Pilot study of humanized glypican-3-targeted zirconium-89 immuno-positron emission tomography for hepatocellular carcinoma.

Purpose: Glypican-3 (GPC3)-targeted radioisotope immuno-positron emission tomography (immunoPET) may lead to earlier and more accurate diagnosis of hepatocellular carcinoma (HCC), thus facilitating curative treatment, decreasing early recurrence, and enhancing patient survival. We previously demonstrated reliable HCC detection using a zirconium-89-labeled murine anti-GPC3 antibody (89Zr-αGPC3M) for immunoPET. This study evaluated the efficacy of the humanized antibody successor (αGPC3H) to further clinical translation of a GPC3-based theranostic for HCC. Methods: In vitro αGPC3 binding to HepG2 cells was assessed by flow cytometry. In vivo 89Zr-αGPC3H and 89Zr-αGPC3M tumor uptake was evaluated by PET/CT and biodistribution studies in an orthotopic xenograft mouse model of HCC. Results: αGPC3H maintained binding to GPC3 in vitro and 89Zr-αGPC3H immunoPET identified liver tumors in vivo. PET/CT and biodistribution analyses demonstrated high 89Zr-αGPC3H tumor uptake and tumor-to-liver ratios, with no difference between groups. Conclusion: Humanized αGPC3 successfully targeted GPC3 in vitro and in vivo. 89Zr-αGPC3H immunoPET had comparable tumor detection to 89Zr-αGPC3M, with highly specific tumor uptake, making it a promising strategy to improve HCC detection.

Cognitive Impairment and Social Determinants of Health Among Indigenous Women.

BACKGROUND AND OBJECTIVES: Cognitive impairment and Alzheimer's disease and related dementias (ADRD) pose significant challenges for Indigenous populations, necessitating urgent research. Limited evidence suggests that high rates of ADRD among Indigenous peoples are associated with social determinants of health (SDOH), such as education, income, health literacy, religion, and social engagement. RESEARCH DESIGN AND METHODS: Collaborating with a Northern Plains tribe, participants were recruited 123 self-identified Indigenous women aged 40-70 through a comprehensive recruitment strategy. Employing the SDOH framework, the research assessed cognitive impairment and Alzheimer's disease knowledge (ADK), utilizing the Ascertain Dementia 8 and Alzheimer's disease knowledge scales (ADK-30). The investigation examined the relationships between selected SDOH variables and cognitive impairment status. RESULTS: More than half of the participants showed signs of cognitive impairment, which correlated with lower income and education levels. Increased knowledge about Alzheimer's disease, particularly in terms of treatment management and its life impact subscales, was associated with lower odds of cognitive impairment. Conversely, higher levels of depressive symptoms and participation in religious activities were linked to increased odds of cognitive impairment. DISCUSSION AND IMPLICATIONS: The findings underscore the importance of culturally grounded tools and SDOH frameworks tailored to Indigenous contexts in addressing ADRD disparities. Future research should integrate historical and cultural factors to advance health equity within Indigenous communities, ultimately mitigating the impact of ADRD and promoting overall well-being.

Select DYRK1A Inhibitors Enhance Both Proliferation and Differentiation in Human Pancreatic Beta Cells.

The small molecule DYRK1A inhibitor, harmine, induces human beta cell proliferation, expands beta cell mass, enhances expression of beta cell phenotypic genes, and improves human beta cell function i n vitro and in vivo . It is unknown whether the "pro-differentiation effect" is a DYRK1A inhibitor class-wide effect. Here we compare multiple commonly studied DYRK1A inhibitors. Harmine, 2-2c and 5-IT increase expression of PDX1, MAFA, NKX6.1, SLC2A2, PCSK1, MAFB, SIX2, SLC2A2, SLC30A8, ENTPD3 in normal and T2D human islets. Unexpectedly, GNF4877, CC-401, INDY, CC-401 and Leucettine fail to induce expression of these essential beta cell molecules. Remarkably, the pro-differentiation effect is independent of DYRK1A inhibition: although silencing DYRK1A induces human beta cell proliferation, it has no effect on differentiation; conversely, harmine treatment enhances beta cell differentiation in DYRK1A-silenced islets. A careful screen of multiple DYRK1A inhibitor kinase candidate targets was unable to identify pro-differentiation pathways. Overall, harmine, 2-2c and 5-IT are unique among DYRK1A inhibitors in their ability to enhance both beta cell proliferation and differentiation. While beta cell proliferation is mediated by DYRK1A inhibition, the pro-differentiation effects of harmine, 2-2c and 5-IT are distinct, and unexplained in mechanistic terms. These considerations have important implications for DYRK1A inhibitor pharmaceutical development.

