Cell-Type-Specific Alternative Splicing Governs Cell Fate in the Developing Cerebral Cortex.

Alternative splicing is prevalent in the mammalian brain. To interrogate the functional role of alternative splicing in neural development, we analyzed purified neural progenitor cells (NPCs) and neurons from developing cerebral cortices, revealing hundreds of differentially spliced exons that preferentially alter key protein domains-especially in cytoskeletal proteins-and can harbor disease-causing mutations. We show that Ptbp1 and Rbfox proteins antagonistically govern the NPC-to-neuron transition by regulating neuron-specific exons. Whereas Ptbp1 maintains apical progenitors partly through suppressing a poison exon of Flna in NPCs, Rbfox proteins promote neuronal differentiation by switching Ninein from a centrosomal splice form in NPCs to a non-centrosomal isoform in neurons. We further uncover an intronic human mutation within a PTBP1-binding site that disrupts normal skipping of the FLNA poison exon in NPCs and causes a brain-specific malformation. Our study indicates that dynamic control of alternative splicing governs cell fate in cerebral cortical development.

Effect of carvedilol versus placebo on cardiac function in anthracycline-exposed survivors of childhood cancer (PREVENT-HF): a randomised, controlled, phase 2b trial.

BACKGROUND: Carvedilol improves cardiac function in patients with heart failure but remains untested as cardioprotective therapy in long-term childhood cancer survivors (ie, those who have completed treatment for childhood cancer and are in remission) at risk for heart failure due to high-dose anthracycline exposure. We aimed to evaluate the activity and safety of low-dose carvedilol for heart failure risk reduction in childhood cancer survivors at highest risk for heart failure. METHODS: PREVENT-HF was a randomised, double-blind, phase 2b trial done at 30 hospitals in the USA and Canada. Patients were eligible if they had any cancer diagnosis that resulted in at least 250 mg/m2 cumulative exposure to anthracycline by age 21 years; completed their cancer treatment at least 2 years previously; an ejection fraction of at least 50% or fractional shortening of at least 25%, or both; and bodyweight of at least 40 kg. Patients were randomly assigned (1:1) with automated computer-generated permuted block randomisation (block size of 4), stratified by age at diagnosis, time since diagnosis, and history of chest-directed radiotherapy, to carvedilol (up-titrated from 3·125 g per day to 12·5 mg per day) or placebo orally for 2 years. Participants, staff, and investigators were masked to study group allocation. The primary endpoint was to establish the effect of carvedilol on standardised left ventricular wall thickness-dimension ratio Z score (LVWT/Dz). Treatment effects were analysed with a linear mixed-effects model for normally distributed data with a linear time effect and testing the significance of treatment*time interaction in the modified intention-to-treat (mITT) cohort (ie, all randomly assigned participants who had a baseline and at least one subsequent echocardiogram measurement). Safety was assessed in the ITT population (ie, all randomly assigned participants). This trial was registered with ClinicalTrials.gov, NCT027175073, and enrolment and follow-up are complete. FINDINGS: Between July 3, 2012, and June 22, 2020, 196 participants were enrolled, of whom 182 (93%) were eligible and randomly assigned to either carvedilol (n=89) or placebo (n=93; ITT population). Median age was 24·7 years (IQR 19·6-36·6), 91 (50%) participants were female, 91 (50%) were male, and 119 (65%) were non-Hispanic White. As of data cutoff (June 10, 2022), median follow-up was 725 days (IQR 378-730). 151 (n=75 in the carvedilol group and n=76 in the placebo group) of 182 participants were included in the mITT population, among whom LVWT/Dz was similar between the two groups (-0·14 [95% CI -0·43 to 0·16] in the carvedilol group vs -0·45 [-0·77 to -0·13] in the placebo group; difference 0·31 [95% CI -0·10 to 0·73]; p=0·14). Two (2%) of 89 patients in the carvedilol group two adverse events of grade 2 or higher (n=1 shortness of breath and n=1 arthralgia) and none in the placebo group. There were no adverse events of grade 3 or higher and no deaths. INTERPRETATION: Low-dose carvedilol appears to be safe in long-term childhood cancer survivors at risk for heart failure, but did not result in significant improvement of LVWT/Dz compared with placebo. These results do not support the use of carvedilol for secondary heart failure prevention in anthracycline-exposed childhood cancer survivors. FUNDING: National Cancer Institute, Leukemia & Lymphoma Society, St Baldrick's Foundation, Altschul Foundation, Rally Foundation, American Lebanese Syrian Associated Charities.

