Myth-busting the provider-user relationship for digital sequence information.

[EN] BACKGROUND: The United Nations Convention on Biological Diversity (CBD) formally recognized the sovereign rights of nations over their biological diversity. Implicit within the treaty is the idea that mega-biodiverse countries will provide genetic resources and grant access to them and scientists in high-income countries will use these resources and share back benefits. However, little research has been conducted on how this framework is reflected in real-life scientific practice. RESULT: Currently, parties to the CBD are debating whether digital sequence information (DSI) should be regulated under a new benefit-sharing framework. At this critical time point in the upcoming international negotiations, we test the fundamental hypothesis of provision and use of DSI by looking at the global patterns of access and use in scientific publications. CONCLUSION: Our data reject the provider-user relationship and suggest a far more complex information flow for DSI. Therefore, any new policy decisions on DSI should be aware of the high level of use of DSI across low- and middle-income countries and seek to preserve open access to this crucial common good.This publication was made possible by the research project WiLDSI (Wissenschaftliche Lösungsansätze für Digitale Sequenzinformation) funded by the German Federal Ministry of Education and Research (BMBF) under funding code 031B0862

Managing hospital visitor admission during Covid-19: A discrete-event simulation by the data of a German University Hospital

The Corona pandemic and the associated need for visitor restrictions have defined an entirely new management task in hospitals: The hospital visitor management. The admission process of hospital visitors and the implementation of associated infection-prevention strategies such as the delivery of face masks thereby pose major challenges. In this work, we evaluate both implemented and planned admission processes in a German University Hospital based on a discrete-event simulation model and provide distinct recommendations for hospital visitor management with special consideration of digitalization, antigen testing, waiting times, space and staff utilization. We find the extraordinary potential of digitalization with a reduction of visitor waiting and service times of up to 90 percent, the significant burden for personnel and room capacity, in terms of antigen testing, especially, and the need for visitor restrictions in terms of a maximum number of visitors per inpatient

Pulsed electrical stimulation of the human eye enhances retinal vessel reaction to flickering light

Recent studies indicate therapeutic benefits of electrical stimulation in cases of specific ophthalmic diseases that are associated with dysfunctional ocular microcirculation. This suggests effects of electrical stimulation on vascular functions. In the present study, we investigated the effects of electrical stimulation on retinal vessel reactions using dynamic vessel analysis (DVA). Eighty healthy subjects were randomly assigned to one of three groups receiving electrical stimulation with different current intensities: 400 μA (n = 26); 800 μA (n = 27); 1200 μA (n = 27). The electrode montage for electrical stimulation consisted of a ring-shaped active electrode surrounding one eye and a square return electrode at the occiput. Rectangular, monophasic, positive current pulses were applied at 10 Hz for a duration of 60 s per stimulation period. DVA was used to observe the stimulation-induced reactions of retinal vessel diameters in response to different provocations. In three DVA measurements, three stimulus conditions were investigated: flicker light stimulation (FLS); electrical stimulation (ES); simultaneous electrical and flicker light stimulation (ES+FLS). Retinal vasodilation caused by these stimuli was compared using paired t-test. The subjects receiving electrical stimulation with 800 μA showed significantly increased retinal vasodilation for ES+FLS compared to FLS (p < 0.05). No significant differences in retinal vessel reactions were found between ES+FLS and FLS in the 400 and 1200 μA groups. No retinal vasodilation was observed for ES for all investigated current intensities. The results indicate that positive pulsed electrical stimulation of an adequate intensity enhances the flicker light-induced retinal vasodilation

Analysis of Lymphocytic DNA Damage in Early Multiple Sclerosis by Automated Gamma-H2AX and 53BP1 Foci Detection: A Case Control Study

Background In response to DNA double-strand breaks, the histone protein H2AX becomes phosphorylated at its C-terminal serine 139 residue, referred to as γ-H2AX. Formation of γ-H2AX foci is associated with recruitment of p53-binding protein 1 (53BP1), a regulator of the cellular response to DNA double-strand breaks. γ-H2AX expression in peripheral blood mononuclear cells (PBMCs) was recently proposed as a diagnostic and disease activity marker for multiple sclerosis (MS). Objective To evaluate the significance of γ-H2AX and 53BP1 foci in PBMCs as diagnostic and disease activity markers in patients with clinically isolated syndrome (CIS) and early relapsing-remitting MS (RRMS) using automated γ-H2AX and 53BP1 foci detection. Methods Immunocytochemistry was performed on freshly isolated PBMCs of patients with CIS/early RRMS (n = 25) and healthy controls (n = 27) with γ-H2AX and 53BP1 specific antibodies. Nuclear γ-H2AX and 53BP1 foci were determined using a fully automated reading system, assessing the numbers of γ-H2AX and 53BP1 foci per total number of cells and the percentage of cells with foci. Patients underwent contrast enhanced 3 Tesla magnetic resonance imaging (MRI) and clinical examination including expanded disability status scale (EDSS) score. γ-H2AX and 53BP1 were also compared in previously frozen PBMCs of each 10 CIS/early RRMS patients with and without contrast enhancing lesions (CEL) and 10 healthy controls. Results The median (range) number of γ-H2AX (0.04 [0–0.5]) and 53BP1 (0.005 [0–0.2]) foci per cell in freshly isolated PBMCs across all study participants was low and similar to previously reported values of healthy individuals. For both, γ-H2AX and 53BP1, the cellular focus number as well as the percentage of positive cells did not differ between patients with CIS/RRMS and healthy controls. γ-H2AX and 53BP1 levels neither correlated with number nor volume of T2-weighted lesions on MRI, nor with the EDSS. Although γ-H2AX, but not 53BP1, levels were higher in previously frozen PBMCs of patients with than without CEL, γ-H2AX values of both groups overlapped and γ-H2AX did not correlate with the number or volume of CEL. Conclusion γ-H2AX and 53BP1 foci do not seem to be promising diagnostic or disease activity biomarkers in patients with early MS. Lymphocytic DNA double-strand breaks are unlikely to play a major role in the pathophysiology of MS