Prevalence of Stroke - Behavioral Risk Factor Surveillance System, United States, 2011-2022.

Stroke was the fifth leading cause of death in the United States in 2021, and cost U.S. residents approximately $56.2 billion during 2019-2020. During 2006-2010, self-reported stroke prevalence among noninstitutionalized adults had a relative decrease of 3.7%. Data from the Behavioral Risk Factor Surveillance System were used to analyze age-standardized stroke prevalence during 2011-2022 among adults aged ≥18 years. From 2011-2013 to 2020-2022, overall self-reported stroke prevalence increased by 7.8% nationwide. Increases occurred among adults aged 18-64 years; females and males; non-Hispanic Black or African American (Black), non-Hispanic White (White), and Hispanic or Latino (Hispanic) persons; and adults with less than a college degree. Stroke prevalence was higher among adults aged ≥65 years than among younger adults; among non-Hispanic American Indian or Alaska Native, non-Hispanic Native Hawaiian or Pacific Islander, and Black adults than among White adults; and among adults with less than a high school education than among those with higher levels of education. Stroke prevalence decreased in the District of Columbia and increased in 10 states. Initiatives to promote knowledge of the signs and symptoms of stroke, and the identification of disparities in stroke prevalence, might help to focus clinical and programmatic interventions, such as the Million Hearts 2027 initiative or the Paul Coverdell National Acute Stroke Program, to improve prevention and treatment of stroke.

Impacts of protein quantity and distribution on body composition.

The importance of meal distribution of dietary protein to optimize muscle mass and body remains unclear, and the findings are intertwined with age, physical activity, and the total quantity and quality of protein consumed. The concept of meal distribution evolved from multiple discoveries about regulating protein synthesis in skeletal muscle. The most significant was the discovery of the role of the branched-chain amino acid leucine as a metabolic signal to initiate a post-meal anabolic period of muscle protein synthesis (MPS) in older adults. Aging is often characterized by loss of muscle mass and function associated with a decline in protein synthesis. The age-related changes in protein synthesis and subsequent muscle atrophy were generally considered inevitable until the discovery of the unique role of leucine for the activation of the mTOR signal complex for the initiation of MPS. Clinical studies demonstrated that older adults (>60 years) require meals with at least 2.8 g of leucine (~30 g of protein) to stimulate MPS. This meal requirement for leucine is not observed in younger adults (<30 years), who produce a nearly linear response of MPS in proportion to the protein content of a meal. These findings suggest that while the efficiency of dietary protein to stimulate MPS declines with aging, the capacity for MPS to respond is maintained if a meal provides adequate protein. While the meal response of MPS to total protein and leucine is established, the long-term impact on muscle mass and body composition remains less clear, at least in part, because the rate of change in muscle mass with aging is small. Because direct diet studies for meal distribution during aging are impractical, research groups have applied meal distribution and the leucine threshold to protein-sparing concepts during acute catabolic conditions such as weight loss. These studies demonstrate enhanced MPS at the first meal after an overnight fast and net sparing of lean body mass during weight loss. While the anabolic benefits of increased protein at the first meal to stimulate MPS are clear, the benefits to long-term changes in muscle mass and body composition in aging adults remain speculative.

Relative efficacy of masks and respirators as source control for viral aerosol shedding from people infected with SARS-CoV-2: a controlled human exhaled breath aerosol experimental study.

