Left ventricular systolic dysfunction during acute pulmonary embolism.

BACKGROUND: Heart failure increases the risk of death in acute pulmonary embolism (PE). The role of the left ventricle (LV) in acute PE is not well defined. OBJECTIVE: To identify the prevalence of LV systolic dysfunction, morphology, and prognosis of the LV during an acute PE. METHODS: Retrospective study (26-months) of patients diagnosed with an acute PE presenting with LV systolic dysfunction at the University of Maryland. RESULTS: Among 769 acute PE patients, 78 (10.5 %) had LV systolic dysfunction and 42 (53.8 %) had history of cardiac disease. Patients without history of cardiac disease were younger (mean age [SD] 54.9 [16.8] vs. 62.6 [16.6]; p = 0.04), had a higher BMI (31.2 [12.2] vs. 29.2 [7.7]; p = 0.005), and less hypertension (20 [34.5 %] vs. 38 [65.5 %]; p = 0.0005). A massive PE was most common in patients without history of cardiac disease (8[22.2 %] vs. 2[4.7 %], p = 0.02). There was no difference in clot burden, but right ventricular strain was more frequently seen in patients without history cardiac disease in the initial CT (p = 0.001). The median troponin and lactate were similar in both groups. In 41 patients with follow-up echocardiograms, improvement in LVEF% was observed in patients without cardiac history (median Δ LVEF% [IQR]; 20 [6.2-25.0]). While patients with cardiac disease did not demonstrate similar changes (median Δ LVEF% [IQR]; 0 [-5-17.5]; p = 0.01). In hospital mortality was 12.8 % with no difference between both groups (p = 0.17). CONCLUSION: Pulmonary embolism can be associated with LV systolic dysfunction, even in patients without history of cardiac disease.

The growth of xenotransplanted hearts can be reduced with growth hormone receptor knockout pig donors.

OBJECTIVE: Genetically engineered pigs are thought to be an alternative organ source for patients in end-stage heart failure unable to receive a timely allograft. However, cardiac xenografts exhibit growth and diastolic heart failure within 1 month after transplantation. Grafts function for up to 6 months, but only after administration of temsirolimus and afterload-reducing agents to reduce this growth. In this study we investigated the growth and hemodynamics of growth hormone receptor (GHR) knockout xenografts, without the use of adjuncts to prevent intrinsic graft growth after transplantation. METHODS: Genetically engineered pig hearts were transplanted orthotopically into weight-matched baboons between 15 and 30 kg, using continuous perfusion preservation before implantation (n = 5). Xenografts included knockout of carbohydrate antigens and knockin of human transgenes for thromboregulation, complement regulation, and inflammation reduction (grafts with intact growth hormone, n = 2). Three grafts contained the additional knockout of GHR (GHR knockout grafts; n = 3). Transthoracic echocardiograms were obtained twice monthly and comprehensively analyzed by a blinded cardiologist. Hemodynamics were measured longitudinally after transplantation. RESULTS: All xenografts demonstrated life-supporting function after transplantation. There was no difference in intrinsic growth, measured using septal and posterior wall thickness and left ventricular mass, on transthoracic echocardiogram out to 1 month in either GHR knockout or GHR intact grafts. However, hypertrophy of the septal and posterior wall was markedly elevated by 2 months post transplantation. There was minimal hypertrophy out to 6 months in GHR knockout grafts. Physiologic mismatch was present in all grafts after transplantation, which is largely independent of growth. CONCLUSIONS: Xenografts with GHR knockout show reduced post-transplantation xenograft growth using echocardiography >6 months after transplantation, without the need for other adjuncts.

Clinical outcomes and echocardiographic characteristics between African American and Caucasian patients with acute pulmonary embolism.

