UNNT: A novel Utility for comparing Neural Net and Tree-based models.

The use of deep learning (DL) is steadily gaining traction in scientific challenges such as cancer research. Advances in enhanced data generation, machine learning algorithms, and compute infrastructure have led to an acceleration in the use of deep learning in various domains of cancer research such as drug response problems. In our study, we explored tree-based models to improve the accuracy of a single drug response model and demonstrate that tree-based models such as XGBoost (eXtreme Gradient Boosting) have advantages over deep learning models, such as a convolutional neural network (CNN), for single drug response problems. However, comparing models is not a trivial task. To make training and comparing CNNs and XGBoost more accessible to users, we developed an open-source library called UNNT (A novel Utility for comparing Neural Net and Tree-based models). The case studies, in this manuscript, focus on cancer drug response datasets however the application can be used on datasets from other domains, such as chemistry.

Transgenerational transmission of aspartame-induced anxiety and changes in glutamate-GABA signaling and gene expression in the amygdala.

We report the effects of aspartame on anxiety-like behavior, neurotransmitter signaling and gene expression in the amygdala, a brain region associated with the regulation of anxiety and fear responses. C57BL/6 mice consumed drinking water containing 0.015% or 0.03% aspartame, a dose equivalent of 8 to 15% of the FDA recommended maximum human daily intake, or plain drinking water. Robust anxiety-like behavior (evaluated using open field test and elevated zero maze) was observed in male and female mice consuming the aspartame-containing water. Diazepam, an allosteric modulator of the GABA-A receptor, alleviated the anxiety-like behavior. RNA sequencing of the amygdala followed by KEGG biological pathway analysis of differentially expressed genes showed glutamatergic and GABAergic synapse pathways as significantly enriched. Quantitative PCR showed upregulation of mRNA for the glutamate NMDA receptor subunit 2D (Grin2d) and metabotropic receptor 4 (Grm4) and downregulation of the GABA-A receptor associated protein (Gabarap) mRNA. Thus, taken together, our diazepam and gene expression data show that aspartame consumption shifted the excitation-inhibition equilibrium in the amygdala toward excitation. Even more strikingly, the anxiety-like behavior, its response to diazepam, and changes in amygdala gene expression were transmitted to male and female offspring in two generations descending from the aspartame-exposed males. Extrapolation of the findings to humans suggests that aspartame consumption at doses below the FDA recommended maximum daily intake may produce neurobehavioral changes in aspartame-consuming individuals and their descendants. Thus, human population at risk of aspartame's potential mental health effects may be larger than current expectations, which only include aspartame-consuming individuals.

Comparative analysis of hospitalization risk for incident heart failure in non-Hispanic Black versus non-Hispanic White individuals with type 2 diabetes on empagliflozin (Empa-AA): Insights from real-world data.

AIM: There are limited data to evaluate hospitalization for heart failure (hHF) in non-Hispanic Black (hereafter Black) or non-Hispanic White (hereafter White) individuals without previous hHF. Our goal was to evaluate the risk of hHF among Black versus White patients with type 2 diabetes (T2DM) who were initially prescribed empagliflozin using real-world data. METHODS: This multicentre retrospective cohort study included participants aged ≥18 years who had T2DM, were either Black or White, had no previous hHF, and were prescribed empagliflozin between August 2014 and December 2019. Our primary outcome was time to first hHF after the initial prescription of empagliflozin. A propensity-score (PS)-weighted analysis was performed to balance characteristics by race. The inverse probability treatment weighting method based on PS was used to make treatment comparisons. To compare Black with White, a PS-weighted Cox's cause-specific hazards model was used. RESULTS: In total, 8789 participants were eligible for inclusion (Black = 3216 vs. White = 5573). The Black cohort was significantly younger, had a higher proportion of females, and had a higher prevalence of chronic kidney disease, hypertension and diabetic retinopathy, while the White cohort had a higher prevalence of coronary artery disease. After adjustment for confounding factors such as age, gender, coronary artery disease, hypertension and diabetic retinopathy, the hazard ratio for first-time hHF was not significantly different between the two racial groups [hazard ratio (95% confidence interval) = 1.09 (0.84-1.42), p = .52]. CONCLUSION: This study showed no significant difference in incident hHF among Black versus White individuals with T2DM following a prescription for empagliflozin.