Secondary analysis of late major gastrointestinal and genitourinary toxicities in unfavorable-risk prostate cancer patients receiving docetaxel: Insights from a randomized trial.

BACKGROUND: This study sought to evaluate the late toxicity associated with neoadjuvant and concurrent docetaxel and radiation therapy in patients with prostate cancer. METHODS: A secondary analysis was performed of the phase 3 multicenter randomized trial (Dana-Farber Cancer Institute 05-043) including 350 patients with nonmetastatic unfavorable-risk prostate cancer. Patients were randomized 1:1 to receive androgen deprivation therapy, radiation therapy, and docetaxel versus androgen deprivation therapy and radiation therapy. The study assessed the cumulative incidence rates of grade 2 and grade 3 or higher gastrointestinal, genitourinary, and sexual toxicity. A multivariable Fine and Gray's competing risks regression model adjusted for age at randomization and pelvic lymph node radiation therapy was used to evaluate the treatment effect of docetaxel on time to late genitourinary and gastrointestinal toxicities. RESULTS: The study included 338 patients who primarily had minimal or no comorbidity (74.9%) and median age 66 years (interquartile range: 61,71). At a median follow-up of 10.2 years, docetaxel was not associated with increased risk of any grade 3 or higher (adjusted hazard ratio [AHR], 0.98; 95% confidence interval [CI], 0.36-2.67; p = .96) or grade 2 gastrointestinal (p = .75), genitourinary (p = .44), and sexual (p = .29) toxicity. Age was associated with increased grade 3 or higher (AHR, 1.08; 95% CI, 1.01-1.16; p = .03) and grade 2 gastrointestinal toxicity (AHR, 1.11; 95% CI, 1.03-1.20; p = .005). A nonsignificant trend (p = .09) toward increased late grade 3 or higher toxicity was observed for pelvic radiation therapy use. CONCLUSIONS: Docetaxel combined with radiotherapy has an acceptable long-term toxicity profile.

Pain/Stress, Mitochondrial Dysfunction and Neurodevelopment in Preterm Infants.

Introduction Preterm infants experience tremendous early life pain/stress during their neonatal intensive care unit (NICU) hospitalization, which impacts their neurodevelopmental outcomes. Mitochondrial function/dysfunction may interface between perinatal stress events and neurodevelopment. Nevertheless, the specific proteins or pathways linking mitochondrial functions to pain-induced neurodevelopmental outcomes in infants are remain unidentified. Our study aims to investigate the associations among pain/stress, proteins associated with mitochondrial function/dysfunction, and neurobehavioral responses in preterm infants. Methods We conducted a prospective cohort study, enrolling 33 preterm infants between September 2017 and July 2022 at two affiliated NICUs located in Hartford and Farmington, CT. NICU Network Neurobehavioral Scale (NNNS) datasets were evaluated to explore potential association with neurobehavioral outcomes. The daily pain/stress experienced by infant's during their NICU stay was documented. At 36-38 weeks post-menstrual age (PMA), neurobehavioral outcomes were evaluated using the NNNS and buccal swabs were collected for further analysis. Mass spectrometry-based proteomics was conducted on epithelial cells obtained from buccal swabs to evaluate protein expression level. Lasso statistical methods were conducted to study the association between protein abundance and infants' NNNS summary scores. Multiple linear regression and Gene Ontology (GO) enrichment analyses were performed to examine how clinical characteristics and neurodevelopmental outcomes may be associated with protein levels and underlying molecular pathways. Results During NICU hospitalization, preterm premature rupture of membrane (PPROM) were negatively associated with neurobehavioral outcomes. The protein functions including leptin receptor binding activity, glutathione disulfide oxidoreductase activity and response to oxidative stress, lipid metabolism, phosphate and proton transmembrane transporter activity were negatively associated with neurobehavioral outcomes, in the contrast, cytoskeletal regulation, epithelial barrier and protection function were found to be associated with the optimal neurodevelopmental outcomes. In addition, mitochondrial function associated proteins including SPRR2A, PAIP1, S100A3, MT-CO2, PiC, GLRX, PHB2, and BNIPL-2 demonstrated positive association with favorable neurodevelopmental outcomes, while proteins of ABLIM1, UNC45A, Keratins, MUC1, and CYB5B showed positive association with adverse neurodevelopmental outcomes. Conclusion Mitochondrial function-related proteins were observed to be associated with early life pain/stress and neurodevelopmental outcomes in infants. Large-scale studies with longitudinal datasets are warranted. Buccal proteins could be used to predict potential neurobehavioral outcomes.

