Vibration Controlled Transient Elastography Based Parameters Predicts Clinical Outcomes in Liver Transplant Recipients.

BACKGROUND & AIMS: Vibration-controlled transient elastography (VCTE) is used in clinical practice to risk stratify liver transplant (LT) recipients, however, there is currently little data demonstrating the relationship between VCTE and clinical outcomes. METHODS: 362 adult LT recipients with successful VCTE examination between 2015 and 2022 were included. Presence of advanced fibrosis was defined as liver stiffness measurement (LSM) ≥10.5kPa and hepatic steatosis as controlled attenuation parameter (CAP)≥ 270 dB/m. The outcomes of interest included all-cause mortality, myocardial infarction (MI), and graft cirrhosis using cumulative incidence analysis that accounted for the competing risks of these outcomes. RESULTS: The LSM was elevated in 64 (18%) and CAP in 163 (45%) of LT recipients. The baseline LSM values were similar in patients with elevated vs. normal CAP values. After a median follow up of 65 (IQR 20, 140) months from LT to baseline VCTE, 66 (18%) of patients died, 12 (3%) developed graft cirrhosis, and 18 (5%) experienced an MI. Baseline high LSM was independently associated with all-cause mortality (HR 1.97, 95% CI 1.11, 3.50, p=0.02) and new onset cirrhosis (HR 6.74, 95% CI 2.08, 21.79, p<0.01). A higher CAP value was significantly and independently associated with increased risk of experiencing a MI over study follow up with HR 4.14 [95% CI 1.29, 13.27, p=0.017]. CONCLUSIONS: The VCTE based parameters are associated with clinical outcomes and offer the potential to be incorporated into clinical risk stratification strategies to improve outcomes among LT recipients.

Burden of Portal Hypertension Complications Is Greater in Liver Transplant Wait-Listed Registrants with End-Stage Liver Disease and Type 2 Diabetes.

BACKGROUND AND AIMS: Impact of type 2 diabetes mellitus (T2DM) in patients with end-stage liver disease (ESLD) awaiting liver transplantation (LT) remains poorly defined. The objective of the present study is to evaluate the relationship between T2DM and clinical outcomes among patients with LT waitlist registrants. We hypothesize that the presence of T2DM will be associated with worse clinical outcomes. METHODS: 593 patients adult (age 18 years or older) who were registered for LT between 1/2010 and 1/2017 were included in this retrospective analysis. The impact of T2DM on liver-associated clinical events (LACE), survival, hospitalizations, need for renal replacement therapy, and likelihood of receiving LT were evaluated over a 12-month period. LACE was defined as variceal hemorrhage, hepatic encephalopathy, and ascites. Kaplan-Meier and Cox regression analysis were used to determine the association between T2DM and clinical outcomes. RESULTS: The baseline prevalence of T2DM was 32% (n = 191) and patients with T2DM were more likely to have esophageal varices (61% vs. 47%, p = 0.002) and history of variceal hemorrhage (23% vs. 16%, p = 0.03). The presence of T2DM was associated with increased risk of incident ascites (HR 1.91, 95% CI 1.11, 3.28, p = 0.019). Patients with T2DM were more likely to require hospitalizations (56% vs. 49%, p = 0.06), hospitalized with portal hypertension-related complications (22% vs. 14%; p = 0.026), and require renal replacement therapy during their hospitalization. Patients with T2DM were less likely to receive a LT (37% vs. 45%; p = 0.03). Regarding MELD labs, patients with T2DM had significantly lower bilirubin at each follow-up; however, no differences in INR and creatinine were noted. CONCLUSION: Patients with T2DM are at increased risk of clinical outcomes. This risk is not captured in MELD score, which may potentially negatively affect their likelihood of receiving LT.

Utility of Lille Score in Predicting 30-Day Survival in Steroid-Treated Alcohol-Associated Hepatitis.