BACKGROUND: Tight-fitting masks and respirators, in manikin studies, improved aerosol source control compared to loose-fitting masks. Whether this translates to humans is not known. METHODS: We compared efficacy of masks (cloth and surgical) and respirators (KN95 and N95) as source control for SARS-CoV-2 viral load in exhaled breath of volunteers with COVID-19 using a controlled human experimental study. Volunteers (N = 44, 43% female) provided paired unmasked and masked breath samples allowing computation of source-control factors. FINDINGS: All masks and respirators significantly reduced exhaled viral load, without fit tests or training. A duckbill N95 reduced exhaled viral load by 98% (95% CI: 97%-99%), and significantly outperformed a KN95 (p < 0.001) as well as cloth and surgical masks. Cloth masks outperformed a surgical mask (p = 0.027) and the tested KN95 (p = 0.014). INTERPRETATION: These results suggest that N95 respirators could be the standard of care in nursing homes and healthcare settings when respiratory viral infections are prevalent in the community and healthcare-associated transmission risk is elevated. FUNDING: Defense Advanced Research Projects Agency, National Institute of Allergy and Infectious Diseases, Centers for Disease Control and Prevention, the Bill & Melinda Gates Foundation, and The Flu Lab.

Changes in Self-Measured Blood Pressure Monitoring Use in 14 States From 2019 to 2021: Impact of the COVID-19 Pandemic.

BACKGROUND: Self-measured blood pressure monitoring (SMBP) is an important out-of-office resource that is effective in improving hypertension control. Changes in SMBP use during the Coronavirus Disease 2019 (COVID-19) pandemic have not been described previously. METHODS: Behavioral Risk Factor Surveillance System (BRFSS) data were used to quantify changes in SMBP use between 2019 (prior COVID-19 pandemic) and 2021 (during the COVID-19 pandemic). Fourteen states administered the SMBP module in both years. All data were self-reported from adults who participated in the BRFSS survey. We assessed the receipt of SMBP recommendations from healthcare professionals and actual use of SMBP among those with hypertension (n = 68,820). Among those who used SMBP, we assessed SMBP use at home and sharing BP readings electronically with healthcare professionals. RESULTS: Among adults with hypertension, there was no significant changes between 2019 and 2021 in those reporting SMBP use (57.0% vs. 55.7%) or receiving recommendations from healthcare professionals to use SMBP (66.4% vs. 66.8%). However, among those who used SMBP, there were significant increases in use at home (87.7% vs. 93.5%) and sharing BP readings electronically (8.6% vs. 13.1%) from 2019 to 2021. Differences were noted by demographic characteristics and residence state. CONCLUSIONS: Receiving a recommendation from the healthcare provider to use SMBP and actual use did not differ before and during the COVID-19 pandemic. However, among those who used SMBP, home use and sharing BP readings electronically with healthcare professional increased significantly, although overall sharing remained low (13.1%). Maximizing advances in virtual connections between clinical and community settings should be leveraged for improved hypertension management.

The first robotic-assisted hysterectomy below the bikini line with the Dexter robotic system™.

Background: Robotic-assisted hysterectomy (RAH) is a widely accepted minimally invasive approach for uterus removal. However, as RAH is typically performed in the umbilical region, it usually results in scars in cosmetically suboptimal locations. This is the first case of RAH with cervicosacropexy performed below the bikini line, using the new Dexter robotic system™. Objectives: The aim of this article is to show the surgical steps of the first RAH with cervicosacropexy performed below the bikini line with the new Dexter robotic system™ (Distalmotion), and furthermore assess the feasibility of this approach using this robotic platform. Materials and Methods: A 43-year-old woman with uterine adenomyosis and recurrent uterine prolapse underwent a robotic-assisted subtotal hysterectomy with cervicosacropexy, performed below the bikini line, using the Dexter robotic system™, at the Clinic of Gynecology and Obstetrics at Universitätsklinikum Schleswig-Holstein (UKHS) in Kiel, Germany. Main outcome measures: Perioperative data, surgical approach specifics, objective, and subjective outcomes of this new approach. Results: The procedure was performed without intra-operative complications; estimated blood loss was 10 ml. Operative time was 150 minutes, console time 120 minutes, total docking time 6 minutes. Dexter performed as expected; no device-related issues or robotic arm collisions occurred. The patient did not require pain medication and was released on the second postoperative day. Conclusion: RAH performed below the bikini line using the Dexter robotic system™ is a feasible, safe, and adequate procedure. These initial results should be confirmed and further extensively refurbished with larger patient cohorts, and functional and psychological outcomes need further investigation.

Mandating indoor air quality for public buildings.

If some countries lead by example, standards may increasingly become normalized.

