The Path to a Match for Interventional Cardiology Fellowship: A Major SCAI Initiative.

The field of interventional cardiology (IC) has evolved dramatically over the past 40 years. Training and certification in IC have kept pace, with the development of accredited IC fellowship training programs, training statements, and subspecialty board certification. The application process, however, remained fragmented with lack of a universal process or time frame. In recent years, growing competition among training programs for the strongest candidates resulted in time-limited offers and high-pressure situations that disadvantaged candidates. A grassroots effort was recently undertaken by a Society for Cardiovascular Angiography & Interventions task force, to create equity in the system by establishing a national Match for IC fellowship. This manuscript explores the rationale, process, and implications of this endeavor.

Implementation of Community Health Worker Support for Tobacco Cessation: A Mixed-Methods Study.

OBJECTIVE: Adults with serious mental illness have high rates of tobacco use disorder and underuse pharmacotherapy for tobacco cessation. In a previous randomized controlled trial, participants receiving community health worker (CHW) support and education for their primary care providers (PCPs) had higher tobacco abstinence rates at 2 years, partly because of increased initiation of tobacco-cessation pharmacotherapy. The authors aimed to determine the association between CHW-participant engagement and tobacco abstinence outcomes. METHODS: The authors conducted a secondary, mixed-methods analysis of 196 participants in the trial's intervention arm. Effects of the number and duration of CHW visits, number of smoking-cessation group sessions attended, and number of CHW-attended PCP visits on initiation of tobacco-cessation pharmacotherapy and tobacco abstinence were modeled via logistic regression. Interviews with 12 CHWs, 17 patient participants, and 17 PCPs were analyzed thematically. RESULTS: Year 2 tobacco abstinence was significantly associated with CHW visit number (OR=1.85, 95% CI=1.29-2.66), visit duration (OR=1.51, 95% CI=1.00-2.28), and number of group sessions attended (OR=1.85, 95% CI=1.33-2.58); effects on pharmacotherapy initiation were similar. One to three CHW visits per month across 2 years were optimal for achieving abstinence. Interviews identified CHW-patient engagement facilitators (i.e., trust, goal accountability, skills reinforcement, assistance in overcoming barriers to treatment access, and adherence). Training and supervision facilitated CHW effectiveness; barriers included PCPs' and care teams' limited understanding of the CHW role. CONCLUSIONS: Greater CHW-participant engagement, within feasible dose ranges, was associated with tobacco abstinence among adults with serious mental illness. Implementation of CHW interventions may benefit from further CHW training and integration within clinical teams.

Association between Smoking Abstinence and Depression and Anxiety Symptoms After Hospital Discharge: The Helping HAND 4 Trial.

OBJECTIVES: Some people who stop smoking experience improved mood, but few studies have examined this relationship after hospitalization or accounted for concomitant substance use and psychological factors. We examined associations between smoking abstinence after a hospital discharge and change in depression and anxiety symptoms. METHODS: We conducted a secondary analysis of data from the Helping HAND 4 smoking cessation trial, which enrolled people who used tobacco when admitted to three academic medical center general hospitals. Participants (n = 986) were categorized as continuously abstinent (CA) or not. We used linear and logistic regression to model continuous and binary measures of depression (Patient Health Questionnaire [PHQ-8] ≥/<10), and anxiety (Generalized Anxiety Disorder Assessment [GAD-7], ≥/<8) over 6 months, adjusting for baseline mood, psychological factors, and substance use. Binary outcomes were defined using established clinical thresholds to aid in the clinical interpretation of the results. RESULTS: Mean age was 52.3 years, 56.5% were female, and the baseline mean cigarettes/day was 16.2 (SD: 3.2). In the adjusted analyses, depression and anxiety scores improved more in CA than non-CA participants over 6 months (difference-in-improvement, 2.43 [95% CI: 1.50-3.36] for PHQ-8; 3.04 [95% CI: 2.16-3.93] for GAD-7). At 6 months, CA participants were more likely to have a PHQ-8 score <10 (aOR = 2.07 [95% CI: 1.36-3.16]) and a GAD-7 score <8 (aOR = 2.90 [95% CI: 1.91-4.39]). CONCLUSIONS: Individuals who were CA, compared to those who were not, had fewer depression and anxiety symptoms at 6 months, and were twice as likely to score below the population screening thresholds for major depression and anxiety disorders. Clinicians should emphasize the association between continuous abstinence and improved mood symptoms after hospital discharge.

