First-in-Human Proof-of-Concept Study: Intralesional Administration of BQ788, an Endothelin Receptor B Antagonist, to Melanoma Skin Metastases.

BACKGROUND: This first-in-human proof-of-concept study aimed to check whether safety and preclinical results obtained by intratumoral administration of BQ788, an endothelin receptor B (EDNRB) antagonist, can be repeated in human melanoma patients. METHODS: Three patients received a single intralesional BQ788 application of 3 mg. After 3-7 days, the lesions were measured and removed for analysis. The administered dose was increased to a cumulative dosage of 8 mg in patient 4 (4 × 2.0 mg, days 0-3; lesion removed on day 4) and to 10 mg in patient 5 (3 × 3.3 mg, days 0, 3, and 10; lesion removed after 14 days). Control lesions were simultaneously treated with phosphate-buffered saline (PBS). All samples were processed and analyzed without knowledge of the clinical findings. RESULTS: No statistical evaluation was possible because of the number of patients (n = 5) and the variability in the mode of administration. No adverse events were observed, regardless of administered dose. All observations were in accordance with results obtained in preclinical studies. Accordingly, no difference in degree of tumor necrosis was detected between BQ788- and PBS-treated samples. In addition, both EDNRB and Ki67 showed decreased expression in patients 2 and 5 and, to a lesser extent, in patient 1. Similarly, decreased expression of EDNRB mRNA in patients 2 and 5 and of BCL2A1 and/or PARP3 in patients 2, 3, and 5 was found. Importantly, semiquantitatively scored immunohistochemistry for CD31 and CD3 revealed more blood vessels and lymphocytes, respectively, in BQ788-treated tumors of patients 2 and 4. Also, in all patients, we observed inverse correlation in expression levels between EDNRB and HIF1A. Finally, in patient 5 (the only patient treated for longer than 1 week), we observed inhibition in lesion growth, as shown by size measurement. CONCLUSION: The intralesional applications of BQ788 were well tolerated and showed signs of directly and indirectly reducing the viability of melanoma cells.

The Health Valley: Global Entrepreneurial Dynamics.

In the space of a decade, the Lake Geneva region has become the Health Valley, a world-class laboratory for discovering and developing healthcare of the future. Through visionary individuals and thanks to exceptional infrastructure this region has become one of the most dynamic in the field of innovation, including leading scientific research and exceptional actors for the commercialization of academic innovation to industrial applications that will improve the lives of patients and their families. Here follows the chronicle of a spectacular expansion into the Health Valley.

The major worldwide stress of healthcare professionals during the first wave of the COVID-19 pandemic - the international COVISTRESS survey.

INTRODUCTION: The COVID-19 pandemic has initiated an upheaval in society and has been the cause of considerable stress during this period. Healthcare professionals have been on the front line during this health crisis, particularly paramedical staff. The aim of this study was to assess the high level of stress of healthcare workers during the first wave of the pandemic. MATERIALS AND METHODS: The COVISTRESS international study is a questionnaire disseminated online collecting demographic and stress-related data over the globe, during the pandemic. Stress levels were evaluated using non-calibrated visual analog scale, from 0 (no stress) to 100 (maximal stress). RESULTS: Among the 13,537 individuals from 44 countries who completed the survey from January to June 2020, we included 10,051 workers (including 1379 healthcare workers, 631 medical doctors and 748 paramedical staff). The stress levels during the first wave of the pandemic were 57.8 ± 33 in the whole cohort, 65.3 ± 29.1 in medical doctors, and 73.6 ± 27.7 in paramedical staff. Healthcare professionals and especially paramedical staff had the highest levels of stress (p < 0.001 vs non-healthcare workers). Across all occupational categories, women had systematically significantly higher levels of work-related stress than men (p < 0.001). There was a negative correlation between age and stress level (r = -0.098, p < 0.001). Healthcare professionals demonstrated an increased risk of very-high stress levels (>80) compared to other workers (OR = 2.13, 95% CI 1.87-2.41). Paramedical staff risk for very-high levels of stress was higher than doctors' (1.88, 1.50-2.34). The risk of high levels of stress also increased in women (1.83, 1.61-2.09; p < 0.001 vs. men) and in people aged <50 (1.45, 1.26-1.66; p < 0.001 vs. aged >50). CONCLUSIONS: The first wave of the pandemic was a major stressful event for healthcare workers, especially paramedical staff. Among individuals, women were the most at risk while age was a protective factor.

Time and Covid-19 stress in the lockdown situation: Time free, «Dying¼ of boredom and sadness.

A lockdown of people has been used as an efficient public health measure to fight against the exponential spread of the coronavirus disease (Covid-19) and allows the health system to manage the number of patients. The aim of this study (clinicaltrials.gov NCT00430818) was to evaluate the impact of both perceived stress aroused by Covid-19 and of emotions triggered by the lockdown situation on the individual experience of time. A large sample of the French population responded to a survey on their experience of the passage of time during the lockdown compared to before the lockdown. The perceived stress resulting from Covid-19 and stress at work and home were also assessed, as were the emotions felt. The results showed that people have experienced a slowing down of time during the lockdown. This time experience was not explained by the levels of perceived stress or anxiety, although these were considerable, but rather by the increase in boredom and sadness felt in the lockdown situation. The increased anger and fear of death only explained a small part of variance in the time judgment. The conscious experience of time therefore reflected the psychological difficulties experienced during lockdown and was not related to their perceived level of stress or anxiety.