons and proximal glia. Transcripts upregulated in early synucleinopathy were mainly associated with an immune response, whereas transcripts downregulated were associated with neurotransmission and the dopamine pathway. A subset of 29 transcripts associated with neurotransmission/vesicular release and the dopamine pathway were verified in a separate cohort of males and females to confirm reproducibility. Within this subset, fluorescent in situ hybridization (FISH) was used to localize decreases in the Syt1 and Slc6a3 transcripts to pSyn inclusion-containing neurons. Identification of transcriptional changes in early synucleinopathy provides insight into the molecular mechanisms driving neurodegeneration.

Abstract Background Vector sand fly colonies are a critical component of studies aimed at improving the understanding of the neglected tropical disease leishmaniasis and alleviating its global impact. However, among laboratory-colonized arthropod vectors of infectious diseases, the labor-intensive nature of sand fly rearing coupled with the low number of colonies worldwide has generally discouraged the widespread use of sand flies in laboratory settings. Among the different factors associated with the low productivity of sand fly colonies, mite infestations are a significant factor. Sand fly colonies are prone to infestation by mites, and the physical interactions between sand flies and mites and metabolites have a negative impact on sand fly larval development. Methods Mites were collected from sand fly larval rearing pots and morphologically identified using taxonomic keys. Upon identification, they were photographed with a scanning electron microscope. Several mite control measures were adopted in two different laboratories, one at the Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases-National Institutes of Health (Rockville, MD, USA), and the other at the University of Calgary (Calgary, AB, Canada). Results The mite species associated with sand fly colonies in the two laboratories were morphologically identified as Tyrophagus sp. and Stratiolaelaps scimitus. While complete eradication of mites in sand fly colonies is considered unrealistic, drastically reducing their population has been associated with higher sand fly productivity. Conclusions We report a case of detrimental interaction between sand flies and Tyrophagus sp. and S. scimitus in a closed laboratory sand fly colony, discuss their impact on sand fly production and provide guidelines for limiting the mite population size in a closed laboratory colony leading to improved sand fly yields. Graphical abstract

AIM: To investigate sex-based differences in the occurrence of intra-operative and post-operative complications and associated visual outcomes following cataract surgery. METHODS: This was a retrospective study of patients who had phacoemulsification cataract surgery at the University of Colorado School of Medicine. Data collected included the patient's health history, ocular comorbidities, operative and post-operative complications, and the post-operative best corrected visual acuity (BCVA). The data were analyzed using univariate and multivariable logistic regression with generalized estimating equations to account for the correlation of some patients having two eyes included in the study. RESULTS: A total of 11 977 eyes from 7253 patients were included in the study. Ocular comorbidities differed by sex, with males having significantly higher percentages of traumatic cataracts (males 0.7% vs females 0.1%), prior ocular surgery (6.7% vs 5.5%), and mature cataracts (2.8% vs 1.9%). Conversely, females had significantly higher rates of pseudoexfoliation (2.0% vs 3.2%). In unadjusted analysis, males had higher rates of posterior capsular rupture (0.8% vs 0.4%) and vitreous loss (1.0% vs 0.6%), but this difference was not significant after adjustment for confounders. Males had a significantly increased risk of post-operative retinal detachment, but in multivariable analysis this was no longer significant. Males were significantly less likely to undergo post-operative neodymium-doped yttrium aluminum garnet (Nd:YAG) laser capsulotomy for posterior capsule opacification (OR=0.8, 95%CI=0.7-0.9, P=0.0005). The BCVA was slightly worse for males pre-operatively; but post-operatively, both sexes exhibited similar visual acuity of Snellen equivalent 20/25. CONCLUSION: The study finds that in a cohort of patients presenting for cataract surgery, sex differences exist in pre-operative comorbidities and surgical characteristics that contribute to higher rates of some complications for males. However, observed surgical complication rates exhibit almost no difference by sex after adjusting for pre-operative differences and post-operative BCVA is similar between sexes.

Summary: Background: The COVID-19 pandemic heightened risks for individuals with hematological malignancies due to compromised immune systems, leading to more severe outcomes and increased mortality. While interventions like vaccines, targeted antivirals, and monoclonal antibodies have been effective for the general population, their benefits for these patients may not be as pronounced. Methods: The EPICOVIDEHA registry (National Clinical Trials Identifier, NCT04733729) gathers COVID-19 data from hematological malignancy patients since the pandemic's start worldwide. It spans various global locations, allowing comprehensive analysis over the first three years (2020–2022). Findings: The EPICOVIDEHA registry collected data from January 2020 to December 2022, involving 8767 COVID-19 cases in hematological malignancy patients from 152 centers across 41 countries, with 42% being female. Over this period, there was a significant reduction in critical infections and an overall decrease in mortality from 29% to 4%. However, hospitalization, particularly in the ICU, remained associated with higher mortality rates. Factors contributing to increased mortality included age, multiple comorbidities, active malignancy at COVID-19 onset, pulmonary symptoms, and hospitalization. On the positive side, vaccination with one to two doses or three or more doses, as well as encountering COVID-19 in 2022, were associated with improved survival. Interpretation: Patients with hematological malignancies still face elevated risks, despite reductions in critical infections and overall mortality rates over time. Hospitalization, especially in ICUs, remains a significant concern. The study underscores the importance of vaccination and the timing of COVID-19 exposure in 2022 for enhanced survival in this patient group. Ongoing monitoring and targeted interventions are essential to support this vulnerable population, emphasizing the critical role of timely diagnosis and prompt treatment in preventing severe COVID-19 cases. Funding: Not applicable.

