CEBPA Overexpression Enhances ß-Cell Proliferation and Survival.

A commonality between type 1 and type 2 diabetes is the decline in functional ß-cell mass. The transcription factor Nkx6.1 regulates ß-cell development and is integral for proper ß-cell function. We have previously demonstrated that Nkx6.1 depends on c-Fos mediated upregulation and the nuclear hormone receptors Nr4a1 and Nr4a3 to increase ß-cell insulin secretion, survival, and replication. Here, we demonstrate that Nkx6.1 overexpression results in upregulation of the bZip transcription factor CEBPA and that CEBPA expression is independent of c-Fos regulation. In turn, CEBPA overexpression is sufficient to enhance INS-1 832/13 ß-cell and primary rat islet proliferation. CEBPA overexpression also increases the survival of ß-cells treated with thapsigargin. We demonstrate that increased survival in response to ER stress corresponds with changes in expression of various genes involved in the unfolded protein response, including decreased Ire1a expression. These data show that CEBPA is sufficient to enhance functional ß-cell mass by increasing ß-cell proliferation and modulating the unfolded protein response.

The Importance of Team Alignment and Retention in Vascular Center Development: A Clinician's Perspective.

The healthcare landscape is in a state of constant evolution, presenting both challenges and opportunities. Recent trends, including the departure or retirement of medical professionals, the rise in travel and per diem positions, and the expansive growth of healthcare networks, have resulted in a palpable divide within the field. This divide often manifests as a shift from prioritizing patient care and staff well-being toward financial security and operational efficiency and productivity. Amid these ongoing changes, vascular centers possess the potential for a positive distinction that extends beyond their specialization to encompass their approaches to patient care and team dynamics. This article presents a 3-phase strategy for vascular clinicians and centers to consider as they seek to attract and retain top-tier staff, provide exceptional patient care, and attain sustainable growth and financial success.

Opioid Use Disorder Stigma and Support for Harm Reduction in Rural Counties.

Background: The opioid crisis is a public health emergency in the United States, particularly in rural Pennsylvania. Stigma in rural communities is a treatment barrier and impacts harm reduction programming availability.Objectives: The current study utilized an observational, cross-sectional design to examine latent subgroups of stigma and differences in support for harm reduction strategies (i.e., safe injection facilities, syringe services programs, fentanyl test strips, Naloxone distribution). Participants included rural Pennsylvanians (n = 252), taken from a statewide survey of opioid use disorder (OUD) stigma. Participants reported OUD public stigma (i.e., attitudes/perceptions about OUD, willingness to engage with individuals with OUD) and support for harm reduction strategies.Results: Latent class analysis identified 4 stigma classes: 1) high stigma (HS), 2) high judgment/low stigmatizing behavior (HJ/LB), 3) high stigmatizing behavior/low stigmatizing attitude (HB/LA), and 4) low stigma (LS). ANCOVAs identified subgroup differences in harm reduction support. The HS group indicated less support for safe injection sites, syringe services programs, and fentanyl test strips, compared to the HB/LA and LS groups. The HS group indicated less support for Naloxone distribution compared to the HJ/LB, HB/LA, and LS groups. Lastly, the HJ/LB group indicated less support for each program compared to the LS group.Conclusions/Importance: Findings highlight that OUD stigma profiles differ across rural Pennsylvania and are associated with varying support for harm reduction strategies. Individuals with less stigma report more support for harm reduction strategies. Interventions to implement harm reduction strategies should consider varying levels of stigma and use a targeted approach to inform implementation and messaging strategies.

Bioavailable Microbial Metabolites of Flavanols Demonstrate Highly Individualized Bioactivity on In Vitro ß-Cell Functions Critical for Metabolic Health.