BACKGROUND/AIMS: In alcohol-associated hepatitis (AH), the Lille score is used to assess futility of steroids. However, the ability of the Lille score to predict 30-day survival in AH is not well-defined. Our aim is to compare the utility of the Lille score in predicting 30-day survival in those with AH treated with steroids. METHODS: Retrospective chart review of 882 patients hospitalized with AH from January 1st, 2012 through December 30th, 2019 was performed. Of these, 201 patients with severe AH met the threshold to receive steroids. Those with data to calculate Lille score < 0.45 on day 4 (n = 29) or 7 (n = 89) who continued steroids were compared to 83 patients with Lille scores ≥ 0.45 on day 4 (n = 18) or 7 (n = 65) who stopped steroids. The primary outcome was 30-day survival. For comparison, a contemporaneous matched control group was also analyzed of 110 patients who were hospitalized with severe AH, but did not receive steroids. RESULTS: In patients with Lille score < 0.45, survival was higher at 30-day when compared to those with Lille score ≥ 0.45 (94.9% vs. 80.72%; p = 0.002). The sensitivity, specificity, positive predictive value and negative predictive value of Lille score (< 0.45) to predict 30-day survival was 95%, 19%, 63%, and 73%, respectively. CONCLUSIONS: In severe AH, those with Lille score < 0.45 at day 4 or 7 have improved 30-day survival compared to those with Lille score ≥ 0.45. In those receiving steroids, Lille score has excellent sensitivity to predict 30-day survival but poor specificity.

Impact of response bias in three surveys on primary care providers' experiences with electronic health records.

OBJECTIVE: To identify impacts of different survey methodologies assessing primary care physicians' (PCPs') experiences with electronic health records (EHRs), we compared three surveys: the 2022 Continuous Certification Questionnaire (CCQ) from the American Board of Family Medicine, the 2022 University of California San Francisco (UCSF) Physician Health IT Survey, and the 2021 National Electronic Health Records Survey (NEHRS). MATERIALS AND METHODS: We evaluated differences between survey pairs using Rao-Scott corrected chi-square tests, which account for weighting. RESULTS: CCQ received 3991 responses from PCPs (100% response rate), UCSF received 1375 (3.6% response rate), and NEHRS received 858 (18.2% response rate). Substantial, statistically significant differences in demographics were detected across the surveys. CCQ respondents were younger and more likely to work in a health system; NEHRS respondents were more likely to work in private practice; and UCSF respondents disproportionately practiced in larger academic settings. Many EHR experience indicators were similar between CCQ and NEHRS, but CCQ respondents reported higher documentation burden. DISCUSSION: The UCSF approach is unlikely to supply reliable data. Significant demographic differences between CCQ and NEHRS raise response bias concerns, and while there were similarities in some reported EHR experiences, there were important, significant differences. CONCLUSION: Federal EHR policy monitoring and maintenance require reliable data. This test of existing and alternative sources suggest that diversified data sources are necessary to understand physicians' experiences with EHRs and interoperability. Comprehensive surveys administered by specialty boards have the potential to contribute to these efforts, since they are likely to be free of response bias.

Loss of 3-O-sulfotransferase enzymes, Hs3st3a1 and Hs3st3b1, reduces kidney and glomerular size and disrupts glomerular architecture.

