Differential CpG methylation at Nnat in the early establishment of beta cell heterogeneity.

AIMS/HYPOTHESIS: Beta cells within the pancreatic islet represent a heterogenous population wherein individual sub-groups of cells make distinct contributions to the overall control of insulin secretion. These include a subpopulation of highly connected 'hub' cells, important for the propagation of intercellular Ca2+ waves. Functional subpopulations have also been demonstrated in human beta cells, with an altered subtype distribution apparent in type 2 diabetes. At present, the molecular mechanisms through which beta cell hierarchy is established are poorly understood. Changes at the level of the epigenome provide one such possibility, which we explore here by focusing on the imprinted gene Nnat (encoding neuronatin [NNAT]), which is required for normal insulin synthesis and secretion. METHODS: Single-cell RNA-seq datasets were examined using Seurat 4.0 and ClusterProfiler running under R. Transgenic mice expressing enhanced GFP under the control of the Nnat enhancer/promoter regions were generated for FACS of beta cells and downstream analysis of CpG methylation by bisulphite sequencing and RNA-seq, respectively. Animals deleted for the de novo methyltransferase DNA methyltransferase 3 alpha (DNMT3A) from the pancreatic progenitor stage were used to explore control of promoter methylation. Proteomics was performed using affinity purification mass spectrometry and Ca2+ dynamics explored by rapid confocal imaging of Cal-520 AM and Cal-590 AM. Insulin secretion was measured using homogeneous time-resolved fluorescence imaging. RESULTS: Nnat mRNA was differentially expressed in a discrete beta cell population in a developmental stage- and DNA methylation (DNMT3A)-dependent manner. Thus, pseudo-time analysis of embryonic datasets demonstrated the early establishment of Nnat-positive and -negative subpopulations during embryogenesis. NNAT expression is also restricted to a subset of beta cells across the human islet that is maintained throughout adult life. NNAT+ beta cells also displayed a discrete transcriptome at adult stages, representing a subpopulation specialised for insulin production, and were diminished in db/db mice. 'Hub' cells were less abundant in the NNAT+ population, consistent with epigenetic control of this functional specialisation. CONCLUSIONS/INTERPRETATION: These findings demonstrate that differential DNA methylation at Nnat represents a novel means through which beta cell heterogeneity is established during development. We therefore hypothesise that changes in methylation at this locus may contribute to a loss of beta cell hierarchy and connectivity, potentially contributing to defective insulin secretion in some forms of diabetes. DATA AVAILABILITY: The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD048465.

The Drosophila brain on cocaine at single-cell resolution.

Whereas the neurological effects of cocaine have been well documented, effects of acute cocaine consumption on genome-wide gene expression across the brain remain largely unexplored. This question cannot be readily addressed in humans but can be approached using the Drosophila melanogaster model, where gene expression in the entire brain can be surveyed at once. Flies exposed to cocaine show impaired locomotor activity, including climbing behavior and startle response (a measure of sensorimotor integration), and increased incidence of seizures and compulsive grooming. To identify specific cell populations that respond to acute cocaine exposure, we analyzed single-cell transcriptional responses in duplicate samples of flies that consumed fixed amounts of sucrose or sucrose supplemented with cocaine, in both sexes. Unsupervised clustering of the transcriptional profiles of a total of 86,224 cells yielded 36 distinct clusters. Annotation of clusters based on gene markers revealed that all major cell types (neuronal and glial) as well as neurotransmitter types from most brain regions were represented. The brain transcriptional responses to cocaine showed profound sexual dimorphism and were considerably more pronounced in males than females. Differential expression analysis within individual clusters indicated cluster-specific responses to cocaine. Clusters corresponding to Kenyon cells of the mushroom bodies and glia showed especially large transcriptional responses following cocaine exposure. Cluster specific coexpression networks and global interaction networks revealed a diverse array of cellular processes affected by acute cocaine exposure. These results provide an atlas of sexually dimorphic cocaine-modulated gene expression in a model brain.

Milvexian vs apixaban for stroke prevention in atrial fibrillation: The LIBREXIA atrial fibrillation trial rationale and design.

