Intention-to-treat outcomes of patients with hepatocellular carcinoma receiving immunotherapy before liver transplant: the multicenter VITALITY study.

BACKGROUND AND AIMS: The use of immune checkpoint inhibitors (ICI) in patients with advanced hepatocellular carcinoma (HCC) has become widespread with encouraging outcomes in the neoadjuvant setting. Safety and intention to treat (ITT) outcomes in the peri transplant setting are currently based on small and heterogenous single center reports. METHODS: This first multiregional US study (2016-2023) included 117 consecutive HCC patients assessed for LT and treated preoperatively with ICIs. Intention to treat ITT and survival analyses were conducted with evaluation of post LT rejection rates. RESULTS: In total, 86 (73.5%) patients exceeded MC and 65 (75.6%) were successfully downstaged (DS) within a median of 5.6 months. 43 (36.7%) underwent transplantation, including 18 (15.4%) within MC and 23 (19.7%) initially beyond and DS. Overall, 94% of the cohort received concurrent ICIs and locoregional therapies. No grade 4-5 adverse events occurred on the waiting list. The 3-year cumulative probability of dropout was 28% for those within MC and 48% for those beyond. Independent predictors of dropout included: being beyond MC (p<0.001), AFP doubling from baseline (p=0.014) and radiographic responses (p<0.001). The 3-year ITT survival was 71.1% (73.5% within MC vs 69.7% beyond MC, p=0.329), with 3-year post LT survival rate of 85%. Post-LT rejection occurred in 7 patients, six received their last dose of ICI less than 3 months prior to LT, resulting in one graft loss. CONCLUSIONS: The first multicenter evaluation of HCC patients receiving ICI pre-LT demonstrates favorable survival and safety outcomes, justifying continued utilization and further evaluation of this strategy in clinical practice. High tumor burden, doubling of AFP levels, and radiographic response were identified as predictors of unfavorable oncologic outcomes. IMPACT AND IMPLICATIONS: The first multicenter evaluation of pre-transplant immune-checkpoint-inhibitors in hepatocellular carcinoma to show promising intention-to-treat survival, safety and rejection rates. Immune-checkpoint-inhibitors, either alone or combined with LRT, demonstrate reliable efficacy. This preoperative strategy could be particularly beneficial for high-risk patients, including those requiring downstaging or with elevated AFP levels despite locoregional treatment. These findings fill current knowledge gaps and offer reassuring evidence for the feasibility of pre-transplant use of immune-checkpoint-inhibitors, pending results from ongoing trials.

Development and Validation of a Noninvasive Model for the Detection of High-Risk Varices in Patients with Unresectable HCC.

BACKGROUND & AIMS: Noninvasive variceal risk stratification systems have not been validated in patients with hepatocellular carcinoma (HCC), which presents logistical barriers for patients in the setting of systemic HCC therapy. We aimed to develop and validate a noninvasive algorithm for the prediction of varices in patients with unresectable HCC. METHODS: We performed a retrospective cohort study in 21 centers in the United States including adult patients with unresectable HCC and Child-Pugh A5-B7 cirrhosis diagnosed between 2007 and 2019. We included patients who completed an esophagogastroduodonoscopy (EGD) within 12 months of index imaging but before HCC treatment. We divided the cohort into a 70:30 training set and validation set, with the goal of maximizing negative predictive value (NPV) to avoid EGD in low-risk patients. RESULTS: We included 707 patients (median age, 64.6 years; 80.6% male; 74.0% White). Median time from HCC diagnosis to EGD was 47 (interquartile range, 114) days, with 25.0% of patients having high-risk varices. A model using clinical variables alone achieved an NPV of 86.3% in the validation cohort, whereas a model integrating clinical and imaging variables had an NPV 97.4% in validation. The clinical and imaging model would avoid EGDs in more than half of low-risk patients while misclassifying 7.7% of high-risk patients. CONCLUSIONS: A model incorporating clinical and imaging data can accurately predict the absence of high-risk varices in patients with HCC and avoid EGD in many low-risk patients before the initiation of systemic therapy, thus expediting their care and avoiding treatment delays.