High-Resolution Depth-Discrete Analysis of PFAS Distribution and Leaching for a Vadose-Zone Source at an AFFF-Impacted Site.

The long-term leaching of polyfluoroalkyl substances (PFAS) within the vadose zone of an AFFF application site for which the depth to groundwater is approximately 100 m was investigated by characterizing the vertical distribution of PFAS in a high spatial resolution. The great majority (99%) of PFAS mass resides in the upper 3 m of the vadose zone. The depths to which each PFAS migrated, quantified by moment analysis, is an inverse function of molar volume, demonstrating chromatographic separation. The PFAS were operationally categorized into three chain-length groups based on the three general patterns of retention observed. The longest-chain (>∼335 cm3/mol molar volume) PFAS remained within the uppermost section of the core, exhibiting minimal leaching. Conversely, the shortest-chain (<∼220 cm3/mol) PFAS accumulated at the bottom of the interval, which coincides with the onset of a calcic horizon. PFAS with intermediate-chain lengths were distributed along the length of the core, exhibiting differential magnitudes of leaching. The minimal or differential leaching observed for the longest- and intermediate-chain-length PFAS, respectively, demonstrates that retention processes significantly impacted migration. The accumulation of shorter-chain PFAS at the bottom of the core is hypothesized to result from limited deep infiltration and potential-enhanced retention associated with the calcic horizon.

The Importance of Fetal Station in the First Stage of Labor.

OBJECTIVE: This study aimed to examine the relationship of fetal station in the first stage of labor to labor curves and cesarean delivery rates among women presenting in spontaneous labor. STUDY DESIGN: Labor curves for patients with nonanomalous singletons who presented in spontaneous labor to our hospital's Obstetric Triage Unit with intact membranes from January 1, 2012, to August 31, 2016 were reviewed. Cervical exams and time of exam were obtained for each patient from presentation to triage until delivery. Station for each presentation and cervical dilation was estimated using a random effects model and the slope of cervical station change was calculated to estimate the change in dilation by hour. Perinatal outcomes, including cesarean delivery rates, were examined according to fetal station at initial presentation. Factors known to affect labor curves-epidural analgesia, infant birthweight, maternal habitus, and parity-were also examined. RESULTS: There were 8,123 patients presented in spontaneous labor with intact membranes. For patients presenting at 6-cm dilation, the rate of change of labor was significantly different when identified to have a station greater than 0 (+1 and more caudad) when compared with those with -1 and more cephalad station (both p < 0.001). This relationship persisted when analyzed according to epidural analgesia, birthweight, maternal habitus, and parity. The frequency of cesarean delivery was significantly higher for women presenting in spontaneous labor with negative fetal station (p < 0.05). When stratified across all dilation (3-9 cm), this trend remained significant (p < 0.001). CONCLUSION: In the first stage of labor, advanced fetal station was significantly associated with differing rates of labor progression, and positive fetal station was significantly less likely to result in cesarean delivery. Physical examination, including station, remains a critical element in labor management. KEY POINTS: · Fetal station is important in labor management.. · Fetal station at initial exam is related to time to delivery.. · Positive fetal station at initial exam is less likely to result in cesarean delivery..

[Evidence-based interventions to treat chronic low back pain: treatment selection for a personalized medicine approach : German version]. / Evidenzbasierte Interventionen zur Behandlung von chronischem Schmerz im unteren Rücken ­ Therapieauswahl für einen personalisierten Behandlungsansatz : Deutsche Fassung.