BACKGROUND: Despite socioeconomic disparities, no association between clinical presentation and poor outcomes explains a higher mortality in African Americans with pulmonary embolism (PE). The objective is to identify the co-morbidities and echocardiographic characteristics associated with increased mortality in African American patients. METHODS: This is a cross-sectional study of Caucasian or African American patients with PE diagnosed between October 2015 and December 2017 at University of Maryland Medical Center. The outcomes were in-hospital death, length of stay, and bleeding. RESULTS: There were 303 African Americans and 343 Caucasians. Caucasians were older (p = 0.007), males (p = 0.01) with history of coronary artery revascularization (CABG (p = 0.001), coronary stents (p = 0.001)), trauma (p = 0.007), and/or recent surgeries (p = 0.0001). African Americans exhibited higher rates of diabetes (p = 0.01), chronic kidney disease (p = 0.0005), and smoking (p = 0.04). Severity of PE was similar between groups and there was no difference in clot burden size. African Americans had more right ventricular strain on Computer Tomography (p = 0.001) and echocardiogram (p = 0.004); also, underfilled left ventricles (p = 0.02) and higher right ventricular systolic pressures (p = 0.001). There was no difference in hospital mortality (7.1% vs. 7.9%, p = 0.71), length of stay (13.1 ± 16.7 vs 12.8 ± 14.9, p = 0.80) and bleeding (9.0% vs.8.3%. p = 0.72). Mortality was higher in African Americans who received advanced therapies (3.8% vs. 18.8%, p = 0.02). The risk of death increased with age (OR 1.04; 95%CI 1.020-1.073) and with advanced therapies (OR 2.43; 95%CI 1.029-5.769). CONCLUSIONS: Differences in co-morbidities, radiologic findings, and echocardiographic characteristics that may contribute to higher mortality in African American patients, specifically those receiving advanced therapies.

The association between dietary sodium intake and osteoporosis.

The association of inadequate dietary sodium intake with bone mineral density (BMD) and the risk of osteoporosis is controversial. To find the association between low sodium diet and the risk of incipient osteoporosis, we performed a population-based cross-sectional analysis using Tanaka method for estimation 24-h urinary sodium excretion (e24hUNaETanaka) as a candidate indicator of sodium intake. We identified 3869 participants without osteoporosis and classified them into quartiles according to their value of e24hUNaETanaka. BMD was measured to find participants at risk of osteoporosis. Lower e24hUNaETanaka was related to decreasing BMD of the distal radius. Multiple Cox-proportional hazard models demonstrated that e24hUNaETanaka had an inverse association with the risk of osteoporosis (adjusted HR = 0.859, 95% CI = 0.751-0.982) and survival analysis revealed that the lowest quartile group had poor osteoporosis-free survival (PLog-rank < 0.0001). Furthermore, our restricted cubic spline analysis revealed that the relationship between e24hUNaETanaka and HR of osteoporosis was negative curvilinear in males and postmenopausal females and positive linear in premenopausal females. Our findings suggest that lower sodium intake was a significant predictor of incipient osteoporosis and there was wide variation in this relationship according to sex and female hormone status.

Immunogenicity of COVID-19 Vaccination in Patients With End-Stage Renal Disease Undergoing Maintenance Hemodialysis: The Efficacy of a Mix-and-Match Strategy.

BACKGROUND: The objective of this study was to evaluate the immunogenicity of coronavirus disease 2019 (COVID-19) vaccination in patients with end-stage renal disease (ESRD) on hemodialysis. METHODS: ESRD patients at the hemodialysis center of a tertiary-care university-affiliated hospital and healthy employees at the clinical laboratory center were prospectively recruited between March and June 2021. For severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody analysis, blood samples were collected serially on days 0, 14, 28, and 56 after the first vaccine dose, and on days 7 and 50 after the second dose. Antibodies against the SARS-CoV-2 spike protein were quantified, and SARS-CoV-2 neutralizing antibodies were measured in the serum and plasma. RESULTS: Thirty-one ESRD patients and 55 healthy employees were regularly monitored. Twenty-five (80.6%) ESRD patients on hemodialysis received a mix-and-match strategy with ChAdOx1-BNT162b2 (AZ-Pf group) and six (19.4%) received two doses of ChAdOx1 (AZ-AZ group). ESRD patients on hemodialysis showed lower binding antibody titers and neutralizing antibody activities compared to healthy participants following the first vaccination with ChAdOx1. After the second dose, AZ-Pf group had higher immunogenicity than healthy people on days 7 and 50. The binding antibody titer and neutralizing antibody activities on days 7 and 50 were significantly higher in the AZ-Pf group than in the AZ-AZ group. CONCLUSION: ESRD patients on hemodialysis receiving the mix-and-match strategy (ChAdOx1-BNT162b2) have COVID-19 vaccine immunogenicity comparable to healthy individuals receiving two doses of ChAdOx1. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04871945.

