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AbstractBackgroundRecent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers.Methods483 BRCA1 and 1318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were 3 versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen receptor (ER)–negative (PRSER-), or ER-positive (PRSER+) breast cancer risk.ResultsPRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07 to 1.83) for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 (OR = 1.73, 95% CI = 1.28 to 2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34 to 1.91) carriers. The estimated breast cancer odds ratios were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions.ConclusionsPopulation-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and informing clinical management.

The mammalian liver's regenerative ability has led researchers to engineer animals as incubators for expansion of human hepatocytes. The expansion properties of human hepatocytes in immunodeficient mice are well known. However, little has been reported about larger animals that are more scalable and practical for clinical purposes. Therefore, we engineered immunodeficient swine to support expansion of human hepatocytes and identify barriers to their clinical application. Immunodeficient swine were engineered by knockout of the recombinase-activating gene 2 ( RAG2 ) and fumarylacetoacetate hydrolase (FAH). Immature human hepatocytes (ihHCs) were injected into fetal swine by intrauterine cell transplantation (IUCT) at day 40 of gestation. Human albumin was measured as a marker of engraftment. Cytotoxicity against ihHCs was measured in transplanted piglets and control swine. We initially detected higher levels of human albumin in cord blood of newborn FAH/ RAG2 -deficient (FR) pigs compared with immunocompetent controls (196.26 ng/dL vs. 39.29 ng/dL, p = 0.008), indicating successful engraftment of ihHCs after IUCT and adaptive immunity in the fetus. Although rare hepatocytes staining positive for human albumin were observed, levels of human albumin did not rise after birth, but declined, suggesting rejection of xenografted ihHCs. Cytotoxicity against ihHCs increased after birth by 3.8% (95% CI: [2.1%–5.4%], p < 0.001) and inversely correlated with declining levels of human albumin ( p = 2.1 × 10 −5 , R 2 = 0.17). Circulating numbers of T cells and B cells were negligible in FR pigs. However, circulating natural killer (NK) cells exerted cytotoxicity against ihHCs. NK cell activity was lower in immunodeficient piglets after IUCT than in naive controls (30.4% vs. 40.1%, p = 0.011, 95% CI for difference [2.7%–16.7%]). In conclusion, ihHCs were successfully engrafted in FR swine after IUCT. NK cells were a significant barrier to expansion of hepatocytes. New approaches are needed to overcome this hurdle and allow large-scale expansion of human hepatocytes in immunodeficient swine. Impact statement There is currently a need for robust expansion of human hepatocytes. We describe an immunodeficient swine model into which we engrafted immature human hepatocytes (ihHCs). We identified the mechanism of the eventual graft rejection by the intact NK cell population, which has not been previously shown to have a significant role in xenograft rejection. By both improving engraftment and reducing NK cell-mediated cytotoxicity toward the graft through intrauterine cell transfer, we confirmed the presence of residual adaptive immunity in this model of immunodeficiency and the ability to induce hyposensitization in the NK cell population by taking advantage of the fetal microenvironment.

AbstractBackgroundPatients with chronic obstructive pulmonary disease (COPD) commonly have comorbidities which may impact both symptoms and prognosis. Endoscopic lung volume reduction (ELVR) with endobronchial valves (EBV) is an innovative, effective and safe treatment for patients with severe emphysema who remain symptomatic despite optimal medical therapy.ObjectivesTo evaluate medical comorbidities associated with increased risk of complications after EBV procedure.MethodThis was a retrospective cohort review of patients with severe, heterogeneous emphysema who underwent Zephyr® EBV installation for ELVR. Demographics, baseline comorbidities, dyspnea scores, data regarding procedure, pulmonary function test, minimal clinically important difference and post‐EBV complications were recorded.ResultsOf a total 82 participants, 24 were identified as having a post procedure complication. There was a significant difference in the incidence of type 2 diabetes mellitus (T2DM) at baseline (25%) in complication group compared with non‐complication group (5.1%) (p value = 0.01). There was also a significant difference between baseline coronary artery disease (CAD) in those with (58.3%) or without (29.3%) complication (p = 0.01). Multivariate analysis of other covariables, identified associations of both CAD and T2DM with a heightened risk of complication (adjusted OR 4.19 CI: 1.23–14.2, p value = 0.02 and adjusted OR of 6.1 CI: 1.3–26.1, p value = 0.02 respectively).ConclusionsOur study found that patients with severe, heterogeneous emphysema who undergo ELVR utilizing Zephyr® EBV and suffer complications during post‐procedure period are more likely to have CAD or T2DM as baseline comorbidity. These data suggest that baseline CAD and T2DM might be predictive of increased risk of complications following ELVR with EBV.