Molecular glues of the regulatory ChREBP/14-3-3 complex protect beta cells from glucolipotoxicity.

The Carbohydrate Response Element Binding Protein (ChREBP) is a glucose-responsive transcription factor (TF) that is characterized by two major splice isoforms (α and ß). In acute hyperglycemia, both ChREBP isoforms regulate adaptive ß-expansion; however, during chronic hyperglycemia and glucolipotoxicity, ChREBPß expression surges, leading to ß-cell dedifferentiation and death. 14-3-3 binding to ChREBPα results in its cytoplasmic retention and concomitant suppression of transcriptional activity, suggesting that small molecule-mediated stabilization of this protein-protein interaction (PPI) via molecular glues may represent an attractive entry for the treatment of metabolic disease. Here, we show that structure-based optimizations of a molecular glue tool compound led not only to more potent ChREBPα/14-3-3 PPI stabilizers but also for the first time cellular active compounds. In primary human ß-cells, the most active compound stabilized the ChREBPα/14-3-3 interaction and thus induced cytoplasmic retention of ChREBPα, resulting in highly efficient ß-cell protection from glucolipotoxicity while maintaining ß-cell identity. This study may thus not only provide the basis for the development of a unique class of compounds for the treatment of Type 2 Diabetes but also showcases an alternative 'molecular glue' approach for achieving small molecule control of notoriously difficult targetable TFs.

Relationship Between Ultra-Processed and Minimally Processed Food Intake and Cardiovascular Health Among US Women of Reproductive Age.

Objectives: Ultra-processed food (UPF) intake is associated with worse cardiovascular health (CVH), but associations between unprocessed/minimally processed foods (MPFs) and CVH are limited, especially among women of reproductive age (WRA). Materials and Methods: For 5,773 WRA (20-44 years) in National Health and Nutrition Examination Survey (NHANES) 2007-2018, we identified UPFs and MPFs using the Nova classification and based on 24-hour dietary recalls. We calculated usual percentages of calories from UPFs and MPFs using the National Cancer Institute's usual intake method. Seven CVH metrics were scored, and CVH levels were grouped by tertile. We used multivariable linear and multinomial logistic regression to assess associations between UPFs and MPFs and CVH. Results: The average usual percentage of calories from UPFs and MPFs was 57.2% and 29.3%, respectively. There was a graded, positive association between higher UPF intake and higher odds of poor CVH: adjusted odds ratios (aORs) for the lowest versus highest CVH were 1.74 (95% confidence interval: 1.51-2.01), 2.67 (2.07-3.44) and 4.66 (3.13-6.97), respectively, comparing quartile 2 (Q2)-Q4 to the lowest quartile (Q1) of UPF intake. Higher MPF intake was associated with lower odds of poor CVH: aORs for the lowest CVH were 0.61 (0.54-0.69), 0.39 (0.31-0.50), and 0.21 (0.14-0.31). Patterns of association remained consistent across subgroups and in sensitivity analyses. Conclusions: Higher UPF intake was associated with worse CVH, while higher MPF intake was associated with better CVH among WRA in the United States. Our analyses highlight an opportunity for WRA to improve nutrition and their CVH.

Prenatal alcohol exposure and white matter microstructural changes across the first 6-7 years of life: A longitudinal diffusion tensor imaging study of a South African birth cohort.

