Citations

A significant proportion of patients diagnosed with symptomatic severe aortic stenosis (ssAS) do not receive treatment with aortic valve replacement (AVR) despite current ACC/AHA guidelines. Delayed care leads to increased hospitalizations, worsening heart failure and death. Timely referral to a cardiac specialist is a critical step in the treatment pathway. We sought to identify the impact of managing provider type on follow-up care for newly diagnosed patients with severe aortic stenosis (sAS). We analyzed Optum® electronic medical records to identify adults with a new outpatient sAS echo diagnosis in the pre-COVID era (1/2017 - 3/2019). We identified integrated delivery network patients alive 1d post echo excluding those with missing data or AVR within 3d of echo, then selected those managed by a primary care provider (PCP) or a cardiologist (n=5,683). Baseline characteristics were used for covariate-adjusted Cumulative Incidence Function and Fine-Gray subdistribution hazard models. We estimated the impact of managing provider type on the specialist follow-up visit rate (cardiologist, interventional cardiologist and/or cardiothoracic surgeon) for all sAS patients and of surgical or transcatheter AVR for ssAS patients within 1 year of diagnosis. Within 90d of sAS diagnosis, 47% of PCP- vs. 73% of cardiologist-managed patients had a follow-up visit (1-year rates: PCP, 69% vs. cardiologist, 90%; Hazard ratio [HR]=0.54, 95% confidence interval [CI]: 0.49-0.59, p<0.0001). Within 1 year of diagnosis, 36% of PCP- vs. 51% of cardiologist-managed ssAS patients underwent AVR (HR=0.72, CI: 0.63-0.82, p<0.0001) (Figure). Analysis suggests lower referral rates for PCP- than cardiologist-managed patients. In ssAS, 1-year AVR rates were low, particularly for PCPs. These data underscore the importance of timely follow up of all severe AS patients for symptom assessment and appropriate treatment, presenting an opportunity for initiatives to drive behavior change.

Purpose To examine the relationship between experiences of discrimination, institutional responses to seminal race events, and depressive symptoms among Black medical students. Method This study collected data from a convenience sample of Black U.S. medical students via an anonymous electronic questionnaire in August 2020 that was distributed through the Student National Medical Association and Organization of Student Representatives listservs and an author’s social media accounts. It included questions on demographics, institutional responses to seminal race events, experiences of discrimination, and symptoms of depression. Path models were used to examine the relationship between experiences of discrimination, institutional responses to seminal race events, and depressive symptoms among Black medical students. Results Of the 750 students completing the survey, 733 (97.7%) were Black. Experiences of discrimination and a lack of institutional responses to seminal race events were associated with more depressive symptoms ( b = 0.19, 95% CI: 0.11, 0.26; P < .001 and b = 0.12, 95% CI: 0.04, 0.20; P = .01). After controlling for gender and clinical diagnosis of depression or anxiety before medical school, there was a relationship between experiences of discrimination and institutional responses to seminal race events such that students who reported more experiences of discrimination were more likely to report that their institution did not respond to seminal race events ( b = 0.41, 95% CI: 0.34, 0.48; P < .001). Experiences of discrimination moderated the relationship between institutional responses to seminal race events and depressive symptoms (i.e., the relationship between a lack of institutional responses to seminal race events and depressive symptoms was stronger among students who reported more frequent experiences of discrimination). Conclusions Institutions dedicated to supporting Black medical student wellness must be diligent in cultivating a culture intolerant of discrimination and deft in their responses to seminal race events in the larger culture.