Exercise-Induced Pulmonary Hypertension in Long-Term Survivors of Congenital Diaphragmatic Hernia.

OBJECTIVE: To determine the prevalence of exercise-induced pulmonary hypertension (PH) among long-survivors of congenital diaphragmatic hernia repair. STUDY DESIGN: This is a single-center, retrospective cohort study of CDH survivors who underwent exercise stress echocardiography (ESE) at Boston Children's Hospital from January 2006 to June 2020. PH severity was assessed by echocardiogram at baseline and after exercise. Patients were categorized by right ventricular systolic pressure (RVSP) after exercise: Group 1 - no or mild PH; and Group 2 - moderate or severe PH (RVSP ≥ 60 mmHg or ≥ ½ systemic blood pressure). RESULTS: Eighty-four patients with CDH underwent 173 ESE with median age 8.1 (4.8 - 19.1) years at first ESE. Sixty-four patients were classified as Group 1, 11 as Group 2, and 9 had indeterminate RVSP with ESE. Moderate to severe PH after exercise was found in 8 (10%) patients with no or mild PH at rest. Exercise-induced PH was associated with larger CDH defect size, patch repair, use of ECMO, supplemental oxygen at discharge, and higher WHO functional class. Higher VE/VCO2 slope, lower peak oxygen saturation, and lower percent predicted FEV1, and FEV1/FVC ratio were associated with Group 2 classification. ESE changed management in 9/11 Group 2 patients. PH was confirmed in all 5 Group 2 patients undergoing cardiac catheterization after ESE. CONCLUSIONS: Among long-term CDH survivors, 10% had moderate-severe exercise-induced PH on ESE, indicating ongoing pulmonary vascular abnormalities. Further studies are needed to optimally define PH screening and treatment for patients with repaired CDH.

LoRaD: Marginal likelihood estimation with haste (but no waste).

The Lowest Radial Distance (LoRaD) method is a modification of the recently introduced Partition-Weighted Kernel method for estimating the marginal likelihood of a model, a quantity important for Bayesian model selection. For analyses involving a fixed tree topology, LoRaD improves upon the Steppingstone or Thermodynamic Integration (Path Sampling) approaches now in common use in phylogenetics because it requires sampling only from the posterior distribution, avoiding the need to sample from a series of ad hoc power posterior distributions, and yet is more accurate than other fast methods such as the Generalized Harmonic Mean (GHM) method. We show that the method performs well in comparison to the Generalized Steppingstone method on an empirical fixed-topology example from molecular phylogenetics involving 180 parameters. The LoRaD method can also be used to obtain the marginal likelihood in the variable-topology case if at least one tree topology occurs with sufficient frequency in the posterior sample to allow accurate estimation of the marginal likelihood conditional on that topology. [Bayesian; marginal likelihood; phylogenetics.].