Prenatal alcohol exposure (PAE) can affect brain development in early life, but few studies have investigated the effects of PAE on trajectories of white matter tract maturation in young children. Here we used diffusion weighted imaging (DWI) repeated over three time points, to measure the effects of PAE on patterns of white matter microstructural development during the pre-school years. Participants were drawn from the Drakenstein Child Health Study (DCHS), an ongoing birth cohort study conducted in a peri-urban community in the Western Cape, South Africa. A total of 342 scans acquired from 237 children as neonates (N = 82 scans: 30 PAE; 52 controls) and at ages 2-3 (N = 121 scans: 27 PAE; 94 controls) and 6-7 years (N = 139 scans: 45 PAE; 94 controls) were included. Maternal alcohol use during pregnancy and other antenatal covariates were collected from 28 to 32 weeks' gestation. Linear mixed effects models with restricted maxium likelihood to accommodate missing data were implemented to investigate the effects of PAE on fractional anisotropy (FA) and mean diffusivity (MD) in specific white matter tracts over time, while adjusting for child sex and maternal education. We found significant PAE-by-time effects on trajectories of FA development in the left superior cerebellar peduncle (SCP-L: p = 0.001; survived FDR correction) and right superior longitudinal fasciculus (SLF-R: p = 0.046), suggesting altered white matter development among children with PAE. Compared with controls, children with PAE demonstrated a more rapid change in FA in these tracts from the neonatal period to 2-3 years of age, followed by a more tapered trajectory for the period from 2-3 to 6-7 years of age, with these trajectories differing from unexposed control children. Given their supporting roles in various aspects of neurocognitive functioning (i.e., motor regulation, learning, memory, language), altered patterns of maturation in the SCP and SLF may contribute to a spectrum of physical, social, emotional, and cognitive difficulties often experienced by children with PAE. This study highlights the value of repeated early imaging in longitudinal studies of PAE, and focus for early childhood as a critical window of potential susceptibility as well as an opportunity for early intervention.

Gelatine-collagen photo-crosslinkable 3D matrixes for skin regeneration.

Immediate care of skin wounds and burns is essential to repair this mechanical and chemical barrier to infections. Hydrogels have become one of the standard methods for wound care. Here, gelatine-collagen photo-crosslinkable matrixes or hydrogels were manufactured by two-photon polymerization (TPP) or one-photon UV exposure using a Digital Light Processing (DLP) setup. Both techniques are able to construct matrixes from computer-aided design models, which is important for future clinical applications in which wound dressings should be customized. Although TPP can mimic the 3D dermo-epidermal junction with a high spatial resolution (i.e., ∼6 µm3), the manufacturing time was too slow to produce large wound dressings. Therefore, a DLP setup was explored in this study to fabricate large 2D matrixes of several cm2 using the same photo-resist as for TPP, except for the photoinitiator. The fibroblast viability, adherence, and proliferation were analysed in time on both 3D and 2D matrixes in vitro using two-photon microscopy. For both types of matrixes, the adherence and proliferation of fibroblasts (3T3-NIH) were optimal for stiff structures with a Young's modulus of 191 ± 35 kPa compared to softer matrixes of 37 ± 12 kPa. Fibroblast showed complete confluence on Day 14 after seeding on these matrixes, which may create the granulation tissue composed of fibronectin, collagen, and various proteoglycans in the future dermis before repair of the epidermis and disintegrating of their host matrix. For the monitoring of this repair, gelatine-collagen matrixes can easily incorporate bio-optical sensors for the simultaneous monitoring of inflammation processes and wound healing in time.

Incidence of Stroke in Indigenous Populations of Countries With a Very High Human Development Index: A Systematic Review.

BACKGROUND AND OBJECTIVES: Cardiovascular disease contributes significantly to disease burden among many Indigenous populations. However, data on stroke incidence in Indigenous populations are sparse. We aimed to investigate what is known of stroke incidence in Indigenous populations of countries with a very high Human Development Index (HDI), locating the research in the broader context of Indigenous health. METHODS: We identified population-based stroke incidence studies published between 1990 and 2022 among Indigenous adult populations of developed countries using PubMed, Embase, and Global Health databases, without language restriction. We excluded non-peer-reviewed sources, studies with fewer than 10 Indigenous people, or not covering a 35- to 64-year minimum age range. Two reviewers independently screened titles, abstracts, and full-text articles and extracted data. We assessed quality using "gold standard" criteria for population-based stroke incidence studies, the Newcastle-Ottawa Scale for risk of bias, and CONSIDER criteria for reporting of Indigenous health research. An Indigenous Advisory Board provided oversight for the study. RESULTS: From 13,041 publications screened, 24 studies (19 full-text articles, 5 abstracts) from 7 countries met the inclusion criteria. Age-standardized stroke incidence rate ratios were greater in Aboriginal and Torres Strait Islander Australians (1.7-3.2), American Indians (1.2), Sámi of Sweden/Norway (1.08-2.14), and Singaporean Malay (1.7-1.9), compared with respective non-Indigenous populations. Studies had substantial heterogeneity in design and risk of bias. Attack rates, male-female rate ratios, and time trends are reported where available. Few investigators reported Indigenous stakeholder involvement, with few studies meeting any of the CONSIDER criteria for research among Indigenous populations. DISCUSSION: In countries with a very high HDI, there are notable, albeit varying, disparities in stroke incidence between Indigenous and non-Indigenous populations, although there are gaps in data availability and quality. A greater understanding of stroke incidence is imperative for informing effective societal responses to socioeconomic and health disparities in these populations. Future studies into stroke incidence in Indigenous populations should be designed and conducted with Indigenous oversight and governance to facilitate improved outcomes and capacity building. REGISTRATION INFORMATION: PROSPERO registration: CRD42021242367.