Role of MEF2C in the Endothelial Cells Derived from Human Induced Pluripotent Stem Cells.

Human induced pluripotent stem cells (hiPSCs) not only provide an abundant source of vascular cells for potential therapeutic applications in vascular disease but also constitute an excellent model for understanding the mechanisms that regulate the differentiation and the functionality of vascular cells. Here, we reported that myocyte enhancer factor 2C (MEF2C) transcription factor, but not any other members of the MEF2 family, was robustly upregulated during the differentiation of vascular progenitors and endothelial cells (ECs) from hiPSCs. Vascular endothelial growth factors (VEGF) strongly induced MEF2C expression in endothelial lineage cells. The specific upregulation of MEF2C during the commitment of endothelial lineage was dependent on the extracellular signal regulated kinase (ERK). Moreover, knockdown of MEF2C with shRNA in hiPSCs did not affect the differentiation of ECs from these hiPSCs, but greatly reduced the migration and tube formation capacity of the hiPSC-derived ECs. Through a chromatin immunoprecipitation-sequencing, genome-wide RNA-sequencing, quantitative RT-PCR, and immunostaining analyses of the hiPSC-derived endothelial lineage cells with MEF2C inhibition or knockdown compared to control hiPSC-derived ECs, we identified TNF-related apoptosis inducing ligand (TRAIL) and transmembrane protein 100 (TMEM100) as novel targets of MEF2C. This study demonstrates an important role for MEF2C in regulating human EC functions and highlights MEF2C and its downstream effectors as potential targets to treat vascular malfunction-associated diseases.

Utilization of Radiomics Features Extracted From Preoperative Medical Images to Detect Metastatic Lymph Nodes in Cholangiocarcinoma and Gallbladder Cancer Patients: A Systemic Review and Meta-analysis.

OBJECTIVES: This study aimed to determine the methodological quality and evaluate the diagnostic performance of radiomics features in detecting lymph node metastasis on preoperative images in patients with cholangiocarcinoma and gallbladder cancer. METHODS: Publications between January 2005 and October 2022 were considered for inclusion. Databases such as Pubmed/Medline, Scopus, Embase, and Google Scholar were searched for relevant studies. The quality of the methodology of the manuscripts was determined using the Radiomics Quality Score and Quality Assessment of Diagnostic Accuracy Studies 2. Pooled results with corresponding 95% confidence intervals (CIs) were calculated using the DerSimonian-Liard method (random-effect model). Forest plots were used to visually represent the diagnostic profile of radiomics signature in each of the data sets pertaining to each study. Fagan plot was used to determine clinical applicability. RESULTS: Overall sensitivity was 0.748 (95% CI, 0.703-0.789). Overall specificity was 0.795 (95% CI, 0.742-0.839). The combined negative likelihood ratio was 0.299 (95% CI, 0.266-0.350), and the positive likelihood ratio was 3.545 (95% CI, 2.850-4.409). The combined odds ratio of the studies was 12.184 (95% CI, 8.477-17.514). The overall summary receiver operating characteristics area under the curve was 0.83 (95% CI, 0.80-0.86). Three studies applied nomograms to 8 data sets and achieved a higher pooled sensitivity and specificity (0.85 [0.80-0.89] and 0.85 [0.71-0.93], respectively). CONCLUSIONS: The pooled analysis showed that predictive models fed with radiomics features achieve good sensitivity and specificity in detecting lymph node metastasis in computed tomography and magnetic resonance imaging images. Supplementation of the models with biological correlates increased sensitivity and specificity in all data sets.

Perceived Constraints to Pickleball Participation Among Black Older Adults.

Pickleball offers sociopsychological and physical activity benefits for older adults but lacks racial diversity. The purpose of this study was to identify constraints to pickleball participation with Black older adults (65+ years) as well as examine differences based on physical activity and sex. A Qualtrics panel included Black older adults (N = 292) who have heard of pickleball and are physically able to play but have not played. Results found Knowledge, Accessibility, Interpersonal, and Interest were the most salient constraints overall. Multivariate analysis of variance found that those who report low physical activity had significantly higher Interpersonal, Psychological, Costs, and Perceived Racism constraints. Additionally, females report significantly higher Knowledge, Psychological, and Cost constraints compared to males. The results further the theoretical application of constraints to physical activity research and provide insights into practitioner implications to grow the sport of pickleball for Black older adults.