BACKGROUND: Direct oral anticoagulants are the standard of care for stroke prevention in eligible patients with atrial fibrillation and atrial flutter; however, bleeding remains a significant concern, limiting their use. Milvexian is an oral Factor XIa inhibitor that may offer similar anticoagulant efficacy with less bleeding risk. METHODS: LIBREXIA AF (NCT05757869) is a global phase III, randomized, double-blind, parallel-group, event-driven trial to compare milvexian with apixaban in participants with atrial fibrillation or atrial flutter. Participants are randomly assigned to milvexian 100 mg or apixaban (5 mg or 2.5 mg per label indication) twice daily. The primary efficacy objective is to evaluate if milvexian is noninferior to apixaban for the prevention of stroke and systemic embolism. The principal safety objective is to evaluate if milvexian is superior to apixaban in reducing the endpoint of International Society of Thrombosis and Hemostasis (ISTH) major bleeding events and the composite endpoint of ISTH major and clinically relevant nonmajor (CRNM) bleeding events. In total, 15,500 participants from approximately 1,000 sites in over 30 countries are planned to be enrolled. They will be followed until both 430 primary efficacy outcome events and 530 principal safety events are observed, which is estimated to take approximately 4 years. CONCLUSION: The LIBREXIA AF study will determine the efficacy and safety of the oral Factor XIa inhibitor milvexian compared with apixaban in participants with either atrial fibrillation or atrial flutter. TRIAL REGISTRATION: ClinicalTrials.gov NCT05757869.

Safeguarding genomic integrity in beta-cells: implications for beta-cell differentiation, growth, and dysfunction.

The maintenance of optimal glucose levels in the body requires a healthy reserve of the insulin producing pancreatic beta-cells. Depletion of this reserve due to beta-cell dysfunction and death results in development of diabetes. Recent findings highlight unresolved DNA damage as a key contributor to beta-cell defects in diabetes. Beta-cells face various stressors and metabolic challenges throughout life, rendering them susceptible to DNA breaks. The post-mitotic, long-lived phenotype of mature beta-cells further warrants robust maintenance of genomic integrity. Failure to resolve DNA damage during beta-cell development, therefore, can result in an unhealthy reserve of beta-cells and predispose to diabetes. Yet, the molecular mechanisms safeguarding beta-cell genomic integrity remain poorly understood. Here, we focus on the significance of DNA damage in beta-cell homeostasis and postulate how cellular expansion, epigenetic programming, and metabolic shifts during development may impact beta-cell genomic integrity and health. We discuss recent findings demonstrating a physiological role for DNA breaks in modulating transcriptional control in neurons, which share many developmental programs with beta-cells. Finally, we highlight key gaps in our understanding of beta-cell genomic integrity and discuss emerging areas of interest.

Artificial Intelligence in Cardiovascular Disease Prevention: Is it Ready for Prime Time?

PURPOSE OF REVIEW: This review evaluates how Artificial Intelligence (AI) enhances atherosclerotic cardiovascular disease (ASCVD) risk assessment, allows for opportunistic screening, and improves adherence to guidelines through the analysis of unstructured clinical data and patient-generated data. Additionally, it discusses strategies for integrating AI into clinical practice in preventive cardiology. RECENT FINDINGS: AI models have shown superior performance in personalized ASCVD risk evaluations compared to traditional risk scores. These models now support automated detection of ASCVD risk markers, including coronary artery calcium (CAC), across various imaging modalities such as dedicated ECG-gated CT scans, chest X-rays, mammograms, coronary angiography, and non-gated chest CT scans. Moreover, large language model (LLM) pipelines are effective in identifying and addressing gaps and disparities in ASCVD preventive care, and can also enhance patient education. AI applications are proving invaluable in preventing and managing ASCVD and are primed for clinical use, provided they are implemented within well-regulated, iterative clinical pathways.

Real-world first-line treatment patterns and outcomes in recurrent/advanced endometrial cancer patients in Europe.

Background: The treatment patterns and clinical outcomes in recurrent/advanced endometrial cancer in Europe are not well known. Materials & methods: Endometrial Cancer Health Outcomes-Europe-First-Line is a multicenter, retrospective chart review study conducted in the UK, Germany, Italy, France and Spain. Patients diagnosed with recurrent/advanced endometrial cancer who initiated first-line systemic therapy between 1 July 2016 and 31 March 2020 were eligible. Results: Among 242 patients, median age was 69 years and 82.2% had stage IIIB-IV disease. In first-line, most patients received platinum-based chemotherapy (78.9%); others received endocrine therapy (6.2%), taxane monotherapy (5.8%) and nonplatinum or taxane-based chemotherapy (4.1%). Median real-world progression-free survival since first-line initiation was 10.8 months and median overall survival was 20.7 months. Conclusion: Poor prognosis with platinum-based first-line chemotherapy suggests significant unmet medical need.