Morphological and phylogenetic analyses reveal a new species of Anthracophyllum (Omphalotaceae, Agaricales) in Zhejiang Province, China.

During the investigations of macrofungi resources in Zhejiang Province, China, an interesting wood rot fungus was collected. Based on morphological and molecular phylogenetic studies, it is described as a new species, Anthracophyllum sinense. A. sinense is characterized by its sessile, charcoal black and pleurotoid pileus, sparse lamellae occasionally branching, clavate basidia with long sterigmata [(3-)6-7(-8) µm], and non-heteromorphous cystidia. A. sinense establishes a separate lineage close to A. archeri and A. lateritium in the phylogenetic tree.

Are the tests overpowered or underpowered? A unified solution to correctly specify type I errors in design of clinical trials for two sample proportions.

As one of the most commonly used data types, methods in testing or designing a trial for binary endpoints from two independent populations are still being developed until recently. However, the power and the minimum required sample size comparisons between different tests may not be valid if their type I errors are not controlled at the same level. In this article, we unify all related testing procedures into a decision framework, including both frequentist and Bayesian methods. Sufficient conditions of the type I error attained at the boundary of hypotheses are derived, which help reduce the magnitude of the exact calculations and lay out a foundation for developing computational algorithms to correctly specify the actual type I error. The efficient algorithms are thus proposed to calculate the cutoff value in a deterministic decision rule and the probability value in a randomized decision rule, such that the actual type I error is under but closest to, or equal to, the intended level, respectively. The algorithm may also be used to calculate the sample size to achieve the prespecified type I error and power. The usefulness of the proposed methodology is further demonstrated in the power calculation for designing superiority and noninferiority trials.

A Bayesian model-based reduced major axis regression.

Reduced major axis (RMA) regression, widely used in the fields of zoology, botany, ecology, biology, spectroscopy, and among others, outweighs the ordinary least square regression by relaxing the assumption that the covariates are without measurement errors. A Bayesian implementation of the RMA regression is presented in this paper, and the equivalence of the estimates of the parameters under the Bayesian and the frequentist frameworks is proved. This model-based Bayesian RMA method is advantageous since the posterior estimates, the standard deviations, as well as the credible intervals of the estimates can be obtained through Markov chain Monte Carlo methods directly. In addition, it is straightforward to extend to the multivariate RMA case. The performance of the Bayesian RMA approach is evaluated in the simulation study, and, finally, the proposed method is applied to analyze a dataset in the plantation.

Multi-Omics Analysis of Gut Microbiota and Host Transcriptomics Reveal Dysregulated Immune Response and Metabolism in Young Adults with Irritable Bowel Syndrome.

The integrated dysbiosis of gut microbiota and altered host transcriptomics in irritable bowel syndrome (IBS) is yet to be known. This study investigated the associations among gut microbiota and host transcriptomics in young adults with IBS. Stool and peripheral blood samples from 20 IBS subjects and 21 healthy controls (HCs) collected at the baseline visit of an RCT were sequenced to depict the gut microbiota and transcriptomic profiles, respectively. The diversities, composition, and predicted metabolic pathways of gut microbiota significantly differed between IBS subjects and HCs. Nine genera were significantly abundant in IBS stool samples, including Akkermansia, Blautia, Coprococcus, Granulicatella, Holdemania, Oribacterium, Oscillospira, Parabacteroides, and Sutterella. There were 2264 DEGs found between IBS subjects and HCs; 768 were upregulated, and 1496 were downregulated in IBS participants compared with HCs. The enriched gene ontology included the immune system process and immune response. The pathway of antigen processing and presentation (hsa04612) in gut microbiota was also significantly different in the RNA-seq data. Akkermansia, Blautia, Holdemania, and Sutterella were significantly correlated with ANXA2P2 (upregulated, positive correlations), PCSK1N (downregulated, negative correlations), and GLTPD2 (downregulated, negative correlations). This study identified the dysregulated immune response and metabolism in IBS participants revealed by the altered gut microbiota and transcriptomic profiles.