Temporal collections to study invasion biology.

Biological invasions represent an extraordinary opportunity to study evolution. This is because accidental or deliberate species introductions have taken place for centuries across large geographical scales, frequently prompting rapid evolutionary transitions in invasive populations. Until recently, however, the utility of invasions as evolutionary experiments has been hampered by limited information on the makeup of populations that were part of earlier invasion stages. Now, developments in ancient and historical DNA technologies, as well as the quickening pace of digitization for millions of specimens that are housed in herbaria and museums globally, promise to help overcome this obstacle. In this review, we first introduce the types of temporal data that can be used to study invasions, highlighting the timescale captured by each approach and their respective limitations. We then discuss how ancient and historical specimens as well as data available from prior invasion studies can be used to answer questions on mechanisms of (mal)adaptation, rates of evolution, or community-level changes during invasions. By bridging the gap between contemporary and historical invasive populations, temporal data can help us connect pattern to process in invasion science. These data will become increasingly important if invasions are to achieve their full potential as experiments of evolution in nature.

Changes in children's dental fear after restorative treatment under different sedation types: Associations with parents' experiences and dental health.

BACKGROUND: Dentists often use sedative medications such as nitrous oxide inhaled sedation and general anesthesia (GA) to help decrease patient fear and manage paediatric patients' behavior during treatment. AIM: The goal of this study was to examine factors associated with dental fear changes after restorative dental treatment under nitrous oxide or GA in children 4-12 years old. DESIGN: A prospective cohort study of 124 children examined changes in dental fear, number of treatment visits, and parental factors among children receiving restorative dental treatment under nitrous oxide (n = 68) or GA (n = 56) sedation. Data were collected at pretreatment (T1), 16 weeks post-treatment (T2), and at 29-month follow-up (T3). RESULTS: Dental fear increased slightly, but not significantly, under both forms of sedation between T1 and T3. Children's dental fear was associated with parents' poor dental experiences and oral health, but not with number of treatment visits. CONCLUSIONS: Progression of children's dental fear seems not dependent solely on the type of sedation used but is likely predicted by factors including pretreatment dental fear and dental needs. Dentists recommending sedation for children's dental care may consider pretreatment dental need, fear levels, and parental factors when determining which type of sedation to use.

Urine DNA biomarkers for hepatocellular carcinoma screening.

BACKGROUND: Hepatocellular carcinoma (HCC) occurs in a well-defined high-risk patient population, but better screening tests are needed to improve sensitivity and efficacy. Therefore, we investigated the use of urine circulating tumour DNA (ctDNA) as a screening test. METHODS: Candidate markers in urine were selected from HCC and controls. We then enrolled 609 patients from five medical centres to test the selected urine panel. A two-stage model was developed to combine AFP and urine panel as a screening test. RESULTS: Mutated TP53, and methylated RASSF1a, and GSTP1 were selected as the urine panel markers. Serum AFP outperformed the urine panel among all cases of HCC, but the urine panel identified 49% of HCC cases with low AFP < 20 ng/ml. Using the two-stage model, the combined AFP and urine panel identified 148 of the 186 HCC cases (79.6% sensitivity at 90% specificity), which was 30% more than the cases detected with serum AFP alone. It also increased early-stage HCC detection from 62% to 92% (BCLC stage 0), and 40% to 77% (BCLC stage A). CONCLUSION: Urine ctDNA has promising diagnostic utility in patients in HCC, especially in those with low AFP and can be used as a potential non-invasive HCC screening test.

HDACs regulate the differentiation of endothelial cells from human iPSCs.