Phylogenetic evidence clarifies the history of the extrusion of Indochina.

The southeastward extrusion of Indochina along the Ailao Shan-Red River shear zone (ARSZ) is one of two of the most prominent consequences of the India-Asia collision. This plate-scale extrusion has greatly changed Southeast Asian topography and drainage patterns and effected regional climate and biotic evolution. However, little is known about how Indochina was extruded toward the southeast over time. Here, we sampled 42 plant and animal clades (together encompassing 1,721 species) that are distributed across the ARSZ and are not expected to disperse across long distances. We first assess the possible role of climate on driving the phylogenetic separations observed across the ARSZ. We then investigate the temporal dynamics of the extrusion of Indochina through a multitaxon analysis. We show that the lineage divergences across the ARSZ were most likely associated with the Indochinese extrusion rather than climatic events. The lineage divergences began at ~53 Ma and increased sharply ~35 Ma, with two peaks at ~19 Ma and ~7 Ma, and one valley at ~13 Ma. Our results suggest a two-phase model for the extrusion of Indochina, and in each phase, the extrusion was subject to periods of acceleration and decrease, in agreement with the changes of the India-Asia convergence rate and angle from the early Eocene to the late Miocene. This study highlights that a multitaxon analysis can illuminate the timing of subtle historical events that may be difficult for geological data to pinpoint and can be used to explore other tectonic events.

PRIMITI: A computational approach for accurate prediction of miRNA-target mRNA interaction.

Current medical research has been demonstrating the roles of miRNAs in a variety of cellular mechanisms, lending credence to the association between miRNA dysregulation and multiple diseases. Understanding the mechanisms of miRNA is critical for developing effective diagnostic and therapeutic strategies. miRNA-mRNA interactions emerge as the most important mechanism to be understood despite their experimental validation constraints. Accordingly, several computational models have been developed to predict miRNA-mRNA interactions, albeit presenting limited predictive capabilities, poor characterisation of miRNA-mRNA interactions, and low usability. To address these drawbacks, we developed PRIMITI, a PRedictive model for the Identification of novel miRNA-Target mRNA Interactions. PRIMITI is a novel machine learning model that utilises CLIP-seq and expression data to characterise functional target sites in 3'-untranslated regions (3'-UTRs) and predict miRNA-target mRNA repression activity. The model was trained using a reliable negative sample selection approach and the robust extreme gradient boosting (XGBoost) model, which was coupled with newly introduced features, including sequence and genetic variation information. PRIMITI achieved an area under the receiver operating characteristic (ROC) curve (AUC) up to 0.96 for a prediction of functional miRNA-target site binding and 0.96 for a prediction of miRNA-target mRNA repression activity on cross-validation and an independent blind test. Additionally, the model outperformed state-of-the-art methods in recovering miRNA-target repressions in an unseen microarray dataset and in a collection of validated miRNA-mRNA interactions, highlighting its utility for preliminary screening. PRIMITI is available on a reliable, scalable, and user-friendly web server at https://biosig.lab.uq.edu.au/primiti.

Hospital readmission for acute kidney injury is independently associated with de novo end-stage renal disease after liver transplantation.

End-stage renal disease (ESRD) after liver transplantation (LT) is associated with high morbidity and mortality. The consequences of hospitalizations for post-LT acute kidney injury (AKI) are poorly understood. Using linked Medicare claims and transplant registry data, we analyzed adult liver alone recipients not receiving pre-transplant dialysis between 1/1/2007-12/31/2016. Covariate-adjusted Cox proportional hazards models stratified by center evaluated factors associated with AKI readmission during the first post-LT year, and whether AKI readmission was associated with de novo early (<1 y) or late (≥1 y) ESRD post-LT. The cohort included 10,559 patients and was 64.5% male, 72.5% White, 8.1% Black and 14.0% Hispanic with median age 62 years. Overall, 2,875 (27.2%) patients had ≥1 AKI hospitalization during the first year. eGFR at LT was associated with AKI readmission (aHR 1.16 per 10 mL/min/1.73m2 decrease; p<0.001). The aHR for early ESRD in patients with ≥1 AKI readmission <90 days post-LT was 1.90 (p<0.001). The aHRs for late ESRD with 1 and ≥2 prior AKI readmissions were 1.57 and 2.80 respectively (p<0.001). AKI readmissions in the first post-LT year impact over one-quarter of recipients. These increase the risk of subsequent ESRD, but may represent an opportunity to intervene and mitigate further renal dysfunction.