Dietary flavanols are known for disease preventative properties but are often poorly absorbed. Gut microbiome flavanol metabolites are more bioavailable and may exert protective activities. Using metabolite mixtures extracted from the urine of rats supplemented with flavanols and treated with or without antibiotics, we investigated their effects on INS-1 832/13 ß-cell glucose stimulated insulin secretion (GSIS) capacity. We measured insulin secretion under non-stimulatory (low) and stimulatory (high) glucose levels, insulin secretion fold induction, and total insulin content. We conducted treatment-level comparisons, individual-level dose responses, and a responder vs. non-responder predictive analysis of metabolite composition. While the first two analyses did not elucidate treatment effects, metabolites from 9 of the 28 animals demonstrated significant dose responses, regardless of treatment. Differentiation of responders vs. non-responder revealed that levels of native flavanols and valerolactones approached significance for predicting enhanced GSIS, regardless of treatment. Although treatment-level patterns were not discernable, we conclude that the high inter-individual variability shows that metabolite bioactivity on GSIS capacity is less related to flavanol supplementation or antibiotic treatment and may be more associated with the unique microbiome or metabolome of each animal. These findings suggest flavanol metabolite activities are individualized and point to the need for personalized nutrition practices.

ER Redox Homeostasis Regulates Proinsulin Trafficking and Insulin Granule Formation in the Pancreatic Islet ß-Cell.

Defects in the pancreatic ß-cell's secretion system are well-described in type 2 diabetes (T2D) and include impaired proinsulin processing and a deficit in mature insulin-containing secretory granules; however, the cellular mechanisms underlying these defects remain poorly understood. To address this, we used an in situ fluorescent pulse-chase strategy to study proinsulin trafficking. We show that insulin granule formation and the appearance of nascent granules at the plasma membrane are decreased in rodent and cell culture models of prediabetes and hyperglycemia. Moreover, we link the defect in insulin granule formation to an early trafficking delay in endoplasmic reticulum (ER) export of proinsulin, which is independent of overt ER stress. Using a ratiometric redox sensor, we show that the ER becomes hyperoxidized in ß-cells from a dietary model of rodent prediabetes and that addition of reducing equivalents restores ER export of proinsulin and insulin granule formation and partially restores ß-cell function. Together, these data identify a critical role for the regulation of ER redox homeostasis in proinsulin trafficking and suggest that alterations in ER redox poise directly contribute to the decline in insulin granule production in T2D. This model highlights a critical link between alterations in ER redox and ER function with defects in proinsulin trafficking in T2D. Hyperoxidation of the ER lumen, shown as hydrogen peroxide, impairs proinsulin folding and disulfide bond formation that prevents efficient exit of proinsulin from the ER to the Golgi. This trafficking defect limits available proinsulin for the formation of insulin secretory granules during the development of T2D.

The Opioid Epidemic and the State of Stigma: A Pennsylvania Statewide Survey.

Background: The opioid epidemic is a public health crisis. Among initiatives surrounding treatment and prevention, opioid use disorder (OUD) stigma has emerged as a subject for intervention. Objectives: This study examines overall results and demographic differences of three subscales of a public stigma survey instrument: general attitudes, social distance, and treatment availability and effectiveness. Methods: A statewide sample of Pennsylvanian adults (N = 1033) completed an online survey about the opioid epidemic. Weighted percentage level of agreement was reported for each item. To determine significant differences in responding across demographic groups (gender, race, and urban/rural status), multiple one-way ANOVAs were analyzed. Significant differences in the level of agreement and disagreement (p < .05) were reported. Results: The majority of respondents agreed that the opioid epidemic is a problem and that anyone can become addicted to opioids; however, many Pennsylvanians still disagree that OUD is a medical disorder and continue to endorse social distance beliefs of people with OUD. Most participants agreed that there are effective treatments available, and that recovery was possible; however, a large portion of participants were unsure whether specific treatments are effective. Subscale mean differences were significant for gender and age. Conclusions/Importance: Findings highlight that stigmatized attitudes, behaviors, and beliefs about individuals who use opioids are still prevalent and that uncertainty remains about the effectiveness of OUD treatment. OUD interventions should use targeted messaging in order to impact the ongoing opioid crisis.

Gut Metabolite Trimethylamine N-Oxide Protects INS-1 ß-Cell and Rat Islet Function under Diabetic Glucolipotoxic Conditions.

