Genetic drivers of heterogeneity in type 2 diabetes pathophysiology.

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.

Hepatocellular carcinoma surveillance may be associated with potential psychological harms in patients with cirrhosis.

BACKGROUND AND AIMS: The value of HCC surveillance is determined by the balance between benefits and harms; however, no studies have enumerated psychological harms. APPROACH AND RESULTS: We fielded surveys measuring psychological harms to patients with cirrhosis in a multicenter randomized trial of HCC surveillance outreach. All patients with positive or indeterminate surveillance results and matched patients with negative results were invited to complete surveys measuring (1) depression through the Patient Health Questionnaire-ninth version, (2) anxiety through State-Trait Anxiety Inventory, (3) HCC-specific worry through Psychological Consequences Questionnaire, and (4) decisional regret. Patients were classified into 4 groups: true positive (TP), false positive (FP), indeterminate, and true negative (TN). Multivariable longitudinal regression analysis using the generalized estimating equation method was performed to compare the means of measures across groups. We conducted 89 semistructured interviews in a subset of patients stratified by health system and test results. Of 2872 patients in the trial, 311 completed 1+ follow-up survey (63 FP, 77 indeterminate, 38 TP, and 133 TN). Moderate depression decreased in TN patients, increased in TP, and had intermittent but mild increases in those with FP and indeterminate results. High anxiety temporarily increased in patients with TP results but resolved over time and was stable in those with FP and indeterminate results. Decisional regret was low and did not differ across groups. In semistructured interviews, patients reported apprehension, anxiety, emotional distress, and coping related to HCC surveillance. CONCLUSIONS: Psychological harms of HCC surveillance appear mild but differ by test result. Future research should determine the impact of psychological harms on the value of HCC surveillance programs.

Increased shear in the North Atlantic upper-level jet stream over the past four decades.

Earth's equator-to-pole temperature gradient drives westerly mid-latitude jet streams through thermal wind balance1. In the upper atmosphere, anthropogenic climate change is strengthening this meridional temperature gradient by cooling the polar lower stratosphere2,3 and warming the tropical upper troposphere4-6, acting to strengthen the upper-level jet stream7. In contrast, in the lower atmosphere, Arctic amplification of global warming is weakening the meridional temperature gradient8-10, acting to weaken the upper-level jet stream. Therefore, trends in the speed of the upper-level jet stream11-13 represent a closely balanced tug-of-war between two competing effects at different altitudes14. It is possible to isolate one of the competing effects by analysing the vertical shear-the change in wind speed with height-instead of the wind speed, but this approach has not previously been taken. Here we show that, although the zonal wind speed in the North Atlantic polar jet stream at 250 hectopascals has not changed since the start of the observational satellite era in 1979, the vertical shear has increased by 15 per cent (with a range of 11-17 per cent) according to three different reanalysis datasets15-17. We further show that this trend is attributable to the thermal wind response to the enhanced upper-level meridional temperature gradient. Our results indicate that climate change may be having a larger impact on the North Atlantic jet stream than previously thought. The increased vertical shear is consistent with the intensification of shear-driven clear-air turbulence expected from climate change18-20, which will affect aviation in the busy transatlantic flight corridor by creating a more turbulent flying environment for aircraft. We conclude that the effects of climate change and variability on the upper-level jet stream are being partly obscured by the traditional focus on wind speed rather than wind shear.

Multiancestry Genome-Wide Association Study of Aortic Stenosis Identifies Multiple Novel Loci in the Million Veteran Program.

