Sex differences in heart failure patients assessed by combined echocardiographic and cardiopulmonary exercise testing

BackgroundWe aimed to test the differences in peak VO2 between males and females in patients diagnosed with heart failure (HF), using combined stress echocardiography (SE) and cardiopulmonary exercise testing (CPET).MethodsPatients who underwent CPET and SE for evaluation of dyspnea or exertional intolerance at our institution, between January 2013 and December 2017, were included and retrospectively assessed. Patients were divided into three groups: HF with preserved ejection fraction (HFpEF), HF with mildly reduced or reduced ejection fraction (HFmrEF/HFrEF), and patients without HF (control). These groups were further stratified by sex.ResultsOne hundred seventy-eight patients underwent CPET-SE testing, of which 40% were females. Females diagnosed with HFpEF showed attenuated increases in end diastolic volume index (P = 0.040 for sex × time interaction), significantly elevated E/e' (P < 0.001), significantly decreased left ventricle (LV) end diastolic volume:E/e ratio (P = 0.040 for sex × time interaction), and lesser increases in A-VO2 difference (P = 0.003 for sex × time interaction), comparing to males with HFpEF. Females diagnosed with HFmrEF/HFrEF showed diminished increases in end diastolic volume index (P = 0.050 for sex × time interaction), mostly after anaerobic threshold was met, comparing to males with HFmrEF/HFrEF. This resulted in reduced increases in peak stroke volume index (P = 0.010 for sex × time interaction) and cardiac output (P = 0.050 for sex × time interaction).ConclusionsCombined CPET-SE testing allows for individualized non-invasive evaluation of exercise physiology stratified by sex. Female patients with HF have lower exercise capacity compared to men with HF. For females diagnosed with HFpEF, this was due to poorer LV compliance and attenuated peripheral oxygen extraction, while for females diagnosed with HFmrEF/HFrEF, this was due to attenuated increase in peak stroke volume and cardiac output. As past studies have shown differences in clinical outcomes between females and males, this study provides an essential understanding of the differences in exercise physiology in HF patients, which may improve patient selection for targeted therapeutics

Medieval Emergencies and the Contemporary Debate

Abstract The contemporary debate on emergencies and the state of exception often relies on historical examples. Yet, the most recent discussions on the state of exception (a legal construct that deals with emergencies) also assume its modern inception. This article shows that medieval France formulated its own state of exception, meant to deal with emergencies, based on the legal principle of necessity. This article has two purposes. First, it challenges the historical narrative inherent in the contemporary debate, which assumes the modern inception of the state of exception. Second, it reinforces the trepidation with which many scholars today view the uses and abuses of the state of exception. This article does so by showing that the French crown used and abused the medieval principle of necessity in ways similar to current uses of the state of exception; it served similar purposes. Just as some scholars fear today, the French medieval state of exception often served as a pretext meant to change the legal order, turning the exception into the ordinary. The French crown used the state of exception to enhance its power, and it was central in the long process of building the early-modern French state

Metabolic networking in Brunfelsia calycina petals after flower opening

Brunfelsia calycina flowers change colour from purple to white due to anthocyanin degradation, parallel to an increase in fragrance and petal size. Here it was tested whether the production of the fragrant benzenoids is dependent on induction of the shikimate pathway, or if they are formed from the anthocyanin degradation products. An extensive characterization of the events taking place in Brunfelsia flowers is presented. Anthocyanin characterization was performed using ultraperfomance liquid chromatography–quadrupole time of flight–tandem mass specrometry (UPLC-QTOF-MS/MS). Volatiles emitted were identified by headspace solid phase microextraction–gas chromatography–mass spectrometry (HS-SPME-GC-MS). Accumulated proteins were identified by 2D gel electrophoresis. Transcription profiles were characterized by cross-species hybridization of Brunfelsia cDNAs to potato cDNA microarrays. Identification of accumulated metabolites was performed by UPLC-QTOF-MS non-targeted metabolite analysis. The results include characterization of the nine main anthocyanins in Brunfelsia flowers. In addition, 146 up-regulated genes, 19 volatiles, seven proteins, and 17 metabolites that increased during anthocyanin degradation were identified. A multilevel analysis suggests induction of the shikimate pathway. This pathway is the most probable source of the phenolic acids, which in turn are precursors of both the benzenoid and lignin production pathways. The knowledge obtained is valuable for future studies on degradation of anthocyanins, formation of volatiles, and the network of secondary metabolism in Brunfelsia and related species