Purpose: Metformin use has been associated with a decreased risk of age-related macular degeneration (AMD) progression in observational studies. We aimed to evaluate the efficacy of oral metformin for slowing geographic atrophy (GA) progression. Design: Parallel-group, multicenter, randomized phase II clinical trial. Participants: Participants aged ≥ 55 years without diabetes who had GA from atrophic AMD in ≥ 1 eye. Methods: We enrolled participants across 12 clinical centers and randomized participants in a 1:1 ratio to receive oral metformin (2000 mg daily) or observation for 18 months. Fundus autofluorescence imaging was obtained at baseline and every 6 months. Main Outcome Measures: The primary efficacy endpoint was the annualized enlargement rate of the square root-transformed GA area. Secondary endpoints included best-corrected visual acuity (BCVA) and low luminance visual acuity (LLVA) at each visit. Results: Of 66 enrolled participants, 34 (57 eyes) were randomized to the observation group and 32 (53 eyes) were randomized to the treatment group. The median follow-up duration was 13.9 and 12.6 months in the observation and metformin groups, respectively. The mean ± standard error annualized enlargement rate of square root transformed GA area was 0.35 ± 0.04 mm/year in the observation group and 0.42 ± 0.04 mm/year in the treatment group (risk difference = 0.07 mm/year, 95% confidence interval = −0.05 to 0.18 mm/year; P = 0.26). The mean ± standard error decline in BCVA was 4.8 ± 1.7 letters/year in the observation group and 3.4 ± 1.1 letters/year in the treatment group (P = 0.56). The mean ± standard error decline in LLVA was 7.3 ± 2.5 letters/year in the observation group and 0.8 ± 2.2 letters/year in the treatment group (P = 0.06). Fourteen participants in the metformin group experienced nonserious adverse events related to metformin, with gastrointestinal side effects as the most common. No serious adverse events were attributed to metformin. Conclusions: The results of this trial as conducted do not support oral metformin having effects on reducing the progression of GA. Additional placebo-controlled trials are needed to explore the role of metformin for AMD, especially for earlier stages of the disease. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Abstract Synthesising knowledge on carbon stocks is an essential tool for understanding the potential of forests to store carbon and its drivers. However, such a synthesis needs to be constructed for the Atlantic Forest due to various methodological approaches and biogeographic heterogeneity. Thus, here we conducted a bibliographic search (2000 to 2021) on carbon stocks in the biomass and necromass of Atlantic Forest ecosystems to understand the variation in stocks and their explanatory variables. Drivers included spatial (altitude, forest size) and climatic (precipitation and temperature) variables, and successional stages. Based on the information in 46 articles, biomass exhibited the highest carbon stock (96%), in Mature Forests (MF), with an average of 125.34±40.3 MgC.ha-1, whereas Secondary Forests (SF) stored 82.7±38.2 MgC.ha-1. The carbon in the necromass varied from 1.63 to 11.47 MgC.ha-1, with SF exhibiting 3.90±2.73 MgC.ha-1 and MF 4.31±2.82 MgC.ha-1. Only average annual precipitation and successional stage positively explained the carbon in Atlantic Forest. This research clarifies the function and potential of Atlantic Forest fragments for storing carbon and reinforces need for conserving mature forest patches throughout the biome since one hectare of mature forest can store almost twice as much carbon as one hectare of secondary young patches.

Dipara trilineata (Diparidae) is a widespread eastern North American parasitoid with apterous females and winged males. Despite its seemingly limited dispersal capabilities, phylogeographic analysis over southern Appalachia reveals little structure, with only limited population level isolation. DNA barcoding surveys also definitively associate the male of the species, which had previously been misattributed, and a description of the correctly associated male is provided.