INTRODUCTION: Chronic low back pain (cLBP) is highly prevalent in the United States and globally, resulting in functional impairment and lowered quality of life. While many treatments are available for cLBP, clinicians have little information about which specific treatment(s) will work best for individual patients or subgroups of patients. The Back Pain Research Consortium, part of the National Institutes of Health Helping to End Addiction Long-termSM (HEAL) Initiative, will conduct a collaborative clinical trial, which seeks to develop a personalized medicine algorithm to optimize patient and provider treatment selection for patients with cLBP. OBJECTIVE: The primary objective of this article is to provide an update on evidence-based cLBP interventions and describe the process of reviewing and selecting interventions for inclusion in the clinical trial. METHODS: A working group of cLBP experts reviewed and selected interventions for inclusion in the clinical trial. The primary evaluation measures were strength of evidence and magnitude of treatment effect. When available in the literature, duration of effect, onset time, carryover effect, multimodal efficacy, responder subgroups, and evidence for the mechanism of treatment effect or biomarkers were considered. CONCLUSION: The working group selected 4 leading, evidence-based treatments for cLBP to be tested in the clinical trial and for use in routine clinical treatment. These treatments include (1) duloxetine, (2) acceptance and commitment therapy, (3) a classification-based exercise and manual therapy intervention, and (4) a self-management approach. These interventions each had a moderate to high level of evidence to support a therapeutic effect and were from different therapeutic classes.

The safety of at home powdered infant formula preparation: A community science project.

Formula fed infants experience gastrointestinal infections at higher rates than breastfed infants, due in part to bacteria in powdered infant formula (PIF) and bacterial contamination of infant feeding equipment. The United Kingdom National Health Service (UK NHS) has adopted the World Health Organization recommendation that water used to reconstitute PIF is ≥70°C to eliminate bacteria. We used community science methods to co-design an at home experiment and online questionnaire ('research diary') to explore the safety of PIF preparation compared to UK NHS guidelines. 200 UK-based parents of infants aged ≤12 months were recruited; 151 provided data on PIF preparation, and 143 were included in the analysis of water temperatures used to reconstitute PIF. Only 14.9% (n = 11) of 74 PIF preparation machines produced a water temperature of ≥70°C compared with 78.3% (n = 54) of 69 kettle users (p < 0.001). The mean temperature of water dispensed by PIF preparation machines was 9°C lower than kettles (Machine M = 65.78°C, Kettle M = 75.29°C). Many parents did not always fully follow NHS safer PIF preparation guidance, and parents did not appear to understand the potential risks of PIF bacterial contamination. Parents should be advised that the water dispensed by PIF preparation machines may be below 70°C, and could result in bacteria remaining in infant formula, potentially leading to gastrointestinal infections. PIF labelling should advise that water used to prepare PIF should be ≥70°C and highight the risks of not using sufficiently hot water, per WHO Europe advice. There is an urgent need for stronger consumer protections regarding PIF preparation devices.

Respiratory and systemic monocytes, dendritic cells, and myeloid-derived suppressor cells in COVID-19: Implications for disease severity.

Since the beginning of the SARS-CoV-2 pandemic in 2020, researchers worldwide have made efforts to understand the mechanisms behind the varying range of COVID-19 disease severity. Since the respiratory tract is the site of infection, and immune cells differ depending on their anatomical location, studying blood is not sufficient to understand the full immunopathogenesis in patients with COVID-19. It is becoming increasingly clear that monocytes, dendritic cells (DCs), and monocytic myeloid-derived suppressor cells (M-MDSCs) are involved in the immunopathology of COVID-19 and may play important roles in determining disease severity. Patients with mild COVID-19 display an early antiviral (interferon) response in the nasopharynx, expansion of activated intermediate monocytes, and low levels of M-MDSCs in blood. In contrast, patients with severe COVID-19 seem to lack an early efficient induction of interferons, and skew towards a more suppressive response in blood. This is characterized by downregulation of activation markers and decreased functional capacity of blood monocytes and DCs, reduced circulating DCs, and increased levels of HLA-DRlo CD14+ M-MDSCs. These suppressive characteristics could potentially contribute to delayed T-cell responses in severe COVID-19 cases. In contrast, airways of patients with severe COVID-19 display hyperinflammation with elevated levels of inflammatory monocytes and monocyte-derived macrophages, and reduced levels of tissue-resident alveolar macrophages. These monocyte-derived cells contribute to excess inflammation by producing cytokines and chemokines. Here, we review the current knowledge on the role of monocytes, DCs, and M-MDSCs in COVID-19 and how alterations and the anatomical distribution of these cell populations may relate to disease severity.