Treatment patterns & survival for recurrent/advanced endometrial cancer patients in Europe who received their first treatmentThe treatments and survival for recurrent/advanced endometrial (uterus lining) cancer patients in real-life European settings are not well known. Endometrial Cancer Health Outcomes-Europe-First-Line is a multicenter study that was conducted in the UK, Germany, Italy, France and Spain and used de-identified information from existing patient medical records. Patients diagnosed with recurrent/advanced endometrial cancer who initiated a first treatment between 1 July 2016 and 31 March 2020 were included. Among 242 included patients, the average age was 69 years and 82.2% had stage IIIB-IV disease (indicating the size and extent of their cancer). As their first treatment, most patients received platinum-based chemotherapy (78.9%), which is a type of drug that kills cancer cells. Overall, patients lived for an average of 20.7 months since their first treatment. The average length of time patients lived without their disease getting worse was 10.8 months since their first treatment. We found that patients who received platinum-based chemotherapy as their first treatment had poor survival, which suggests significant unmet medical need.

Real-world prevalence of microsatellite instability testing and related status in women with advanced endometrial cancer in Europe.

PURPOSE: To assess the real-world prevalence of microsatellite instability (MSI)/mismatch repair (MMR) testing and related tumor status in recurrent/advanced endometrial cancer patients in Europe. METHODS: Data were from two multi-center, retrospective patient chart review studies conducted in the United Kingdom, Germany, Italy, France and Spain: The Endometrial Cancer Health Outcomes-Europe-First-Line (ECHO-EU-1L) study and the ECHO-EU-Second-Line (ECHO-EU-2L) study. ECHO-EU-1L included recurrent/advanced endometrial cancer patients who received first-line systemic therapy between 1/JUN/2016 and 31/MAR/2020 after recurrent/advanced diagnosis. ECHO-EU-2L included patients with recurrent/advanced endometrial cancer who progressed between 1/JUN/2016 and 30/JUN/2019 following prior first-line systemic therapy. Data collected included patient demographics, MSI/MMR tumor testing and results, and clinical/treatment characteristics. RESULTS: ECHO-EU-1L included 242 first-line patients and ECHO-EU-2L included 475 s-line patients. For all patients, median age at recurrent/advanced diagnosis was 69 years, roughly half had endometrioid carcinoma histology and over 75% had Stage IIIB-IV disease at initial diagnosis. The prevalence of MSI/MMR testing in the first-line and second-line cohorts was similar (36.4 and 34.9%, respectively). Among those tested, a majority had non-MSI-high/MMR proficient tumors (80.7 and 74.7% among first- and second-line patients, respectively). About 15% had MSI-high/MMR deficient tumors in both cohorts, and a few patients had discordant results (3.4 and 10.8% among first- and second-line patients, respectively). CONCLUSION: Prior to the approvals of biomarker-directed therapies for recurrent/advanced endometrial cancer patients in Europe, there were low MSI/MMR testing rates for these patients of just over one-third. Given the availability of biomarker-directed therapies, increased MSI/MMR testing may help inform treatment decisions for recurrent/advanced endometrial cancer patients in Europe.

COVID-19-Associated Sepsis: Potential Role of Phytochemicals as Functional Foods and Nutraceuticals.

The acute manifestations of coronavirus disease 2019 (COVID-19) exhibit the hallmarks of sepsis-associated complications that reflect multiple organ failure. The inflammatory cytokine storm accompanied by an imbalance in the pro-inflammatory and anti-inflammatory host response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leads to severe and critical septic shock. The sepsis signature in severely afflicted COVID-19 patients includes cellular reprogramming and organ dysfunction that leads to high mortality rates, emphasizing the importance of improved clinical care and advanced therapeutic interventions for sepsis associated with COVID-19. Phytochemicals of functional foods and nutraceutical importance have an incredible impact on the healthcare system, which includes the prevention and/or treatment of chronic diseases. Hence, in the present review, we aim to explore the pathogenesis of sepsis associated with COVID-19 that disrupts the physiological homeostasis of the body, resulting in severe organ damage. Furthermore, we have summarized the diverse pharmacological properties of some potent phytochemicals, which can be used as functional foods as well as nutraceuticals against sepsis-associated complications of SARS-CoV-2 infection. The phytochemicals explored in this article include quercetin, curcumin, luteolin, apigenin, resveratrol, and naringenin, which are the major phytoconstituents of our daily food intake. We have compiled the findings from various studies, including clinical trials in humans, to explore more into the therapeutic potential of each phytochemical against sepsis and COVID-19, which highlights their possible importance in sepsis-associated COVID-19 pathogenesis. We conclude that our review will open a new research avenue for exploring phytochemical-derived therapeutic agents for preventing or treating the life-threatening complications of sepsis associated with COVID-19.