Objectives: Elderly patients with hematologic malignancies face the highest risk of severe COVID-19 outcomes. The infection's impact on different age groups remains unstudied in detail. Methods: We analyzed elderly patients (age groups: 65-70, 71-75, 76-80, and >80 years old) with hematologic malignancies included in the EPICOVIDEHA registry between January 2020 and July 2022. Univariable and multivariable Cox regression models were conducted to identify factors influencing death in COVID-19 patients with hematological malignancy. Results: The study included data from 3,603 elderly patients (aged 65 or older) with hematological malignancy, with a majority being male (58.1%) and a significant proportion having comorbidities. The patients were divided into four age groups, and the analysis assessed COVID-19 outcomes, vaccination status, and other variables in relation to age and pandemic waves. The 90-day survival rate for patients with COVID-19 was 71.2%, with significant differences between groups. The pandemic waves had varying impacts, with the first wave affecting patients over 80 years old, the second being more severe in 65-70, and the third being the least severe in all age groups. Factors contributing to 90-day mortality included age, comorbidities, lymphopenia, active malignancy, acute leukemia, less than three vaccine doses, severe COVID-19, and using only corticosteroids as treatment. Conclusion: These data underscore the heterogeneity of elderly hematological patients, highlight the different impacts of COVID-19 waves and the pivotal importance of vaccination, and may help in planning future healthcare efforts.

Abstract Where sufficiently large genome-wide association study (GWAS) samples are not currently available or feasible, methods that leverage increasing knowledge of the biological function of variants may illuminate discoveries without increasing sample size. We comprehensively evaluated 17 functional weighting methods for identifying novel associations. We assessed the performance of these methods using published results from multiple GWAS waves across each of five complex traits. Although no method achieved both high sensitivity and positive predictive value (PPV) for any trait, a subset of methods utilizing pleiotropy and expression quantitative trait loci nominated variants with high PPV (>75%) for multiple traits. Application of functionally weighting methods to enhance GWAS power for locus discovery is unlikely to circumvent the need for larger sample sizes in truly underpowered GWAS, but these results suggest that applying functional weighting to GWAS can accurately nominate additional novel loci from available samples for follow-up studies.

Abstract In acute skin injury, healing is impaired by the excessive release of reactive oxygen species (ROS). Melanin, an efficient scavenger of radical species in the skin, performs a key role in ROS scavenging in response to UV radiation and is upregulated in response to toxic insult. In a chemical injury model in mice, we demonstrate that the topical application of synthetic melanin particles (SMPs) significantly decreases edema, reduces eschar detachment time, and increases the rate of wound area reduction compared to vehicle controls. Furthermore, these results were replicated in a UV-injury model. Immune array analysis shows downregulated gene expression in apoptotic and inflammatory signaling pathways consistent with histological reduction in apoptosis. Mechanistically, synthetic melanin intervention increases superoxide dismutase (SOD) activity, decreases Mmp9 expression, and suppresses ERK1/2 phosphorylation. Furthermore, we observed that the application of SMPs caused increased populations of anti-inflammatory immune cells to accumulate in the skin, mirroring their decrease from splenic populations. To enhance antioxidant capacity, an engineered biomimetic High Surface Area SMP was deployed, exhibiting increased wound healing efficiency. Finally, in human skin explants, SMP intervention significantly decreased the damage caused by chemical injury. Therefore, SMPs are promising and effective candidates as topical therapies for accelerated wound healing, including via pathways validated in human skin.

Background: The purpose of this study is to evaluate the impact of the COVID-19 pandemic on shoulder procedure volumes reported to the Accreditation Council for Graduate Medical Education by orthopedic surgery residents. Methods: We performed a retrospective review of Accreditation Council for Graduate Medical Education case logs reporting data from graduating orthopedic surgery residents during the academic years of 2006-2022. Data were queried for all patients for the following shoulder Current Procedural Terminology codes: incision, excision, intro or removal, repair/revision/reconstruction, fracture and/or dislocation, manipulation, arthroscopy, trauma, and total procedures performed. Individual t-tests were used to compare case log trends of graduating academic years before (classes of 2018 and 2019) and during (classes of 2020, 2021, and 2022) the COVID-19 pandemic. Statistical significance was established to be P

Mammals are protected from changes in environmental temperature by altering energetic processes that modify heat production. Insulin is the dominant stimulus of glucose uptake and metabolism, which are fundamental for thermogenic processes. The purpose of this work was to determine the interaction of ambient temperature induced changes in energy expenditure (EE) on the insulin sensitivity of glucose fluxes. Short-term and adaptive responses to thermoneutral temperature (TN, ∼28 °C) and room (laboratory) temperature (RT, ∼22 °C) were studied in mice. This range of temperature does not cause detectable changes in circulating catecholamines or shivering and postabsorptive glucose homeostasis is maintained. We tested the hypothesis that a decrease in EE that occurs with TN causes insulin resistance and that this reduction in insulin action and EE is reversed upon short term (