KLS-13019, a novel structural analogue of cannabidiol (CBD) and GPR55 receptor antagonist, Prevents and Reverses Chemotherapy-Induced Peripheral Neuropathy (CIPN) in Rats.

Neuropathic pain is a form of chronic pain that develops because of damage to the nervous system. Treatment of neuropathic pain is often incompletely effective, and most available therapeutics have only moderate efficacy and present side effects that limit their use. Opioids are commonly prescribed for the management of neuropathic pain despite equivocal results in clinical studies and significant abuse potential. Thus, neuropathic pain represents an area of critical unmet medical and novel classes of therapeutics with improved efficacy and safety profiles are urgently needed. The cannabidiol (CBD) structural analogue and novel antagonist of GPR55, KLS-13019, was screened in rat models of neuropathic pain. Tactile sensitivity associated with chemotherapy exposure was induced in rats with once daily 1mg/kg paclitaxel injections for 4 days or 5 mg/kg oxaliplatin every third day for one week. Rats were then administered KLS-13019 or comparator drugs on day 7 in an acute dosing paradigm or days 7-10 in a chronic dosing paradigm and mechanical or cold allodynia was assessed. Allodynia was reversed in a dose-dependent manner in the rats treated with KLS-13019, with the highest dose reverting the response to pre-paclitaxel injection baseline levels with both I.P. and P.O. administration after acute dosing. In the chronic dosing paradigm, 4 consecutive doses of KLS-13019 completely reversed allodynia for the duration of the phenotype in control animals. Additionally, co-administration of KLS -13019 with paclitaxel prevented the allodynic phenotype from developing. Together, these data suggest that KLS-13019 represents a potential new drug for the treatment of neuropathic pain. Significance Statement Chemotherapy-induced neuropathic pain (CIPN) is a common, debilitating side effect of cancer treatment with no known cure. GPR55 antagonist KLS-13019 represents a novel class of drug for this condition that is a potent, durable inhibitor of allodynia associated with CIPN in rats in both prevention and reversal dosing paradigms. This novel therapeutic approach addresses a critical area of unmet medical need.

nQuack: An R package for predicting ploidal level from sequence data using site-based heterozygosity.

Premise: Traditional methods of ploidal-level estimation are tedious; using DNA sequence data for cytotype estimation is an ideal alternative. Multiple statistical approaches to leverage sequence data for ploidy inference based on site-based heterozygosity have been developed. However, these approaches may require high-coverage sequence data, use inappropriate probability distributions, or have additional statistical shortcomings that limit inference abilities. We introduce nQuack, an open-source R package that addresses the main shortcomings of current methods. Methods and Results: nQuack performs model selection for improved ploidy predictions. Here, we implement expectation maximization algorithms with normal, beta, and beta-binomial distributions. Using extensive computer simulations that account for variability in sequencing depth, as well as real data sets, we demonstrate the utility and limitations of nQuack. Conclusions: Inferring ploidy based on site-based heterozygosity alone is difficult. Even though nQuack is more accurate than similar methods, we suggest caution when relying on any site-based heterozygosity method to infer ploidy.

AI-Driven Automated Lung Sizing from Chest Radiographs.

Lung size measurements play an important role in transplantation, as optimal donor-recipient size matching is necessary to ensure the best possible outcome. While several strategies for size matching are currently used, all have limitations, and none has proven superior. In this pilot study, we leveraged deep learning and computer vision to develop an automated system for generating standardized lung size measurements using portable chest radiographs to improve accuracy, reduce variability, and streamline donor/recipient matching. We developed a two-step framework involving lung mask extraction from chest radiographs followed by feature points detection to generate six distinct lung height and width measurements, which we validated against measurements reported by two radiologists for 50 lung transplant recipients. Our system demonstrated <2.5% error (< 7 mm) with robust inter- and intra-rater agreement compared to expert radiologist review. This is especially promising given that the radiographs used in this study were purposely chosen to include images with technical challenges such as consolidations, effusions, and patient rotation. While validation in a larger cohort is necessary, this study highlights AI's potential to both provide reproducible lung size assessment in real patients and enable studies on the effect of lung size matching on transplant outcomes in large datasets.