Beyond conventional risk factors for cardiovascular disease, women face an additional burden of sex-specific risk factors. Key stages of a woman’s reproductive history may influence or reveal short- and long-term cardiometabolic and cardiovascular trajectories. Early and late menarche, polycystic ovary syndrome, infertility, adverse pregnancy outcomes (eg, hypertensive disorders of pregnancy, gestational diabetes, preterm delivery, and intrauterine growth restriction), and absence of breastfeeding are all associated with increased future cardiovascular disease risk. The menopause transition additionally represents a period of accelerated cardiovascular disease risk, with timing (eg, premature menopause), mechanism, and symptoms of menopause, as well as treatment of menopause symptoms, each contributing to this risk. Differences in conventional cardiovascular disease risk factors appear to explain some, but not all, of the observed associations between reproductive history and later-life cardiovascular disease; further research is needed to elucidate hormonal effects and unique sex-specific disease mechanisms. A history of reproductive risk factors represents an opportunity for comprehensive risk factor screening, refinement of cardiovascular disease risk assessment, and implementation of primordial and primary prevention to optimize long-term cardiometabolic health in women.

Abstract Background To describe response to therapy of small bowel (SB) Crohn’s disease (CD) at CT or MR enterography (CTE/MRE) in patients on vedolizumab. Methods Patients with SB CD who underwent CTE/MRE exams greater than 12 months apart on vedolizumab therapy were included. Length (in cm) and inflammation severity (EMBARK score) of inflamed SB segments were assessed. Changes in inflammation length of 3.4 cm or greater or inflammation severity of 2 EMBARK points or greater was categorized as response or progression, as appropriate, with development of newly inflamed segments, strictures, or penetrating complications also indicating progression. Patients not meeting the criteria for response or progression were categorized as having stable disease. Results Of 36 SB CD patients, the large majority had prior surgery (86%; 31), anti-TNF use (92%; 33), and internal penetrating (78%; 28) disease. Thirty-two patients had paired baseline and follow-up CTE/MRE exams without interval surgery, with clinical response observed in 24/32 (75%). Based on imaging response criteria, 22% (7/32; 95% CI: 9%–40%) had response, 50% (16/32; 95% CI: 32%–68%) were stable, and 28% (9/32; 95% CI: 14%–47%) had disease progression. Fifty-six percent of (18/32; 95% CI: 38%–74%) patients had clinical improvement with response or stable disease by imaging. Patients with stable disease had shorter median baseline lengths of SB inflammation (P = .012). Proportion of patients with colonic inflammation, perianal disease, or penetrating complications did not change. Conclusions Most patients on vedolizumab for over 12 months demonstrated response or stable SB disease when using objective cross-sectional radiologic imaging criteria using CTE/MRE.

63 Background: Population-based colorectal cancer (CRC) screening can reduce mortality by detecting and removing advanced precancerous lesions (APL) and early-stage invasive disease. One guideline-included strategy is the multi-target stool DNA test (mt-sDNA), which combines detection of methylation DNA markers (MDMs), KRAS mutations, and fecal hemoglobin. Since the mt-sDNA pivotal study was conducted, novel biomarkers have been discovered. A panel of highly discriminant MDMs ( LASS4, LRRC4, PPP2R5C, and reference marker ZDHHC1) was identified through a blinded, case-control study of archival specimens. Here, we evaluated the performance of this novel mt-sDNA panel, combined with fecal hemoglobin, in archival stool samples weighted to early-stage CRC and prospectively collected APL, simulating a screening population. Methods: The verification study featured 777 samples—210 cases (112 CRC [49 stage I, 38 stage II, 17 stage III, and 8 stage IV] and 98 APL) and 567 controls (176 non-APL and 391 colonoscopy-negative)—from three trials (NCT01397747, NCT01260168, and NCT02503631). Median APL size was 12 mm (interquartile range: 10 mm to 15 mm), with 86.7% adenomas (n = 85) and 13.3% sessile serrated polyps (SSPs; n = 13). The average age was 65.5 years for cases (57% men) and 63.2 for controls (47% men). Samples were processed through homogenization, targeted MDM capture, bisulfite conversion, and MDM quantitation using Long‐probe Quantitative Amplified Signal (LQAS). Fecal hemoglobin was quantified using enzyme-linked immunosorbent assay (ELISA). Samples were split into stratified 75%/25% training-testing sets and model outcomes were cross-validated 1,000 times. Results: Mean performance from the cross-validation analysis is summarized in the table below. Overall sensitivity was 95.2% for CRC and 57.2% for APL, with specificities of 89.8% (no CRC/APL) and 92.4% (no neoplasia). Subgroup analyses showed high sensitivity for early-stage CRC, with 93.4% at stage I and 94.2% at stage II. By APL subtype, sensitivity was 82.9% for high-grade dysplasia, 73.4% for villous lesions, 49.8% for tubular lesions, and 30.2% for SSPs. Conclusions: These data support high sensitivity and specificity for a second-generation mt-sDNA panel. A multicenter pivotal trial evaluating the panel is underway (NCT04144738). [Table: see text]