NRF2 is required for neonatal mouse beta cell growth by maintaining redox balance and promoting mitochondrial biogenesis and function.

AIMS/HYPOTHESIS: All forms of diabetes result from insufficient functional beta cell mass. Due to the relatively limited expression of several antioxidant enzymes, beta cells are highly vulnerable to pathological levels of reactive oxygen species (ROS), which can lead to the reduction of functional beta cell mass. During early postnatal ages, both human and rodent beta cells go through a burst of proliferation that quickly declines with age. The exact mechanisms that account for neonatal beta cell proliferation are understudied but mitochondrial release of moderated ROS levels has been suggested as one of the main drivers. We previously showed that, apart from its conventional role in protecting beta cells from oxidative stress, the nuclear factor erythroid 2-related factor 2 (NRF2) is also essential for beta cell proliferation. We therefore hypothesised that NRF2, which is activated by ROS, plays an essential role in beta cell proliferation at early postnatal ages. METHODS: Beta cell NRF2 levels and beta cell proliferation were measured in pancreatic sections from non-diabetic human cadaveric donors at different postnatal ages, childhood and adulthood. Pancreatic sections from 1-, 7-, 14- and 28-day-old beta cell-specific Nrf2 (also known as Nfe2l2)-knockout mice (ßNrf2KO) or control (Nrf2lox/lox) mice were assessed for beta cell NRF2 levels, beta cell proliferation, beta cell oxidative stress, beta cell death, nuclear beta cell pancreatic duodenal homeobox protein 1 (PDX1) levels and beta cell mass. Seven-day-old ßNrf2KO and Nrf2lox/lox mice were injected daily with N-acetylcysteine (NAC) or saline (154 mmol/l NaCl) to explore the potential contribution of oxidative stress to the phenotypes seen in ßNrf2KO mice at early postnatal ages. RNA-seq was performed on 7-day-old ßNrf2KO and Nrf2lox/lox mice to investigate the mechanisms by which NRF2 stimulates beta cell proliferation at early postnatal ages. Mitochondrial biogenesis and function were determined using dispersed islets from 7-day-old ßNrf2KO and Nrf2lox/lox mice by measuring MitoTracker intensity, mtDNA/gDNA ratio and ATP/ADP ratio. To study the effect of neonatal beta cell-specific Nrf2 deletion on glucose homeostasis in adulthood, blood glucose, plasma insulin and insulin secretion were determined and a GTT was performed on 3-month-old ßNrf2KO and Nrf2lox/lox mice fed on regular diet (RD) or high-fat diet (HFD). RESULTS: The expression of the master antioxidant regulator NRF2 was increased at early postnatal ages in both human (1 day to 19 months old, 31%) and mouse (7 days old, 57%) beta cells, and gradually declined with age (8% in adult humans, 3.77% in adult mice). A significant correlation (R2=0.568; p=0.001) was found between beta cell proliferation and NRF2 levels in human beta cells. Seven-day-old ßNrf2KO mice showed reduced beta cell proliferation (by 65%), beta cell nuclear PDX1 levels (by 23%) and beta cell mass (by 67%), and increased beta cell oxidative stress (threefold) and beta cell death compared with Nrf2lox/lox control mice. NAC injections increased beta cell proliferation in 7-day-old ßNrf2KO mice (3.4-fold) compared with saline-injected ßNrf2KO mice. Interestingly, RNA-seq of islets isolated from 7-day-old ßNrf2KO mice revealed reduced expression of mitochondrial RNA genes and genes involved in the electron transport chain. Islets isolated from 7-day old ßNrf2KO mice presented reduced MitoTracker intensity (by 47%), mtDNA/gDNA ratio (by 75%) and ATP/ADP ratio (by 68%) compared with islets from Nrf2lox/lox littermates. Lastly, HFD-fed 3-month-old ßNrf2KO male mice displayed a significant reduction in beta cell mass (by 35%), a mild increase in non-fasting blood glucose (1.2-fold), decreased plasma insulin (by 14%), and reduced glucose tolerance (1.3-fold) compared with HFD-fed Nrf2lox/lox mice. CONCLUSIONS/INTERPRETATION: Our study highlights NRF2 as an essential transcription factor for maintaining neonatal redox balance, mitochondrial biogenesis and function and beta cell growth, and for preserving functional beta cell mass in adulthood under metabolic stress. DATA AVAILABILITY: Sequencing data are available in the NCBI Gene Expression Omnibus, accession number GSE242718 ( https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE242718 ).