Human induced pluripotent stem cells (hiPSCs) possess the potential to differentiate toward vascular cells including endothelial cells (ECs), pericytes, and smooth muscle cells. Epigenetic mechanisms including DNA methylation and histone modification play a crucial role in regulating lineage differentiation and specification. Herein, we utilized a three-stage protocol to induce differentiation of mesoderm, vascular progenitors, and ECs from hiPSCs and investigated the regulatory effects of histone acetylation on the differentiation processes. We found that the expression of several histone deacetylases (HDACs), including HDAC1, HDAC5, and HDAC7, were greatly upregulated at the second stage and downregulated at the third stage. Interestingly, although HDAC1 remained in the nucleus during the EC differentiation, HDAC5 and HDAC7 displayed cytosol/nuclear translocation during the differentiation process. Inhibition of HDACs with sodium butyrate (NaBt) or BML210 could hinder the differentiation of vascular progenitors at the second stage and facilitate EC induction at the third stage. Further investigation revealed that HDAC may modulate the stepwise EC differentiation via regulating the expression of endothelial transcription factors ERG, ETS1, and MEF2C. Opposite to the expression of EC markers, the smooth muscle/pericyte marker ACTA2 was upregulated at the second stage and downregulated at the third stage by NaBt. The stage-specific regulation of ACTA2 by HDAC inhibition was likely through regulating the expression of TGFß2 and PDGFB. This study suggests that HDACs play different roles at different stages of EC induction by promoting the commitment of vascular progenitors and impeding the later stage differentiation of ECs.

Development, Practice Patterns, and Early Clinical Outcomes of a Multidisciplinary Liver Cancer Clinic.

Multidisciplinary care has been associated with improved survival in patients with primary liver cancers. We report the practice patterns and real world clinical outcomes for patients presenting to the Johns Hopkins Hospital (JHH) multidisciplinary liver clinic (MDLC). We analyzed hepatocellular carcinoma (HCC, n = 100) and biliary tract cancer (BTC, n = 76) patients evaluated at the JHH MDLC in 2019. We describe the conduct of the clinic, consensus decisions for patient management based on stage categories, and describe treatment approaches and outcomes based on these categories. We describe subclassification of BCLC stage C into 2 parts, and subclassification of cholangiocarcinoma into 4 stages. A treatment consensus was finalized on the day of MDLC for the majority of patients (89% in HCC, 87% in BTC), with high adherence to MDLC recommendations (91% in HCC, 100% in BTC). Among patients presenting for a second opinion regarding management, 28% of HCC and 31% of BTC patients were given new therapeutic recommendations. For HCC patients, at a median follow up of 11.7 months (0.7-19.4 months), median OS was not reached in BCLC A and B patients. In BTC patients, at a median follow up of 14.2 months (0.9-21.1 months) the median OS was not reached in patients with resectable or borderline resectable disease, and was 11.9 months in patients with unresectable or metastatic disease. Coordinated expert multidisciplinary care is feasible for primary liver cancers with high adherence to recommendations and a change in treatment for a sizeable minority of patients.

Interdisciplinary Approach to Building Functionality for Weather Hazards.

It is estimated that in the United States, people spend 90% of their time in buildings. In order to ensure quality of life for communities, we propose a human-centric design approach to building "functionality." "Functionality" is defined as the set of "essential services" to meet occupant needs for safety and well-being. These services include lighting, heating and cooling, ventilation, water supply, and wastewater management. At present, a multidisciplinary top-down approach exists where owners dictate the building operations to architects. Our central thesis is that a bottom-up approach based on occupant safety and well-being should drive the functionality design process. Research on occupant well-being conducted by social scientists should be considered by architects in creating the building functionality layout. One of the results of this research should be a set of the type and level of services required for well-being. Architects and engineers should work together to design physical systems to ensure that the derived acceptable levels of the services not be exceeded for various frequencies of occurrence tied to the weather conditions at the site. In order to make this approach viable, minimal amounts of continuous electric power must be made available such as through building integrated photovoltaic panels. The corresponding onsite power generation and storage needs are therefore a critical aspect of the proposed formulation. It is anticipated that significant interactions during the iterative building design process among the architects and social scientists with the engineering disciplines will change an existing multidisciplinary approach into an interdisciplinary one.

Integrating shared decision-making into primary care: lessons learned from a multi-centre feasibility randomized controlled trial.