Mammalian target of rapamycin (mTOR) inhibitors have been shown to reduce proliferation of lymphoid cells; thus, their use for immunosuppression after heart transplantation (HT) may reduce post-transplant lymphoproliferative disorder (PTLD) risk. This study sought to investigate whether the sirolimus (SRL)-based immunosuppression regimen is associated with a decreased risk of PTLD compared with the calcineurin inhibitor (CNI)-based regimen in HT recipients. We retrospectively analyzed 590 patients who received HTs at two large institutions between 1 June 1988 and 31 December 2014. Cox proportional-hazard modeling was used to examine the association between type of primary immunosuppression and PTLD after adjustment for potential confounders, including Epstein–Barr virus (EBV) status, type of induction therapy, and rejection. Conversion from CNI to SRL as primary immunosuppression occurred in 249 patients (42.2%). During a median follow-up of 6.3 years, 30 patients developed PTLD (5.1%). In a univariate analysis, EBV mismatch was strongly associated with increased risk of PTLD (HR 10.0, 95% CI: 3.8–26.6; p < 0.001), and conversion to SRL was found to be protective against development of PTLD (HR 0.19, 95% CI: 0.04–0.80; p = 0.02). In a multivariable model and after adjusting for EBV mismatch, conversion to SRL remained protective against risk of PTLD compared with continued CNI use (HR 0.12, 95% CI: 0.03–0.55; p = 0.006). In conclusion, SRL-based immunosuppression is associated with lower incidence of PTLD after HT. These findings provide evidence of a benefit from conversion to SRL as maintenance therapy for mitigating the risk of PTLD, particularly among patients at high PTLD risk.

Abstract Aims In heart failure (HF), pulmonary venous hypertension (PVH) produces pulmonary hypertension (PH) with remodeling of pulmonary veins (PV) and arteries (PA). In a porcine PVH model, we performed proteomic-based bioinformatics to investigate unique pathophysiologic mechanisms mediating PA and PV remodeling. Methods and results Large PV were banded (PVH, n = 10) or not (Sham, n = 9) in piglets. At sacrifice, PV and PA were perfusion labelled for vessel-specific histology and proteomics. The PA and PV were separately sampled with laser-capture micro-dissection for mass spectrometry. Pulmonary vascular resistance [Wood Units; 8.6 (95% confidence interval: 6.3, 12.3) vs. 2.0 (1.7, 2.3)] and PA [19.9 (standard error of mean, 1.1) vs. 10.3 (1.1)] and PV [14.2 (1.2) vs. 7.6 (1.1)] wall thickness/external diameter (%) were increased in PVH (P &lt; 0.05 for all). Similar numbers of proteins were identified in PA (2093) and PV (2085) with 94% overlap, but biological processes differed. There were more differentially expressed proteins (287 vs. 161), altered canonical pathways (17 vs. 3), and predicted upstream regulators (PUSR; 22 vs. 6) in PV than PA. In PA and PV, bioinformatics indicated activation of the integrated stress response and mammalian target of rapamycin signalling with dysregulated growth. In PV, there was also activation of Rho/Rho-kinase signalling with decreased actin cytoskeletal signalling and altered tight and adherens junctions, ephrin B, and caveolae-mediated endocytosis signalling; all indicating disrupted endothelial barrier function. Indeed, protein biomarkers and the top PUSR in PV (transforming growth factor-beta) suggested endothelial to mesenchymal transition in PV. Findings were similar in human autopsy specimens. Conclusion These findings provide new therapeutic targets to oppose pulmonary vascular remodeling in HF-related PH.