Serum accumulation of the gut microbial metabolite trimethylamine N-oxide (TMAO) is associated with high caloric intake and type 2 diabetes (T2D). Impaired pancreatic ß-cell function is a hallmark of diet-induced T2D, which is linked to hyperglycemia and hyperlipidemia. While TMAO production via the gut microbiome-liver axis is well defined, its molecular effects on metabolic tissues are unclear, since studies in various tissues show deleterious and beneficial TMAO effects. We investigated the molecular effects of TMAO on functional ß-cell mass. We hypothesized that TMAO may damage functional ß-cell mass by inhibiting ß-cell viability, survival, proliferation, or function to promote T2D pathogenesis. We treated INS-1 832/13 ß-cells and primary rat islets with physiological TMAO concentrations and compared functional ß-cell mass under healthy standard cell culture (SCC) and T2D-like glucolipotoxic (GLT) conditions. GLT significantly impeded ß-cell mass and function by inducing oxidative and endoplasmic reticulum (ER) stress. TMAO normalized GLT-mediated damage in ß-cells and primary islet function. Acute 40µM TMAO recovered insulin production, insulin granule formation, and insulin secretion by upregulating the IRE1α unfolded protein response to GLT-induced ER and oxidative stress. These novel results demonstrate that TMAO protects ß-cell function and suggest that TMAO may play a beneficial molecular role in diet-induced T2D conditions.

Opportunities to Integrate Mobile App-Based Interventions Into Mental Health and Substance Use Disorder Treatment Services in the Wake of COVID-19.

The COVID-19 pandemic has heightened concerns about the impact of depression, anxiety, alcohol, and drug use on public health. Mobile apps to address these problems were increasingly popular even before the pandemic, and may help reach people who otherwise have limited treatment access. In this review, we describe pandemic-related substance use and mental health problems, the growing evidence for mobile app efficacy, how health systems can integrate apps into patient care, and future research directions. If equity in access and effective implementation can be addressed, mobile apps are likely to play an important role in mental health and substance use disorder treatment.

An experimental study of how hydraulic transients cause mobilisation of material within drinking water distribution systems.

This paper provides new insight into how the hydraulic transients that occur within drinking water distribution networks can mobilise material adhered to the pipe wall and hence cause unacceptable water quality and customer dissatisfaction. Results are reported from extensive, representative, physical experiments covering a wide range of repeatable rapidly accelerating and decelerating hydraulic conditions. Novel time synchronous analysis shows that mobilisation always occurs in the first dynamic surge of the transient; however, differences in the physical processes that govern mobilisation were observed between the two groups of transient type studied. A function to estimate the mobilising force is proposed and applied to the physical experiments performed. The research provides important insights for identifying and understanding the mechanisms and forces induced during transients, vital for ensuring the supply of safe drinking water in operational distribution systems.

A Review of Per- and Polyfluorinated Alkyl Substance Impairment of Reproduction.

In this review article, we compiled peer-reviewed literature describing PFAS exposure and reproductive effects in animals and humans. The aim was to compare environmental occurrence and effects of the most prominent long-chain PFAS compounds and their short-chain replacements. Long-chain PFAS compounds are known to persist in the environment due to their chemical stability, and also known to bioaccumulate; hence, these compounds are being replaced globally. Indeed, PFOA and PFOS are considered long-chain "forever pollutants," and thus the potential reproductive risk may continue for decades. Much less is known about their short-chain replacements despite the fact that they becoming more widespread in the environment. Short-chain PFAS are generally less bioaccumulative than long-chain, but they are more mobile and persistent in aquatic ecosystems. The three most prominent of these are commonly referred to as GenX, ADONA and F53B. The short-chain PFAS have similar physical and chemical properties as their predecessors; however, because they are relatively new, much less is known about the potential to disrupt reproduction. Indeed, high-quality epidemiological studies are needed to determine associations between short-chain PFAS exposure and effects on reproductive health. However, epidemiological evidence is mounting that long-chain PFAS exposure is associated with reproductive effects (i.e., decrease in fertility, reduced fetal growth and birth weight, pregnancy-induced hypertension and preeclampsia, thyroid hormone disruption during pregnancy, and preterm birth). Evidence from animal models and human cell lines indicates that short-chain PFAS similarly affect reproductive endpoints; however, epidemiological studies are scarce and inconsistent. Although short-chain PFAS have been quantified in drinking water and sediment worldwide, most of these studies did not focus on quantitation of GenX, ADONA, and F53B. There are also many other short-chain PFAS byproducts of manufacturing that have yet to be identified and studied. When sum total concentration of long- and short-chain PFAS are considered, the concentration rises by an order or magnitude or greater, as will the risk of exposure and subsequent reproductive effects.