A high-throughput screening system for SARS-CoV-2 entry inhibition, syncytia formation and cell toxicity.

BACKGROUND: The entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into the host cell is mediated through the binding of the SARS-CoV-2 Spike protein via the receptor binding domain (RBD) to human angiotensin-converting enzyme 2 (hACE2). Identifying compounds that inhibit Spike-ACE2 binding would be a promising and safe antiviral approach against COVID-19. METHODS: In this study, we used a BSL-2 compatible replication-competent vesicular stomatitis virus (VSV) expressing Spike protein of SARS-CoV-2 with eGFP reporter system (VSV-eGFP-SARS-CoV-2) in a recombinant permissive cell system for high-throughput screening of viral entry blockers. The SARS-CoV-2 permissive reporter system encompasses cells that stably express hACE2-tagged cerulean and H2B tagged with mCherry, as a marker of nuclear condensation, which also enables imaging of fused cells among infected EGFP positive cells and could provide real-time information on syncytia formation. RESULTS: A limited high-throughput screening identified six natural products that markedly inhibited VSV-eGFP-SARS-CoV-2 with minimum toxicity. Further studies of Spike-S1 binding using the permissive cells showed Scillaren A and 17-Aminodemethoxygeldanamycin could inhibit S1 binding to ACE2 among the six leads. A real-time imaging revealed delayed inhibition of syncytia by Scillaren A, Proscillaridin, Acetoxycycloheximide and complete inhibition by Didemnin B indicating that the assay is a reliable platform for any image-based drug screening. CONCLUSION: A BSL-2 compatible assay system that is equivalent to the infectious SARS-CoV-2 is a promising tool for high-throughput screening of large compound libraries for viral entry inhibitors against SARS-CoV-2 along with toxicity and effects on syncytia. Studies using clinical isolates of SARS-CoV-2 are warranted to confirm the antiviral potency of the leads and the utility of the screening system.

Post-acute Ambulatory Care Service Use Among Patients Discharged Home After Stroke or TIA: The Cluster-randomized COMPASS Study.

BACKGROUND AND OBJECTIVES: We examined transitional care management within 90 days and 1 year following discharge home among acute stroke and transient ischemic attack patients from the Comprehensive Post-Acute Stroke Services (COMPASS) Study, a cluster-randomized pragmatic trial of early supported discharge conducted in 41 hospitals (40 hospital units) in North Carolina, United States. METHODS: Data for 2262 of the total 6024 (37.6%; 1069 intervention and 1193 usual care) COMPASS patients were linked with the Centers for Medicare and Medicaid Services fee-for-service Medicare claims. Time to the first ambulatory care visit was examined using Cox proportional hazard models adjusted for patient characteristics not included in the randomization protocol. RESULTS: Only 6% of the patients [mean (SD) age 74.9 (10.2) years, 52.1% women, 80.3% White)] did not have an ambulatory care visit within 90 days postdischarge. Mean time (SD) to first ambulatory care visit was 12.0 (26.0) and 16.3 (35.1) days in intervention and usual care arms, respectively, with the majority of visits in both study arms to primary care providers. The COMPASS intervention resulted in a 27% greater use of ambulatory care services within 1 year postdischarge, relative to usual care [HR=1.27 (95% CI: 1.14-1.41)]. The use of transitional care billing codes was significantly greater in the intervention arm as compared with usual care [OR=1.87 (95% CI: 1.54-2.27)]. DISCUSSION: The COMPASS intervention, which was aimed at improving stroke post-acute care, was associated with an increase in the use of ambulatory care services by stroke and transient ischemic attack patients discharged home and an increased use of transitional care billing codes by ambulatory providers.

Traffic-related air pollution is associated with spontaneous extremely preterm birth and other adverse perinatal outcomes.