Background: Atrial fibrillation (AF) ablation targets improvement in quality of life (QoL). Data is scarce on predictors of QoL improvement following ablation. We aimed to investigate the clinical characteristics underlying differential response in QoL after AF ablation (with or without arrhythmia recurrence). Methods: All patients undergoing AF ablation (2013–2016) at our center were prospectively enrolled in a fully automated patient-reported outcomes registry. A large number of variables were collected including AF symptom severity scale and AF burden (as indicated by AF frequency and duration scores). Patients were divided into 3 groups based on self-report of QoL improvement: remarkable (super responders), mild/moderate, and unchanged or worse (nonresponders). Univariable and multivariable logistic regression models assessed clinical characteristics and QoL outcomes. Results: A total of 956 patients were included (25% females, mean age 63.9). Most patients (≈80%) were super responders (n=761), 138 (14.4%) had mild/moderate improvement, and 57 (5.9%) were nonresponders. The strongest predictors of remarkable QoL improvement were freedom of arrhythmia recurrence (OR, 2.42 [95% CI, 1.27–4.59], P =0.007) and lower AF burden at 12 months. Similarly, higher AF burden was significantly associated with clinical nonresponse. In patients with observed clinical recurrence-QoL mismatch, changes in AF burden at 12 months were the main predictors of QoL outcome, with lower burden predicting higher improvement in QoL and vice versa. Conclusions: Most patients derive significant QoL benefit from AF ablation. Freedom from arrhythmia recurrence and lower AF burden predict remarkable QoL improvement following ablation.

Abstract Aim The aim of this study was to assess the prognostic value of ABCDE-SE in a prospective, large scale, multicentre, international, effectiveness study. Stress echocardiography (SE) was recently upgraded to the ABCDE protocol: step A, regional wall motion abnormalities; step B, B lines; step C, left ventricular contractile reserve; step D, Doppler-based coronary flow velocity reserve in left anterior descending coronary artery; and step E, electrocardiogram-based heart rate reserve. Methods and results From July 2016 to November 2020, we enrolled 3574 all-comers (age 65 ± 11 years, 2070 males, 58%; ejection fraction 60 ± 10%) with known or suspected chronic coronary syndromes referred from 13 certified laboratories. All patients underwent clinically indicated ABCDE-SE. The employed stress modality was exercise (n = 952, with semi-supine bike, n = 887, or treadmill, n = 65 with adenosine for step D) or pharmacological stress (n = 2622, with vasodilator, n = 2151; or dobutamine, n = 471). SE response ranged from score 0 (all steps normal) to score 5 (all steps abnormal). All-cause death was the only endpoint. Rate of abnormal results was 16% for A, 30% for B, 36% for C, 28% for D, and 37% for E steps. During a median follow-up of 21 months (interquartile range: 13–36), 73 deaths occurred. Global X 2 was 49.5 considering clinical variables, 50.7 after step A only (P = NS (not significant)) and 80.6 after B–E steps (P &lt; 0.001 vs. step A). Annual mortality rate ranged from 0.4% person-year for score 0 up to 2.7% person-year for score 5. Conclusion ABCDE-SE allows an effective prediction of survival in patients with chronic coronary syndromes.

Sex differences have been well identified in many brain tumors. Even though glioblastoma (GBM) is the most common primary malignant brain tumor in adults and has the worst outcome, well-established differences between men and women are limited to incidence and outcome. Little is known about sex differences in GBM at the disease phenotype and genetical/molecular level. This review focuses on a deep understanding of the pathophysiology of GBM, including hormones, metabolic pathways, the immune system, and molecular changes, along with differences between men and women and how these dimorphisms affect disease outcome. The information analyzed in this review shows a greater incidence and worse outcome in male patients with GBM compared with female patients. We highlight the protective role of estrogen and the upregulation of androgen receptors and testosterone having detrimental effects on GBM. Moreover, hormones and the immune system work in synergy to directly affect the GBM microenvironment. Genetic and molecular differences have also recently been identified. Specific genes and molecular pathways, either upregulated or downregulated depending on sex, could potentially directly dictate GBM outcome differences. It appears that sexual dimorphism in GBM affects patient outcome and requires an individualized approach to management considering the sex of the patient, especially in relation to differences at the molecular level.

Abstract Context There are scarce data on the management of chronic hypoparathyroidism (hypoPT) in pregnant women. Objective The aim of this study was to evaluate pregnancy outcome and total number of births in maternal chronic hypoPT. Methods The Swedish National Patient Register, The Swedish Prescribed Drug Register, Swedish Medical Birth Register, and the Total Population Register were used to identify 97 women with chronic hypoPT and 1030 age-matched controls who delivered 139 and 1577 singleton infants, respectively, following diagnosis between 1997 and 2017. Results Women in the chronic hypoPT group had more frequent diabetes (DM) and chronic kidney disease (CKD) compared with the control group (P = 0.043 and P &lt; 0.001, respectively). After adjusting for DM, CKD, maternal age at delivery, and calendar year of delivery, chronic hypoPT cases were associated with increased risk of induction of labor (OR, 1.82; 95% CI, 1.13-2.94) and birth of infants with lower birth weight (β-coefficient −188 g; 95% CI, −312.2 to −63.8) compared with controls. No difference was found in infant length, small for gestational age, or head circumference after adjustments. Mean gestational age at delivery after controlling for DM, CKD, and pre-eclampsia was not significantly younger (P = 0.119). There was no difference in congenital malformations or perinatal death and no difference in the total number of infants born between groups (P = 0.518). Conclusion The majority of women with chronic hypoPT had normal pregnancy outcomes, and the overall risks appear low. Maternal chronic hypoPT is, however, associated with higher risk of induction of labor and slightly lower infant birth weight.