Function of Nr4a Orphan Nuclear Receptors in Proliferation, Apoptosis and Fuel Utilization Across Tissues.

The Nr4a family of nuclear hormone receptors is composed of three members-Nr4a1/Nur77, Nr4a2/Nurr1 and Nr4a3/Nor1. While currently defined as ligandless, these transcription factors have been shown to regulate varied processes across a host of tissues. Of particular interest, the Nr4a family impinge, in a tissue dependent fashion, on cellular proliferation, apoptosis and fuel utilization. The regulation of these processes occurs through both nuclear and non-genomic pathways. The purpose of this review is to provide a balanced perspective of the tissue specific and Nr4a family member specific, effects on cellular proliferation, apoptosis and fuel utilization.

Interferon-Induced Transmembrane Protein 1 Restricts Replication of Viruses That Enter Cells via the Plasma Membrane.

The acute antiviral response is mediated by a family of interferon-stimulated genes (ISGs), providing cell-intrinsic immunity. Mutations in genes encoding these proteins are often associated with increased susceptibility to viral infections. One family of ISGs with antiviral function is the interferon-inducible transmembrane proteins (IFITMs), of which IFITM3 has been studied extensively. In contrast, IFITM1 has not been studied in detail. Since IFITM1 can localize to the plasma membrane, we investigated its function with a range of enveloped viruses thought to infect cells by fusion with the plasma membrane. Overexpression of IFITM1 prevented infection by a number of Paramyxoviridae and Pneumoviridae, including respiratory syncytial virus (RSV), mumps virus, and human metapneumovirus (HMPV). IFITM1 also restricted infection with an enveloped DNA virus that can enter via the plasma membrane, herpes simplex virus 1 (HSV-1). To test the importance of plasma membrane localization for IFITM1 function, we identified blocks of amino acids in the conserved intracellular loop (CIL) domain that altered the subcellular localization of the protein and reduced antiviral activity. By screening reported data sets, 12 rare nonsynonymous single nucleotide polymorphisms (SNPs) were identified in human IFITM1, some of which are in the CIL domain. Using an Ifitm1-/- mouse, we show that RSV infection was more severe, thereby extending the range of viruses restricted in vivo by IFITM proteins and suggesting overall that IFITM1 is broadly antiviral and that this antiviral function is associated with cell surface localization.IMPORTANCE Host susceptibility to viral infection is multifactorial, but early control of viruses not previously encountered is predominantly mediated by the interferon-stimulated gene (ISG) family. There are upwards of 300 of these genes, the majority of which do not have a clearly defined function or mechanism of action. The cellular location of these proteins may have an important effect on their function. One ISG located at the plasma membrane is interferon-inducible transmembrane protein 1 (IFITM1). Here we demonstrate that IFITM1 can inhibit infection with a range of viruses that enter via the plasma membrane. Mutant IFITM1 proteins that were unable to localize to the plasma membrane did not restrict viral infection. We also observed for the first time that IFITM1 plays a role in vivo, and Ifitm1-/- mice were more susceptible to viral lung infection. These data contribute to our understanding of how ISGs prevent viral infections.

The Psychiatric Assessment and Brief Intervention Program: Partnering With Primary Care Providers.