Heparan sulfate (HS) is an important component of the kidney anionic filtration barrier, the glomerular basement membrane (GBM). HS chains attached to proteoglycan protein cores are modified by sulfotransferases in a highly ordered series of biosynthetic steps resulting in immense structural diversity due to negatively charged sulfate modifications. 3-O-sulfation is the least abundant modification generated by a family of seven isoforms but creates the most highly sulfated HS domains. We analyzed the kidney phenotypes in the Hs3st3a1, Hs3st3b1 and Hs3st6 -knockout (KO) mice, the isoforms enriched in kidney podocytes. Individual KO mice show no overt kidney phenotype, although Hs3st3b1 kidneys were smaller than wildtype (WT). Furthermore, Hs3st3a1-/-; Hs3st3b1-/- double knockout (DKO) kidneys were smaller but also had a reduction in glomerular size relative to wildtype (WT). Mass spectrometry analysis of kidney HS showed reduced 3-O-sulfation in Hs3st3a1-/- and Hs3st3b1-/-, but not in Hs3st6-/- kidneys. Glomerular HS showed reduced HS staining and reduced ligand-and-carbohydrate engagement (LACE) assay, a tool that detects changes in binding of growth factor receptor-ligand complexes to HS. Interestingly, DKO mice have increased levels of blood urea nitrogen, although no differences were detected in urinary levels of albumin, creatinine and nephrin. Finally, transmission electron microscopy showed irregular and thickened GBM and podocyte foot process effacement in the DKO compared to WT. Together, our data suggest that loss of 3-O-HS domains disrupts the kidney glomerular architecture without affecting the glomerular filtration barrier and overall kidney function.

Physicians in ACOs report greater documentation burden.

OBJECTIVES: First, to analyze the relationship between value-based payment (VBP) program participation and documentation burden among office-based physicians. Second, to analyze the relationship between specific VBP programs (eg, accountable care organizations [ACOs]) and documentation burden. STUDY DESIGN: Retrospective analyses of US office-based physicians in 2019 and 2021. METHODS: We used cross-sectional data from the National Electronic Health Records Survey to measure VBP program participation and our outcomes of reported electronic health record (EHR) documentation burden. We used ordinary least squares regression models adjusting for physician and practice characteristics to estimate the relationship between participation in any VBP program and EHR burden outcomes. We also estimated the relationship between participation in 6 distinct VBP programs and our outcomes to decompose the aggregate relationship into program-specific estimates. RESULTS: In adjusted analyses, participation in any VBP program was associated with 10.5% greater probability of reporting more than 1 hour per day of after-hours documentation time (P = .01), which corresponded to an estimated additional 11 minutes per day (P = .03). Program-specific estimates illustrated that ACO participation drove the aggregate relationship, with ACO participants reporting greater after-hours documentation time (18 additional minutes per day; P < .001), more difficulty documenting (30.6% more likely; P < .001), and more inappropriateness of time spent documenting (21.7% more likely; P < .001). CONCLUSIONS: Office-based physicians participating in ACOs report greater documentation burden across several measures; the same is not true for other VBP programs. Although many ACOs relax documentation requirements for reimbursement, documentation for quality reporting and risk adjustment may lead to a net increase in burden, especially for physicians exposed to numerous programs and payers.

Utility of scores to predict alcohol use after liver transplant (lt): take them with a grain of salt.

BACKGROUND AIMS: The Sustained Alcohol use post-Liver Transplant (SALT) and the High-Risk Alcohol Relapse (HRAR) scores were developed to predict return to alcohol use after liver transplant (LT) for alcohol associated liver disease (ALD). METHODS: A retrospective analysis of deceased donor LT 10/2018 to 4/2022 was performed. All patients (pts) underwent careful pre-LT psychosocial evaluation. Data on alcohol use, substance abuse, prior rehabilitation, and legal issues were collected. Post-LT, all were encouraged to participate in rehabilitation programs and underwent interval phosphatidylethanol (PeTH) testing. Pts with ALD were stratified by < or > 6 month sobriety prior to listing. Those with <6 month were further stratified as acute alcoholic hepatitis (AH) by NIAAA criteria and non-AH. The primary outcome was utility of the SALT (<5 vs. ≥5) and HRAR (<3 vs. ≥3) scores to predict return to alcohol use (+PeTH) within 1 year after LT. RESULTS: Of the 365 LT, 86 had > 6 month sobriety and 85 had <6 month sobriety; 41 with AH and 44 non-AH. In those with AH, the mean time of abstinence to LT was 58 days, and 71% failed prior rehabilitation. Following LT, return to drinking was similar in the AH (24%) compared to <6M non-AH (15%) and >6M ALD (22%). Only 4% had returned to heavy drinking. The accuracy of both the SALT and HRAR scores to predict return to alcohol was low (accuracy 61-63%) with poor sensitivity (46% and 37%), specificity (67-68%), positive predictive value (22-26%) with moderate negative predictive value (NPV) (81-83%), respectively with higher NPVs (95%) in predicting return to heavy drinking. CONCLUSIONS: Both SALT and HRAR scores had good NPV in identifying patients at low risk for recidivism.

