Individual dosage of digoxin in patients with heart failure

Backgroud: After the publication of DIG trial, the therapeutic target of serum digoxin concentration (SDC) for the treatment of heart failure (HF) has been lowered (0.40-1.00 ng/ml). However, the majority of equations to calculate digoxin dosages were developed for higher SDCs. Recently, a new equation was validated in Asian population for low SDCs by Konishi et al., but results in Caucasians are unknown. Aim: This study was aimed to test the Konishi equation in Caucasians specifically targeting low SDCs. Furthermore, the Konishi equation was compared with other frequently used equations. Design: This was a prospective, multicenter study. Methods: Clinically indicated digoxin was given in 40 HF patients. The dosage was calculated with the Konishi equation. The SDC was measured at 1 and 6 months after starting digoxin. Adherence to digoxin was monitored with a specific questionnaire. Results: After exclusion of patients admitting poor adherence, we found a reasonable correlation between predicted and measured SDC (r = 0.48; P < 0.01) by the Konishi equation. Excluding patients with poor adherence and relevant worsening of renal function, the measured SDC (n = 54 measurements) was within the pre-defined therapeutic range in 95% of the cases. The mean, maximal and minimal measured SDC were 0.69 ± 0.19, 1.00 and 0.32 ng/ml, respectively. The correlation was weaker for the Jelliffe, the Koup and Jusko, and the Bauman equations. Conclusions: This study supports the clinical validity of the Konishi equation for calculating individual digoxin dosage in Caucasians, targeting SDCs according to current HF guideline

Prognostic impact of systemic inflammatory diseases in elderly patients with congestive heart failure

Background and aims: Inflammation is part of the pathophysiology of congestive heart failure (CHF). However, little is known about the impact of the presence of systemic inflammatory disease (SID), defined as inflammatory syndrome with constitutional symptoms and involvement of at least two organs as co-morbidity on the clinical course and prognosis of patients with CHF. Methods and results: This is an analysis of all 622 patients included in TIME-CHF. After an 18 months follow-up, outcomes of patients with and without SID were compared. Primary endpoint was all-cause hospitalization free survival. Secondary endpoints were overall survival and CHF hospitalization free survival. At baseline, 38 patients had history of SID (6.1%). These patients had higher N-terminal pro brain natriuretic peptide and worse renal function than patients without SID. SID was a risk factor for adverse outcome [primary endpoint: hazard ratio (HR) = 1.73 (95% confidence interval: 1.18-2.55, P = 0.005); survival: HR = 2.60 (1.49-4.55, P = 0.001); CHF hospitalization free survival: HR = 2.3 (1.45-3.65, P < 0.001)]. In multivariate models, SID remained the strongest independent risk factor for survival and CHF hospitalization free survival. Conclusions: In elderly patients with CHF, SID is independently accompanied with adverse outcome. Given the increasing prevalence of SID in the elderly population, these findings are clinically important for both risk stratification and patient managemen

Students Take Lead to Educate Faculty on the Use of Sex and Gender Terminology in Pre-clinical Courses

TOP WINNER Student leaders in the Lesbian, Gay, Bisexual and Transgender People in Medicine student run organization at the Medical College of Wisconsin noticed that curricular language around sex and gender was absent and/or incorrect in the pre-clinical medical school (M1/M2) courses. After reaching out to the M2 Endocrine/Repro Unit course director, students prepared a report to present to all M1/M2 Course Directors. Objectives: One goal of the report was to “educate the educators” so that faculty would have better understanding of the distinction between sex and gender. Ultimately this would translate to the students and improve overall future patient care. Methods: A presentation was developed and given at the quarterly M1/M2 course director meeting (Fall 2019). Information included statistics from the 2015 US Transgender Survey which underscored that ignorance surrounding sex versus gender terminology could result in an environment in which patients do not seek care. The student presentation comprehensively explained the definitions of sex, gender, cisgender and transgender. Course directors were given action items to evaluate their courses and afirm that terms were used appropriately. Student leaders provided contact information for faculty feedback. Conclusions/Impact: In February 2020, students reported of changes in some courses. For example, the M2 cardiovascular unit led off the session on women and heart disease with sex and gender definitions provided by students. Cardiovascular risks of hormonal therapy for transgender patients was included. Students noted that language around sex and gender in the M2 endocrine-repro unit was consistently correct (female not woman when discussing XX fetus). A M1 pharmacology lecture included the student\u27s definition slide as prelude to discussion of male/female differences in drug response. With little effort, students played an integral role in improving curricular content related to sex and gender medicine and further supporting the model that students are important drivers of change.https://jdc.jefferson.edu/sexandgenderhealth/1019/thumbnail.jp