Treatment patterns and real-world clinical outcomes in patients with advanced endometrial cancer who are microsatellite instability (MSI)-high or are mismatch repair deficient (dMMR) in the United States.

OBJECTIVES: Microsatellite instability-high (MSI-H) and deficient DNA mismatch repair (dMMR) status have emerged as actionable biomarkers for advanced endometrial cancer (aEC). The objective of this study was to assess clinical outcomes and treatment patterns among MSI-H/dMMR aEC patients who had disease progression following prior systemic therapy (FPST) in the US. METHODS: Endometrial Cancer Health Outcomes (ECHO) was a retrospective, medical chart review study of patients with MSI-H/dMMR aEC who had disease progression between 07/01/2016 and 12/31/2018 FPST and were not candidates for curative surgery. Data on patient demographics, clinical and treatment characteristics, and clinical outcomes were collected. Kaplan-Meier analyses were performed to estimate real-world progression-free survival (rwPFS) and overall survival (OS), stratified by drug class. RESULTS: A total of 124 eligible patients who initiated second-line chemotherapy ± bevacizumab or immunotherapy were included. Mean age was 61.4 years at aEC diagnosis and 86.3% of patients were stage IIIB-IV. Median rwPFS and OS were 4.0 months (95% CI: 2.0-9.0) and 7.0 months (95% CI: 5.0-18.0), respectively, among 21 patients who received chemotherapy ± bevacizumab, and 29.0 months (95% CI: 18.0-NE) and not reached (95% CI: 30.0-NA), respectively, among 103 patients who received immunotherapy. Most patients (n = 92) received pembrolizumab; among these patients, rwPFS and OS were 29.0 months (95% CI: 18.0-NE) and 30 months (95% CI: 30.0-NA), respectively. CONCLUSIONS: Real-world evidence suggests that pembrolizumab monotherapy provides considerable clinical benefits and has become the standard of care for MSI-H/dMMR aEC patients FPST who are not candidates for curative surgery in real-world settings.

Environmental tobacco smoke and children's health: a bibliometric and altmetric analysis of 100 most cited articles.

BACKGROUND: Exposure to environmental tobacco smoke (ETS) is arguably the most ubiquitous and hazardous, even at very low levels, starting in early life. The objective of this study was to describe the state of research and future trends on ETS exposure and Children's Health (CH) topics with bibliometrics and altmetrics. METHODS: An electronic search was performed in Scopus database on January 31, 2023. Consensus was arrived on 100 most-cited articles by two reviewers. These papers were then cross matched with citations harvested from Web of Science (WoS) and Google Scholar. Altmetric Attention Score (AAS) and Dimension counts were also collected. Analysis and network visualization of authors, countries, and keywords were generated using VOSviewer software. RESULTS: Among a total of 1107 articles published on ETS and CH, the 100 top-cited articles appeared in 54 journals, with Pediatrics (n = 12) contributing a maximum number of articles. The time period between 2000 and 2009 accounted for 44% of all publications. With respect to the research design employed across these studies, cross-sectional design took precedence over others accounting for approximately 40%. Predominantly, articles focused on childhood asthma; however, current research trends have shifted towards emerging fields such as children's oral health and DNA methylation. Twitter, policy documents, and news outlets were the main platforms where outputs were discussed. The AAS was not associated with journal impact factor or access type. Weak correlations were observed between AAS and citation count in Scopus, WoS, and Google Scholar (r = 0.17 to 0.27) while a positive association existed between dimension count and the number of citations across all three databases (r = 0.84 to 0.98). CONCLUSION: This study demonstrates the evolution, digital dissemination and research hotspots in the field of ETS and CH, predicting the possible future research directions. High-quality studies with more specific exposure classification are warranted to better understand the relationship between ETS and CH.