Genetically Modified Porcine-to-Human Cardiac Xenotransplantation.

A 57-year-old man with nonischemic cardiomyopathy who was dependent on venoarterial extracorporeal membrane oxygenation (ECMO) and was not a candidate for standard therapeutics, including a traditional allograft, received a heart from a genetically modified pig source animal that had 10 individual gene edits. Immunosuppression was based on CD40 blockade. The patient was weaned from ECMO, and the xenograft functioned normally without apparent rejection. Sudden diastolic thickening and failure of the xenograft occurred on day 49 after transplantation, and life support was withdrawn on day 60. On autopsy, the xenograft was found to be edematous, having nearly doubled in weight. Histologic examination revealed scattered myocyte necrosis, interstitial edema, and red-cell extravasation, without evidence of microvascular thrombosis - findings that were not consistent with typical rejection. Studies are under way to identify the mechanisms responsible for these changes. (Funded by the University of Maryland Medical Center and School of Medicine.).

Causal effects of psychostimulants on neural connectivity: a mechanistic, randomized clinical trial.

BACKGROUND: Psychostimulants are frequently used to treat attention-deficit/hyperactivity disorder (ADHD), but side effects are common leading to many patients discontinuing treatment. Identifying neural mechanisms by which psychostimulants attenuate symptoms may guide the development of more refined and tolerable therapeutics. METHODS: We conducted a 12-week, randomized, placebo-controlled trial (RCT) of a long-acting amphetamine, lisdexamfetamine (LDEX), in patients with ADHD, ages 6-25 years old. Of the 58 participants who participated in the RCT, 49 completed pre- and post-RCT magnetic resonance imaging scanning with adequate data quality. Healthy controls (HCs; n = 46) were included for comparison. Treatment effects on striatal and thalamic functional connectivity (FC) were identified using static (time-averaged) and dynamic (time-varying) measures and then correlated with symptom improvement. Analyses were repeated in independent samples from the Adolescent Brain Cognitive Development study (n = 103) and the ADHD-200 Consortium (n = 213). RESULTS: In 49 participants (25 LDEX; 24 Placebo), LDEX increased static and decreased dynamic FC (DFC). However, only DFC was associated with the therapeutic effects of LDEX. Additionally, at baseline, DFC was elevated in unmedicated-ADHD participants relative to HCs. Independent samples yielded similar findings - ADHD was associated with increased DFC, and psychostimulants with reduced DFC. Static FC findings were inconsistent across samples. CONCLUSIONS: Changes in dynamic, but not static, FC were associated with the therapeutic effects of psychostimulants. While prior research has focused on static FC, DFC may offer a more reliable target for new ADHD interventions aimed at stabilizing network dynamics, though this needs confirmation with subsequent investigations.

Genetic Variants Associated With Unexplained Sudden Cardiac Death in Adult White and African American Individuals.