Sustainable and Eco-Friendly DLC Fabrication for Replacing Chrome on a Gravure Cylinder Surface.

This paper evaluates the potential of diamond-like carbon (DLC) as a durable surface protection to replace the chromium (Cr) layer, which is traditionally applied to gravure print cylinders and other components through a galvanic electroplating process. The fabrication of DLC is more eco-friendly and could reduce the environmental hazard posed by hexavalent chromium in liquid form that is used in Cr application and better adhere to environmental regulations. This could encourage businesses to bring the DLC fabrication process in-house, sharing resources such as materials, labor, and equipment, to help reduce costs. Four DLC variants (standard DLC, A-DLC, S-DLC, and organic silica) and chrome were analyzed and tested for their surface properties and durability. Data suggest that both standard DLC and S-DLC had higher surface free energy, allowing for good ink wetting on the surface when compared to chrome. In addition, the standard DLC and S-DLC surfaces are generally smoother than the chrome, resulting in lower relative hydrophilicity and allowing for easier removal of ink in the nonimage regions with the doctor blade. The elcometer adhesion test demonstrated that the bond strength of the DLC variants to their base layer was comparable to the bond strength of chrome, indicating that the adhesion strength of the two materials was similar. Furthermore, in the abrasion test, the wear on the standard DLC surface and the corresponding wear on the lamella tip of the metal doctor blades were notably lower than that observed on chrome. This distinction is particularly evident in each of the test trials, specifically run 1, which involved 2,000,000 wiping actions of a metal doctor blade in the presence of abrasive TiO2 ink pigments. Statistical analysis on standard DLC versus chrome suggests that DLC fabrication is effective and durable on plain and patterned surfaces. Therefore, from a sustainable and eco-friendly perspective, standard DLC and S-DLC would be good alternative durable surfaces for print cylinders and other components used in various industries due to superior wear resistance properties.

Financial barriers and inequity in medical education in India: challenges to training a diverse and representative healthcare workforce.

India has been historically challenged by an insufficient and heterogeneously clustered distribution of healthcare infrastructure. While resource-limited healthcare settings, such as major parts of India, require multidisciplinary approaches for improvement, one key approach is the recruitment and training of a healthcare workforce representative of its population. This requires overcoming barriers to equity and representation in Indian medical education that are multi-faceted, historical, and rooted in inequality. However, literature is lacking regarding the financial or economic barriers, and their implications on equity and representation in the Indian allopathic physician workforce, which this review sought to describe. Keyword-based searches were carried out in PubMed, Google Scholar, and Scopus in order to identify relevant literature published till November 2023. This state-of-the-art narrative review describes the existing multi-pronged economic barriers, recent and forthcoming changes deepening these barriers, and how these may limit opportunities for having a diverse workforce. Three sets of major economic barriers exist to becoming a specialized medical practitioner in India - resources required to get selected into an Indian medical school, resources required to pursue medical school, and resources required to get a residency position. The resources in this endeavor have historically included substantial efforts, finances, and privilege, but rising barriers in the medical education system have worsened the state of inequity. Preparation costs for medical school and residency entrance tests have risen steadily, which may be further exacerbated by recent major policy changes regarding licensing and residency selection. Additionally, considerable increases in direct and indirect costs of medical education have recently occurred. Urgent action in these areas may help the Indian population get access to a diverse and representative healthcare workforce and also help alleviate the shortage of primary care physicians in the country. Discussed are the reasons for rural healthcare disparities in India and potential solutions related to medical education.