Metarhizium indicum, a new species of entomopathogenic fungus infecting leafhopper, Busoniomimus manjunathi from India.

A new species of entomopathogenic fungus, Metarhizium indicum, which derives its species epithet after its Indian origin is reported here. The fungus was found to cause natural epizootics in leafhopper (Busoniomimus manjunathi) infesting Garcinia gummi-gutta (Malabar tamarind), an evergreen spice tree native to South and Southeast Asia, known for its use as a culinary flavourant, dietary supplement and traditional remedy for various human ailments. The fungus was found to cause more than 60% mortality in field collected insects. The identity of the new species was established based on its distinct morphological characteristics and multi-gene sequence data analyses. Phylogenetic analyses using internal transcribed spacer region (ITS), DNA lyase (APN2) and a concatenated set of four marker genes [translation elongation factor 1-alpha (TEF), ß-tubulin (BTUB), RNA polymerase II largest subunit (RPB1) and RNA polymerase II second largest subunit (RPB2)] along with marked differences in nucleotide composition and genetic distance unambiguously support our claim that the present fungus infecting Garcinia leafhopper is a new addition to the genus Metarhizium.

Proteomic Determinants of Variation in Cholesterol Efflux: Observations from the Dallas Heart Study.

High-density lipoproteins (HDLs) are promising targets for predicting and treating atherosclerotic cardiovascular disease (ASCVD), as they mediate removal of excess cholesterol from lipid-laden macrophages that accumulate in the vasculature. This functional property of HDLs, termed cholesterol efflux capacity (CEC), is inversely associated with ASCVD. HDLs are compositionally diverse, associating with >250 different proteins, but their relative contribution to CEC remains poorly understood. Our goal was to identify and define key HDL-associated proteins that modulate CEC in humans. The proteomic signature of plasma HDL was quantified in 36 individuals in the multi-ethnic population-based Dallas Heart Study (DHS) cohort that exhibited persistent extremely high (>=90th%) or extremely low CEC (<=10th%) over 15 years. Levels of apolipoprotein (Apo)A-I associated ApoC-II, ApoC-III, and ApoA-IV were differentially correlated with CEC in high (r = 0.49, 0.41, and -0.21 respectively) and low (r = -0.46, -0.41, and 0.66 respectively) CEC groups (p for heterogeneity (pHet) = 0.03, 0.04, and 0.003 respectively). Further, we observed that levels of ApoA-I with ApoC-III, complement C3 (CO3), ApoE, and plasminogen (PLMG) were inversely associated with CEC in individuals within the low CEC group (r = -0.11 to -0.25 for subspecies with these proteins vs. r = 0.58 to 0.65 for subspecies lacking these proteins; p < 0.05 for heterogeneity). These findings suggest that enrichment of specific proteins on HDLs and, thus, different subspecies of HDLs, differentially modulate the removal of cholesterol from the vasculature.

Systematic review of clinical practice guidelines for traumatic dental injuries.

BACKGROUND/AIMS: Traumatic dental injuries (TDI) are considered a public health problem due to their high prevalence and associated physical, economic, psychological and social consequences. Hence, good Clinical Practice Guidelines are essential to achieving a favourable prognosis. The aim of this review was to appraise the existing Clinical Practice Guidelines (CPGs) on TDI using AGREE II and AGREE-REX. MATERIALS AND METHODS: A systematic search for existing guidelines on TDI was performed on PubMed, EMBASE, CINAHL, Cochrane Library, ProQuest, National Institute for Health Care Excellence, BMJ Best Practice, Trip database, Guideline International Network, Scottish Intercollegiate Guidelines Network, World Health Organisation, Web of Science and 'Ministry of Health worldwide' databases. Four appraisers independently appraised the included CPGs. The AGREE II tool was applied to assess the methodological quality, while AGREE REX assessed the quality of recommendations of the included guidelines. RESULTS: Of the 7736 titles screened, three guidelines, namely the International Association of Dental Traumatology Guidelines (IADT), and the Italian and Malaysian guidelines, were included for the final analysis. These guidelines were published between 2019 and 2020. The AGREE II analysis demonstrated scores above 80% for the IADT and Italian guidelines for the scope and purpose domain. Overall, the Malaysian guidelines achieved the highest score for all domains. The AGREE REX analysis indicated variability in implementation across the nine items, with five that scored above the midpoint of 4.0 on the response scale. Both the Italian and the IADT guidelines had a similar score for the values and preference domains (36.36%). CONCLUSIONS: Several deficiencies exist in the methodological quality of existing CPGs on TDI. Future guidelines should consider improvements for domains such as 'rigour of development', 'stakeholder involvement' and 'applicability' to overcome the existing limitations.