BACKGROUND: Although there is growing awareness of the relationship between air pollution and preterm birth, limited data exist regarding the relationship with spontaneous preterm birth and severe neonatal outcomes. OBJECTIVE: This study aimed to examine the association between traffic-associated air pollution exposure in pregnancy and adverse perinatal outcomes including extremes of preterm birth, neonatal intensive care unit admissions, low birthweight, neonatal respiratory diagnosis, neonatal respiratory support, and neonatal sepsis evaluation. STUDY DESIGN: This was a retrospective cohort study of singleton pregnancies of patients residing in a metropolitan area in the southern United States. Using monitors strategically located across the region, average nitrogen dioxide concentrations were obtained from the Environmental Protection Agency Air Quality System database. For patients living within 10 miles of a monitoring station, average exposure to nitrogen dioxide was estimated for individual patients' pregnancy by trimester. Logistic regression models were used to assess the effect of pollutant exposure on gestational age at birth, indicated vs spontaneous delivery, and neonatal outcomes while adjusting for maternal age, self-reported race, parity, season of conception, diabetes mellitus, body mass index, registered Health Equity Index, and nitrogen dioxide monitor region. Adjusted odds ratios and 95% confidence intervals were calculated for an interquartile increase in average nitrogen dioxide exposure. RESULTS: Between January 1, 2013 and December 31, 2021, 93,164 patients delivered a singleton infant. Of these, 62,189 had measured nitrogen dioxide exposure during the pregnancy from a nearby monitoring station. Higher average nitrogen dioxide exposure throughout pregnancy was significantly associated with preterm birth (adjusted odds ratio, 1.94; 95% confidence interval, 1.77-2.12) and an increase in neonatal intensive care unit admissions, low birthweight infants, neonatal respiratory diagnosis, neonatal respiratory support, and neonatal sepsis evaluation. This relationship persisted for nulliparous patients and spontaneous preterm birth, and had a greater association with earlier preterm birth. CONCLUSION: In a metropolitan area, increased exposure to the air pollutant nitrogen dioxide in pregnancy was associated with spontaneous preterm birth and had a greater association with extremely preterm birth. A greater association with neonatal intensive care unit admissions, low-birthweight infants, neonatal respiratory diagnosis, neonatal respiratory support, and neonatal sepsis evaluation was found even in term infants.

Following the human point: Research with nonhuman animals since Povinelli, Nelson, and Boysen (1990).

For this special issue in honor of Dr. Sarah (Sally) Boysen's career, we review studies on point following in nonhuman animals. Of the 126 papers that we documented on this topic published since the publication of Povinelli, Nelson, and Boysen (1990, Journal of Comparative Psychology, 104, 203-210), 94 (75%) were published in the past 15 years, including 22 in the past 5 years, indicating that this topic is still an active area of interest in the field of animal behavior and cognition. We present results of a survey of publication trends, discussing the species tested and the sample sizes, and we note methodological considerations and current multilaboratory approaches. We then categorize and synthesize the research questions addressed in these studies, which have been at both the ultimate level (e.g., questions related to evolutionary adaptiveness and phylogenetic differences) and proximate level (e.g., questions related to experiential and temperamental processes). Throughout, we consider future directions for this area of research.

Kappa Opioid Receptors Reduce Serotonin Uptake and Escitalopram Efficacy in the Mouse Substantia Nigra Pars Reticulata.

The serotonin and kappa opioid receptor (KOR) systems are strongly implicated in disorders of negative affect, such as anxiety and depression. KORs expressed on axon terminals inhibit the release of neurotransmitters, including serotonin. The substantia nigra pars reticulata (SNr) is involved in regulating affective behaviors. It receives the densest serotonergic innervation in the brain and has high KOR expression; however, the influence of KORs on serotonin transmission in this region is yet to be explored. Here, we used ex vivo fast-scan cyclic voltammetry (FSCV) to investigate the effects of a KOR agonist, U50, 488 (U50), and a selective serotonin reuptake inhibitor, escitalopram, on serotonin release and reuptake in the SNr. U50 alone reduced serotonin release and uptake, and escitalopram alone augmented serotonin release and slowed reuptake, while pretreatment with U50 blunted both the release and uptake effects of escitalopram. Here, we show that the KOR influences serotonin signaling in the SNr in multiple ways and short-term activation of the KOR alters serotonin responses to escitalopram. These interactions between KORs and serotonin may contribute to the complexity in the responses to treatments for disorders of negative affect. Ultimately, the KOR system may prove to be a promising pharmacological target, alongside traditional antidepressant treatments.