Development of Clinical Algorithm Utilizing Vibration-Controlled Transient Elastography to Detect Advanced Hepatic Fibrosis in Liver Transplant Recipients.

INTRODUCTION: Vibration-controlled transient elastography (VCTE) based liver stiffness measurement (LSM) is an excellent 'rule-out' test for advanced hepatic fibrosis in liver transplant (LT) recipients, however, its ability to 'rule-in' the disease is suboptimal. The study aimed to improve diagnostic performance of LSM in LT recipients. METHODS: Adult LT recipients with a liver biopsy and VCTE were included (N = 150). Sequential covering analysis was performed to create rules to identify patients at low or high risk for advanced fibrosis (stage 3-4). RESULTS: Advanced hepatic fibrosis was excluded in patients with either LSM < 7.45 kPa (n = 72) or 7.45 ≤ LSM < 12.1 kPa and time from LT < 5.6 years (n = 25). Conversely, likelihood of advanced fibrosis was 95% if patients had LSM > 14.1 and controlled attenuation parameter > 279 dB/m (n = 21). Thus, 118 (79%) were correctly identified and 32 (21%) would have required a biopsy to establish the diagnosis. Compared to previously established LSM based cutoff values of 10.5 kPa (Youden index) and 13.3 kPa (maximized specificity), the false positive rates of sequential covering analysis was 1% compared to 16.5% with LSM ≥ 10.5 kPa and 8.3% with LSM ≥ 13.3 kPa. The true positive rates were comparable at 87% for sequential covering analysis, 93% for LSM ≥ 10.5 kPa and 83% for LSM ≥ 13.3 kPa. CONCLUSION: The proposed clinical sequential covering analysis allows for better risk stratification when evaluating for advanced fibrosis in LT recipients compared to LSM alone. Additional efforts are necessary to further reduce the number of patients with indeterminate results in whom a liver biopsy may be required.

Primary Care Physicians' Satisfaction With Interoperable Health Information Technology.

Importance: Enabling widespread interoperability-the ability of health information technology systems to exchange information and to use that information without special effort-is a primary focus of public policy on health information technology. More information on clinicians' experience using that technology can serve as one measure of the impact of that policy. Objective: To assess primary care physician perspectives on the state of interoperability. Design, Setting, and Participants: A cross-sectional survey of family medicine physicians in the US was conducted from December 12, 2021, to October 12, 2022. A sample of family medicine physicians who completed the Continuous Certification Questionnaire (CCQ), a required part of the American Board of Family Medicine certification process, which has a 100% response rate, were invited to participate. Main Outcomes and Measures: Eighteen items on the CCQ assessed experience accessing and using various information from outside organizations, including medications, immunizations, and allergies. Results: A total of 2088 physicians (1053 women [50%]; age reported categorically as either ≥50 years or <50 years) completed the CCQ interoperability questions in 2022. Of these respondents, 35% practiced in hospital or health system-owned practices, while 27% practiced in independently owned practices. Eleven percent were very satisfied with their ability to electronically access all 10 types of information from outside organizations included on the questionnaire, and a mean of 70% were at least somewhat satisfied. A total of 23% of family medicine physicians reported information from outside organizations was very easy to use, and an additional 65% reported that information was somewhat easy to use. Only 8% reported that information from different electronic health record (EHR) developers' products was very easy to use compared with 38% who reported information from the same EHR developer's product was very easy to use. Conclusions and Relevance: This survey study of family medicine physicians found modest and uneven improvement in physicians' experience with interoperability. These findings suggest that substantial heterogeneity in satisfaction by information type, source of information, EHR, practice type, ownership, and patient population necessitates diverse policy and strategies to improve interoperability.