BACKGROUND: Calcific aortic stenosis (CAS) is the most common valvular heart disease in older adults and has no effective preventive therapies. Genome-wide association studies (GWAS) can identify genes influencing disease and may help prioritize therapeutic targets for CAS. METHODS: We performed a GWAS and gene association study of 14 451 patients with CAS and 398 544 controls in the Million Veteran Program. Replication was performed in the Million Veteran Program, Penn Medicine Biobank, Mass General Brigham Biobank, BioVU, and BioMe, totaling 12 889 cases and 348 094 controls. Causal genes were prioritized from genome-wide significant variants using polygenic priority score gene localization, expression quantitative trait locus colocalization, and nearest gene methods. CAS genetic architecture was compared with that of atherosclerotic cardiovascular disease. Causal inference for cardiometabolic biomarkers in CAS was performed using Mendelian randomization and genome-wide significant loci were characterized further through phenome-wide association study. RESULTS: We identified 23 genome-wide significant lead variants in our GWAS representing 17 unique genomic regions. Of the 23 lead variants, 14 were significant in replication, representing 11 unique genomic regions. Five replicated genomic regions were previously known risk loci for CAS (PALMD, TEX41, IL6, LPA, FADS) and 6 were novel (CEP85L, FTO, SLMAP, CELSR2, MECOM, CDAN1). Two novel lead variants were associated in non-White individuals (P<0.05): rs12740374 (CELSR2) in Black and Hispanic individuals and rs1522387 (SLMAP) in Black individuals. Of the 14 replicated lead variants, only 2 (rs10455872 [LPA], rs12740374 [CELSR2]) were also significant in atherosclerotic cardiovascular disease GWAS. In Mendelian randomization, lipoprotein(a) and low-density lipoprotein cholesterol were both associated with CAS, but the association between low-density lipoprotein cholesterol and CAS was attenuated when adjusting for lipoprotein(a). Phenome-wide association study highlighted varying degrees of pleiotropy, including between CAS and obesity at the FTO locus. However, the FTO locus remained associated with CAS after adjusting for body mass index and maintained a significant independent effect on CAS in mediation analysis. CONCLUSIONS: We performed a multiancestry GWAS in CAS and identified 6 novel genomic regions in the disease. Secondary analyses highlighted the roles of lipid metabolism, inflammation, cellular senescence, and adiposity in the pathobiology of CAS and clarified the shared and differential genetic architectures of CAS with atherosclerotic cardiovascular diseases.

Financial Burden of Hepatocellular Carcinoma Screening in Patients With Cirrhosis.

BACKGROUND: The overall value of hepatocellular carcinoma screening is defined by the balance of benefits and harms. Studies have only reported physical harms with none describing financial harms. METHODS: We conducted a multicenter pragmatic randomized clinical trial of hepatocellular carcinoma screening outreach among 2872 patients with cirrhosis from March 2018 to April 2021. Patients with positive or indeterminate results and matched patients with negative results completed surveys at baseline and at follow-up measuring financial harms via Cancer Self-Administered Questionnaire and financial burden via Comprehensive Score for Financial Toxicity Functional Assessment of Chronic Illness Therapy. Univariable and multivariable longitudinal regression analyses were performed to compare changes in financial harms across groups: true positive, true negative, false positive, and indeterminate. Semistructured interviews were conducted in a subset of patients, sampled by center and test result. RESULTS: Of 311 patients who completed at least 1 follow-up survey (75% response rate), 37 had true positive, 133 true negative, 64 false positive, and 77 indeterminate results. Financial harms increased in true positive and false positive patients with no significant changes noted among those with true negative or indeterminate results. At follow-up, 21.8% of patients reported moderate-severe financial burden, which was not significantly associated with test results. Semistructured interviews revealed variation in the frequency and severity of financial harms based on test results, with increased harm in those with false positive results. CONCLUSIONS: Financial harms of hepatocellular carcinoma screening vary by test result and can pose a barrier that must be considered when determining the optimal screening program.

Psychiatric diagnoses are common after liver transplantation and are associated with increased health care utilization and patient financial burden.