ABSTRACT: Euthanasia is an essential task performed daily on commercial poultry farms around the world to safeguard animal welfare. Manual cervical dislocation (MCD) is the most common euthanasia method but can be challenging to perform given the physical strength required to implement this technique. Therefore, the objective of this study was to evaluate the efficacy of a novel cervical dislocation tool (NCDT) compared to MCD. A total of 60 Ross 308 chickens (6-wk old) and 60 Ross 706 parent stock breeders (21-wk old) were enrolled in the study. Birds were sexed, blocked by body weight, and allocated to 1 of 2 treatments: 1) MCD and 2) NCDT. Immediately following euthanasia application, insensibility, and death were monitored. Once death was confirmed, gross evaluation, radiograph, and macroscopic/microscopic scoring were performed. Both euthanasia methods were 100% effective in achieving insensibility followed by cardiac and respiratory arrest in both age groups. In 6-wk-old broilers, there were no differences in insensibility measures or location and severity of the dislocation site by treatment. The NCDT treatment group showed an increased frequency of fractures located at the tooth-like process that projects from the cranial aspect of the centrum of the axis (dens) but had no impact on bird insensibility. For parent stock, differences in nictitating membrane reflex (NMR) and laceration scores for birds euthanized with NCDT were found and likely associated with additional force exerted with the tool. The NCDT is a promising replacement for MCD and future work should address the development of free and accessible training materials for on-farm use.

With the growing global need for housing and infrastructure, 3D concrete printing (3DCP) has emerged as an innovative construction method offering several potential benefits including design flexibility, speed, and sustainability. However, enhancing the reliability of 3DCP involves managing a variety of parameters that influence various aspects of the 3D printed structure. Process parameters like nozzle velocity, nozzle diameter, nozzle height, and material flow velocity have a major impact on the structural stability and filament shape. This project aimed to develop fast and accurate data-driven models for predicting and classifying filament shape based on process parameters. A print experiment systematically varied process parameters across 144 samples. The resulting filament geometry (width, height, contact width) was measured and classified by quality. Models were trained on this data to predict filament width, contact width, filament height, and classify filaments. These models can be utilized with any buildable material - a material with a high enough yield stress to bear the weight of upper layers without significant deformation. This condition does not restrict this study’s scope as it is a prerequisite for all 3DCP applications. The models’ robustness and generalizability were confirmed through validation on literature data across various printable materials and setups. These data-driven models can aid in optimizing parameters, generating variable width filaments, and printing non-planar layers. By linking print inputs to filament outputs, this comprehensive modeling approach advances 3DCP research for more reliable and versatile concrete printing.

BackgroundDifferential access to healthcare has contributed to a higher burden of illness and mortality among First Nations compared to other people in Canada. Throughout the Coronavirus Disease 2019 (COVID-19) pandemic, First Nations organizations in Manitoba partnered with public health and Manitoba government officials to ensure First Nations had early, equitable and culturally safe access to COVID-19 diagnostic testing and vaccination. In this study, we examined whether prioritizing First Nations for vaccination was associated with faster uptake of COVID-19 vaccines among First Nations versus All Other Manitobans (AOM).Methods and findingsIn this retrospective cohort study, we used linked, whole-population administrative data from the Manitoba healthcare system (February 2020 to December 2021) to determine rates of COVID-19 diagnostic testing, infection, and vaccination, and used adjusted restricted mean survival time (RMST) models to test whether First Nations received their first and second vaccine doses more quickly than other Manitobans. The cohort comprised 114,816 First Nations (50.6% female) and 1,262,760 AOM (50.1% female). First Nations were younger (72.3% were age 0 to 39 years) compared to AOM (51% were age 0 to 39 years) and were overrepresented in the lowest 2 income quintiles (81.6% versus 35.6% for AOM). The 2 groups had a similar burden of comorbidities (65.8% of First Nations had none and 6.3% had 3 or more; 65.9% of AOM had none and 6.0% had 3 or more) and existing mental disorders (36.9% of First Nations were diagnosed with a mood/anxiety disorder, psychosis, personality disorder, or substance use disorder versus 35.2% of AOM). First Nations had crude infection rates of up to 17.20 (95% CI 17.15 to 17.24) COVID-19 infections/1,000 person-months compared with up to 6.24 (95% CI 6.16 to 6.32) infections/1,000 person-months among AOM. First Nations had crude diagnostic testing rates of up to 103.19 (95% CI 103.06 to 103.32) diagnostic COVID-19 tests/1,000 person-months compared with up to 61.52 (95% CI 61.47 to 61.57) tests/1,000 person-months among AOM. Prioritizing First Nations to receive vaccines was associated with faster vaccine uptake among First Nations versus other Manitobans. After adjusting for age, sex, income, region of residence, mental health conditions, and comorbidities, we found that First Nations residents received their first vaccine dose an average of 15.5 (95% CI 14.9 to 16.0) days sooner and their second dose 13.9 (95% CI 13.3 to 14.5) days sooner than other Manitobans in the same age group. The study was limited by the discontinuation of population-based COVID-19 testing and data collection in December 2021. As well, it would have been valuable to have contextual data on potential barriers to COVID-19 testing or vaccination, including, for example, information on social and structural barriers faced by Indigenous and other racialized people, or the distrust Indigenous people may have in governments due to historical harms.ConclusionIn this study, we observed that the partnered COVID-19 response between First Nations and the Manitoba government, which oversaw creation and enactment of policies prioritizing First Nations for vaccines, was associated with vaccine acceptance and quick uptake among First Nations. This approach may serve as a useful framework for future public health efforts in Manitoba and other jurisdictions across Canada.