Discovery of novel anticancer flavonoids as potential HDAC2 inhibitors: virtual screening approach based on molecular docking, DFT and molecular dynamics simulations studies.

Virtual screening of a library of 329 flavonoids obtained from the NPACT database was performed to find out potential novel HDAC2 inhibitors. Eleven out of 329 selected flavonoids were screened based on molecular docking studies, as they have higher binding affinities than the standard drugs vorinostat and panobinostat. All screened compounds occupying the catalytic site of HDAC2 showed important molecular interaction with Zn2+ and other important amino acids in the binding pocket. The screened compounds were validated using ADMET filtration and bioactivity prediction from which we obtained six compounds, NPACT00270, NPACT00676, NPACT00700, NPACT001008, NPACT001054, and NPACT001407, which were analyzed using DFT studies. DFT studies were performed for all six screened flavonoids. In DFT studies, three flavonoids, NPACT00700, NPACT001008, and NPACT001407, were found to be better based on HOMO-LUMO and molecular electrostatic potential (MEP) analyses. Furthermore, MD simulations were performed for 100 ns for the three compounds. In the MD analysis, NPACT001407 was found to be more stable in the active site of HDAC2 as zinc formed a coordination bond with ASP181, HIS183, ASP269, and GLY305, along with two hydroxyl groups of the ligand. Our findings reveal that these flavonoids can interact as ligands with the active site of HDAC2. Because of the absence of a hydroxamate group in flavonoids, there are no possibilities for the formation of isocyanate. This suggests that the major drawback of current HDACs inhibitors may be solved. Further experimental validation is needed to understand the selectivity of flavonoids as HDAC2 inhibitors. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03912-5.

Impact of Liver Transplantation on Adipose Tissue Compartments and Its Association With Metabolic Sequela.

BACKGROUND: Loss of skeletal muscle can be accompanied by an increase in adipose tissue leading to sarcopenic obesity. There are limited data on how liver transplantation (LT) might impact adipose tissue compartments, particularly among patients with metabolically active disease, such as nonalcoholic steatohepatitis (NASH) and subsequent metabolic sequela. METHODS: Skeletal muscle, visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) were measured using cross-sectional imaging performed in 190 patients pre-LT, 6 mo post-LT and 12 mo post-LT. Changes in adipose tissue and their impact on metabolic diseases were determined in patients transplanted for NASH versus non-NASH. RESULTS: Skeletal muscle, VAT, and SAT were similar in patients with NASH and non-NASH pre-LT despite a higher burden of metabolic diseases in patients with NASH. Following LT, no significant differences between skeletal muscle and SAT were observed in the entire cohort and among patients with NASH (versus non-NASH). LT recipients with the highest muscle mass pre-LT were at the greatest risk for muscle loss post-LT. A time-dependent increase in VAT was noted post-LT, which was more robust among patients with a history of NASH cirrhosis. In adjusted multivariate analysis, NASH versus non-NASH was a strong predictor of post-LT increase in VAT (ß-coefficient 3.00, P = 0.04). Pre-LT VAT was an independent predictor of post-LT serum triglycerides (ß-coefficient 5.49 ± 2.78, P = 0.05) and low-density lipoprotein cholesterol (ß-coefficient 1.80 ± 0.75, P = 0.02). A trend between pre-LT VAT and diabetes was noted but did not reach statistical significance. CONCLUSIONS: VAT but not SAT increases rapidly after LT, especially among patients transplanted for NASH cirrhosis and predicts future metabolic burden.

Reduced metabolic flexibility is a predictor of weight gain among liver transplant recipients.