Psychiatric disorders after liver transplantation (LT) are associated with worse patient and graft outcomes, which may be amplified by inadequate treatment. We aimed to characterize the burden of psychiatric disorders, treatment patterns, and associated financial burden among liver transplantation recipients (LTRs). IQVIA PharMetrics (R) Plus for Academics-a large health plan claims database representative of the commercially insured US population-was used to identify psychiatric diagnoses among adult LTRs and assess treatment. Multivariable logistic regression analysis identified factors associated with post-LT psychiatric diagnoses and receipt of pharmacotherapy. Patient financial liability was estimated using adjudicated medical/pharmacy claims for LTRs with and without psychiatric diagnoses. Post-LT psychiatric diagnoses were identified in 395 (29.5%) of 1338 LTRs, of which 106 (26.8%) were incident cases. Treatment varied, with 67.3% receiving pharmacotherapy, 32.1% psychotherapy, 21.0% combination therapy, and 21.5% no treatment. Among 340 LTRs on psychotropic medications before transplant, 24% did not continue them post-LT. Post-LT psychiatric diagnoses were independently associated with female sex, alcohol-associated liver disease (ALD), prolonged LT hospitalization (>2 wk), and pre-LT psychiatric diagnosis. Incident psychiatric diagnoses were associated with female sex, ALD, and prolonged LT hospitalization. Patients with a post-LT psychiatric diagnosis had higher rates of hospitalization (89.6% vs. 81.5%, p <0.001) and financial liability (median $5.5K vs. $4.6K USD, p =0.006). Having a psychiatric diagnosis post-LT was independently associated with experiencing high financial liability >$5K. Over 1 in 4 LTRs had a psychiatric diagnosis in a large national cohort, yet nearly a quarter received no treatment. LTRs with psychiatric diagnoses experienced increased health care utilization and higher financial liability. Sociodemographic and clinical risk factors could inform high-risk subgroups who may benefit from screening and mitigation strategies.

Cardiovascular health assessment in routine cancer follow-up in community settings: survivor risk awareness and perspectives.

BACKGROUND: Guidelines recommend cardiovascular risk assessment and counseling for cancer survivors. For effective implementation, it is critical to understand survivor cardiovascular health (CVH) profiles and perspectives in community settings. We aimed to (1) Assess survivor CVH profiles, (2) compare self-reported and EHR-based categorization of CVH factors, and (3) describe perceptions regarding addressing CVH during oncology encounters. METHODS: This cross-sectional analysis utilized data from an ongoing NCI Community Oncology Research Program trial of an EHR heart health tool for cancer survivors (WF-1804CD). Survivors presenting for routine care after potentially curative treatment recruited from 8 oncology practices completed a pre-visit survey, including American Heart Association Simple 7 CVH factors (classified as ideal, intermediate, or poor). Medical record abstraction ascertained CVD risk factors and cancer characteristics. Likert-type questions assessed desired discussion during oncology care. RESULTS: Of 502 enrolled survivors (95.6% female; mean time since diagnosis = 4.2 years), most had breast cancer (79.7%). Many survivors had common cardiovascular comorbidities, including high cholesterol (48.3%), hypertension or high BP (47.8%) obesity (33.1%), and diabetes (20.5%); 30.5% of survivors received high cardiotoxicity potential cancer treatment. Less than half had ideal/non-missing levels for physical activity (48.0%), BMI (18.9%), cholesterol (17.9%), blood pressure (14.1%), healthy diet (11.0%), and glucose/ HbA1c (6.0%). While > 50% of survivors had concordant EHR-self-report categorization for smoking, BMI, and blood pressure; cholesterol, glucose, and A1C were unknown by survivors and/or missing in the EHR for most. Most survivors agreed oncology providers should talk about heart health (78.9%). CONCLUSIONS: Tools to promote CVH discussion can fill gaps in CVH knowledge and are likely to be well-received by survivors in community settings. TRIAL REGISTRATION: NCT03935282, Registered 10/01/2020.

A new invertebrate NPY-like polypeptide, ZoaNPY, from the Zoanthus sociatus, as a novel ligand of human NPY Y2 receptor rescues vascular insufficiency via PLC/PKC and Src- FAK-dependent signaling pathways.