Importance: Unexplained sudden cardiac death (SCD) describes SCD with no cause identified. Genetic testing helps to diagnose inherited cardiac diseases in unexplained SCD; however, the associations between pathogenic or likely pathogenic (P/LP) variants of inherited cardiomyopathies (CMs) and arrhythmia syndromes and the risk of unexplained SCD in both White and African American adults living the United States has never been systematically examined. Objective: To investigate cases of unexplained SCD to determine the frequency of P/LP genetic variants of inherited CMs and arrhythmia syndromes. Design, Setting, and Participants: This genetic association study included 683 African American and White adults who died of unexplained SCD and were included in an autopsy registry. Overall, 413 individuals had DNA of acceptable quality for genetic sequencing. Data were collected from January 1995 to December 2015. A total of 30 CM genes and 38 arrhythmia genes were sequenced, and variants in these genes, curated as P/LP, were examined to study their frequency. Data analysis was performed from June 2018 to March 2021. Main Outcomes and Measures: The frequency of P/LP variants for CM or arrhythmia in individuals with unexplained SCD. Results: The median (interquartile range) age at death of the 413 included individuals was 41 (29-48) years, 259 (62.7%) were men, and 208 (50.4%) were African American adults. A total of 76 patients (18.4%) with unexplained SCD carried variants considered P/LP for CM and arrhythmia genes. In total, 52 patients (12.6%) had 49 P/LP variants for CM, 22 (5.3%) carried 23 P/LP variants for arrhythmia, and 2 (0.5%) had P/LP variants for both CM and arrhythmia. Overall, 41 P/LP variants for hypertrophic CM were found in 45 patients (10.9%), 9 P/LP variants for dilated CM were found in 11 patients (2.7%), and 10 P/LP variants for long QT syndrome were found in 11 patients (2.7%). No significant difference was found in clinical and heart characteristics between individuals with or without P/LP variants. African American and White patients were equally likely to harbor P/LP variants. Conclusions and Relevance: In this large genetic association study of community cases of unexplained SCD, nearly 20% of patients carried P/LP variants, suggesting that genetics may contribute to a significant number of cases of unexplained SCD. Our findings regarding both the association of unexplained SCD with CM genes and race-specific genetic variants suggest new avenues of study for this poorly understood entity.

Prevalence and clinical characteristics of antibiotics associated drug induced liver injury.

BACKGROUND: The use of antibiotics increases recently. Accordingly, the incidence of antibiotics associated with drug induced liver injury (DILI) also increases. The purpose of this study is to evaluate the proportion and the clinical characteristics of antibiotic associated with DILI. METHODS: This study is a retrospective study of analyzed adult patients who were referred to the department of hepatology for the elevation of liver function tests and the frequency of elevated liver enzyme of patients with prescribed antibiotics during the same period at outpatient setting as a validation set. RESULTS: Antibiotics associated with DILI (64.0%) are the most common reason agent among consulting to hepatology department. Rheumatoid arthritis related drugs (11.0%), health supplements (5.0%), herbal medicines (4.0%), anti-viral drugs, anti-inflammatory analgesics/acetaminophen and lipid-lowering agents (3.0%) were next common causative drug for DILI in inpatients setting (training set). The frequency of antibiotics associated with DILI was high in order of flomoxef, cetrazole, ceftriaxone, vancomycin, piperacillin/tazobactam and amoxicillin/clavulanate. In the same period, 32% of the patients who prescribed flomoxef showed elevated liver enzyme levels above the upper normal limit. The prevalence of flomoxef induced DILI (>3 folds of ALT) was 13% and liver enzyme levels were five times higher than upper normal limits in 5% of flomoxef groups. Hypertension or diabetes was the risk factor of flomoxef associated with DILI. CONCLUSIONS: The Prevalence of antibiotics associated with DILI was 2-14%. Co-morbidity with diabetes and hypertension was the risk factor of flomoxef associated with DILI.

Differences in brain structure and function in children with the FTO obesity-risk allele.

OBJECTIVE: Noncoding alleles of the fat mass and obesity-associated (FTO) gene have been associated with obesity risk, yet the underlying mechanisms remain unknown. Risk allele carriers show alterations in brain structure and function, but previous studies have not disassociated the effects of genotype from those of body mass index (BMI). METHODS: Differences in brain structure and function were examined in children without obesity grouped by their number of copies (0,1,2) of the FTO obesity-risk single-nucleotide polymorphism (SNP) rs1421085. One hundred five 5- to 10-year-olds (5th-95th percentile body fat) were eligible to participate. Usable scans were obtained from 93 participants (15 CC [homozygous risk], 31 CT [heterozygous] and 47 TT [homozygous low risk]). RESULTS: Homozygous C allele carriers (CCs) showed greater grey matter volume in the cerebellum and temporal fusiform gyrus. CCs also demonstrated increased bilateral cerebellar white matter fibre density and increased resting-state functional connectivity between the bilateral cerebellum and regions in the frontotemporal cortices. CONCLUSIONS: This is the first study to examine brain structure and function related to FTO alleles in young children not yet manifesting obesity. This study lends support to the notion that the cerebellum may be involved in FTO-related risk for obesity, yet replication and further longitudinal study are required.