Systematic review and updated recommendations for cardiomyopathy surveillance for survivors of childhood, adolescent, and young adult cancer from the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Survivors of childhood, adolescent, and young adult cancer, previously treated with anthracycline chemotherapy (including mitoxantrone) or radiotherapy in which the heart was exposed, are at increased risk of cardiomyopathy. Symptomatic cardiomyopathy is typically preceded by a series of gradually progressive, asymptomatic changes in structure and function of the heart that can be ameliorated with treatment, prompting specialist organisations to endorse guidelines on cardiac surveillance in at-risk survivors of cancer. In 2015, the International Late Effects of Childhood Cancer Guideline Harmonization Group compiled these guidelines into a uniform set of recommendations applicable to a broad spectrum of clinical environments with varying resource availabilities. Since then, additional studies have provided insight into dose thresholds associated with a risk of asymptomatic and symptomatic cardiomyopathy, have characterised risk over time, and have established the cost-effectiveness of different surveillance strategies. This systematic Review and guideline provides updated recommendations based on the evidence published up to September, 2020.

High-quality nuclei isolation from postmortem human heart muscle tissues for single-cell studies.

Single-cell approaches have become an increasingly popular way of understanding the genetic factors behind disease. Isolation of DNA and RNA from human tissues is necessary to analyze multi-omic data sets, providing information on the single-cell genome, transcriptome, and epigenome. Here, we isolated high-quality single-nuclei from postmortem human heart tissues for DNA and RNA analysis. Postmortem human tissues were obtained from 106 individuals, 33 with a history of myocardial disease, diabetes, or smoking, and 73 controls without heart disease. We demonstrated that the Qiagen EZ1 instrument and kit consistently isolated genomic DNA of high yield, which can be used for checking DNA quality before conducting single-cell experiments. Here, we provide a method for single-nuclei isolation from cardiac tissue, otherwise known as the SoNIC method, which allows for the isolation of single cardiomyocyte nuclei from postmortem tissue by nuclear ploidy status. We also provide a detailed quality control measure for single-nuclei whole genome amplification and a pre-amplification method for confirming genomic integrity.

SUMO Protease SMT7 Modulates Ribosomal Protein L30 and Regulates Cell-Size Checkpoint Function.

Proliferating cells actively coordinate growth and cell division to ensure cell-size homeostasis; however, the underlying mechanism through which size is controlled is poorly understood. Defect in a SUMO protease protein, suppressor of mat3 7 (SMT7), has been shown to reduce cell division number and increase cell size of the small-size mutant mating type locus 3-4 (mat3-4), which contains a defective retinoblastoma tumor suppressor-related protein of Chlamydomonas (Chlamydomonas reinhardtii). Here we describe development of an in vitro SUMOylation system using Chlamydomonas components and use it to provide evidence that SMT7 is a bona fide SUMO protease. We further demonstrate that the SUMO protease activity is required for supernumerous mitotic divisions of the mat3-4 cells. In addition, we identified RIBOSOMAL PROTEIN L30 (RPL30) as a prime SMT7 target and demonstrated that its SUMOylation is an important modulator of cell division in mat3-4 cells. Loss of SMT7 caused elevated SUMOylated RPL30 levels. Importantly, overexpression of the translational fusion version of RPL30-SUMO4, which mimics elevation of the SUMOylated RPL30 protein in mat3-4, caused a decrease in mitotic division and recapitulated the size-increasing phenotype of the smt7-1 mat3-4 cells. In summary, our study reveals a novel mechanism through which a SUMO protease regulates cell division in the mat3-4 mutant of Chlamydomonas and provides yet another important example of the role that protein SUMOylation can play in regulating key cellular processes, including cell division.

Fruit juice and childhood obesity: a review of epidemiologic studies.