In contrast to the decreasing burden related to cardiovascular disease (CVD), the burden related to dysglycemia and adiposity complications is increasing in Czechia, and local drivers must be identified. A comprehensive literature review was performed to evaluate biological, behavioral, and environmental drivers of dysglycemia and abnormal adiposity in Czechia. Additionally, the structure of the Czech healthcare system was described. The prevalence of obesity in men and diabetes in both sexes has been increasing over the past 30 years. Possible reasons include the Eastern European eating pattern, high prevalence of physical inactivity and health illiteracy, education, and income-related health inequalities. Despite the advanced healthcare system based on the compulsory insurance model with free-for-service healthcare and a wide range of health-promoting initiatives, more effective strategies to tackle the adiposity/dysglycemia are needed. In conclusion, the disease burden related to dysglycemia and adiposity in Czechia remains high but is not translated into greater CVD. This discordant relationship likely depends more on other factors, such as improvements in dyslipidemia and hypertension control. A reconceptualization of abnormal adiposity and dysglycemia into a more actionable cardiometabolic-based chronic disease model is needed to improve the approach to these conditions. This review can serve as a platform to investigate causal mechanisms and secure effective management of cardiometabolic-based chronic disease.

Abstract Purpose: Taste and smell abnormalities (TSA) are common in patients receiving chemotherapy and may lead to altered nutritional intake, treatment withdrawal, and impaired quality of life. Lipid peroxidation in the oral cavity is one cause of TSA. Lactoferrin (LFN), an iron-binding salivary protein, reduces production of lipid oxidation byproducts and has been shown to reduce perception of unpleasant flavors. To assess the feasibility of LFN as a treatment for TSA, we conducted pilot investigations among patients with cancer who self-reported TSA following onset of chemotherapy. The primary objective was to assess change in subjective taste and smell perception from baseline to completion of 30-days of LFN supplementation.Methods: Patients were treated with 750mg LFN daily for 30 days and followed for an additional 30 days without LFN. TSA was measured via the taste and smell questionnaire (TSQ) including taste (score 0-10), smell (score 0-6), and composite scores (0-16, 0=no TSA) at baseline, day 30, and day 60.Results: 26 patients enrolled; 19 remained on study at day 30 and 17 at day 60. Baseline mean TSQ scores were 6.5 (taste), 3.1 (smell) and 9.6 (composite). By day 30, mean composite TSQ score improved by 1.7 (p=0.018); taste and smell improved by 0.6 (p=.062) and 1.1 (p=.042) respectively. From baseline to day 60, mean composite TSQ score improved by 3.8 (p<.0001); taste and smell improved by 1.9 (p=.001) and 1.8 (p=.003). Conclusions: Further evaluation of LFN is warranted to determine its value for improving self-reported TSA among patients receiving chemotherapy.

AbstractThis first Guideline for Reasonable and Appropriate Care in the Emergency Department (GRACE‐1) from the Society for Academic Emergency Medicine is on the topic: Recurrent, Low‐risk Chest Pain in the Emergency Department. The multidisciplinary guideline panel used The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess the certainty of evidence and strength of recommendations regarding eight priority questions for adult patients with recurrent, low‐risk chest pain and have derived the following evidence based recommendations: (1) for those >3 h chest pain duration we suggest a single, high‐sensitivity troponin below a validated threshold to reasonably exclude acute coronary syndrome (ACS) within 30 days; (2) for those with a normal stress test within the previous 12 months, we do not recommend repeat routine stress testing as a means to decrease rates of major adverse cardiac events at 30 days; (3) insufficient evidence to recommend hospitalization (either standard inpatient admission or observation stay) versus discharge as a strategy to mitigate major adverse cardiac events within 30 days; (4) for those with non‐obstructive (<50% stenosis) coronary artery disease (CAD) on prior angiography within 5 years, we suggest referral for expedited outpatient testing as warranted rather than admission for inpatient evaluation; (5) for those with no occlusive CAD (0% stenosis) on prior angiography within 5 years, we recommend referral for expedited outpatient testing as warranted rather than admission for inpatient evaluation; (6) for those with a prior coronary computed tomographic angiography within the past 2 years with no coronary stenosis, we suggest no further diagnostic testing other than a single, normal high‐sensitivity troponin below a validated threshold to exclude ACS within that 2 year time frame; (7) we suggest the use of depression and anxiety screening tools as these might have an effect on healthcare use and return emergency department (ED) visits; and (8) we suggest referral for anxiety or depression management, as this might have an impact on healthcare use and return ED visits.