Semiparametric Additive Modeling of the Restricted Mean Survival Time.

Analysis of the restricted mean survival time (RMST) has become increasingly common in biomedical studies during the last decade as a means of estimating treatment or covariate effects on survival. Advantages of RMST over the hazard ratio (HR) include increased interpretability and lack of reliance on the often tenuous proportional hazards assumption. Some authors have argued that RMST regression should generally be the frontline analysis as opposed to methods based on counting process increments. However, in order for the use of the RMST to be more mainstream, it is necessary to broaden the range of data structures to which pertinent methods can be applied. In this report, we address this issue from two angles. First, most of existing methodological development for directly modeling RMST has focused on multiplicative models. An additive model may be preferred due to goodness of fit and/or parameter interpretation. Second, many settings encountered nowadays feature high-dimensional categorical (nuisance) covariates, for which parameter estimation is best avoided. Motivated by these considerations, we propose stratified additive models for direct RMST analysis. The proposed methods feature additive covariate effects. Moreover, nuisance factors can be factored out of the estimation, akin to stratification in Cox regression, such that focus can be appropriately awarded to the parameters of chief interest. Large-sample properties of the proposed estimators are derived, and a simulation study is performed to assess finite-sample performance. In addition, we provide techniques for evaluating a fitted model with respect to risk discrimination and predictive accuracy. The proposed methods are then applied to liver transplant data to estimate the effects of donor characteristics on posttransplant survival time.

Less is more: An analysis of venetoclax and hypomethylating agent post-induction treatment modifications in AML.

Venetoclax (Ven) combined with a hypomethylating agent (HMA) enhances survival in elderly/unfit acute myeloid leukemia (AML) patients, yet often necessitates regimen modifications due to intolerance. However, it is unclear how these modifications affect patient outcome. This retrospective cohort study evaluates the impact of post-induction HMA/Ven regimen modifications on disease progression and survival. This study reviewed 142 AML patients treated with HMA/Ven within the Northwell Health System from January 2019 to December 2022. To assess the impact of post-induction regimen modifications, patients were grouped according to median days between cycles (≤34 or ≥35 days cycle intervals) and median Ven days per cycle (≤14 or ≥15 days/cycle) based on only cycle 3 and beyond. Kaplan-Meier and Cox proportional hazard regression analyses were employed for univariate and multivariate assessments, respectively. There was no significant difference in median progression-free survival (mPFS)(11.6 vs 11.8 months, p = 0.73) or median overall survival (mOS)(15.1 vs 21.8 months, p = 0.16) between cycle interval groups. However, there was a clinically and statistically significant advantage in mPFS (15.8 vs 8.7 months, p = 0.01) and mOS (24.7 vs 11.3 months, p = 0.006) for patients with a median of ≤14 Ven days/cycle compared to ≥15 Ven days/cycle. Multivariate analysis demonstrated that ≤14 days of Ven for cycle 3 and beyond was an independent predictor of decreased mortality (HR 0.18, CI 0.07-0.48, p = 0.0007). Extended cycle intervals did not adversely affect mortality while reduced Ven duration per cycle post-induction was associated with improved survival in elderly AML patients.

Network spillover effects associated with the ChooseWell 365 workplace randomized controlled trial to promote healthy food choices.

Food choices are closely linked to culture, social relationships, and health. Because many adults spend up to half their time at work, the workplace provides a venue for changing population health-related behaviors and norms. It is unknown whether the effects of a workplace intervention to improve health behaviors might spread beyond participating employees due to social influence. ChooseWell 365 was a randomized controlled trial testing a 12-month healthy eating intervention grounded in principles of behavioral economics. This intervention leveraged an existing cafeteria traffic-light labeling system (green = healthy; red = unhealthy) in a large hospital workplace and demonstrated significant improvements in healthy food choices by employees in the intervention vs. control group. The current study used data from over 29 million dyadic purchasing events during the trial to test whether social ties to a trial participant co-worker (n = 299 intervention, n = 302 control) influenced the workplace food choices of non-participants (n = 7900). There was robust evidence that non-participants who were socially tied to more intervention group participants made healthier workplace food purchases overall, and purchased a greater proportion of healthy (i.e., green) food and beverages, and fewer unhealthy (i.e., red) beverages and modest evidence that the benefit of being tied to intervention participants was greater than being tied to control participants. Although individual-level effect sizes were small, a range of consistent findings indicated that this light-touch intervention yielded spillover effects of healthy eating behaviors on non-participants. Results suggest that workplace healthy eating interventions could have population benefits extending beyond participants.