Childhood obesity is a national epidemic, and many efforts have been made to understand its risk factors. The purpose of this review was to provide an updated account of the observational studies evaluating the relationship between 100% fruit juice intake and obesity in children and adolescents, and to highlight the major risk factors that may impact this relationship. PubMed and Scopus were searched for terms related to fruit juice and childhood obesity, and studies assessing 100% fruit juice intake in participants ≤ 19 years old, with obesity-related outcomes (BMI or adiposity), and published before March 9, 2021 were included. There were 17 prospective cohort and 14 cross-sectional studies included in the analysis. Overall, the evidence does not support a relationship between 100% fruit juice intake and measures of obesity in most children. There is some evidence to suggest a minor positive association in some overweight or very young children, but due to fundamental differences and limitations in methodology, further investigation is required. Significant gaps in literature on this topic exist particularly in regards to randomized clinical trials in children, and in studies in racially diverse populations.

Modeling and maximum likelihood based inference of interval-censored data with unknown upper limits and time-dependent covariates.

Due to the nature of study design or other reasons, the upper limits of the interval-censored data with multiple visits are unknown. A naïve approach is to treat the last observed time as the exact event time, which may induce biased estimators of the model parameters. In this paper, we first develop a Cox model with time-dependent covariates for the event time and a proportional hazards model with frailty for the gap time. We then construct the upper limits using the latent gap times to resolve the issue of interval-censored event time data with unknown upper limits. A data-augmentation technique and a Monte Carlo EM (MCEM) algorithm are developed to facilitate computation. Theoretical properties of the computational algorithm are also investigated. Additionally, new model comparison criteria are developed to assess the fit of the gap time data as well as the fit of the event time data conditional on the gap time data. Our proposed method compares favorably with competing methods in both simulation study and real data analysis.

New C-indices for assessing importance of longitudinal biomarkers in fitting competing risks survival data in the presence of partially masked causes.

Competing risks survival data in the presence of partially masked causes are frequently encountered in medical research or clinical trials. When longitudinal biomarkers are also available, it is of great clinical importance to examine associations between the longitudinal biomarkers and the cause-specific survival outcomes. In this article, we propose a cause-specific C-index for joint models of longitudinal and competing risks survival data accounting for masked causes. We also develop a posterior predictive algorithm for computing the out-of-sample cause-specific C-index using Markov chain Monte Carlo samples from the joint posterior of the in-sample longitudinal and competing risks survival data. We further construct the Δ $$ \Delta $$ C-index to quantify the strength of association between the longitudinal and cause-specific survival data, or between the out-of-sample longitudinal and survival data. Empirical performance of the proposed assessment criteria is examined through an extensive simulation study. An in-depth analysis of the real data from large cancer prevention trials is carried out to demonstrate the usefulness of the proposed methodology.

Clinical response to lifestyle counseling for dyslipidemia and elevated blood pressure in childhood cancer survivors.

BACKGROUND: Childhood cancer survivors (CCS) have increased risk of premature cardiovascular disease. Whether they respond similarly to lifestyle changes for elevated blood pressure (BP), body mass index (BMI), and dyslipidemia to those without history of childhood cancer is unknown. PROCEDURE: This retrospective cohort study included CCS and 3:1 age- and sex-matched controls treated at Boston Children's Hospital Preventive Cardiology (2010-2019) using lifestyle management based on National Heart, Lung, and Blood Institute (NHLBI) guidelines. Change in BMI, BP, and lipids were analyzed. RESULTS: We included 52 CCS and 162 controls with a median age of approximately 16 years. More CCS (84.3%) had elevated baseline fasting triglycerides (TG) than controls (49.4%) (p < .001). More CCS (62.5%) also had abnormal baseline high-density lipoprotein cholesterol (HDL-C) compared to controls (35.2%) (p = .001). Baseline BMI, BP, total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) were similar between groups. Over 15 weeks [IQR: 10.5-26], CCS had greater decrease in TG than controls (72.5 vs. 17 mg/dl decrease, p = .095). BP improved in 5% of CCS versus 38% of controls (p = .008). For both, BMI, TC, LDL-C, and HDL-C remained stable. CCS with stem cell transplantation (SCT) had a TC increase of 5% (6 mg/dl) compared to a decrease of 9% (19 mg/dl) among CCS without SCT (p = .02). CONCLUSIONS: CCS demonstrated similar improvement in lipids, but impaired BP lowering in response to lifestyle management compared to controls. Further prospective studies are needed to determine if earlier pharmaceutical treatment is warranted in this higher risk population and for the long-term risk reductions of these approaches.