Our recent multi-omics studies have revealed rich sources of novel bioactive proteins and polypeptides from marine organisms including cnidarians. In the present study, we initially conducted a transcriptomic analysis to review the composition profile of polypeptides from Zoanthus sociatus. Then, a newly discovered NPY-like polypeptide-ZoaNPY was selected for further in silico structural, binding and virtually pharmacological studies. To evaluate the pro-angiogenic effects of ZoaNPY, we employed an in vitro HUVECs model and an in vivo zebrafish model. Our results indicate that ZoaNPY, at 1-100 pmol, enhances cell survival, migration and tube formation in the endothelial cells. Besides, treatment with ZoaNPY could restore a chemically-induced vascular insufficiency in zebrafish embryos. Western blot results demonstrated the application of ZoaNPY could increase the phosphorylation of proteins related to angiogenesis signaling including PKC, PLC, FAK, Src, Akt, mTOR, MEK, and ERK1/2. Furthermore, through molecular docking and surface plasmon resonance (SPR) verification, ZoaNPY was shown to directly and physically interact with NPY Y2 receptor. In view of this, all evidence showed that the pro-angiogenic effects of ZoaNPY involve the activation of NPY Y2 receptor, thereby activating the Akt/mTOR, PLC/PKC, ERK/MEK and Src- FAK-dependent signaling pathways. Furthermore, in an excision wound model, the treatment with ZoaNPY was shown to accelerate the wound healing process in mice. Our findings provide new insights into the discovery and development of novel pro-angiogenic drugs derived from NPY-like polypeptides in the future.

Effect of Patient Navigation on Completion of Lung Cancer Screening in Vulnerable Populations.

BACKGROUND: Although low-dose, CT-based lung cancer screening (LCS) can decrease lung cancer mortality in high-risk individuals, the process may be complex and pose challenges to patients, particularly those from minority underinsured and uninsured populations. We conducted a randomized controlled trial of telephone-based navigation for LCS within an integrated, urban, safety-net health care system. PATIENTS AND METHODS: Patients eligible for LCS were randomized (1:1) to usual care with or without navigation at Parkland Health in Dallas, Texas. The primary endpoint was completion of the first 3 consecutive steps in a patient's LCS process. We explored differences in completion of LCS steps between navigation and usual care groups, controlling for patient characteristics using the chi-square test. RESULTS: Patients (N=447) were randomized to either navigation (n=225) or usual care (n=222). Mean patient age was 62 years, 46% were female, and 69% were racial/ethnic minorities. There was no difference in completion of the first 3 steps of the LCS algorithm between arms (12% vs 9%, respectively; P=.30). For ordered LCS steps, completion rates were higher among patients who received navigation (86% vs 79%; P=.03). The primary reason for step noncompletion was lack of order placement. CONCLUSIONS: In this study, lack of order placement was a key reason for incomplete LCS steps. When orders were placed, patients who received navigation had higher rates of completion. Clinical team education and enhanced electronic health record processes to simplify order placement, coupled with patient navigation, may improve LCS in safety-net health care systems.

Geographic Accessibility and Completion of Initial Low-Dose CT-Based Lung Cancer Screening in an Urban Safety-Net Population.