The angiotensin II/type 1 angiotensin II receptor pathway is implicated in the dysfunction of albumin endocytosis in renal proximal tubule epithelial cells induced by high glucose levels.

It is well-established that dysfunction of megalin-mediated albumin endocytosis by proximal tubule epithelial cells (PTECs) and the activation of the Renin-Angiotensin System (RAS) play significant roles in the development of Diabetic Kidney Disease (DKD). However, the precise correlation between these factors still requires further investigation. In this study, we aimed to elucidate the potential role of angiotensin II (Ang II), a known effector of RAS, as the mediator of albumin endocytosis dysfunction induced by high glucose (HG) in PTECs. To achieve this, we utilized LLC-PK1 and HK-2 cells, which are well-established in vitro models of PTECs. Using albumin-FITC or DQ-albumin as tracers, we observed that incubation of LLC-PK1 and HK-2 cells with HG (25 mM for 48 h) significantly reduced canonical receptor-mediated albumin endocytosis, primarily due to the decrease in megalin expression. HG increased the concentration of Ang II in the LLC-PK1 cell supernatant, a phenomenon associated with an increase in angiotensin-converting enzyme (ACE) expression and a decrease in prolyl carboxypeptidase (PRCP) expression. ACE type 2 (ACE2) expression remained unchanged. To investigate the potential impact of Ang II on HG effects, the cells were co-incubated with angiotensin receptor inhibitors. Only co-incubation with 10-7 M losartan (an antagonist for type 1 angiotensin receptor, AT1R) attenuated the inhibitory effect of HG on albumin endocytosis, as well as megalin expression. Our findings contribute to understanding the genesis of tubular albuminuria observed in the early stages of DKD, which involves the activation of the Ang II/AT1R axis by HG.

A temperate super-Jupiter imaged with JWST in the mid-infrared.

Of the approximately 25 directly imaged planets to date, all are younger than 500 Myr, and all but six are younger than 100 Myr (ref. 1). Eps Ind A (HD209100, HIP108870) is a K5V star of roughly solar age (recently derived as 3.7-5.7 Gyr (ref. 2) and 3.5 - 1.3 + 0.8 Gyr (ref. 3)). A long-term radial-velocity trend4,5 and an astrometric acceleration6,7 led to claims of a giant planet2,8,9 orbiting the nearby star (3.6384 ± 0.0013 pc; ref. 10). Here we report JWST coronagraphic images which reveal a giant exoplanet that is consistent with these radial and astrometric measurements but inconsistent with the previously claimed planet properties. The new planet has a temperature of approximately 275 K and is remarkably bright at 10.65 and 15.50 µm. Non-detections between 3.5 and 5.0 µm indicate an unknown opacity source in the atmosphere, possibly suggesting a high-metallicity, high carbon-to-oxygen ratio planet. The best-fitting temperature of the planet is consistent with theoretical thermal evolution models, which were previously untested at this temperature range. The data indicate that this is probably the only giant planet in the system, and therefore we refer to it as b, despite it having significantly different orbital properties than the previously claimed planet b.

The first complete mitochondrional genome of Anopheles gibbinsi using a skimming sequencing approach.