Cardioembolic stroke in a young male with cor triatriatum sinister: a case report.

BACKGROUND: Cor triatriatum sinister (CTS) is a rare congenital cardiac anomaly defined by a fibromuscular membrane which bisects the left atrium. Cor triatriatum sinister has been associated with cardioembolic stroke through mechanisms including stagnation of blood flow within the left atrium, an association with atrial fibrillation (AF), and/or an accompanying atrial septal defect (ASD) or patent foramen ovale. We describe a case highlighting the role that CTS may play in cardioembolic stroke, provide high-quality computed tomography angiography and two- and three-dimensional echocardiography of the CTS membrane, and outline management strategies for this uncommon clinical scenario. CASE SUMMARY: A 35-year-old man with no prior medical history presented with acute onset weakness and aphasia. He was found to have an embolic stroke with left M1 and A1 occlusions and received tissue plasminogen activator followed by mechanical thrombectomy with successful recanalization. A thorough stroke workup revealed CTS with an associated ASD as well as potential protein C deficiency. He was managed with indefinite anticoagulation with apixaban. DISCUSSION: This is the 13th reported case of CTS associated with stroke. In most previous cases evidence of blood stasis or frank thrombus was associated with the CTS membrane, and/or existing AF was noted. In this case, none of these were identified, particularly highlighting the surreptitious risk of CTS. In addition, the presence of potential protein C deficiency in this case compounded the risk for thromboembolism and factored into multidisciplinary management decisions.

Left ventricular hypertrophy in a contemporary cohort of autosomal dominant polycystic kidney disease patients.

BACKGROUND: Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) often develop hypertension in childhood or early adulthood. Although this could result in left ventricular hypertrophy (LVH), a major risk factor for cardiovascular morbidity and mortality, prior studies of LVH in ADPKD have yielded conflicting results. We estimated the prevalence of LVH using consensus echocardiography criteria and examined the independent association of ADPKD severity with LV mass in a contemporary cohort of ADPKD patients. METHODS: Adults with ADPKD and eGFR> 15 ml/min/1.73m2 were enrolled in a single-center study. Left Ventricular Mass (LVM) was quantified using 2D echocardiography, and LVH was defined using gender-specific cut-points of LVM and LVM indexed to body surface area (LVMI) from consensus guidelines. Total Kidney Volume (TKV) was quantified using Magnetic Resonance Imaging, and GFR was estimated from serum creatinine using the CKD-Epi equation. Multiple linear regression was used to estimate the association of TKV and eGFR with LVM and LVMI, adjusting for potential confounders. RESULTS: Among 126 participants (78% with hypertension), median age was 46 years, median eGFR 63 ml/min/1.73 m2, and median [IQR] systolic blood pressure was 125 [116-133] mmHg. Prevalence of LVH was 21.4% as defined by LVMI and was not significantly different (p = 0.8) between those with and without HTN, and was similar (21.4%) after excluding those (N = 21) with known cardiac disease. Greater TKV and lower eGFR were directly correlated with greater LVMI (p = .016 and p < .001, respectively). In multiple linear regression models accounting for potential confounders including blood pressure, greater TKV was positively associated with LVM ([Formula: see text] =0.19, p = 0.04). CONCLUSIONS: In a contemporary cohort of ADPKD patients with well-controlled blood pressure, the prevalence of LVH is high, and ADPKD severity as reflected by TKV is independently associated with greater LV mass. These results may suggest a relationship between ADPKD pathophysiology and increased LV mass.

Cardiac function assessed by myocardial deformation in adult polycystic kidney disease patients.