Targeted Radiation Delivery before Haploidentical HCT for High-risk Leukemia or MDS Patients Yields Long-term Survivors.

PURPOSE: Hematopoietic cell transplantation (HCT) has curative potential for myeloid malignancies, though many patients cannot tolerate myeloablative conditioning with high-dose chemotherapy alone or with total-body irradiation (TBI). Here we report long-term outcomes from a phase I/II study using iodine-131 (131I)-anti-CD45 antibody BC8 combined with nonmyeloablative conditioning prior to HLA-haploidentical HCT in adults with high-risk relapsed/ refractory acute myeloid or lymphoid leukemia (AML or ALL), or myelodysplastic syndrome (MDS; ClinicalTrials.gov, NCT00589316). PATIENTS AND METHODS: Patients received a tracer diagnostic dose before a therapeutic infusion of 131I-anti-CD45 to deliver escalating doses (12-26 Gy) to the dose-limiting organ. Patients subsequently received fludarabine, cyclophosphamide (CY), and 2 Gy TBI conditioning before haploidentical marrow HCT. GVHD prophylaxis was posttransplant CY plus tacrolimus and mycophenolate mofetil. RESULTS: Twenty-five patients (20 with AML, 4 ALL and 1 high-risk MDS) were treated; 8 had ≥ 5% blasts by morphology (range 9%-20%), and 7 had previously failed HCT. All 25 patients achieved a morphologic remission 28 days after HCT, with only 2 patients showing minimal residual disease (0.002-1.8%) by flow cytometry. Median time to engraftment was 15 days for neutrophils and 23 days for platelets. Point estimates for overall survival and progression-free survival were 40% and 32% at 1 year, and 24% at 2 years, respectively. Point estimates of relapse and nonrelapse mortality at 1 year were 56% and 12%, respectively. CONCLUSIONS: 131I-anti-CD45 radioimmunotherapy prior to haploidentical HCT is feasible and can be curative in some patients, including those with disease, without additional toxicity.

Transcriptional activation of the Myc gene by glucose in ß-cells requires a ChREBP-dependent 3-D chromatin interaction between the Myc and Pvt1 genes.

OBJECTIVE: All forms of diabetes result from insufficient functional ß-cell mass. Thus, achieving the therapeutic goal of expanding ß-cell mass requires a better mechanistic understanding of how ß-cells proliferate. Glucose is a natural ß-cell mitogen that mediates its effects in part through the glucose-responsive transcription factor, carbohydrate response element binding protein (ChREBP) and the anabolic transcription factor, MYC. However, mechanistic details by which glucose activates Myc at the transcriptional level are poorly understood. METHODS: Here, siRNA was used to test the role of ChREBP in the glucose response of MYC, ChIP and ChIPseq to identify potential regulatory binding sites, chromatin conformation capture to identify DNA/DNA interactions, and an adenovirus was constructed to expresses x-dCas9 and an sgRNA that specifically disrupts the recruitment of ChREBP to a specific targeted ChoRE. RESULTS: We found that ChREBP is essential for glucose-mediated transcriptional induction of Myc, and for increases in Myc mRNA and protein abundance. Further, ChIPseq revealed that the carbohydrate response element (ChoRE) nearest to the Myc transcriptional start site (TSS) is immediately upstream of the gene encoding the lncRNA, Pvt1, 60,000 bp downstream of the Myc gene. Chromatin Conformation Capture (3C) confirmed a glucose-dependent interaction between these two sites. Transduction with an adenovirus expressing x-dCas9 and an sgRNA specifically targeting the highly conserved Pvt1 ChoRE, attenuates ChREBP recruitment, decreases Myc-Pvt1 DNA/DNA interaction, and decreases expression of the Pvt1 and Myc genes in response to glucose. Importantly, isolated and dispersed rat islet cells transduced with the ChoRE-disrupting adenovirus also display specific decreases in ChREBP-dependent, glucose-mediated expression of Pvt1 and Myc, as well as decreased glucose-stimulated ß-cell proliferation. CONCLUSIONS: The mitogenic glucose response of Myc is mediated via glucose-dependent recruitment of ChREBP to the promoter of the Pvt1 gene and subsequent DNA looping with the Myc promoter.