Functional Diversification, Redundancy, and Epistasis among Paralogs of the Drosophila melanogaster Obp50a-d Gene Cluster.

Large multigene families, such as the insect odorant-binding proteins (OBPs), are thought to arise through functional diversification after repeated gene duplications. Whereas many OBPs function in chemoreception, members of this family are also expressed in tissues outside chemosensory organs. Paralogs of the Obp50 gene cluster are expressed in metabolic and male reproductive tissues, but their functions and interrelationships remain unknown. Here, we report the genetic dissection of four members of the Obp50 cluster, which are in close physical proximity without intervening genes. We used CRISPR technology to excise the entire cluster while introducing a PhiC31 reintegration site to reinsert constructs in which different combinations of the constituent Obp genes were either intact or rendered inactive. We performed whole transcriptome sequencing and assessed sexually dimorphic changes in transcript abundances (transcriptional niches) associated with each gene-edited genotype. Using this approach, we were able to estimate redundancy, additivity, diversification, and epistasis among Obp50 paralogs. We analyzed the effects of gene editing of this cluster on organismal phenotypes and found a significant skewing of sex ratios attributable to Obp50a, and sex-specific effects on starvation stress resistance attributable to Obp50d. Thus, there is functional diversification within the Obp50 cluster with Obp50a contributing to development and Obp50d to stress resistance. The deletion-reinsertion approach we applied to the Obp50 cluster provides a general paradigm for the genetic dissection of paralogs of multigene families.

Early Childhood Caries and Iron Deficiency Anaemia: A Systematic Review and Meta-Analysis.

Identification of the association between Early Childhood Caries (ECC) and Iron Deficiency Anaemia (IDA) will aid paediatricians and paediatric dentists to enhance health promotion measures to reduce the related morbidity in children. This systematic review aims to determine an evidence-based association between ECC and IDA. A systematic search was carried out from MEDLINE via PubMed, EMBASE, LILACS, Cochrane Oral Health Group's Specialized Register, CINAHL via EBSCO, Web of Science, and Scopus up to May 2020. Hand searching and grey literature screening were also conducted. Cross-sectional, case-control, and cohort studies in English language which assessed the association was included. Two reviewers independently assessed the study quality and extracted the outcome data. A total of 1,434 studies were identified. Fourteen studies qualified for qualitative review and 7 of them for a meta-analysis. In comparison with children not affected by ECC, those affected had an increased likelihood of IDA (OR = 6.07 [3.61, 10.21]). The meta-analysis showed no statistical difference when comparing blood parameters (Hb, MCV, and serum ferritin) in children with and without ECC. This systematic review demonstrates an association between ECC and increased odds of IDA rather than it being the cause for IDA. Further longitudinal studies with robust methodology are required to determine an evidence-based association.

COVID-19 and Cardiovascular Disease.

Coronavirus disease 2019 (COVID-19) is a global pandemic affecting 185 countries and >3 000 000 patients worldwide as of April 28, 2020. COVID-19 is caused by severe acute respiratory syndrome coronavirus 2, which invades cells through the angiotensin-converting enzyme 2 receptor. Among patients with COVID-19, there is a high prevalence of cardiovascular disease, and >7% of patients experience myocardial injury from the infection (22% of critically ill patients). Although angiotensin-converting enzyme 2 serves as the portal for infection, the role of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers requires further investigation. COVID-19 poses a challenge for heart transplantation, affecting donor selection, immunosuppression, and posttransplant management. There are a number of promising therapies under active investigation to treat and prevent COVID-19.

Prevalence of the Cusp of Carabelli: a systematic review and meta-analysis.