OBJECTIVE: To present the structure and outcomes to date for the Psychiatric Assessment and Brief Intervention (PABI), a pilot program developed at University of California, San Francisco, to improve access of primary care patients to mental health services. PABI offers diagnostic evaluations and brief (up to 3 months) evidence-based treatment, including pharmacologic management and psychotherapy, to medical patients 18 years of age and older. Core PABI features are ensuring prompt access, actively partnering with patients and referring providers, and coordinating seamless transitions of care. METHODS: Demographic and clinical variables and outcome indicators were collected for all patients seen in PABI from October 2015 to June 2017. Descriptive statistics and mixed-effects linear models were used to analyze the data. RESULTS: During the study period, 139 patients (54% women, mean [SD] age of 48.2 [17.5] years) with a mean of 2 DSM-5 psychiatric diagnoses each (range, 1-5) were seen. Mean time to access was 8 days, with a mean length of stay in the program of 11 weeks. Compared to baseline, final behavioral health measure scores showed significant improvement: the mean Patient Health Questionnaire-9 score decreased by 5.9 points (95% CI, 4.6-7.2), and the mean 7-item Generalized Anxiety Disorder scale score was 4.4 points lower (95% CI, 3.2-5.6; both P values < .0001). CONCLUSIONS: This brief psychiatric treatment program provides prompt access to quality mental health care for patients with medical comorbidities. Results to date suggest that this program leads to significantly improved clinical outcomes. Further research is needed to determine its long-term sustainability and generalizability.

Characterisation of flattening filter free (FFF) beam properties for initial beam set-up and routine QA, independent of flattened beams.

Flattening filter free (FFF) beams have reached widespread use for clinical treatment deliveries. The usual methods for FFF beam characterisation for their quality assurance (QA) require the use of associated conventional flattened beams (cFF). Methods for QA of FFF without the need to use associated cFF beams are presented and evaluated against current methods for both FFF and cFF beams. Inflection point normalisation is evaluated against conventional methods for the determination of field size and penumbra for field sizes from 3 cm × 3 cm to 40 cm × 40cm at depths from dmax to 20 cm in water for matched and unmatched FFF beams and for cFF beams. A method for measuring symmetry in the cross plane direction is suggested and evaluated as FFF beams are insensitive to symmetry changes in this direction. Methods for characterising beam energy are evaluated and the impact of beam energy on profile shape compared to that of cFF beams. In-plane symmetry can be measured, as can cFF beams, using observed changes in profile, whereas cross-plane symmetry can be measured by acquiring profiles at collimator angles 0 and 180. Beam energy and 'unflatness' can be measured as with cFF beams from observed shifts in profile with changing beam energy. Normalising the inflection points of FFF beams to 55% results in an equivalent penumbra and field size measurement within 0.5 mm of conventional methods with the exception of 40 cm × 40 cm fields at a depth of 20 cm. New proposed methods are presented that make it possible to independently carry out set up and QA measurements on beam energy, flatness, symmetry and field size of an FFF beam without the need to reference to an equivalent flattened beam of the same energy. The methods proposed can also be used to carry out this QA for flattened beams, resulting in universal definitions and methods for MV beams. This is presented for beams produced by an Elekta linear accelerator, but is anticipated to also apply to other manufacturers' beams.

Perceptions of Health Care and Access to Preventive Services Among Young Adults.

The enactment of the Affordable Care Act increased the emphasis on health promotion and disease prevention by making preventive care accessible for many Americans, especially young adults, who could remain on their parents or legal guardians' health insurance until the age of 26. Yet, many Americans receive only half of the recommended preventive care services, which highlight the need for the improvement of health promotion and prevention services. The aim of this study was to assess the relationship among access to health care insurance, perceptions about health insurance, and use of preventive care services among young adults. Nine hundred and forty-six participants ages 19-34 completed a 40 question web-based survey. Data analysis suggested that while the majority of participants had health insurance, there were significant differences in opinions about the ACA, health insurance, and use of preventive services by gender, education level, and health insurance status. Overall, participants with health insurance were more likely to have received at least three of the basic preventive care services; however, most of them were not getting the preventive care as recommended. Results reaffirm the need for further studies on the impact of health insurance among young adults and the need for the emphasis on health promotion to educate young adults about the importance of disease prevention and preventive services.