Background This retrospective review aimed to assess if open payments made by industry arthroplasty companies to physicians and hospital systems were significantly affected by implant type and geographic variation. Methods Data was obtained from the Centers for Medicare and Medicaid Services (CMS) publicly available open payment datasets (2016-2019). Geographic locations were identified using regions as defined by the US Census Bureau. A linear regression was calculated to predict the open payment made based on the created variable region, the most used implant type (reverse vs anatomic, n > 30 to be included), and their hypothesized interaction. Results A significant regression equation was found for the hypothesized interaction between implant and region, F (13,11 186) = 3.446, P

Conclusion: Care should be taken to prevent drills from plunging beyond the medial femoral cortex during surgery. Cautious observation of patient’s vitals and clinical course can allow for early detection of vascular complication.

Benzalkonium chloride (BZK), alkyldimethylbenzlamonium chloride, is a cationic surfactant that is used as an antiseptic. BZK is classified as a quaternary ammonium compound composed of molecules of several alkyl chains of differing lengths, that dictate its effectiveness towards different microbes. As a result, BZK has become one of the most used preservatives in antibacterial solutions. Despite its widespread use, it is not clear whether BZK penetrates human skin. To answer this question, BZK treated skin was analyzed using matrix assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry imaging. Solutions containing BZK and differing excipients, including citric acid, caprylyl glycol, and vitamin E, were applied ex vivo to excised human skin using Franz diffusion cells. Treated skin was embedded in gelatin and sectioned prior to MALDI-TOF imaging. BZK penetrates through the epidermis and into the dermis, and the penetration depth was significantly altered by pH and additives in tested solutions.

The two-planet transiting system LHS 1140 has been extensively observed since its discovery in 2017, notably with Spitzer, HST, TESS, and ESPRESSO, placing strong constraints on the parameters of the M4.5 host star and its small temperate exoplanets, LHS 1140 b and c. Here, we reanalyze the ESPRESSO observations of LHS 1140 with the novel line-by-line framework designed to fully exploit the radial velocity content of a stellar spectrum while being resilient to outlier measurements. The improved radial velocities, combined with updated stellar parameters, consolidate our knowledge of the mass of LHS 1140 b (5.60 ± 0.19 M _⊕ ) and LHS 1140 c (1.91 ± 0.06 M _⊕ ) with an unprecedented precision of 3%. Transits from Spitzer, HST, and TESS are jointly analyzed for the first time, allowing us to refine the planetary radii of b (1.730 ± 0.025 R _⊕ ) and c (1.272 ± 0.026 R _⊕ ). Stellar abundance measurements of refractory elements (Fe, Mg, and Si) obtained with NIRPS are used to constrain the internal structure of LHS 1140 b. This planet is unlikely to be a rocky super-Earth, as previously reported, but rather a mini-Neptune with a ∼0.1% H/He envelope by mass or a water world with a water-mass fraction between 9% and 19%, depending on the atmospheric composition and relative abundance of Fe and Mg. While the mini-Neptune case would not be habitable, a water-abundant LHS 1140 b potentially has habitable surface conditions according to 3D global climate models, suggesting liquid water at the substellar point for atmospheres with relatively low CO _2 concentration, from Earth-like to a few bars.

Abstract The interplay between magnetism and electronic band topology enriches topological phases and has promising applications. However, the role of topology in magnetic fluctuations has been elusive. Here, we report evidence for topology stabilized magnetism above the magnetic transition temperature in magnetic Weyl semimetal candidate CeAlGe. Electrical transport, thermal transport, resonant elastic X-ray scattering, and dilatometry consistently indicate the presence of locally correlated magnetism within a narrow temperature window well above the thermodynamic magnetic transition temperature. The wavevector of this short-range order is consistent with the nesting condition of topological Weyl nodes, suggesting that it arises from the interaction between magnetic fluctuations and the emergent Weyl fermions. Effective field theory shows that this topology stabilized order is wavevector dependent and can be stabilized when the interband Weyl fermion scattering is dominant. Our work highlights the role of electronic band topology in stabilizing magnetic order even in the classically disordered regime.

Abstract Here, we study the upper critical solution temperature triggered phase transition of thermally responsive poly(ethylene glycol)-block-poly(ethylene glycol) methyl ether acrylate-co-poly(ethylene glycol) phenyl ether acrylate-block-polystyrene nanoassemblies in isopropanol. To gain mechanistic insight into the organic solution-phase dynamics of the upper critical solution temperature polymer, we leverage variable temperature liquid-cell transmission electron microscopy correlated with variable temperature liquid resonant soft X-ray scattering. Heating above the upper critical solution temperature triggers a reduction in particle size and a morphological transition from a spherical core shell particle with a complex, multiphase core to a micelle with a uniform core and Gaussian polymer chains attached to the surface. These correlated solution phase methods, coupled with mass spectral validation and modeling, provide unique insight into these thermoresponsive materials. Moreover, we detail a generalizable workflow for studying complex, solution-phase nanomaterials via correlative methods.