BACKGROUND: MyDiabetesPlan is a web-based, interactive patient decision aid that facilitates patient-centred, diabetes-specific, goal-setting and shared decision-making (SDM) with interprofessional health care teams. OBJECTIVE: Assess the feasibility of (1) conducting a cluster randomized controlled trial (RCT) and (2) integrating MyDiabetesPlan into interprofessional primary care clinics. METHODS: We conducted a cluster RCT in 10 interprofessional primary care clinics with patients living with diabetes and at least two other comorbidities; half of the clinics were assigned to MyDiabetesPlan and half were assigned to usual care. To assess recruitment, retention, and resource use, we used RCT conduct logs and financial account summaries. To assess intervention fidelity, we used RCT conduct logs and website usage logs. To identify barriers and facilitators to integration of MyDiabetesPlan into clinical care across the IP team, we used audiotapes of clinical encounters in the intervention groups. RESULTS: One thousand five hundred and ninety-seven potentially eligible patients were identified through searches of electronic medical records, of which 1113 patients met the eligibility criteria upon detailed chart review. A total of 425 patients were randomly selected; of these, 213 were able to participate and were allocated (intervention: n = 102; control: n = 111), for a recruitment rate of 50.1%. One hundred and fifty-one patients completed the study, for a retention rate of 70.9%. A total of 5745 personnel-hours and $6104 CAD were attributed to recruitment and retention activities. A total of 179 appointments occurred (out of 204 expected appointments-two per participant over the 12-month study period; 87.7%). Forty (36%), 25 (23%), and 32 (29%) patients completed MyDiabetesPlan at least twice, once, and zero times, respectively. Mean time for completion of MyDiabetesPlan by the clinician and the patient during initial appointments was 37 min. From the clinical encounter transcripts, we identified diverse strategies used by clinicians and patients to integrate MyDiabetesPlan into the appointment, characterized by rapport building and individualization. Barriers to use included clinician-related, patient-related, and technical factors. CONCLUSION: An interprofessional approach to SDM using a decision aid was feasible. Lower than expected numbers of diabetes-specific appointments and use of MyDiabetesPlan were observed. Addressing facilitators and barriers identified in this study will promote more seamless integration into clinical care. Trial registration Clinicaltrials.gov Identifier: NCT02379078. Date of Registration: February 11, 2015. Protocol version: Version 1; February 26, 2015.

New Avenues for the Treatment of Huntington's Disease.

Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG expansion in the HD gene. The disease is characterized by neurodegeneration, particularly in the striatum and cortex. The first symptoms usually appear in mid-life and include cognitive deficits and motor disturbances that progress over time. Despite being a genetic disorder with a known cause, several mechanisms are thought to contribute to neurodegeneration in HD, and numerous pre-clinical and clinical studies have been conducted and are currently underway to test the efficacy of therapeutic approaches targeting some of these mechanisms with varying degrees of success. Although current clinical trials may lead to the identification or refinement of treatments that are likely to improve the quality of life of those living with HD, major efforts continue to be invested at the pre-clinical level, with numerous studies testing novel approaches that show promise as disease-modifying strategies. This review offers a detailed overview of the currently approved treatment options for HD and the clinical trials for this neurodegenerative disorder that are underway and concludes by discussing potential disease-modifying treatments that have shown promise in pre-clinical studies, including increasing neurotropic support, modulating autophagy, epigenetic and genetic manipulations, and the use of nanocarriers and stem cells.

Cardiac adaptation to exercise training in health and disease.

The heart is the primary pump that circulates blood through the entire cardiovascular system, serving many important functions in the body. Exercise training provides favorable anatomical and physiological changes that reduce the risk of heart disease and failure. Compared with pathological cardiac hypertrophy, exercise-induced physiological cardiac hypertrophy leads to an improvement in heart function. Exercise-induced cardiac remodeling is associated with gene regulatory mechanisms and cellular signaling pathways underlying cellular, molecular, and metabolic adaptations. Exercise training also promotes mitochondrial biogenesis and oxidative capacity leading to a decrease in cardiovascular disease. In this review, we summarized the exercise-induced adaptation in cardiac structure and function to understand cellular and molecular signaling pathways and mechanisms in preclinical and clinical trials.

Clinical course of COVID-19 in a liver transplant recipient on hemodialysis and response to tocilizumab therapy: A case report.