Novel Anti-Melanoma Immunotherapies: Disarming Tumor Escape Mechanisms

The immune system fights cancer and sometimes temporarily eliminates it or reaches an equilibrium stage of tumor growth. However, continuous immunological pressure also selects poorly immunogenic tumor variants that eventually escape the immune control system. Here, we focus on metastatic melanoma, a highly immunogenic tumor, and on anti-melanoma immunotherapies, which recently, especially following the FDA approval of Ipilimumab, gained interest from drug development companies. We describe new immunomodulatory approaches currently in the development pipeline, focus on the novel CEACAM1 immune checkpoint, and compare its potential to the extensively described targets, CTLA4 and PD1. This paper combines multi-disciplinary approaches and describes anti-melanoma immunotherapies from molecular, medical, and business angles

Sustainable Elimination of Schistosomiasis in Ethiopia—A Five-Year Follow-Up Study

In 2009, Mekele, the capital of the Tigray Region in Ethiopia, presented a mean prevalence of 44.7% of schistosomiasis (S. mansoni) in school children. Termed a public health problem, NALA, an international public health non-governmental organization, and their partners implemented a novel model of intervention, which aimed to compliment mass drug administration (MDA) campaigns with behavioral change (BC) and improved sanitation to achieve sustained elimination of schistosomiasis. The four-year intervention (2009–2012) covered 38 primary schools. The objective of this study was to examine factors associated with control or resurgence of the disease, and the association between the behavioral change program and disease prevalence, ten years after initiation. Eleven primary schools were selected for this follow-up study. All students provided a stool sample and filled in a knowledge, attitude and practice (KAP) questionnaire. In seven out of eleven schools (63.6%) the prevalence of schistosomiasis was maintained below 2% ten years after the initiation of the intervention. In four schools, prevalence returned to pre-intervention levels, defining them as persistent hot spots (PHS). Students from PHS schools scored lower on KAP questionnaires compared to students from responder schools; 3.9 ± 0.9 vs. 4.2 ± 0.9 (p-value < 0.001) for practice questions and 4.4 ± 1.4 vs. 4.6 ± 1.5 (p-value = 0.03) for attitude questions. The prevalence of schistosomiasis correlated positively with age, (p-value = 0.049), sex (relative risk = 1.7, p-value < 0.001), and location. Semi-urban locations (n = 382) had higher disease prevalence than urban locations (n = 242), (22.7% vs. 5.5%, p-value < 0.001). Students residing in semi-urban areas and close to a river (<500 m) were at higher risk of contracting schistosomiasis than those living in urban areas far from the river (RR = 5.95, p-value < 0.001). Finally, a correlation between prevalence and proximity of schools to rivers was found (semi-urban areas; RR = −0.91, p-value = 0.001 vs. urban areas; RR = −0.51, p-value = 0.001). Soil-transmitted-helminths prevalence in 2009 was 8.1% and declined during the intervention years to 0.5%. Prevalence in 2018 was found to be stable at 0.8%. These results demonstrate the long-term success of NALAs’ comprehensive model of intervention for elimination of schistosomiasis in school children, combining behavioral change and improved sanitation with MDA

Comparison of non-myeloablative lymphodepleting preconditioning regimens in patients undergoing adoptive T cell therapy