Open top chambers (OTCs) were adopted as the recommended warming mechanism by the International Tundra Experiment network in the early 1990s. Since then, OTCs have been deployed across the globe. Hundreds of papers have reported the impacts of OTCs on the abiotic environment and the biota. Here, we review the impacts of the OTC on the physical environment, with comments on the appropriateness of using OTCs to characterize the response of biota to warming. The purpose of this review is to guide readers to previously published work and to provide recommendations for continued use of OTCs to understand the implications of warming on low stature ecosystems. In short, the OTC is a useful tool to experimentally manipulate temperature; however, the characteristics and magnitude of warming varies greatly in different environments; therefore, it is important to document chamber performance to maximize the interpretation of biotic response. When coupled with long-term monitoring, warming experiments are a valuable means to understand the impacts of climate change on natural ecosystems.

Abstract In sexual reproduction, sperm contribute half the genomic material required for creation of offspring yet core molecular mechanisms essential for their formation are undefined. Here, the α-arrestin molecule arrestin-domain containing 5 (ARRDC5) is identified as an essential regulator of mammalian spermatogenesis. Multispecies testicular tissue transcriptome profiling indicates that expression of Arrdc5 is testis enriched, if not specific, in mice, pigs, cattle, and humans. Knockout of Arrdc5 in mice leads to male specific sterility due to production of low numbers of sperm that are immotile and malformed. Spermiogenesis, the final phase of spermatogenesis when round spermatids transform to spermatozoa, is defective in testes of Arrdc5 deficient mice. Also, epididymal sperm in Arrdc5 knockouts are unable to capacitate and fertilize oocytes. These findings establish ARRDC5 as an essential regulator of mammalian spermatogenesis. Considering the role of arrestin molecules as modulators of cellular signaling and ubiquitination, ARRDC5 is a potential male contraceptive target.

Much of the foundation for lifelong spermatogenesis is established prior to puberty, and disruptions during this developmental window negatively impact fertility long into adulthood. However, the factors that coordinate prepubertal germline development are incompletely understood. Here, we report that core-binding factor subunit-β (CBFβ) plays critical roles in prepubertal development and the onset of spermatogenesis. Using a mouse conditional knockout (cKO) approach, inactivation of Cbfb in the male germline resulted in rapid degeneration of the germline during the onset of spermatogenesis, impaired overall sperm production, and adult infertility. Utilizing a different Cre driver to generate another Cbfb cKO model, we determined that the function of CBFβ in the male germline is likely limited to undifferentiated spermatogonia despite expression in other germ cell types. Within undifferentiated spermatogonia, CBFβ regulates proliferation, survival, and overall maintenance of the undifferentiated spermatogonia population. Paradoxically, we discovered that CBFβ also distally regulates meiotic progression and spermatid formation but only with Cbfb cKO within undifferentiated spermatogonia. Spatial transcriptomics revealed that CBFβ modulates cell cycle checkpoint control genes associated with both proliferation and meiosis. Taken together, our findings demonstrate that core programs established within the prepubertal undifferentiated spermatogonia population are necessary for both germline maintenance and sperm production.

Summary: Coronary artery disease (CAD) is characterized by atherosclerotic plaque formation in the arterial wall. CAD progression involves complex interactions and phenotypic plasticity among vascular and immune cell lineages. Single-cell RNA-seq (scRNA-seq) studies have highlighted lineage-specific transcriptomic signatures, but human cell phenotypes remain controversial. Here, we perform an integrated meta-analysis of 22 scRNA-seq libraries to generate a comprehensive map of human atherosclerosis with 118,578 cells. Besides characterizing granular cell-type diversity and communication, we leverage this atlas to provide insights into smooth muscle cell (SMC) modulation. We integrate genome-wide association study data and uncover a critical role for modulated SMC phenotypes in CAD, myocardial infarction, and coronary calcification. Finally, we identify fibromyocyte/fibrochondrogenic SMC markers (LTBP1 and CRTAC1) as proxies of atherosclerosis progression and validate these through omics and spatial imaging analyses. Altogether, we create a unified atlas of human atherosclerosis informing cell state-specific mechanistic and translational studies of cardiovascular diseases.