The novel coronavirus disease 2019 (COVID-19) is a highly infectious and rapidly spreading disease. There are limited published data on the epidemiology and outcomes of COVID-19 infection among organ transplant recipients. After initial flulike symptoms, progression to an inflammatory phase may occur, characterized by cytokine release rapidly leading to respiratory and multiorgan failure. We report the clinical course and management of a liver transplant recipient on hemodialysis, who presented with COVID-19 pneumonia, and despite completing a 5-day course of hydroxychloroquine, later developed marked inflammatory manifestations with rapid improvement after administration of off-label, single-dose tocilizumab. We also highlight the role of lung ultrasonography in early diagnosis of the inflammatory phase of COVID-19. Future investigation of the effects of immunomodulators among transplant recipients with COVID-19 infection will be important.

Transient c-Src Suppression During Endodermal Commitment of Human Induced Pluripotent Stem Cells Results in Abnormal Profibrotic Cholangiocyte-Like Cells.

Directed differentiation of human induced pluripotent stem cells (iPSCs) toward hepatobiliary lineages has been increasingly used as models of human liver development/diseases. As protein kinases are important components of signaling pathways regulating cell fate changes, we sought to define the key molecular mediators regulating human liver development using inhibitors targeting tyrosine kinases during hepatic differentiation of human iPSCs. A library of tyrosine kinase inhibitors was used for initial screening during the multistage differentiation of human iPSCs to hepatic lineage. Among the 80 kinase inhibitors tested, only Src inhibitors suppressed endoderm formation while none had significant effect on later stages of hepatic differentiation. Transient inhibition of c-Src during endodermal induction of human iPSCs reduced endodermal commitment and expression of endodermal markers, including SOX17 and FOXA2, in a dose-dependent manner. Interestingly, the transiently treated cells later developed into profibrogenic cholangiocyte-like cells expressing both cholangiocyte markers, such as CK7 and CK19, and fibrosis markers, including Collagen1 and smooth muscle actin. Further analysis of these cells revealed colocalized expression of collagen and yes-associated protein (YAP; a marker associated with bile duct proliferation/fibrosis) and an increased production of interleukin-6 and tumor necrosis factor-α. Moreover, treatment with verteporfin, a YAP inhibitor, significantly reduced expression of fibrosis markers. In summary, these results suggest that c-Src has a critical role in cell fate determination during endodermal commitment of human iPSCs, and its alteration in early liver development in human may lead to increased production of abnormal YAP expressing profibrogenic proinflammatory cholangiocytes, similar to those seen in livers of patients with biliary fibrosis. Stem Cells 2019;37:306-317.

Predicting PM2.5 in Well-Mixed Indoor Air for a Large Office Building Using Regression and Artificial Neural Network Models.

Although the exposure to PM2.5 has serious health implications, indoor PM2.5 monitoring is not a widely applied practice. Regulations on the indoor PM2.5 level and measurement schemes are not well established. Compared to other indoor settings, PM2.5 prediction models for large office buildings are particularly lacking. In response to these challenges, statistical models were developed in this paper to predict the PM2.5 concentration in well-mixed indoor air in a commercial office building. The performances of different modeling methods, including multiple linear regression (MLR), partial least squares regression (PLS), distributed lag model (DLM), least absolute shrinkage selector operator (LASSO), simple artificial neural networks (ANN), and long-short term memory (LSTM), were compared. Various combinations of environmental and meteorological parameters were used as predictors. The root-mean-square error (RMSE) of the predicted hourly PM2.5 was 1.73 µg/m3 for the LSTM model and in the range of 2.20-4.71 µg/m3 for the other models when regulatory ambient PM2.5 data were used as predictors. The LSTM models outperformed other modeling approaches across the performance metrics used by learning the predictors' temporal patterns. Even without any ambient PM2.5 information, the developed models still demonstrated relatively high skill in predicting the PM2.5 levels in well-mixed indoor air.

Readmission rates following heart failure: a scoping review of sex and gender based considerations.