BACKGROUND: Recent modifications to low-dose CT (LDCT)-based lung cancer screening guidelines increase the number of eligible individuals, particularly among racial and ethnic minorities. Because these populations disproportionately live in metropolitan areas, we analyzed the association between travel time and initial LDCT completion within an integrated, urban safety-net health care system. METHODS: Using Esri's StreetMap Premium, OpenStreetMap, and the r5r package in R, we determined projected private vehicle and public transportation travel times between patient residence and the screening facility for LDCT ordered in March 2017 through December 2022 at Parkland Memorial Hospital in Dallas, Texas. We characterized associations between travel time and LDCT completion in univariable and multivariable analyses. We tested these associations in a simulation of 10,000 permutations of private vehicle and public transportation distribution. RESULTS: A total of 2,287 patients were included in the analysis, of whom 1,553 (68%) completed the initial ordered LDCT. Mean age was 63 years, and 73% were underrepresented minorities. Median travel time from patient residence to the LDCT screening facility was 17 minutes by private vehicle and 67 minutes by public transportation. There was a small difference in travel time to the LDCT screening facility by public transportation for patients who completed LDCT versus those who did not (67 vs 66 min, respectively; P=.04) but no difference in travel time by private vehicle for these patients (17 min for both; P=.67). In multivariable analysis, LDCT completion was not associated with projected travel time to the LDCT facility by private vehicle (odds ratio, 1.01; 95% CI, 0.82-1.25) or public transportation (odds ratio, 1.14; 95% CI, 0.89-1.44). Similar results were noted across travel-type permutations. Black individuals were 29% less likely to complete LDCT screening compared with White individuals. CONCLUSIONS: In an urban population comprising predominantly underrepresented minorities, projected travel time is not associated with initial LDCT completion in an integrated health care system. Other reasons for differences in LDCT completion warrant investigation.

Design and implementation of multicenter pediatric and congenital studies with cardiovascular magnetic resonance: Big data in smaller bodies.

Cardiovascular magnetic resonance (CMR) has become the reference standard for quantitative and qualitative assessment of ventricular function, blood flow, and myocardial tissue characterization. There is a preponderance of large CMR studies and registries in adults; However, similarly powered studies are lacking for the pediatric and congenital heart disease (PCHD) population. To date, most CMR studies in children are limited to small single or multicenter studies, thereby limiting the conclusions that can be drawn. Within the PCHD CMR community, a collaborative effort has been successfully employed to recognize knowledge gaps with the aim to embolden the development and initiation of high-quality, large-scale multicenter research. In this publication, we highlight the underlying challenges and provide a practical guide toward the development of larger, multicenter initiatives focusing on PCHD populations, which can serve as a model for future multicenter efforts.

The Society for Cardiovascular Magnetic Resonance Registry at 150,000.

OBJECTIVES: To summarize the status of the SCMR Registry at 150,000 exams. BACKGROUND: Cardiovascular magnetic resonance (CMR) is increasingly utilized to evaluate expanding cardiovascular conditions. The SCMR Registry is a central repository for real-world clinical data to support cardiovascular research, including those relating to outcomes, quality improvement, and machine learning. The SCMR Registry is built on a regulatory-compliant, cloud-based infrastructure that houses searchable content and Digital Imaging and Communications in Medicine (DICOM) images. METHODS: The processes for data security, data submission, and research access are outlined. We interrogated the Registry and present a summary of its contents. RESULTS: Data were compiled from 154,458 CMR scans across 20 United States sites, containing 299,622,066 total images (~100 terabytes of storage). The human subjects had an average age of 58 years (range 1 month to >90 years old), were 44% female, 72% Caucasian, and had a mortality rate of 8%. The most common indication was cardiomyopathy (27%), and most frequently used current procedural terminology (CPT) code was 75561 (35%). Macrocyclic gadolinium-based contrast agents represented 89% of contrast utilization after 2015. Short-axis cines were performed in 99% of scans, short-axis LGE in 66%, and stress perfusion sequences in 30%. Mortality data demonstrated increased mortality in patients with left ventricular ejection fraction (LVEF) < 35%, the presence of wall motion abnormalities, stress perfusion defects, and infarct late gadolinium enhancement (LGE), compared to those without these markers. There were 456,678 patient-years of all-cause mortality follow-up, with a median follow-up time of 3.6 years. CONCLUSIONS: The vision of the SCMR Registry is to promote evidence-based utilization of CMR through a collaborative effort by providing a web mechanism for centers to securely upload de-identified data and images for research, education, and quality control. The Registry quantifies changing practice over time and supports large-scale real-world multicenter observational studies of prognostic utility. CONDENSED ABSTRACT: The SCMR Registry is a central regulatory-compliant cloud-based repository for real-world clinical data and DICOM images for multicenter cardiovascular research, including outcomes-based data. The Registry contains 299,622,066 DICOM images and 456,678 patient-years follow-up. Data compiled from 154,458 CMR scans across 20 US sites demonstrated cardiomyopathy as the most common indication and 89% macrocyclic gadolinium contrast utilization after 2015. There was an overall mortality rate of 8%, with higher rates in those with LVEF<35%, abnormal wall motion, ischemia presence, or infarct LGE. The Registry aims to promote evidence-based CMR utilization through a collaborative effort to positively impact cardiovascular outcomes.