End-of-life preferences of elderly patients with chronic heart failure

Aims Elderly heart failure (HF) patients are assumed to prefer improved quality of life over longevity, but sufficient data are lacking. Therefore, we assessed the willingness to trade survival time for quality-of-life (QoL) and the preferences for resuscitation. Methods and results At baseline and after 12 and 18 months, 622 HF patients aged ≥60 years (77 ± 8 years, 74% NYHA-class ≥III) participating in the Trial of Intensified vs. standard Medical therapy in Elderly patients with Congestive Heart Failure had prospective evaluation of end-of-life preferences by answering trade-off questions (willingness to accept a shorter life span in return for living without symptoms) and preferences for resuscitation if necessary. The time trade-off question was answered by 555 patients (89%), 74% of whom were not willing to trade survival time for improved QoL. This proportion increased over time (Month 12: 85%, Month 18: 87%, P < 0.001). In multivariable analysis, willingness to trade survival time increased with age, female sex, a reduced Duke Activity Status Index, Geriatric Depression Score, and history of gout, exercise intolerance, constipation and oedema, but even combining these variables did not result in reliable prediction. Of 603 (97%) patients expressing their resuscitation preference, 51% wished resuscitation, 39% did not, and 10% were undecided, with little changes over time. In 430 patients resuscitation orders were known; they differed from patients' preferences 32% of the time. End-of-life preferences were not correlated to 18-month outcome. Conclusion Elderly HF patients are willing to address their end-of-life preferences. The majority prefers longevity over QoL and half wished resuscitation if necessary. Prediction of individual preferences was inaccurate. Trial Registration: isrctn.org Identifier: ISRCTN4359647

Molecularly defined diffuse leptomeningeal glioneuronal tumor (DLGNT) comprises two subgroups with distinct clinical and genetic features

Diffuse leptomeningeal glioneuronal tumors (DLGNT) represent rare CNS neoplasms which have been included in the 2016 update of the WHO classification. The wide spectrum of histopathological and radiological features can make this enigmatic tumor entity difficult to diagnose. In recent years, large-scale genomic and epigenomic analyses have afforded insight into key genetic alterations occurring in multiple types of brain tumors and provide unbiased, complementary tools to improve diagnostic accuracy. Through genome-wide DNA methylation screening of &gt; 25,000 tumors, we discovered a molecularly distinct class comprising 30 tumors, mostly diagnosed histologically as DLGNTs. Copy-number profiles derived from the methylation arrays revealed unifying characteristics, including loss of chromosomal arm 1p in all cases. Furthermore, this molecular DLGNT class can be subdivided into two subgroups [DLGNT methylation class (MC)-1 and DLGNT methylation class (MC)-2], with all DLGNT-MC-2 additionally displaying a gain of chromosomal arm 1q. Co-deletion of 1p/19q, commonly seen in IDH-mutant oligodendroglioma, was frequently observed in DLGNT, especially in DLGNT-MC-1 cases. Both subgroups also had recurrent genetic alterations leading to an aberrant MAPK/ERK pathway, with KIAA1549:BRAF fusion being the most frequent event. Other alterations included fusions of NTRK1/2/3 and TRIM33:RAF1, adding up to an MAPK/ERK pathway activation identified in 80% of cases. In the DLGNT-MC-1 group, age at diagnosis was significantly lower (median 5 vs 14 years, p &lt; 0.01) and clinical course less aggressive (5-year OS 100, vs 43% in DLGNT-MC-2). Our study proposes an additional molecular layer to the current histopathological classification of DLGNT, of particular use for cases without typical morphological or radiological characteristics, such as diffuse growth and radiologic leptomeningeal dissemination. Recurrent 1p deletion and MAPK/ERK pathway activation represent diagnostic biomarkers and therapeutic targets, respectively—laying the foundation for future clinical trials with, e.g., MEK inhibitors that may improve the clinical outcome of patients with DLGNT

Nutrition, diet and immunosenescence

Ageing is characterized by immunosenescence and the progressive decline in immunity in association with an increased frequency of infections and chronic disease. This complex process affects both the innate and adaptive immune systems with a progressive decline in most immune cell populations and defects in activation resulting in loss of function. Although host genetics and environmental factors, such as stress, exercise and diet can impact on the onset or course of immunosenescence, the mechanisms involved are largely unknown. This review focusses on identifying the most significant aspects of immunosenescence and on the evidence that nutritional intervention might delay this process, and consequently improve the quality of life of the elderly

Proteomic analysis of the Plasmodium male gamete reveals the key role for glycolysis in flagellar motility.