Mosquitoes belonging to the genus Anopheles are the only vectors of human malaria. Anopheles gibbinsi has been linked to malaria transmission in Kenya, with recent collections in Zambia reporting the mosquito species exhibiting zoophilic and exophilic behavioral patterns with occasional contact with humans. Given the paucity of genetic data, and challenges to identification and molecular taxonomy of the mosquitoes belonging to the Anopheles genus; we report the first complete mitochondrial genome of An. gibbinsi using a genome skimming approach. An Illumina Novaseq 6000 platform was used for sequencing, the length of the mitochondrial genome was 15401 bp, with 78.5% AT content comprised of 37 genes. Phylogenetic analysis by maximum likelihood using concatenation of the 13 protein coding genes demonstrated that An. marshallii was the closest relative based on existing sequence data. This study demonstrates that the skimming approach is an inexpensive and efficient approach for mosquito species identification and concurrent taxonomic rectification, which may be a useful alternative for generating reference sequence data for evolutionary studies among the Culicidae.

Precision arbovirus serology with a pan-arbovirus peptidome.

Arthropod-borne viruses represent a crucial public health threat. Current arboviral serology assays are either labor intensive or incapable of distinguishing closely related viruses, and many zoonotic arboviruses that may transition to humans lack any serologic assays. In this study, we present a programmable phage display platform, ArboScan, that evaluates antibody binding to overlapping peptides that represent the proteomes of 691 human and zoonotic arboviruses. We confirm that ArboScan provides detailed antibody binding information from animal sera, human sera, and an arthropod blood meal. ArboScan identifies distinguishing features of antibody responses based on exposure history in a Colombian cohort of Zika patients. Finally, ArboScan details epitope level information that rapidly identifies candidate epitopes with potential protective significance. ArboScan thus represents a resource for characterizing human and animal arbovirus antibody responses at cohort scale.

Design considerations for developing measures of policy implementation in quantitative evaluations of public health policy.

Typical quantitative evaluations of public policies treat policies as a binary condition, without further attention to how policies are implemented. However, policy implementation plays an important role in how the policy impacts behavioral and health outcomes. The field of policy-focused implementation science is beginning to consider how policy implementation may be conceptualized in quantitative analyses (e.g., as a mediator or moderator), but less work has considered how to measure policy implementation for inclusion in quantitative work. To help address this gap, we discuss four design considerations for researchers interested in developing or identifying measures of policy implementation using three independent NIH-funded research projects studying e-cigarette, food, and mental health policies. Mini case studies of these considerations were developed via group discussions; we used the implementation research logic model to structure our discussions. Design considerations include (1) clearly specifying the implementation logic of the policy under study, (2) developing an interdisciplinary team consisting of policy practitioners and researchers with expertise in quantitative methods, public policy and law, implementation science, and subject matter knowledge, (3) using mixed methods to identify, measure, and analyze relevant policy implementation determinants and processes, and (4) building flexibility into project timelines to manage delays and challenges due to the real-world nature of policy. By applying these considerations in their own work, researchers can better identify or develop measures of policy implementation that fit their needs. The experiences of the three projects highlighted in this paper reinforce the need for high-quality and transferrable measures of policy implementation, an area where collaboration between implementation scientists and policy experts could be particularly fruitful. These measurement practices provide a foundation for the field to build on as attention to incorporating measures of policy implementation into quantitative evaluations grows and will help ensure that researchers are developing a more complete understanding of how policies impact health outcomes.

Monolithic three-dimensional integration of complementary two-dimensional field-effect transistors.

The semiconductor industry is transitioning to the 'More Moore' era, driven by the adoption of three-dimensional (3D) integration schemes surpassing the limitations of traditional two-dimensional scaling. Although innovative packaging solutions have made 3D integrated circuits (ICs) commercially viable, the inclusion of through-silicon vias and microbumps brings about increased area overhead and introduces parasitic capacitances that limit overall performance. Monolithic 3D integration (M3D) is regarded as the future of 3D ICs, yet its application faces hurdles in silicon ICs due to restricted thermal processing budgets in upper tiers, which can degrade device performance. To overcome these limitations, emerging materials like carbon nanotubes and two-dimensional semiconductors have been integrated into the back end of silicon ICs. Here we report the M3D integration of complementary WSe2 FETs, in which n-type FETs are placed in tier 1 and p-type FETs are placed in tier 2. In particular, we achieve dense and scaled integration through 300 nm vias with a pitch of <1 µm, connecting more than 300 devices in tiers 1 and 2. Moreover, we have effectively implemented vertically integrated logic gates, encompassing inverters, NAND gates and NOR gates. Our demonstration highlights the two-dimensional materials' role in advancing M3D integration in complementary metal-oxide-semiconductor circuits.