CONTEXT: The Cusp of Carabelli (CoC) is the most commonly occurring dental morphological trait. OBJECTIVE: To provide a pancontinental overview on the prevalence of the CoC in primary maxillary second molars and permanent maxillary molars. METHODS: An electronic search was conducted on ten databases without year restrictions up to July 2020. All cross-sectional studies published in the English language reporting prevalence estimate of CoC were included. A modified version of the Newcastle-Ottawa scale was used to assess study quality. Meta-analyses were conducted for studies that reported data using Dahlberg and ASUDAS classification across continents. RESULTS: For qualitative synthesis, 142 studies (45,327 participants) were included, of which 130 studies had moderate risk of bias. Random effects meta-analysis was performed for 41 studies. For prevalence of CoC in primary maxillary second molars, the estimate was 72% (2,829 participants). The overall percentage attained for permanent maxillary molars was 59% (16,607 participants) for first molars; 8% (2,277 participants) for second molars; and 10% (89 participants) for third molars. Subgroup analysis revealed the European continent reported the highest prevalence in permanent maxillary first and second molars. CONCLUSION: Primary maxillary second molars recorded highest prevalence of CoC followed by permanent maxillary first, third and second molars. Pancontinental studies with regard to primary maxillary second molars are warranted.

Implementation of a Pharmacist-Driven Detailed Penicillin Allergy Interview.

Background: Self-reported penicillin allergies may be outdated or inaccurate, leading to the use of alternative antimicrobials that may be less effective, more toxic, and/or more expensive. Although penicillin skin tests can provide accurate assessments of penicillin allergies, these procedures are not feasible at all institutions. Another solution is to conduct a detailed penicillin allergy interview (DPAI), which can potentially lead to optimization of antimicrobial therapy. Objective: The purpose of this study was to assess the impact of a pharmacist-driven DPAI protocol. The primary objective was to measure the number of patients requiring a change to their allergy profile following DPAI. Secondary objectives included characterizing allergy profile updates and measuring the number of recommendations to switch to a ß-lactam agent, provider acceptance rate, and patient tolerance. Methods: Standardized pharmacist-driven DPAIs were conducted prospectively on adult patients admitted with a documented penicillin allergy. The allergy profile within the electronic health record (EHR) was updated and a recommendation to switch to noncarbapenem ß-lactam therapy was made when indicated by a decision algorithm. Results: A total of 175 (37.5%) patients received a DPAI. Of these, 133 (76.0%) required a change to their allergy profile. Additionally, 135 (77.1%) patients interviewed were on antimicrobial therapy, with 42 (31.1%) meeting criteria to switch to noncarbapenem ß-lactam therapy; of which 31 (73.8%) patients were successfully transitioned, with no signs or symptoms of intolerance. Conclusions and Relevance: Implementation of pharmacist-driven DPAIs can provide updated and corrected allergy information within the EHR, allowing for de-escalation and/or optimization of antimicrobial therapy.

Elucidating Potential Profibrotic Mechanisms of Emerging Biomarkers for Early Prognosis of Hepatic Fibrosis.

Hepatic fibrosis has been associated with a series of pathophysiological processes causing excessive accumulation of extracellular matrix proteins. Several cellular processes and molecular mechanisms have been implicated in the diseased liver that augments fibrogenesis, fibrogenic cytokines and associated liver complications. Liver biopsy remains an essential diagnostic tool for histological evaluation of hepatic fibrosis to establish a prognosis. In addition to being invasive, this methodology presents with several limitations including poor cost-effectiveness, prolonged hospitalizations, and risks of peritoneal bleeding, while the clinical use of this method does not reveal underlying pathogenic mechanisms. Several alternate noninvasive diagnostic strategies have been developed, to determine the extent of hepatic fibrosis, including the use of direct and indirect biomarkers. Immediate diagnosis of hepatic fibrosis by noninvasive means would be more palatable than a biopsy and could assist clinicians in taking early interventions timely, avoiding fatal complications, and improving prognosis. Therefore, we sought to review some common biomarkers of liver fibrosis along with some emerging candidates, including the oxidative stress-mediated biomarkers, epigenetic and genetic markers, exosomes, and miRNAs that needs further evaluation and would have better sensitivity and specificity. We also aim to elucidate the potential role of cardiotonic steroids (CTS) and evaluate the pro-inflammatory and profibrotic effects of CTS in exacerbating hepatic fibrosis. By understanding the underlying pathogenic processes, the efficacy of these biomarkers could allow for early diagnosis and treatment of hepatic fibrosis in chronic liver diseases, once validated.