Determinants of career development in cardiology – results from a Swiss national survey

BACKGROUND: Despite the rising proportion of female medical students and specialised female doctors in Switzerland, the field of cardiology remains one of the most male-dominated. OBJECTIVES: The goal of this study was to identify determinants of and obstacles to career development for cardiologists with special regard to an academic and interventional career. METHODS: Under the direction of the Swiss working group Women in Cardiology (IG-WIC), an online survey was conducted among Swiss cardiologists and cardiologists in training. RESULTS: 140 participants (43.6% female, 56.4% male; median age 45.0) were included. Women were more often single (27.9% vs 10.1%, p = 0.013) and less likely to have children (52.5% vs 70.9%, p = 0.034). If they had children, they were more likely to provide childcare themselves (37.5% vs 10.7%, p = 0.006) or to have interrupted their work in favour of parenting (40.6% vs 8.9%, p <0.001). A majority of women indicated a negative impact of their gender on their career development (78.7%), and 36.3% reported sexual harassment at their workplace. Women felt less supported in their professional training, especially concerning research activities. As a hindrance for pursuit of a career in academic medicine, both sexes stated lack of compatibility of work and family (44.6%) and the competitive work environment (55.4%) being most important. Women also identified gender-specific disadvantages as one of the main reasons for not choosing an academic or interventional career. CONCLUSIONS: The overall satisfaction among Swiss cardiologists is high regarding training in health care and the working atmosphere. However, women and men plead for better compatibility of work and family and better structured training curricula. Several gender-specific aspects hindering women from advancing in cardiology training should be addressed

Unmet needs in pneumonia research: a comprehensive approach by the CAPNETZ study group

INTRODUCTION: Despite improvements in medical science and public health, mortality of community-acquired pneumonia (CAP) has barely changed throughout the last 15 years. The current SARS-CoV-2 pandemic has once again highlighted the central importance of acute respiratory infections to human health. The “network of excellence on Community Acquired Pneumonia” (CAPNETZ) hosts the most comprehensive CAP database worldwide including more than 12,000 patients. CAPNETZ connects physicians, microbiologists, virologists, epidemiologists, and computer scientists throughout Europe. Our aim was to summarize the current situation in CAP research and identify the most pressing unmet needs in CAP research. METHODS: To identify areas of future CAP research, CAPNETZ followed a multiple-step procedure. First, research members of CAPNETZ were individually asked to identify unmet needs. Second, the top 100 experts in the field of CAP research were asked for their insights about the unmet needs in CAP (Delphi approach). Third, internal and external experts discussed unmet needs in CAP at a scientific retreat. RESULTS: Eleven topics for future CAP research were identified: detection of causative pathogens, next generation sequencing for antimicrobial treatment guidance, imaging diagnostics, biomarkers, risk stratification, antiviral and antibiotic treatment, adjunctive therapy, vaccines and prevention, systemic and local immune response, comorbidities, and long-term cardio-vascular complications. CONCLUSION: Pneumonia is a complex disease where the interplay between pathogens, immune system and comorbidities not only impose an immediate risk of mortality but also affect the patients’ risk of developing comorbidities as well as mortality for up to a decade after pneumonia has resolved. Our review of unmet needs in CAP research has shown that there are still major shortcomings in our knowledge of CAP

VoiceS: voice quality after transoral CO2 laser surgery versus single vocal cord irradiation for unilateral stage 0 and I glottic larynx cancer-a randomized phase III trial [study protocol].

BACKGROUND Surgery and radiotherapy are well-established standards of care for unilateral stage 0 and I early-stage glottic cancer (ESGC). Based on comparative studies and meta-analyses, functional and oncological outcomes after both treatment modalities are similar. Historically, radiotherapy (RT) has been performed by irradiation of the whole larynx. However, only the involved vocal cord is being treated with recently introduced hypofractionated concepts that result in 8 to 10-fold smaller target volumes. Retrospective data argues for an improvement in voice quality with non-inferior local control. Based on these findings, single vocal cord irradiation (SVCI) has been implemented as a routine approach in some institutions for ESGC in recent years. However, prospective data directly comparing SVCI with surgery is lacking. The aim of VoiceS is to fill this gap. METHODS In this prospective randomized multi-center open-label phase III study with a superiority design, 34 patients with histopathologically confirmed, untreated, unilateral stage 0-I ESGC (unilateral cTis or cT1a) will be randomized to SVCI or transoral CO2-laser microsurgical cordectomy (TLM). Average difference in voice quality, measured by using the voice handicap index (VHI) will be modeled over four time points (6, 12, 18, and 24 months). Primary endpoint of this study will be the patient-reported subjective voice quality between 6 to 24 months after randomization. Secondary endpoints will include perceptual impression of the voice via roughness - breathiness - hoarseness (RBH) assessment at the above-mentioned time points. Additionally, quantitative characteristics of voice, loco-regional tumor control at 2 and 5 years, and treatment toxicity at 2 and 5 years based on CTCAE v.5.0 will be reported. DISCUSSION To our knowledge, VoiceS is the first randomized phase III trial comparing SVCI with TLM. Results of this study may lead to improved decision-making in the treatment of ESGC. TRIAL REGISTRATION ClinicalTrials.gov NCT04057209. Registered on 15 August 2019. Cantonal Ethics Committee KEK-BE 2019-01506