BACKGROUND: Although hospital readmission for heart failure (HF) is an issue for both men and women, little is known about differences in readmission rates by sex. Consequently, strategies to optimize readmission reduction programs and care strategies for women and men remain unclear. Our study aims were: (1) to identify studies examining readmission rates according to sex, and (2) to provide a qualitative overview of possible considerations for the impact of sex or gender. METHODS: We conducted a scoping review using the Arksey and O'Malley framework to include full text articles published between 2002 and 2017 drawn from multiple databases (MEDLINE, EMBASE), grey literature (i.e. National Technical information, Duck Duck Go), and expert consultation. Eligible articles included an index heart failure episode, readmission rates, and sex/gender-based analysis. RESULTS: The search generated 5887 articles, of which 746 underwent full abstract text consideration for eligibility. Of 164 eligible articles, 34 studies addressed the primary outcome, 103 studies considered sex differences as a secondary outcome and 25 studies stratified data for sex. Good inter-rater agreement was reached: 83% title/abstract; 88% full text; kappa: 0.69 (95%CI: 0.53-0.85). Twelve of 34 studies reported higher heart failure readmission rates for men and six studies reported higher heart failure readmission rates for women. Using non composite endpoints, five studies reported higher HF readmission rates for men compared to three studies reporting higher HF readmission rates for women. Overall, there was heterogeneity between studies when examined by sex, but one observation emerged that was related to the timing of readmissions. Readmission rates for men were higher when follow-up duration was longer than 1 year. Women were more likely to experience higher readmission rates than men when time to event was less than 1 year. CONCLUSIONS: Future studies should consider different time horizons in their designs and avoid the use of composite measures, such as readmission rates combined with mortality, which are highly skewed by sex. Co-interventions and targeted post-discharge approaches with attention to sex would be of benefit to the HF patient population.

Developing Registries and Effective Care Models for the Management of Hip Fractures: Aligning Political, Organizational Drivers with Clinical Outcomes.

PURPOSE OF REVIEW: The aim of the review is to conduct a literature search on cost-effectiveness or cost savings of osteoporosis fracture liaison services. RECENT FINDINGS: We identified four types of FLS. A total of 11 cost-effectiveness studies examining 15 models of secondary fracture prevention models were identified. Nine models were found to be cost-saving, and five were found to be cost-effective. It is possible to adopt a cost-effective model for fracture liaison services and expand across geographical regions. Adopting registries can have the added benefit of monitoring quality improvement practices and treatment outcomes. Challenges exist in implementing registries where centralized data collections across different chronic conditions are politically driving agendas. In order to align political and organizational strategic plans, a core set of outcome evaluations that are both focused on patient and provider experience in addition to treatment outcomes can be a step toward achieving better health and services.

Metabolic disposition of H3B-8800, an orally available small-molecule splicing modulator, in rats, monkeys, and humans.

H3B-8800, a novel orally available modulator of the SF3b complex, which potently and preferentially kills spliceosome-mutant tumor cells, is in clinical development for the treatment of advanced myeloid malignancies. We characterized the pharmacokinetics, metabolism and disposition of H3B-8800 in rats, monkeys and humans.In vitro, H3B-8800 is a substrate of CYP3A4/5, flavin-containing monooxygenases (FMOs) and P-glycoprotein (P-gp), and showed a favorable drug-drug interaction profile as a perpetrator.Following oral dosing of 14C-H3B-8800 in bile-duct cannulated SD rats, 54.7% of the dosed radioactivity was excreted in the bile, with less found in feces (36.8%). The low amount in urine (3.7%), suggests that renal elimination is a minor pathway of clearance for H3B-8800.In Long-Evans rats, radioactivity derived from 14C-H3B-8800 was rapidly absorbed, with the highest distribution in the ocular, metabolic/excretory, and gastrointestinal tract tissues. No radioactivity was detected in the central nervous system.Seven metabolites were observed in human plasma following 4 daily doses of 40 mg H3B-8800. H3B-68736 (N-desmethyl), H3B-77176 (N-oxide), and unchanged H3B-8800 were the prominent components in human plasma, at 27.3%, 18.1%, and 33.2%, respectively, of the total drug-related material in a pooled AUC0-24h sample. The same 7 metabolites were observed in monkey plasma.