Society for Cardiovascular Magnetic Resonance 2022 Cases of SCMR case series.

"Cases of SCMR" is a case series on the SCMR website (https://www.scmr.org) for the purpose of education. The cases reflect the clinical presentation, and the use of cardiovascular magnetic resonance (CMR) in the diagnosis and management of cardiovascular disease. The 2022 digital collection of cases are presented in this manuscript.

Prevention of anthracycline-t and trastuzumabinduced decline in left ventricular ejection fraction with angiotensin-converting enzyme inhibitors or angiotensin receptor blocker: a narrative systematic review of randomised controlled trials.

Cancer therapy-related cardiac dysfunction (CTRCD) is a complication of selected cancer therapy agents associated with decline in left ventricular ejection fraction (LVEF). Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have established benefits in heart failure with reduced ejection fraction, but their efficacy for preventing CTRCD remains controversial. This narrative systematic review assessed the efficacy and safety of ACEI/ARB in the prevention of cancer therapy LVEF decline. We systematically searched PubMed, Embase and Cochrane from January 1980 to June 2022. Studies of interest were randomised controlled trials of patients with normal LVEF and active malignancy receiving cancer therapy, randomised to receive either an ACEI or ARB compared with a control group. The outcome was the change in LVEF from baseline to the end of the follow-up period. Death, clinical heart failure and adverse drug reactions were recorded. A total of 3731 search records were screened and 12 studies were included, comprising a total of 1645 participants. Nine studies assessed the prevention of anthracycline-induced LVEF decline, of which five showed a beneficial effect (1%-14% higher LVEF in treated groups), whereas four studies showed no effect. Three studies assessed the prevention of trastuzumab-induced LVEF decline, of which one showed a beneficial effect (4% higher LVEF) in a subset of participants. There are mixed data regarding the efficacy of ACEI/ARB in preventing the LVEF decline in patients undergoing anthracycline or trastuzumab therapy, with evidence suggesting no clinically meaningful benefit observed in recent studies.

Impact of pulmonary stenosis on right ventricular global longitudinal strain in repaired tetralogy of Fallot patients post transcatheter pulmonary valve replacement.

BACKGROUND: Mixed pulmonary disease with pulmonary regurgitation (PR) and stenosis (PS) in repaired tetralogy of Fallot (rTOF) can negatively impact ventricular health. Myocardial strain has been shown to be more sensitive at detecting occult ventricular dysfunction compared to right ventricular ejection fraction (RV EF). We hypothesize that rTOF patients with predominant PS will have lower RV global longitudinal strain (RV GLS) prior to and post-transcatheter pulmonary valve replacement (TPVR). METHODS: A retrospective cohort of rTOF patients who underwent cardiac magnetic resonance (CMR) and cardiac catheterization for right ventricular pressure (RVSP) measurement were analyzed at three time points: before valve implantation, at discharge and within 18 months post-TPVR. Patients were dichotomized into three groups based on RVSP: 0%-49%, 50%-74%, and >75%. RV GLS and left ventricular (LV) GLS by speckle tracking echocardiography (STE) were obtained from the apical 4-chamber using TomTec software (TOMTEC IS, Germany). RESULTS: Forty-eight patients were included. Every 14.3% increase in preimplantation RVSP above 28% was associated with an absolute magnitude 1% lower RV GLS (p = .001). Preimplantation RVSP when 75% or higher had 3.36% worse RV GLS than the lowest bin (p = .014). Overall, average RV strain magnitude was higher when preimplantation RVSP was less than 50% and had greater improvement over the three time points. Higher post implantation RVSP correlated with lower strain magnitude. CONCLUSION: Patients with significant PS (>50%) may benefit from earlier PVR and not depend solely on RV size and EF. Myocardial strain may be a more sensitive marker of function; however, larger, prospective studies are needed.