Reference point insensitive molecular data analysis

Motivation: In biomedicine, every molecular measurement is relative to a reference point, like a fixed aliquot of RNA extracted from a tissue, a defined number of blood cells, or a defined volume of biofluid. Reference points are often chosen for practical reasons. For example, we might want to assess the metabolome of a diseased organ but can only measure metabolites in blood or urine. In this case, the observable data only indirectly reflects the disease state. The statistical implications of these discrepancies in reference points have not yet been discussed. Results: Here, we show that reference point discrepancies compromise the performance of regression models like the LASSO. As an alternative, we suggest zero-sum regression for a reference point insensitive analysis. We show that zero-sum regression is superior to the LASSO in case of a poor choice of reference point both in simulations and in an application that integrates intestinal microbiome analysis with metabolomics. Moreover, we describe a novel coordinate descent based algorithm to fit zero-sum elastic nets

D-2-hydroxyglutarate interferes with HIF-1α stability skewing T-cell metabolism towards oxidative phosphorylation and impairing Th17 polarization

D-2-hydroxyglutarate (D-2HG) is released by various types of malignant cells including acute myeloid leukemia (AML) blasts carrying isocitrate dehydrogenase (IDH) gain-of-function mutations. D-2HG acting as an oncometabolite promotes proliferation, anoikis, and differentiation block of hematopoietic cells in an autocrine fashion. However, prognostic impact of IDH mutations and high D-2HG levels remains controversial and might depend on the overall mutational context. An increasing number of studies focus on the permissive environment created by AML blasts to promote immune evasion. Impact of D-2HG on immune cells remains incompletely understood. Here, we sought out to investigate the effects of D-2HG on T-cells as key mediators of anti-AML immunity. D-2HG was efficiently taken up by T-cells in vitro, which is in line with high 2-HG levels measured in T-cells isolated from AML patients carrying IDH mutations. T-cell activation was slightly impacted by D-2HG. However, D-2HG triggered HIF-1a protein destabilization resulting in metabolic skewing towards oxidative phosphorylation, increased regulatory T-cell (Treg) frequency, and reduced T helper 17 (Th17) polarization. Our data suggest for the first time that D-2HG might contribute to fine tuning of immune responses

Glutamine synthetase expression rescues human dendritic cell survival in a glutamine-deprived environment

Introduction: Glutamine deficiency is a well-known feature of the tumor environment. Here we analyzed the impact of glutamine deprivation on human myeloid cell survival and function. Methods: Different types of myeloid cells were cultured in the absence or presence of glutamine and/or with L-methionine-S-sulfoximine (MSO), an irreversible glutamine synthetase (GS) inhibitor. GS expression was analyzed on mRNA and protein level. GS activity and the conversion of glutamate to glutamine by myeloid cells was followed by 13C tracing analyses. Results: The absence of extracellular glutamine only slightly affected postmitotic human monocyte to dendritic cell (DC) differentiation, function and survival. Similar results were obtained for monocyte-derived macrophages. In contrast, proliferation of the monocytic leukemia cell line THP-1 was significantly suppressed. While macrophages exhibited high constitutive GS expression, glutamine deprivation induced GS in DC and THP-1. Accordingly, proliferation of THP-1 was rescued by addition of the GS substrate glutamate and 13C tracing analyses revealed conversion of glutamate to glutamine. Supplementation with the GS inhibitor MSO reduced the survival of DC and macrophages and counteracted the proliferation rescue of THP-1 by glutamate. Discussion: Our results show that GS supports myeloid cell survival in a glutamine poor environment. Notably, in addition to suppressing proliferation and survival of tumor cells, the blockade of GS also targets immune cells such as DCs and macrophages

Distributed Acoustic Sensing in Volcano-Glacial Environments - Mount Meager, British Columbia

We demonstrate the logistic feasibility and scientific potential of distributed acoustic sensing (DAS) in alpine volcano-glacial environments that are subject to a broad range of natural hazards. Our work considers the Mount Meager massif, an active volcanic complex in British Columbia, estimated to have the largest geothermal potential in Canada, and home of Canada's largest recorded landslide in 2010. From September to October 2019, we acquired continuous strain data, using a 3-km long fiber-optic cable, deployed on a ridge of Mount Meager and on the uppermost part of a glacier above 2,000 m altitude. The data analysis detected a broad range of unexpectedly intense, low-magnitude, local seismicity. The most prominent events include long-lasting, intermediate-frequency (0.01–1 Hz) tremor, and high-frequency (5–45 Hz) earthquakes that form distinct spatial clusters and often repeat with nearly identical waveforms. We conservatively estimate that the number of detectable high-frequency events varied between several tens and nearly 400 per day. We also develop a beamforming algorithm that uses the signal-to-noise ratio (SNR) of individual channels, and implicitly takes the direction-dependent sensitivity of DAS into account. Both the tremor and the high-frequency earthquakes are most likely related to fluid movement within Mount Meager's geothermal reservoir. Our work illustrates that DAS carries the potential to reveal previously undiscovered seismicity in challenging environments, where comparably dense arrays of conventional seismometers are difficult to install. We hope that the logistics and deployment details provided here may serve as a starting point for future DAS experiments.ISSN:2169-9313ISSN:0148-0227ISSN:2169-935