BackgroundAlthough ET is a phenomenologically heterogeneous condition, thalamic DBS appears to be equally effective across subtypes. We hypothesized stimulation sites optimized for individuals with essential tremor (ET) would differ from individuals with essential tremor plus syndrome (ET-plus). We examined group differences in optimal stimulation sites within the ventral thalamus and their overlap of with relevant white matter tracts. By capturing these differences, we sought to determine whether ET subtypes are associated with anatomically distinct neural pathways.MethodsA retrospective chart review was conducted on ET patients undergoing VIM DBS at MUSC between 01/2012 and 02/2022. Clinical, demographic, neuroimaging, and DBS stimulation parameter data were collected. Clinical characteristics and pre-DBS videos were reviewed to classify ET and ET-plus cohorts. Patients in ET-plus cohorts were further divided into ET with dystonia, ET with ataxia, and ET with others. DBS leads were reconstructed using Lead-DBS1 and the volume of tissue activated (VTA) overlap was performed using normative connectomes. Tremor improvement was measured by reduction in a subscore of tremor rating scale (TRS) post-DBS lateralized to the more affected limb.ResultsSixty-eight ET patients were enrolled after initial screening, of these 10 ET and 24 ET-plus patients were included in the final analyses. ET group had an earlier age at onset (p = 0.185) and underwent surgery at a younger age (p = 0.096). Both groups achieved effective tremor control. No significant differences were found in lead placement or VTA overlap within ventral thalamus. The VTA center of gravity (COG) in the ET-plus cohort was located dorsal to that of the ET cohort. No significant differences were found in VTA overlap with the dentato-rubral-thalamic (DRTT) tracts or the ansa lenticularis. Dystonia was more prevalent than ataxia in the ET-plus subgroups (n = 18 and n = 5, respectively). ET-plus with dystonia subgroup had a more medial COG compared to ET-plus with ataxia.ConclusionVIM DBS therapy is efficacious in patients with ET and ET-plus. There were no significant differences in optimal stimulation site or VTA overlap with white-matter tracts between ET, ET-plus and ET-plus subgroups.

Studies of the mouse visual system have revealed a variety of visual brain areas that are thought to support a multitude of behavioral capacities, ranging from stimulus-reward associations, to goal-directed navigation, and object-centric discriminations. However, an overall understanding of the mouse's visual cortex, and how it supports a range of behaviors, remains unknown. Here, we take a computational approach to help address these questions, providing a high-fidelity quantitative model of mouse visual cortex and identifying key structural and functional principles underlying that model's success. Structurally, we find that a comparatively shallow network structure with a low-resolution input is optimal for modeling mouse visual cortex. Our main finding is functional-that models trained with task-agnostic, self-supervised objective functions based on the concept of contrastive embeddings are much better matches to mouse cortex, than models trained on supervised objectives or alternative self-supervised methods. This result is very much unlike in primates where prior work showed that the two were roughly equivalent, naturally leading us to ask the question of why these self-supervised objectives are better matches than supervised ones in mouse. To this end, we show that the self-supervised, contrastive objective builds a general-purpose visual representation that enables the system to achieve better transfer on out-of-distribution visual scene understanding and reward-based navigation tasks. Our results suggest that mouse visual cortex is a low-resolution, shallow network that makes best use of the mouse's limited resources to create a light-weight, general-purpose visual system-in contrast to the deep, high-resolution, and more categorization-dominated visual system of primates.

The dysregulation of the m6A epitranscriptomic networks have been reported to contribute to the development of gliomas. Here, the authors utilize induced pluripotent stem cell-derived astrocytes with a p53 mutation and demonstrate that mutant p53 upregulates the m6A reader YTHDF2, resulting in the initiation of gliomas.

As available genomic interval data increase in scale, we require fast systems to search them. A common approach is simple string matching to compare a search term to metadata, but this is limited by incomplete or inaccurate annotations. An alternative is to compare data directly through genomic region overlap analysis, but this approach leads to challenges like sparsity, high dimensionality, and computational expense. We require novel methods to quickly and flexibly query large, messy genomic interval databases. Here, we develop a genomic interval search system using representation learning. We train numerical embeddings for a collection of region sets simultaneously with their metadata labels, capturing similarity between region sets and their metadata in a low-dimensional space. Using these learned co-embeddings, we develop a system that solves three related information retrieval tasks using embedding distance computations: retrieving region sets related to a user query string, suggesting new labels for database region sets, and retrieving database region sets similar to a query region set. We evaluate these use cases and show that jointly learned representations of region sets and metadata are a promising approach for fast, flexible, and accurate genomic region information retrieval.