Abstract Background While evaluating COVID-19 vaccine responses using a rapid neutralizing antibody (NAb) test, we observed that 25% of RNA vaccine recipients did not neutralize >50%. We termed this group “vaccine poor responders” (VPRs). The objective of this study was to determine if individuals who neutralized <50% would remain VPRs, or if a third dose would elicit high levels of NAbs. Methods 269 healthy individuals ranging in age from 19 to 80 (Average age = 51; 165 females and 104 males) who received either BNT162b2 (Pfizer) or mRNA1273 (Moderna) vaccines were evaluated. NAb levels were measured: i) 2-4 weeks after a second vaccine dose, ii) 2-4 months after the second dose, iii) within 1-2 weeks prior to a third dose and iv) 2-4 weeks after a third RNA vaccine dose. Results Analysis of vaccine recipients revealed that 25% did not neutralize above 50% (Median neutralization = 21%, titers <1:80) within a month after their second dose. Twenty-three of these VPRs obtained a third dose of either BNT162b2 or mRNA-1273 vaccine 1-8 months (average = 5 months) after their second dose. Within a month after their third dose, VPRs showed an average 20-fold increase in NAb levels (range: 46%-99%). Conclusions The results suggest that VPRs are not permanently poor responders; they can generate high NAb levels with an additional vaccine dose. Although it is not known what levels of NAbs protect from infection or disease, those in high-risk professions may wish to keep peripheral NAb levels high, limiting infection, and potential transmission.

Thirty-three cases of corrected transposition of the great vessels are analyzed: 31 of corrected transposition in situs solitus, and two of corrected transposition in situs inversus. In 18 of these 33 cases, of which 64% were males, diagnosis was confirmed by necropsy or operation. There was no history of congenital heart disease in the families of any of these patients. The person whose sole anomaly is corrected transposition has no hemodynamic basis for symptoms. Symptoms are the result of associated lesions, the most common of which are anomalies of the left atrioventricular valve usually causing incompetence, ventricular septal defects, pulmonary valvular stenosis, and advanced disturbances of atrioventricular conduction. Physical findings in corrected transposition depend upon these associated defects. Noncardiac associated anomalies are rare. Anteroposterior thoracic roentgenograms may suggest the diagnosis, particularly when a narrow waist is present at the base of the heart, accompanied by the absence of a pulmonary-artery "knob" and the presence of an enlarged left atrium. Electrocardiographic features that should suggest corrected transposition are atrioventricular block (particularly 2:1 or complete heart block), abnormal P waves, absent or low R voltage in aVR, an initial Q wave in leads 3, aVR, aVF and V1, absence of a Q wave in lead V6, upright T waves across the precordium in children, and a clockwise spatial loop in the frontal plane. Cardiac catheterization may be diagnostic in this malformation when careful documentation is made of the location of the atrioventricular valves and their relation to the semilunar valves, together with the position of the great vessels in the anteroposterior and lateral views. Alteration of hemodynamics is secondary to associated malformations. Inability to enter the pulmonary artery during catheterization should arouse suspicion, and in these cases, particularly, angiocardiography can be diagnostic. The decision as to whether the most frequently associated malformations exist as isolated entities, or whether they are present in combination with corrected transposition, appears to be the main differential problem–together with the differentiation of corrected transposition with associated cyanosis from complete (that is, uncorrected) transposition. Surgical treatment of corrected transposition has been difficult because of complete atrioventricular block before or after operation, residual incompetence when deformed left atrioventricular valves were present, and the mirror-image arrangement for the coronary arteries. The most common cause of death was cardiac failure, often with a terminal bout of pulmonary edema. The average age at death in this series was about 14 years, with a median age at death of about 4 years. A review of the literature again emphasizes the association of corrected transposition with some degree of atrioventricular block evidenced on the electrocardiogram. The most frequently reported associated cardiac lesions were ventricular septal defect, pulmonary stenosis or atresia, patent ductus arteriosus, and dextrocardia. The incidence of anomalies of the left atrioventricular valve in these reported cases has probably been underestimated.