Cell State Transitions and Phenotypic Heterogeneity in Luminal Breast Cancer Implicating MicroRNAs as Potential Regulators.

Luminal breast cancer subtypes respond poorly to endocrine and trastuzumab treatments due to cellular heterogeneity arising from the phenotype transitions, accounted for mainly by the loss of receptor expression. The origins of basal-like and human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer subtypes have been attributed to genetic and protein modifications in stem-like cells and luminal progenitor cell populations, respectively. The post-transcriptional regulation of protein expression is known to be influenced by microRNAs (miRNAs) that are deemed to be master regulators of several biological processes in breast tumorigenesis and progression. Our objective was to identify the fractions of luminal breast cancer cells that share stemness potentials and marker profiles and to elucidate the molecular regulatory mechanism that drives transitions between fractions, leading to receptor discordances. Established breast cancer cell lines of all prominent subtypes were screened for the expression of putative cancer stem cell (CSC) markers and drug transporter proteins using a side population (SP) assay. Flow-cytometry-sorted fractions of luminal cancer cells implanted in immunocompromised mice generated a pre-clinical estrogen receptor alpha (ERα+) animal model with multiple tumorigenic fractions displaying differential expression of drug transporters and hormone receptors. Despite an abundance of estrogen receptor 1 (ESR1) gene transcripts, few fractions transitioned to the triple-negative breast cancer (TNBC) phenotype with a visible loss of ER protein expression and a distinct microRNA expression profile that is reportedly enriched in breast CSCs. The translation of this study has the potential to provide novel therapeutic miRNA-based targets to counter the dreaded subtype transitions and the failure of antihormonal therapies in the luminal breast cancer subtype.

Role Distinctions and Role Overlap Among Behavioral Health Providers.

Integrated behavioral health care (IBHC) models are a growing trend for health care delivery, particularly in the primary setting. Clinicians working within IBHC contexts provide a spectrum of behavioral health services, including screening, prevention and health promotion, assessment, and treatment services. Integration of behavioral health providers into primary and specialty medical settings addresses the significant need for behavioral health services, improves care quality, improves patient experience, and reduces costs of care, access issues, and delays in service provision. While benefits are clear, what type of model to implement and which behavioral health care providers to include in that model remain elusive. This is partly due to the failure of IBHC models to include all behavioral health providers in their design, a lack of clarity of the expertise of each provider, and how providers work together. IBHC models are also complicated by contextual issues such as the relative availability of each profession, population health needs in different clinic populations, and financial factors. The purpose of this manuscript is to the clarify roles and responsibilities of different behavioral health professions including similarities and differences in their training, areas of unique expertise (role distinctions), shared responsibilities (role overlap), and relative cost and availability in the United States.

Regional and sex differences in spontaneous striatal dopamine transmission.

Striatal dopamine release is key for learning and motivation and is composed of subregions including the dorsal striatum (DS), nucleus accumbens core, and the nucleus accumbens shell. Spontaneously occurring dopamine release was compared across these subregions. Dopamine release/uptake dynamics differ across striatal subregions, with dopamine transient release amplitude and release frequency greatest in male mice, and the largest signals observed in the DS. Surprisingly, female mice exhibited little regional differences in dopamine release for DS and nucleus accumbens core regions, but lower release in the nucleus accumbens shell. Blocking voltage-gated K+ channel (Kv channels) with 4-aminopyridine enhanced dopamine detection without affecting reuptake. The 4-aminopyridine effects were greatest in ventral regions of female mice, suggesting regional differences in Kv channel expression. The dopamine transporter blocker cocaine also enhanced detection across subregions in both sexes, with greater overall increased release in females than males. Thus, sex differences in dopamine transmission are apparent and likely include differences in the Kv channel and dopamine transporter function. The lack of regional differences in dopamine release observed in females indicates differential regulation of spontaneous and evoked dopamine release.