Plastic debris is a growing threat in freshwater ecosystems and transport models predict that many plastics will sink to the benthos. Among the most common plastics found in the Laurentian Great Lakes sediments are polyethylene terephthalate (especially fibers; PET), polyvinylchloride (particles; PVC), and styrene-butadiene rubber resulting from tire wear (“crumb rubber”; SBR). These materials vary substantially in physical and chemical properties, and their impacts on benthic biogeochemistry and microbial community structure and function are largely unknown. We used a microcosm approach to evaluate the impact of these three plastics on benthic-pelagic coupling, sediment properties, and sediment microbial community structure and function using sediments from Irondequoit Bay, a major embayment of Lake Ontario in Rochester, New York, USA. Benthic metabolism and nitrogen and phosphorous cycling were all uniquely impacted by the different polymers. PET fibers and PVC particles demonstrated the most unique effects, with decreased ecosystem metabolism in sediments containing PET and greater nutrient uptake in sediments with PVC. Microbial diversity was reduced in all treatments containing plastic, but SBR had the most substantial impact on microbial community function, increasing the relative importance of metabolic pathways such as hydrocarbon degradation and sulfur metabolism. Our results suggest that individual polymers have unique impacts on the benthos, with divergent implications for ecosystem function. This provides deeper insight into the myriad ways plastic pollution may impact aquatic ecosystems and will help to inform risk assessment and policy interventions by highlighting which materials pose the greatest risk.

Promoting online peer support beyond the informal sector to statutory health services requires ethical considerations and evidence-based knowledge about its impact on patients, health care professionals, and the wider health care system. Evidence on the effectiveness of digital interventions in primary care is sparse, and definitive guidance is lacking on the ethical concerns arising from the use of social media as a means for health-related interventions and research. Existing literature examining ethical issues with digital interventions in health care mainly focuses on apps, electronic health records, wearables, and telephone or video consultations, without necessarily covering digital social interventions, and does not always account for primary care settings specifically. Here we address the ethical and information governance aspects of undertaking research on the promotion of online peer support to patients by primary care clinicians, related to medical and public health ethics.

Introduction: Despite their inclination to induce tolerance, addictive states, and respiratory depression, synthetic opioids are among the most effective clinically administered drugs to treat severe acute/chronic pain and induce surgical anesthesia. Current medical interventions for opioid-induced respiratory depression (OIRD), wooden chest syndrome, and opioid use disorder (OUD) show limited efficacy and are marked by low success in the face of highly potent synthetic opioids such as fentanyl. D-Cysteine ethylester (D-CYSee) prevents OIRD and post-treatment withdrawal in male/female rats and mice with minimal effect on analgesic status. However, the potential aversive or rewarding effects of D-CYSee have yet to be fully characterized and its efficacy could be compromised by interactions with opioid-reward pathology.Methods: Using a model of fentanyl-induced conditioned place preference (CPP), this study evaluated 1) the dose and sex dependent effects of fentanyl to induce rewarding states, and 2) the extent to which D-CYSee alters affective state and the acquisition of fentanyl-induced seeking behaviors.Results: Fentanyl reward-related effects were found to be dose and sex dependent. Male rats exhibited a range-bound dose response centered at 5 µg/kg. Female rats exhibited a CPP only at 50 µg/kg. This dose was effective in 25% of females with the remaining 75% showing no significant CPP at any dose. Pretreatment with 100 mg/kg, but not 10 mg/kg, D-CYSee prevented acquisition of fentanyl seeking in males while both doses were effective at preventing acquisition in females.Discussion: These findings suggest that D-CYSee is an effective co-treatment with prescribed opioids to reduce the development of OUD.

Aim: To evaluate the effects of a hands-off recorder/time coach versus an additional hands-on healthcare provider on Neonatal Resuscitation Program (NRP) algorithm compliance and team member workload in neonatal resuscitations. Methods: Two interventions were studied using a 2 × 2 factorial design: an additional hands-on team member and the presence of a designated, hands-off recorder/time coach. The recorder/time coach documented interventions and delivered pre-specified prompts at defined points during the resuscitation. The primary outcome was cumulative time error. Secondary outcomes were time to first dose of IV epinephrine, overall team performance as assessed by the Neonatal Resuscitation Performance Evaluation (NRPE) score, and workload assessed by the NASA Task Load Index (NASA TLX). Results: 64 teams were studied. Teams with a recorder had a significantly lower cumulative time error compared to teams without a recorder (p

Summary: Identifying molecular circuits that control adipose tissue macrophage (ATM) function is necessary to understand how ATMs contribute to tissue homeostasis and obesity-induced insulin resistance. In this study, we find that mice with a myeloid-specific knockout of the miR-23-27-24 clusters of microRNAs (miRNAs) gain less weight on a high-fat diet but exhibit worsened glucose and insulin tolerance. Analysis of ATMs from these mice shows selectively reduced numbers and proliferation of a recently reported subset of lipid-associated CD9+Trem2+ ATMs (lipid-associated macrophages [LAMs]). Leveraging the role of miRNAs to control networks of genes, we use RNA sequencing (RNA-seq), functional screens, and biochemical assays to identify candidate target transcripts that regulate proliferation-associated signaling. We determine that miR-23 directly targets the mRNA of Eif4ebp2, a gene that restricts protein synthesis and proliferation in macrophages. Altogether, our study demonstrates that control of proliferation of a protective subset of LAMs by noncoding RNAs contributes to protection against diet-induced obesity metabolic dysfunction.