Comparative genomics provides insights into the aquatic adaptations of mammals.

The ancestors of marine mammals once roamed the land and independently committed to an aquatic lifestyle. These macroevolutionary transitions have intrigued scientists for centuries. Here, we generated high-quality genome assemblies of 17 marine mammals (11 cetaceans and six pinnipeds), including eight assemblies at the chromosome level. Incorporating previously published data, we reconstructed the marine mammal phylogeny and population histories and identified numerous idiosyncratic and convergent genomic variations that possibly contributed to the transition from land to water in marine mammal lineages. Genes associated with the formation of blubber (NFIA), vascular development (SEMA3E), and heat production by brown adipose tissue (UCP1) had unique changes that may contribute to marine mammal thermoregulation. We also observed many lineage-specific changes in the marine mammals, including genes associated with deep diving and navigation. Our study advances understanding of the timing, pattern, and molecular changes associated with the evolution of mammalian lineages adapting to aquatic life.

Incidence of Fetal Arrhythmia Before and During the COVID-19 Pandemic: A Single-Center Experience.

Fetal arrhythmias are rare and carry significant morbidity and mortality without appropriate treatment. Initial reports exist of fetal arrhythmia in the setting of maternal COVID-19 infection. Our study sought to evaluate incidence of fetal arrhythmia before and during the COVID-19 pandemic at our institution. This retrospective cohort study from a tertiary care fetal cardiac center utilized the institutional REDCap database to search fetal arrhythmia diagnostic codes. Medical records of mother-fetus dyads were reviewed and data were collected on diagnoses, gestational age, treatment regimen, and postnatal outcomes. Patients were divided into pre-COVID and peri-COVID segments. 8368 total pregnancies were evaluated during the 7.3 years of study period. Forty-five patients (0.5%) had a significant fetal arrhythmia and were included in this study: 19 (42%) in the pre-COVID-19 group and 26 (58%) in the peri-COVID-19 group. No patients had associated congenital heart disease. There was a notable increase in the incidence of fetal supraventricular tachycardia (SVT) (1.82 per 1000 vs 2.65 per 1000 pregnancies) and complete heart block (1.04 per 1000 vs 1.77 per 1000 pregnancies) but no apparent change in other tachyarrhythmias during the COVID era. The proportion of antibody-mediated complete heart block increased from 50 to 87.5%. There was also an increase in the percentage of SVT patients requiring postnatal treatment during COVID-19 (53.8% vs 62.5%). Our experience shows an increased incidence of some fetal arrhythmia diagnoses during the COVID-19 pandemic. Additional multi-center studies will be necessary to fully evaluate the increased burden of fetal arrhythmias during the COVID-19 era as well as to elucidate etiology.

6-benzylaminopurine causes endothelial dysfunctions to human umbilical vein endothelial cells and exacerbates atorvastatin-induced cerebral hemorrhage in zebrafish.

6-benzylaminopurine (6-BA), a multifunctional plant growth regulator, which is frequently used worldwide to improve qualities of various crops, is an important ingredient in production of "toxic bean sprouts." Although there is no direct evidence of adverse effects, its hazardous effects, as well as joint toxicity with other chemicals, have received particular attention and aroused furious debate between proponents and environmental regulators. By use of human umbilical vein endothelial cells (HUVECs), adverse effects of 6-BA to human-derived cells were first demonstrated in this study. A total of 25-50 mg 6-BA/L inhibited proliferation, migration, and formation of tubular-like structures by 50% in vitro. Results of Western blot analyses revealed that exposure to 6-BA differentially modulated the MAPK signal transduction pathway in HUVECs. Specifically, 6-BA decreased phosphorylation of MEK and ERK, but increased phosphorylation of JNK and P38. In addition, 6-BA exacerbated atorvastatin-induced cerebral hemorrhage via increasing hemorrhagic occurrence by 60% and areas by 4 times in zebrafish larvae. In summary, 6-BA elicited toxicity to the endothelial system of HUVECs and zebrafish. This was due, at least in part, to discoordination of MAPK signaling pathway, which should pose potential risks to the cerebral vascular system.