BACKGROUND: Patients with autosomal dominant polycystic kidney disease (ADPKD) have an increased risk of cardiovascular morbidity and mortality. Impaired left ventricular (LV) global longitudinal strain (GLS) can be a sign of subclinical cardiac dysfunction even in patients with otherwise preserved ejection fraction (EF). Transmitral early filling velocity to early diastolic strain rate (E/SRe) is a novel measure of LV filling pressure, which is often affected early in cardiac disease. METHODS: A total of 110 ADPKD patients not on dialysis were included in this prospective study. All patients underwent an extensive echocardiographic examination including two-dimensional speckle tracking. GLS and strain rates were measured. The distribution of GLS and E/SRe was determined and patient characteristics were compared by median levels of GLS (- 17.8%) and E/SRe (91.4 cm). Twenty healthy participants were included as control group. RESULTS: There was a significantly worse GLS in the ADPKD patients (mean: - 17.8 ± 2.5%) compared to the healthy controls (mean: - 21.9 ± 1.9%), p < 0.001. The same was true for E/SRe (mean: 10.0 ± 0.3 cm) compared to the control group (mean: 6.5 ± 0.3 cm), p < 0.001. In simple logistic regression, male gender (OR: 4.74 [2.10-10.71], p < 0.001), fasting glucose (odds ratio (OR) 1.05 [1.01-1.10], p = 0.024), htTKV (OR: 1.07 [1.01-1.13], p = 0.013), HDL cholesterol (OR: 0.97 [0.94, 0.996], p = 0.025), triglycerides (OR: 1.01 [1.00-1.02], p = 0.039), hemoglobin (OR: 1.50 [1.11-2.04], p = 0.009), and ß-blocker use (OR: 1.07 [1.01, 1.13], p = 0.013) were all associated with higher GLS. After multivariate logistic regression with backward model selection, only male gender (OR: 5.78 [2.27-14.71], p < 0.001) and ß-blocker use (OR: 14.00 [1.60, 122.51], p = 0.017) remained significant. In simple logistic regression models, BMI (OR: 1.11 [1.02-1.20], p = 0.015), systolic blood pressure (OR: 1.03 [1.00-1.06], p = 0.027) and ß-blocker use (OR: 17.12 [2.15-136.20], p = 0.007) were associated with higher E/SRe - a novel measure of left ventricular filling pressure. After backward elimination, only ß-blocker use (OR: 17.22 [2.16, 137.14], p = 0.007) remained significant. CONCLUSION: Higher GLS and E/SRe are common in ADPKD patients, even in patients with preserved eGFR and normal left ventricular EF. GLS and E/SRe may aid in cardiovascular risk stratification in patients with ADPKD as they represent early markers of cardiac dysfunction.

The association between antidepressant treatment and brain connectivity in two double-blind, placebo-controlled clinical trials: a treatment mechanism study.

BACKGROUND: Antidepressant medications offer an effective treatment for depression, yet nearly 50% of patients either do not respond or have side-effects rendering them unable to continue the course of treatment. Mechanistic studies might help advance the pharmacology of depression by identifying pathways through which treatments exert their effects. Toward this goal, we aimed to identify the effects of antidepressant treatment on neural connectivity, the relationship with symptom improvement, and to test whether these effects were reproducible across two studies. METHODS: We completed two double-blind, placebo-controlled trials of SNRI antidepressant medications with MRI scans obtained before and after treatment. One was a 10-week trial of duloxetine (30-120 mg daily; mean 92·1 mg/day [SD 30·00]) and the other was a 12-week trial of desvenlafaxine (50-100 mg daily; 93·6 mg/day [16·47]). Participants consisted of adults with persistent depressive disorder. Adjusting for sex and age, we examined the effect of treatment on whole-brain functional connectivity. We also examined correlations between change in functional connectivity and improvement in symptoms of depression (24-item Hamilton Depression Rating Scale) and pain symptom severity (Symptom Checklist-90-Revised). FINDINGS: Participants were enrolled between Jan 26, 2006, and Nov 22, 2011, for the duloxetine RCT and Aug 5, 2012, and Jan 28, 2016, for the desvenlafaxine RCT. Before and after treatment MRI scans were collected in 32 participants for the duloxetine RCT and 34 participants for the desvenlafaxine RCT. In both studies, antidepressants decreased functional connectivity compared with placebo (duloxetine study: ß=-0·06; 95% CI -0·08 to -0·03; p<0·0001, ηp2=0·44; desvenlafaxine study: -0·06, -0·09 to -0·03; p<0·0001, ηp2=0·35) within a thalamo-cortico-periaqueductal network that has previously been associated with the experience of pain. Within the active drug groups, reductions in functional connectivity within this network correlated with improvements in depressive symptom severity in both studies (duloxetine study: r=0·38, 95% CI 0·01-0·65; p=0·0426; desvenlafaxine study: 0·44, 0·10-0·69; p=0·0138) and pain symptoms in the desvenlafaxine study (0·39, 0·04 to 0·65; p=0·0299). INTERPRETATION: The findings suggest the thalamo-cortico-periaqueductal network associated with the experience of pain is a new and potentially important target for novel antidepressant therapeutics. FUNDING: National Mental Health Institute, Eli Lilly and Company, Pfizer Pharmaceuticals, and the Edwin S Webster Foundation.