The AUSTRAL VLBI observing program.

The AUSTRAL observing program was started in 2011, performing geodetic and astrometric very long baseline interferometry (VLBI) sessions using the new Australian AuScope VLBI antennas at Hobart, Katherine, and Yarragadee, with contribution from the Warkworth (New Zealand) 12 m and Hartebeesthoek (South Africa) 15 m antennas to make a southern hemisphere array of telescopes with similar design and capability. Designed in the style of the next-generation VLBI system, these small and fast antennas allow for a new way of observing, comprising higher data rates and more observations than the standard observing sessions coordinated by the International VLBI Service for Geodesy and Astrometry (IVS). In this contribution, the continuous development of the AUSTRAL sessions is described, leading to an improvement of the results in terms of baseline length repeatabilities by a factor of two since the start of this program. The focus is on the scheduling strategy and increased number of observations, aspects of automated operation, and data logistics, as well as results of the 151 AUSTRAL sessions performed so far. The high number of the AUSTRAL sessions makes them an important contributor to VLBI end-products, such as the terrestrial and celestial reference frames and Earth orientation parameters. We compare AUSTRAL results with other IVS sessions and discuss their suitability for the determination of baselines, station coordinates, source coordinates, and Earth orientation parameters.

Identification of predictive CT angiographic factors in the development of high-risk type 2 endoleaks after endovascular aneurysm repair in patients with infrarenal aortic aneurysms.

PURPOSE: An extensive analysis of the value of computed tomography (CT) parameters as potential predictors of the clinical outcome of type 2 endoleaks after endovascular aortic aneurysm repair (EVAR). MATERIALS AND METHODS: Initial CT scans of 130 patients with abdominal aortic aneurysms (AAAs) were retrospectively reviewed. On the basis of postoperative CT scans and angiographies, patients were stratified into a low-risk group (LRG; without or transient type 2 endoleak; n = 80) and a high-risk group (HRG, persistent type 2 endoleak or need for reintervention; n = 50). Statistical analysis comprised a univariate and multivariate analysis. RESULTS: Anatomical, thrombus-specific, as well as aortic side branch parameters were assessed on the initial CT scan. Of all anatomical parameters, the diameter of the immediate infrarenal aorta was significantly different in the univariate analysis (LRG 22.4 ±â€Š3.8 mm; HRG 23.6 ±â€Š2.5 mm; p = 0.03). The investigation of the thrombus-specific parameters showed a trend towards statistical significance for the relative thrombus load (LRG 31.7 ±â€Š18.0%; HRG 25.3 ±â€Š17.5%; p = 0.09). Assessment of aortic side branches revealed only for the univariate analysis significant differences in the patency of the inferior mesenteric artery (LRG 71.3%; HRG 92.0%; p = 0.003) and their diameter (LRG 3.3 ±â€Š0.7 mm; HRG 3.8 ±â€Š0.9 mm; p = 0.004). In contrast, the number of lumbar arteries (LAs; LRG 2.7 ±â€Š1.4; HRG 3.6 ±â€Š1.2; univariate: p = 0.01; multivariate: p = 0.006) as well as their diameter (LRG 2.1 ±â€Š0.4 mm; HRG 2.4 ±â€Š0.4 mm; univariate: p < 0.001; multivariate: p = 0.006) were highly significantly associated with the development of type 2 endoleaks of the HRG. CONCLUSION: The most important predictive factors for the development of high-risk type 2 endoleaks were mainly the number and the diameter of the LAs which perfused the AAA. KEY POINTS: • This study is a very detailed and comprehensive analysis of the value of various CT parameters as potential predictors of the clinical outcome of type 2 endoleaks after EVAR. • Anatomical as well as thrombus-specific parameters were unsuitable as predictors. • The most important predictive factors were mainly the number and the diameter of the LAs which perfused the AAA.