Medulla Tetrapanacis water extract alleviates inflammation and infection by regulating macrophage polarization through MAPK signaling pathway.

Medulla Tetrapanacis (MT) is a commonly used herb to promote lactation and manage mastitis in lactating mothers. However, its anti-inflammatory and anti-bacterial effects are currently unknown. We hypothesized that MT water extract possesses anti-inflammatory and anti-bacterial effects by modulating macrophage polarization to reduce the release of inflammatory mediators and phagocytosis via inactivation of MAPKs pathways. The chemical composition of the MT water extract was analyzed by UPLC-Orbitrap-mass spectrometry. The anti-inflammatory and anti-bacterial properties of the MT water extract were examined using LPS-stimulated inflammation and Staphylococcus aureus infection model in RAW 264.7 cells, respectively. The underlying mechanism of action of the MT water extract was also investigated. We identified eight compounds by UPLC-Orbitrap-mass spectrometry that are abundant within the MT water extract. MT water extract significantly suppressed LPS-induced nitric oxide, TNF-α and IL-6 secretion in RAW 264.7 cells which was accompanied by the promotion of macrophage polarization from pro-inflammatory towards anti-inflammatory phenotypes. MT water extract significantly suppressed the LPS-induced MAPK activation. Finally, MT water extract decreased the phagocytic capacity of the RAW 264.7 cells against S. aureus infection. MT water extract could suppress LPS-induced inflammation by promoting macrophages towards an anti-inflammatory phenotype. In addition, MT also inhibited the growth of S. aureus.

Commercial Immunoglobulin Products Contain Neutralizing Antibodies Against Severe Acute Respiratory Syndrome Coronavirus 2 Spike Protein.

BACKGROUND: Patients with antibody deficiency respond poorly to coronavirus disease 2019 (COVID-19) vaccination and are at risk of severe or prolonged infection. They are given long-term immunoglobulin replacement therapy (IRT) prepared from healthy donor plasma to confer passive immunity against infection. Following widespread COVID-19 vaccination alongside natural exposure, we hypothesized that immunoglobulin preparations will now contain neutralizing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike antibodies, which confer protection against COVID-19 disease and may help to treat chronic infection. METHODS: We evaluated anti-SARS-CoV-2 spike antibody in a cohort of patients before and after immunoglobulin infusion. Neutralizing capacity of patient samples and immunoglobulin products was assessed using in vitro pseudovirus and live-virus neutralization assays, the latter investigating multiple batches against current circulating Omicron variants. We describe the clinical course of 9 patients started on IRT during treatment of COVID-19. RESULTS: In 35 individuals with antibody deficiency established on IRT, median anti-spike antibody titer increased from 2123 to 10 600 U/mL postinfusion, with corresponding increase in pseudovirus neutralization titers to levels comparable to healthy donors. Testing immunoglobulin products directly in the live-virus assay confirmed neutralization, including of BQ1.1 and XBB variants, but with variation between immunoglobulin products and batches.Initiation of IRT alongside remdesivir in patients with antibody deficiency and prolonged COVID-19 infection (median 189 days, maximum >900 days with an ancestral viral strain) resulted in clearance of SARS-CoV-2 at a median of 20 days. CONCLUSIONS: Immunoglobulin preparations now contain neutralizing anti-SARS-CoV-2 antibodies that are transmitted to patients and help to treat COVID-19 in individuals with failure of humoral immunity.