Associations Between Brain Structure and Connectivity in Infants and Exposure to Selective Serotonin Reuptake Inhibitors During Pregnancy.

Importance: Selective serotonin reuptake inhibitor (SSRI) use among pregnant women is increasing, yet the association between prenatal SSRI exposure and fetal neurodevelopment is poorly understood. Animal studies show that perinatal SSRI exposure alters limbic circuitry and produces anxiety and depressive-like behaviors after adolescence, but literature on prenatal SSRI exposure in humans is limited and mixed. Objective: To examine associations between prenatal SSRI exposure and brain development using structural and diffusion magnetic resonance imaging (MRI). Design, Setting, and Participants: A cohort study conducted at Columbia University Medical Center and New York State Psychiatric Institute included 98 infants: 16 with in utero SSRI exposure, 21 with in utero untreated maternal depression exposure, and 61 healthy controls. Data were collected between January 6, 2011, and October 25, 2016. Exposures: Selective serotonin reuptake inhibitors and untreated maternal depression. Main Outcomes and Measures: Gray matter volume estimates using structural MRI with voxel-based morphometry and white matter structural connectivity (connectome) using diffusion MRI with probabilistic tractography. Results: The sample included 98 mother (31 [32%] white, 26 [27%] Hispanic/Latina, 26 [27%] black/African American, 15 [15%] other) and infant (46 [47%] boys, 52 [53%] girls) dyads. Mean (SD) age of the infants at the time of the scan was 3.43 (1.50) weeks. Voxel-based morphometry showed significant gray matter volume expansion in the right amygdala (Cohen d = 0.65; 95% CI, 0.06-1.23) and right insula (Cohen d = 0.86; 95% CI, 0.26-1.14) in SSRI-exposed infants compared with both healthy controls and infants exposed to untreated maternal depression (P < .05; whole-brain correction). In connectome-level analysis of white matter structural connectivity, the SSRI group showed a significant increase in connectivity between the right amygdala and the right insula with a large effect size (Cohen d = 0.99; 95% CI, 0.40-1.57) compared with healthy controls and untreated depression (P < .05; whole connectome correction). Conclusions and Relevance: Our findings suggest that prenatal SSRI exposure has an association with fetal brain development, particularly in brain regions critical to emotional processing. The study highlights the need for further research on the potential long-term behavioral and psychological outcomes of these neurodevelopmental changes.

High-Sensitive Cardiac Troponin T as an Early Biochemical Signature for Clinical and Subclinical Heart Failure: MESA (Multi-Ethnic Study of Atherosclerosis).