The absolute risk of incident type 2 diabetes following exposure to systemic corticosteroids in selected steroid-related and phenotypic groups.

AIMS: Exposure to corticosteroids is known to increase the risk of developing type 2 diabetes. We estimated the risk of incident type 2 diabetes in selected patient groups exposed to systemic corticosteroids. MATERIALS AND METHODS: In a retrospective, observational cohort study, using real-world data from UK primary care, patients were selected who had at least one episode of exposure to oral or intravenous corticosteroids for any indication. Corticosteroid-exposed patients were matched with non-exposed patients. Relative dosage was estimated as a weight-based, prednisolone-equivalent dose. Crude rates of progression to type 2 diabetes were determined for patient groups defined by relevant steroid-related and phenotypic characteristics present at corticosteroid exposure. RESULTS: Overall, rates of incidence of type 2 diabetes were 12.5 and 6.7 events per thousand person-years' (pkpy) exposure, respectively, in those who received at least one dose of corticosteroids versus those never exposed. This represented a rate ratio of 1.85 (95% CI 1.74-1.97). The incidence of type 2 diabetes was found to be associated with several of the selected characteristics, both individually and multi-dimensionally. The highest rate of incident type 2 diabetes was observed in very severely obese men aged 46-55 years having had the longest corticosteroid exposure and highest corticosteroid dose (190 incident events pkpy exposure). CONCLUSIONS: Corticosteroid exposure increased the risk of incident type 2 diabetes, and there was evidence of both a dose-response and a duration response. The impact of corticosteroid exposure upon the rate of incident type 2 diabetes appeared, however, to involve a complex, multi-dimensional interaction between the selected characteristics, some of which might be impacted by reverse causality.

Skilled Nursing and Inpatient Rehabilitation Facility Use by Medicare Fee-for-Service Beneficiaries Discharged Home After a Stroke: Findings From the COMPASS Trial.

OBJECTIVES: To examine the effect of a comprehensive transitional care model on the use of skilled nursing facility (SNF) and inpatient rehabilitation facility (IRF) care in the 12 months after acute care discharge home following stroke; and to identify predictors of experiencing a SNF or IRF admission following discharge home after stroke. DESIGN: Cluster randomized pragmatic trial SETTING: Forty-one acute care hospitals in North Carolina. PARTICIPANTS: 2262 Medicare fee-for-service beneficiaries with transient ischemic attack or stroke discharged home. The sample was 80.3% White and 52.1% female, with a mean (SD) age of 74.9 (10.2) years and a mean ± SD National Institutes of Health stroke scale score of 2.3 (3.7). INTERVENTION: Comprehensive transitional care model (COMPASS-TC), which consisted of a 2-day follow-up phone call from the postacute care coordinator and 14-day in-person visit with the postacute care coordinator and advanced practice provider. MAIN OUTCOME MEASURES: Time to first SNF or IRF and SNF or IRF admission (yes/no) in the 12 months following discharge home. All analyses utilized multivariable mixed models including a hospital-specific random effect to account for the non-independence of measures within hospital. Intent to treat analyses using Cox proportional hazards regression assessed the effect of COMPASS-TC on time to SNF/IRF admission. Logistic regression was used to identify clinical and non-clinical predictors of SNF/IRF admission. RESULTS: Only 34% of patients in the intervention arm received COMPASS-TC per protocol. COMPASS-TC was not associated with a reduced hazard of a SNF/ IRF admission in the 12 months post-discharge (hazard ratio, 1.20, with a range of 0.95-1.52) compared to usual care. This estimate was robust to additional covariate adjustment (hazard ratio, 1.23) (0.93-1.64). Both clinical and non-clinical factors (ie, insurance, geography) were predictors of SNF/IRF use. CONCLUSIONS: COMPASS-TC was not consistently incorporated into real-world clinical practice. The use of a comprehensive transitional care model for patients discharged home after stroke was not associated with SNF or IRF admissions in a 12-month follow-up period. Non-clinical factors predictive of SNF/IRF use suggest potential issues with access to this type of care.