Tailored to a Woman's Heart: Gender Cardio-Oncology Across the Lifespan.

PURPOSE OF REVIEW: Females outnumber males among long-term cancer survivors, primarily as a result of the prevalence of breast cancer. Late cardiovascular effects of cancer develop over several decades, which for many women, may overlap with reproductive and lifecycle events. Thus, women require longitudinal cardio-oncology care that anticipates and responds to their evolving cardiovascular risk. RECENT FINDINGS: Women may experience greater cardiotoxicity from cancer treatments compared to men and a range of treatment-associated hormonal changes that increase cardiometabolic risk. Biological changes at critical life stages, including menarche, pregnancy, and menopause, put female cancer patients and survivors at a unique risk of cardiovascular disease. Women also face distinct psychosocial and physical barriers to accessing cardiovascular care. We describe the need for a lifespan-based approach to cardio-oncology for women. Cardio-oncology care tailored to women should rigorously consider cancer treatment/outcomes and concurrent reproductive/hormonal changes, which collectively shape quality of life and cardiovascular outcomes.

Challenges in Cardiovascular Imaging in Women with Breast Cancer.

Cardiovascular imaging in breast cancer patients is paramount for the surveillance of cancer therapy-related cardiac dysfunction (CTRCD); however, it comes with specific limitations. PURPOSE OF REVIEW: This review aims to describe the unique challenges faced in cardiovascular imaging of breast cancer patients, discuss evidence to support the utility of various imaging modalities, and provide solutions for improvement in imaging this unique population. RECENT FINDINGS: Updated clinical society guidelines have introduced more unifying surveillance of CTRCD, although there remains a lack of a universally accepted definition. Traditional and novel multi-modality imaging can be used to detect CTRCD and myocarditis in breast cancer patients. Cardiovascular imaging in breast cancer patients is difficult due to reconstructive surgery. Although echocardiography with myocardial strain is the cornerstone, multi-modality imaging can be used to evaluate for CTRCD and myocarditis. Novel imaging techniques to improve the diagnosis of cardiotoxicities in breast cancer patients are needed.

On efficient posterior inference in normalized power prior Bayesian analysis.

The power prior has been widely used to discount the amount of information borrowed from historical data in the design and analysis of clinical trials. It is realized by raising the likelihood function of the historical data to a power parameter δ ∈ [ 0 , 1 ] $\delta \in [0, 1]$ , which quantifies the heterogeneity between the historical and the new study. In a fully Bayesian approach, a natural extension is to assign a hyperprior to δ such that the posterior of δ can reflect the degree of similarity between the historical and current data. To comply with the likelihood principle, an extra normalizing factor needs to be calculated and such prior is known as the normalized power prior. However, the normalizing factor involves an integral of a prior multiplied by a fractional likelihood and needs to be computed repeatedly over different δ during the posterior sampling. This makes its use prohibitive in practice for most elaborate models. This work provides an efficient framework to implement the normalized power prior in clinical studies. It bypasses the aforementioned efforts by sampling from the power prior with δ = 0 $\delta = 0$ and δ = 1 $\delta = 1$ only. Such a posterior sampling procedure can facilitate the use of a random δ with adaptive borrowing capability in general models. The numerical efficiency of the proposed method is illustrated via extensive simulation studies, a toxicological study, and an oncology study.