BACKGROUND: Gametogenesis and fertilization play crucial roles in malaria transmission. While male gametes are thought to be amongst the simplest eukaryotic cells and are proven targets of transmission blocking immunity, little is known about their molecular organization. For example, the pathway of energy metabolism that power motility, a feature that facilitates gamete encounter and fertilization, is unknown. METHODS: Plasmodium berghei microgametes were purified and analysed by whole-cell proteomic analysis for the first time. Data are available via ProteomeXchange with identifier PXD001163. RESULTS: 615 proteins were recovered, they included all male gamete proteins described thus far. Amongst them were the 11 enzymes of the glycolytic pathway. The hexose transporter was localized to the gamete plasma membrane and it was shown that microgamete motility can be suppressed effectively by inhibitors of this transporter and of the glycolytic pathway. CONCLUSIONS: This study describes the first whole-cell proteomic analysis of the malaria male gamete. It identifies glycolysis as the likely exclusive source of energy for flagellar beat, and provides new insights in original features of Plasmodium flagellar organization

Multidecadal climate variability over northern France during the past 500 years and its relation to large-scale atmospheric circulation

(IF 3.76; Q1)International audienceWe examine secular changes and multidecadal climate variability on a seasonal scale in northern France over the last 500 years and examine the extent to which they are driven by large‐scale atmospheric variability. Multiscale trend analysis and segmentation procedures show statistically significant increases of winter and spring precipitation amounts in Paris since the end of the 19th century. This changes the seasonal precipitation distribution from one with a pronounced summer peak at the end of the Little Ice Age to an almost uniform distribution in the 20th century. This switch is linked to an early warming trend in winter temperature. Changes in spring precipitation are also correlated with winter precipitation for time scales greater than 50 years, which suggests a seasonal persistence. Hydrological modelling results show similar rising trends in river flow for the Seine at Paris. However, such secular trends in the seasonal climatic conditions over northern France are substantially modulated by irregular multidecadal (50–80 years) fluctuations. Furthermore, since the end of the 19th century, we find an increasing variance in multidecadal hydroclimatic winter and spring, and this coincides with an increase in the multidecadal North Atlantic Oscillation (NAO) variability, suggesting a significant influence of large‐scale atmospheric circulation patterns. However, multidecadal NAO variability has decreased in summer. Using Empirical Orthogonal Function analysis, we detect multidecadal North Atlantic sea‐level pressure anomalies, which are significantly linked to the NAO during the Modern period. In particular, a south‐eastward (south‐westward) shift of the Icelandic Low (Azores High) drives substantial multidecadal changes in spring. Wetter springs are likely to be driven by potential changes in moisture advection from the Atlantic, in response to northward shifts of North Atlantic storm tracks over European regions, linked to periods of positive NAO. Similar, but smaller, changes in rainfall are observed in winter

Adaptive Mutations in the JC Virus Protein Capsid Are Associated with Progressive Multifocal Leukoencephalopathy (PML)

PML is a progressive and mostly fatal demyelinating disease caused by JC virus infection and destruction of infected oligodendrocytes in multiple brain foci of susceptible individuals. While JC virus is highly prevalent in the human population, PML is a rare disease that exclusively afflicts only a small percentage of immunocompromised individuals including those affected by HIV (AIDS) or immunosuppressive drugs. Viral- and/or host-specific factors, and not simply immune status, must be at play to account for the very large discrepancy between viral prevalence and low disease incidence. Here, we show that several amino acids on the surface of the JC virus capsid protein VP1 display accelerated evolution in viral sequences isolated from PML patients but not in sequences isolated from healthy subjects. We provide strong evidence that at least some of these mutations are involved in binding of sialic acid, a known receptor for the JC virus. Using statistical methods of molecular evolution, we performed a comprehensive analysis of JC virus VP1 sequences isolated from 55 PML patients and 253 sequences isolated from the urine of healthy individuals and found that a subset of amino acids found exclusively among PML VP1 sequences is acquired via adaptive evolution. By modeling of the 3-D structure of the JC virus capsid, we showed that these residues are located within the sialic acid binding site, a JC virus receptor for cell infection. Finally, we go on to demonstrate the involvement of some of these sites in receptor binding by demonstrating a profound reduction in hemagglutination properties of viral-like particles made of the VP1 protein carrying these mutations. Collectively, these results suggest that a more virulent PML causing phenotype of JC virus is acquired via adaptive evolution that changes viral specificity for its cellular receptor(s)