Metabolic flexibility is the ability to match biofuel availability to utilization and is inversely associated with increased metabolic burden among liver transplant (LT) recipients. The present study evaluated the impact of metabolic flexibility on weight gain following LT. LT recipients were enrolled prospectively (n = 47) and followed for 6 months. Metabolic flexibility was measured using whole-room calorimetry and is expressed as a respiratory quotient (RQ). Peak RQ represents maximal carbohydrate metabolism and occurs in the post-prandial state, while trough RQ represents maximal fatty acid metabolism occurring in the fasted state. The clinical, metabolic, and laboratory characteristics of the study cohort of lost weight (n = 14) and gained weight (n = 33) were similar at baseline. Patients who lost weight were more likely to reach maximal RQ (maximal carbohydrate oxidation) early and rapidly transitioned to trough RQ (maximal fatty acid oxidation). In contrast, patients who gained weight had delayed time to peak RQ and trough RQ. In multivariate modeling, time to peak RQ (ß-coefficient 0.509, p = 0.01), time from peak RQ to trough RQ (ß-coefficient 0.634, p = 0.006), and interaction between time to peak RQ to trough RQ and fasting RQ (ß-coefficient 0.447, p = 0.02) directly correlated with the severity of weight gain. No statistically significant relationship between peak RQ, trough RQ, and weight change was demonstrated. Inefficient transition between biofuels (carbohydrates and fatty acids) is associated with weight gain in LT recipients that is independent of clinical metabolic risk. These data offer novel insight into the physiology of obesity after LT with the potential to develop new diagnostics and therapeutics.

Isolated Colonic Varices in Pancreatic Adenocarcinoma.

Colonic varices are a rare subtype of ectopic varices and form due to portal hypertension, splenic or portal vein thrombosis, and mesenteric vein obstruction. When present, they are most common in the rectum. We discuss a patient with hematochezia who had isolated right-sided colonic varices related to pancreatic cancer, which is rare. The mass involved the superior mesenteric vein, leading to left-sided portal hypertension and resultant varices. These are difficult to diagnosis because they flatten with insufflation on colonoscopy, so computed tomography or angiography is the gold standard. Treatment options are limited and may require a multidisciplinary approach.

Hospitals' electronic access to information needed to treat COVID-19.

Objective: To understand whether hospitals had electronic access to information needed to treat COVID-19 patients and identify factors contributing to differences in information availability. Materials and methods: Using 2021 data from the American Hospital Association IT Supplement, we produced national estimates on the electronic availability of information needed to treat COVID-19 at US non-federal acute care hospitals (N = 1976) and assessed differences in information availability by hospital characteristics and engagement in interoperable exchange. Results: In 2021, 38% of hospitals electronically received information needed to effectively treat COVID-19 patients. Information availability was significantly higher among higher-resourced hospitals and those engaged in interoperable exchange (44%) compared to their counterparts. In adjusted analyses, hospitals engaged in interoperable exchange were 140% more likely to receive needed information electronically compared to those not engaged in exchange (relative risk [RR]=2.40, 95% CI, 1.82-3.17, P<.001). System member hospitals (RR = 1.62, 95% CI, 1.36-1.92, P<.001) and major teaching hospitals (RR = 1.35, 95% CI, 1.10-1.64, P=.004) were more likely to have information available; for-profit hospitals (RR = 0.14, 95% CI, 0.08-0.24, P<.001) and hospitals in high social deprivation areas (RR = 0.83, 95% CI, 0.71-0.98, P = .02) were less likely to have information available. Discussion: Despite high rates of hospitals' engagement in interoperable exchange, hospitals' electronic access to information needed to support the care of COVID-19 patients was limited. Conclusion: Limited electronic access to patient information from outside sources may impede hospitals' ability to effectively treat COVID-19 and support patient care during public health emergencies.