BACKGROUND: Although small elevations of high-sensitive cardiac troponin T (hs-cTnT) are associated with incident heart failure (HF) in the general population, the underlying mechanisms are not well defined. Evaluating the association of hs-cTnT with replacement fibrosis and progression of structural heart disease before symptoms is fundamental to understanding the potential of this biomarker in a HF prevention strategy. METHODS: We measured hs-cTnT at baseline among 4986 participants in MESA (Multi-Ethnic Study of Atherosclerosis), a cohort initially free of overt cardiovascular disease (CVD). Cardiac magnetic resonance imaging was performed at baseline. Repeat cardiac magnetic resonance was performed 10 years later among 2831 participants who remained free of interim CVD events; of these, 1723 received gadolinium-enhanced cardiac magnetic resonance for characterization of replacement fibrosis by late gadolinium enhancement. Progression of subclinical CVD was defined by 10-year change in left ventricular structure and function. Associations of hs-cTnT with incident HF, CV-related mortality, and coronary heart disease were estimated using Cox regression models. RESULTS: Late gadolinium enhancement for replacement fibrosis was detectable in 6.3% participants without interim CVD events by follow-up cardiac magnetic resonance. A graded association was observed between higher baseline hs-cTnT categories and late gadolinium enhancement (≥7.42 ng/L versus 12% (highest category versus

Enhancement Characteristics of the Computed Tomography Pulmonary Angiography Test Bolus Curve and Its Use in Predicting Right Ventricular Dysfunction and Mortality in Patients With Acute Pulmonary Embolism.

PURPOSE: The purpose of the study was to evaluate the relationship between computed tomography pulmonary angiography (CTPA) test bolus curve data and mortality in patients with pulmonary embolism (PE) in comparison with conventional methods of right ventricular (RV) dysfunction. MATERIALS AND METHODS: The study was approved by our institutional review board and is HIPAA-compliant. We retrospectively evaluated consecutive CTPA studies performed with a test bolus technique in a 2-year period. A time-density curve was derived from each test bolus. For comparison, left ventricular (LV) and RV dimensions (area, diameter) and PE load score (Qanadli method) were measured using CT data. A cardiologist blinded to the clinical and other imaging data reviewed a subset of the corresponding echocardiographic images to assess for RV dysfunction. Demographic data, mode of treatment, and patient outcome information were gathered using electronic medical records. Test bolus and anatomic data were correlated with PE-related mortality. RESULTS: A total of 71 patients (34 men and 37 women, average age 54.4 y) who had a CTPA performed using a test bolus technique were diagnosed with acute PE. Factors that significantly correlated with PE-related mortality on univariate analysis were: age above 60 years (odds ratio 19.1, P = 0.05), RV/LV diameter >1.5 (odds ratio 48.8, P < 0.001), RV/LV area >1 (odds ratio 8.6, P = 0.06), bolus curve upslope time >6 seconds (odds ratio 23.3, P = 0.04), 50% downslope time >6 seconds (odds ratio 20, P = 0.01), and embolus load score >15 (odds ratio 25, P = 0.03). The predictive value of upslope time (Exp(B) 1.65, P = 0.05), RV/LV diameter (Exp(B) 43.8, P = 0.01), and RV/LV area (Exp(B) 16.7, P = 0.01) were confirmed to be statistically significant in multivariate analyses. CONCLUSIONS: Data from the CTPA timing bolus curve provide prognostic value similar to the best conventional methods for predicting PE-related mortality.

Case of mild Schmid-type metaphyseal chondrodysplasia with novel sequence variation involving an unusual mutational site of the COL10A1 gene.

Schmid-type metaphyseal chondrodysplasia (MCDS) is characterized by short stature with short legs, bowing of the long bones, coxa vara, and waddling gait. MCDS is a relatively common form of MCD. Most mutations that cause MCDS occur within the carboxyl-terminal non-collagenous domain (NC1) of the COL10A1 gene. We performed mutational analysis of the COL10A1 genes in 4 unrelated Korean patients with diagnosed MCDS. Mutational analysis of COL10A1 identified c.1904_1915delinsT (p.Gln635LeufsX10) and c.1969dupG (p.Ala657GlyfsX10), 2 novel frameshift mutations, and c.2030T>A (p.Val677Glu) and c.862G>C (p.Gly288Arg) at unusual mutational sites, which could be pathogenic. We present the first report of the molecular characteristics of MCDS in 4 Korean patients. Our findings suggest that a novel sequence variation involving an unusual mutational site of the COL10A1 gene can cause mild MCDS.