Natriuretic peptides and integrated risk assessment for cardiovascular disease. an individual-participant-data meta-analysis

BACKGROUND: Guidelines for primary prevention of cardiovascular diseases focus on prediction of coronary heart disease and stroke. We assessed whether or not measurement of N-terminal-pro-B-type natriuretic peptide (NT-proBNP) concentration could enable a more integrated approach than at present by predicting heart failure and enhancing coronary heart disease and stroke risk assessment. METHODS: In this individual-participant-data meta-analysis, we generated and harmonised individual-participant data from relevant prospective studies via both de-novo NT-proBNP concentration measurement of stored samples and collection of data from studies identified through a systematic search of the literature (PubMed, Scientific Citation Index Expanded, and Embase) for articles published up to Sept 4, 2014, using search terms related to natriuretic peptide family members and the primary outcomes, with no language restrictions. We calculated risk ratios and measures of risk discrimination and reclassification across predicted 10 year risk categories (ie, <5%, 5% to <7·5%, and ≥7·5%), adding assessment of NT-proBNP concentration to that of conventional risk factors (ie, age, sex, smoking status, systolic blood pressure, history of diabetes, and total and HDL cholesterol concentrations). Primary outcomes were the combination of coronary heart disease and stroke, and the combination of coronary heart disease, stroke, and heart failure. FINDINGS: We recorded 5500 coronary heart disease, 4002 stroke, and 2212 heart failure outcomes among 95 617 participants without a history of cardiovascular disease in 40 prospective studies. Risk ratios (for a comparison of the top third vs bottom third of NT-proBNP concentrations, adjusted for conventional risk factors) were 1·76 (95% CI 1·56-1·98) for the combination of coronary heart disease and stroke and 2·00 (1·77-2·26) for the combination of coronary heart disease, stroke, and heart failure. Addition of information about NT-proBNP concentration to a model containing conventional risk factors was associated with a C-index increase of 0·012 (0·010-0·014) and a net reclassification improvement of 0·027 (0·019-0·036) for the combination of coronary heart disease and stroke and a C-index increase of 0·019 (0·016-0·022) and a net reclassification improvement of 0·028 (0·019-0·038) for the combination of coronary heart disease, stroke, and heart failure. INTERPRETATION: In people without baseline cardiovascular disease, NT-proBNP concentration assessment strongly predicted first-onset heart failure and augmented coronary heart disease and stroke prediction, suggesting that NT-proBNP concentration assessment could be used to integrate heart failure into cardiovascular disease primary prevention

Phase I/II intra-patient dose escalation study of vorinostat in children with relapsed solid tumor, lymphoma, or leukemia

Background: Until today, adult and pediatric clinical trials investigating single-agent or combinatorial HDAC inhibitors including vorinostat in solid tumors have largely failed to demonstrate efficacy. These results may in part be explained by data from preclinical models showing significant activity only at higher concentrations compared to those achieved with current dosing regimens. In the current pediatric trial, we applied an intra-patient dose escalation design. The purpose of this trial was to determine a safe dose recommendation (SDR) of single-agent vorinostat for intra-patient dose escalation, pharmacokinetic analyses (PK), and activity evaluation in children (3-18 years) with relapsed or therapy-refractory malignancies. Results: A phase I intra-patient dose (de)escalation was performed until individual maximum tolerated dose (MTD). The starting dose was 180 mg/m(2)/day with weekly dose escalations of 50 mg/m(2) until DLT/maximum dose. After MTD determination, patients seamlessly continued in phase II with disease assessments every 3 months. PK and plasma cytokine profiles were determined. Fifty of 52 patients received treatment. n = 27/50 (54%) completed the intra-patient (de)escalation and entered phase II. An SDR of 130 mg/m(2)/day was determined (maximum, 580 mg/m(2)/day). n = 46/50 (92%) patients experienced treatment-related AEs which were mostly reversible and included thrombocytopenia, fatigue, nausea, diarrhea, anemia, and vomiting. n = 6/50 (12%) had treatment-related SAEs. No treatment-related deaths occurred. Higher dose levels resulted in higher C-max. Five patients achieved prolonged disease control (> 12 months) and showed a higher C-max (> 270 ng/mL) and MTDs. Best overall response (combining PR and SD, no CR observed) rate in phase II was 6/27 (22%) with a median PFS and OS of 5.3 and 22.4 months. Low levels of baseline cytokine expression were significantly correlated with favorable outcome. Conclusion: An SDR of 130 mg/m(2)/day for individual dose escalation was determined. Higher drug exposure was associated with responses and long-term disease stabilization with manageable toxicity. Patients with low expression of plasma cytokine levels at baseline were able to tolerate higher doses of vorinostat and benefited from treatment. Baseline cytokine profile is a promising potential predictive biomarker