Enhancing the dissolution rate of poorly soluble drug Febuxostat using spray dried amorphous solid dispersion technique / Mejora de la tasa de disolución del fármaco poco soluble Febuxostat utilizando la técnica de dispersión de sólido amorfo secado por aspersión

Introducción: El febuxostat pertenece a los fármacos clase II del Sistema de Clasificación Biofarmacéutica, los cuales presentan baja solubilidad y alta permeabilidad. La dispersión sólida amorfa es una de las técnicas que pueden ser útiles para mejorar la solubilidad y las características del polvo. Objetivo: optimizar la concentración de polímeros hidrofílicos e hidrofóbicos para mejorar la velocidad de disolución y la solubilidad de las tabletas de febuxostat. Métodos: La dispersión sólida amorfa de febuxostat se preparó mediante el método de secado por aspersión utilizando Kolliphor P237 (1:2). Esta dispersión sólida amorfa se utilizó además para comprimir el comprimido. Para mejorar la solubilidad y la tasa de disolución, se aplicó un diseño factorial completo para optimizar la concentración crítica de KollidonSR e hidroxi propil metil celulosa (HPMC K4M). Los comprimidos preparados se caracterizaron por parámetros de precompresión y poscompresión. Resultados: La velocidad de liberación del fármaco se mantuvo mediante la formulación de una técnica de dispersión sólida amorfa. Se encontró que el lote optimizado (FSRT-OB) era apto para la liberación promedio del 93,30 % del fármaco en forma de liberación sostenida hasta 12 horas. Los datos de la cinética de liberación sugieren que la liberación del fármaco estuvo controlada por una combinación de mecanismo de relajación de cadena y difusión. Se encontró que la concentración optimizada para Kollidon SR y HPMC K4M era 38,50 % y 7,72 % respectivamente. Conclusión: La técnica de dispersión sólida amorfa es útil para mejorar la solubilidad, la velocidad de disolución y la biodisponibilidad de la tableta de Febuxostat. (AU)

Introduction: Febuxostat belongs to Biopharmaceutical classification system (BCS) class II drugs, which have low solubility and high permeability. Amorphous solid dispersion is one of the techniques which can be useful to improve solubility and powder characteristics. Objective: To optimize the concentration of hydrophilic and hydrophobic polymers to improve the dissolution rate and solubility of febuxostat tablets. Methods: The amorphous solid dispersion of febuxostat was prepared by spray drying method using Kolliphor P237 (1:2). This amorphous solid dispersion was further used to compress the tablet. To improve solubility and dissolu-tion rate, a full factorial design was applied to optimize the critical concentration of Kollidon SR and hydroxypropyl methyl cellulose (HPMC K4M). The prepared tablets were characterized by pre-compression and post-compression parameters. Result: The rate of drug release was sustained by formulating an amorphous solid dispersion technique. The optimized batch (FSRT-OB) was found to be fit for release average 93.30 % of the drug in sustain release manner up to 12hrs. The release kinetic data suggests that the drug release was controlled by combination of diffusion and chain relaxation mechanism. The optimized concentration for Kollidon SR and HPMC K4Mwas found to be 38.50 % and 7.72 % respectively. Conclusion: Amorphous solid dispersion technique is useful to enhance solubility, dissolution rate, and bioavail-ability of the Febuxostat tablet. (AU)

Increased 3-O-sulfated heparan sulfate in Alzheimer's disease brain is associated with genetic risk gene HS3ST1.

HS3ST1 is a genetic risk gene associated with Alzheimer's disease (AD) and overexpressed in patients, but how it contributes to the disease progression is unknown. We report the analysis of brain heparan sulfate (HS) from AD and other tauopathies using a LC-MS/MS method. A specific 3-O-sulfated HS displayed sevenfold increase in the AD group (n = 14, P < 0.0005). Analysis of the HS modified by recombinant sulfotransferases and HS from genetic knockout mice revealed that the specific 3-O-sulfated HS is made by 3-O-sulfotransferase isoform 1 (3-OST-1), which is encoded by the HS3ST1 gene. A synthetic tetradecasaccharide (14-mer) carrying the specific 3-O-sulfated domain displayed stronger inhibition for tau internalization than a 14-mer without the domain, suggesting that the 3-O-sulfated HS is used in tau cellular uptake. Our findings suggest that the overexpression of HS3ST1 gene may enhance the spread of tau pathology, uncovering a previously unidentified therapeutic target for AD.