Altered Accumbal Dopamine Terminal Dynamics Following Chronic Heroin Self-Administration.

Administration of heroin results in the engagement of multiple brain regions and the rewarding and addictive effects are mediated, at least partially, through activation of the mesolimbic dopamine system. However, less is known about dopamine system function following chronic exposure to heroin. Withdrawal from chronic heroin exposure is likely to drive a state of low dopamine in the nucleus accumbens (NAc), as previously observed during withdrawal from other drug classes. Thus, we aimed to investigate alterations in NAc dopamine terminal function following chronic heroin self-administration to identify a mechanism for dopaminergic adaptations. Adult male Long Evans rats were trained to self-administer heroin (0.05 mg/kg/inf, IV) and then placed on a long access (FR1, 6-h, unlimited inf, 0.05 mg/kg/inf) protocol to induce escalation of intake. Following heroin self-administration, rats had decreased basal extracellular levels of dopamine and blunted dopamine response following a heroin challenge (0.1 mg/kg/inf, IV) in the NAc compared to saline controls. FSCV revealed that heroin-exposed rats exhibited reduced stimulated dopamine release during tonic-like, single-pulse stimulations, but increased phasic-like dopamine release during multi-pulse stimulation trains (5 pulses, 5-100 Hz) in addition to an altered dynamic range of release stimulation intensities when compared to controls. Further, we found that presynaptic D3 autoreceptor and kappa-opioid receptor agonist responsivity were increased following heroin self-administration. These results reveal a marked low dopamine state following heroin exposure and suggest the combination of altered dopamine release dynamics may contribute to increased heroin seeking.

Antigenic Restimulation of Virus-Specific Memory CD8+ T Cells Requires Days of Lytic Protein Accumulation for Maximal Cytotoxic Capacity.

In various infections or vaccinations of mice or humans, reports of the persistence and the requirements for restimulation of the cytotoxic mediators granzyme B (GrB) and perforin (PRF) in CD8+ T cells have yielded disparate results. In this study, we examined the kinetics of PRF and GrB mRNA and protein expression after stimulation and associated changes in cytotoxic capacity in virus-specific memory cells in detail. In patients with controlled HIV or cleared respiratory syncytial virus (RSV) or influenza virus infections, all virus-specific CD8+ T cells expressed low PRF levels without restimulation. Following stimulation, they displayed similarly delayed kinetics for lytic protein expression, with significant increases occurring by days 1 to 3 before peaking on days 4 to 6. These increases were strongly correlated with, but were not dependent upon, proliferation. Incremental changes in PRF and GrB percent expression and mean fluorescence intensity (MFI) were highly correlated with increases in HIV-specific cytotoxicity. mRNA levels in HIV-specific CD8+ T-cells exhibited delayed kinetics after stimulation as with protein expression, peaking on day 5. In contrast to GrB, PRF mRNA transcripts were little changed over 5 days of stimulation (94-fold versus 2.8-fold, respectively), consistent with posttranscriptional regulation. Changes in expression of some microRNAs, including miR-17, miR-150, and miR-155, suggested that microRNAs might play a significant role in regulation of PRF expression. Therefore, under conditions of extremely low or absent antigen levels, memory virus-specific CD8+ T cells require prolonged stimulation over days to achieve maximal lytic protein expression and cytotoxic capacity.IMPORTANCE Antigen-specific CD8+ T cells play a major role in controlling most virus infections, primarily by perforin (PRF)- and granzyme B (GrB)-mediated apoptosis. There is considerable controversy regarding whether PRF is constitutively expressed, rapidly increased similarly to a cytokine, or delayed in its expression with more prolonged stimulation in virus-specific memory CD8+ T cells. In this study, the degree of cytotoxic capacity of virus-specific memory CD8+ T cells was directly proportional to the content of lytic molecules, which required antigenic stimulation over several days for maximal levels. This appeared to be modulated by increases in GrB transcription and microRNA-mediated posttranscriptional regulation of PRF expression. Clarifying the requirements for maximal cytotoxic capacity is critical to understanding how viral clearance might be mediated by memory cells and what functions should be induced by vaccines and immunotherapies.