Background Adoptive cell therapy with T cells genetically engineered to express a chimeric antigen receptor (CAR-T) or tumor-infiltrating T lymphocytes (TIL) demonstrates impressive clinical results in patients with cancer. Lymphodepleting preconditioning prior to cell infusion is an integral part of all adoptive T cell therapies. However, to date, there is no standardization and no data comparing different non-myeloablative (NMA) regimens.Methods In this study, we compared NMA therapies with different doses of cyclophosphamide or total body irradiation (TBI) in combination with fludarabine and evaluated bone marrow suppression and recovery, cytokine serum levels, clinical response and adverse events.Results We demonstrate that a cumulative dose of 120 mg/kg cyclophosphamide and 125 mg/m2 fludarabine (120Cy/125Flu) and 60Cy/125Flu preconditioning were equally efficient in achieving deep lymphopenia and neutropenia in patients with metastatic melanoma, whereas absolute lymphocyte counts (ALCs) and absolute neutrophil counts were significantly higher following 200 cGyTBI/75Flu-induced NMA. Thrombocytopenia was most profound in 120Cy/125Flu patients. 30Cy/75Flu-induced preconditioning in patients with acute lymphoblastic leukemia resulted in a minor ALC decrease, had no impact on platelet counts and did not yield deep neutropenia. Following cell infusion, 120Cy/125Flu patients with objective tumor response had significantly higher ALC and significant lower inflammatory indexes, such as neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR). Receiver-operating characteristics curve analysis 7 days after cell infusion was performed to determine the cut-offs, which distinguish between responding and non-responding patients in the 120Cy/125Flu cohort. NLR≤1.79 and PLR≤32.7 were associated with clinical response and overall survival. Cytokine serum levels did not associate with clinical response in patients with TIL. Patients in the 120Cy/125Flu cohort developed significantly more acute NMA-related adverse events, including thrombocytopenia, febrile neutropenia and cardiotoxicity, and stayed significantly longer in hospital compared with the 60Cy/125Flu and TBI/75Flu cohorts.Conclusions Bone marrow depletion and recovery were equally affected by 120Cy/125Flu and 60Cy/125Flu preconditioning; however, toxicity and consequently duration of hospitalization were significantly lower in the 60Cy/125Flu cohort. Patients in the 30Cy/75Flu and TBI/75Flu groups rarely developed NMA-induced adverse events; however, both regimens were not efficient in achieving deep bone marrow suppression. Among the regimens, 60Cy/125Flu preconditioning seems to achieve maximum effect with minimum toxicity

Video_1_Development and validation of virtual reality-based Rey Auditory Verbal Learning Test.MP4

ObjectiveTranslations and adaptations of traditional neuropsychological tests to virtual reality (VR) technology bear the potential to increase their ecological validity since the technology enables simulating everyday life conditions in a controlled manner. The current paper describes our translation of a commonly used neuropsychological test to VR, the Rey Auditory Verbal Learning Test (RAVLT). For this aim, we developed a VR adaptation of the RAVLT (VR-RAVLT) Which is based on a conversation with a secretary in a virtual office using a fully immersive VR system. To validate the VR-RAVLT, we tested its construct validity, its age-related discriminant validity and its test-retest validity in reference to the original gold standard RAVLT (GS-RAVLT).MethodSeventy-eight participants from different age groups performed the GS-RAVLT and the VR-RAVLT tests in a counterbalanced order in addition to other neuropsychological tests. Construct validity was validated using Pearson’s correlations coefficients and serial position effects; discriminant validity was validated using receiver operating characteristic area under the curve values and test-retest reliability was validated using intraclass correlation coefficients.ResultsComparing both RAVLTs’ format results indicates that the VR-RAVLT has comparable construct, discriminant and test–retest validities.Conclusionthe novel VR-RAVLT and the GS-RAVLT share similar psychometric properties suggesting that the two tests measure the same cognitive construct. This is an indication of the feasibility of adapting the RAVLT to the VR environment. Future developments will employ this approach for clinical diagnosis and treatment.</p