Interoperability among hospitals treating populations that have been marginalized.

OBJECTIVE: To test whether differences in hospital interoperability are related to the extent to which hospitals treat groups that have been economically and socially marginalized. DATA SOURCES AND STUDY SETTING: Data on 2393 non-federal acute care hospitals in the United States from the American Hospital Association Information Technology Supplement fielded in 2021, the 2019 Medicare Cost Report, and the 2019 Social Deprivation Index. STUDY DESIGN: Cross-sectional analysis. DATA COLLECTION/EXTRACTION METHODS: We identified five proxy measures related to marginalization and assessed the relationship between those measures and the likelihood that hospitals engaged in all four domains of interoperable information exchange and participated in national interoperability networks in cross-sectional analysis. PRINCIPAL FINDINGS: In unadjusted analysis, hospitals that treated patients from zip codes with high social deprivation were 33% less likely to engage in interoperable exchange (Relative Risk = 0.67, 95% CI: 0.58-0.76) and 24% less likely to participate in a national network than all other hospitals (RR = 0.76; 95% CI: 0.66-0.87). Critical Access Hospitals (CAH) were 24 percent less likely to engage in interoperable exchange (RR = 0.76; 95% CI: 0.69-0.83) but not less likely to participate in a national network (RR = 0.97; 95% CI: 0.88-1.06). No difference was detected for 2 measures (high Disproportionate Share Hospital percentage and Medicaid case mix) while 1 was associated with a greater likelihood to engage (high uncompensated care burden). The association between social deprivation and interoperable exchange persisted in an analysis examining metropolitan and rural areas separately and in adjusted analyses accounting for hospital characteristics. CONCLUSIONS: Hospitals that treat patients from areas with high social deprivation were less likely to engage in interoperable exchange than other hospitals, but other measures were not associated with lower interoperability. The use of area deprivation data may be important to monitor and address hospital clinical data interoperability disparities to avoid related health care disparities.

Experiences with information blocking in the United States: a national survey of hospitals.

OBJECTIVE: The 21st Century Cures Act Final Rule's information blocking provisions, which prohibited practices likely to interfere with, prevent, or materially discourage access, exchange, or use of electronic health information (EHI), began to apply to a limited set of data elements in April 2021 and expanded to all EHI in October 2022. We sought to describe hospital leaders' perceptions of the prevalence of practices that may constitute information blocking, by actor and hospital characteristics, following the rule's applicability date. MATERIALS AND METHODS: Cross-sectional analysis of a national survey of hospitals fielded in 2021. The analytic sample included 2092 nonfederal acute care hospitals in the United States. We present descriptive statistics on the perception of the prevalence of information blocking and results of multivariate regression models examining the association between hospital, health information technology (IT) developer and market characteristics and the perception of information blocking. RESULTS: Overall, 42% of hospitals reported observing some behavior they perceived to be information blocking. Thirty-six percent of responding hospitals perceived that healthcare providers either sometimes or often engaged in practices that may constitute information blocking, while 17% and 19% perceived that health IT developers (such as EHR developers) and State, regional and/or local health information exchanges did the same, respectively. Prevalence varied by health IT developer market share, hospital for-profit status, and health system market share. CONCLUSIONS AND RELEVANCE: These results support the value of efforts to further reduce friction in the exchange of EHI and support the need for continued observation to provide a sense of the prevalence of information blocking practices and for education and awareness of information blocking regulations.