Venous Leak Embolization in Patients with Venogenic Erectile Dysfunction via Deep Dorsal Penile Vein Access: Safety and Early Efficacy.

PURPOSE: This all-comers registry aimed to assess safety and early efficacy of venous embolization in patients with venogenic erectile dysfunction due to venous leak in an unselected cohort. METHODS: Between October 2019 and September 2022, patients with venogenic erectile dysfunction resistant to phosphodiesterase-5-inhibitors were treated with venous embolization using ultrasound-guided anterograde access via a deep dorsal penile vein in a single center. A mix of ethiodized oil and modified cyanoacrylate-based glue n-butyl 2 cyanoacrylate (NBCA) monomer plus methacryloxy-sulpholane monomer (Glubran-2, GEM, Italy) was used as liquid embolic agent. Prior to embolization, venous leak had been verified based on penile duplex sonography and computed tomography cavernosography. Procedural success was defined as technically successful and complete target vein embolization. The primary safety outcome measure was any major adverse event 6 weeks after the procedure. The primary feasibility outcome measure was IIEF-15 (International Index of Erectile Function-15) score improvement ≥ 4 points in ≥ 50% of subjects on 6 weeks follow-up post intervention. RESULTS: Fifty consecutive patients (mean age 61.8 ± 10.0 years) with severe erectile dysfunction due to venous leak underwent venous embolization. Procedural success was achieved in 49/50 (98%) of patients with no major adverse events on follow-up. The primary feasibility outcome measure at 6 weeks was reached by 34/50 (68%) of patients. CONCLUSION: Venous leak embolization via deep dorsal penile vein access using a liquid embolic agent was safe for all and efficacious in the majority of patients with severe venogenic erectile dysfunction on 6 weeks follow-up.

Sampling designs for rare time-dependent exposures: a comparison of the nested exposure case-control design and exposure density sampling.

In extensive cohort studies, the ascertainment of covariate information on all individuals can be challenging. In hospital epidemiology, an additional issue is often the time-dependency of the exposure of interest. We revisit and compare two sampling designs constructed for rare time-dependent exposures and possibly common outcomes - the nested exposure case-control design and exposure density sampling. Both designs enable efficient hazard ratio estimation by sampling all exposed individuals but only a small fraction of the unexposed ones. Moreover, they account for time-dependent exposure to avoid immortal time bias. We evaluate and compare their performance using data of patients hospitalised in the neuro-intensive care unit at the Burdenko Neurosurgery Institute in Moscow, Russia. Three different types of hospital-acquired infections with different prevalence are considered. Additionally, inflation factors, a primary performance measure, are discussed. We enhance both designs to allow for a competitive analysis of combined and competing endpoints compared to the full cohort approach while substantially reducing the amount of necessary information. Nonetheless, exposure density sampling outperforms the nested exposure case-control design concerning efficiency and accuracy in most considered settings.

Mesoporous bioactive glass composition effects on degradation and bioactivity.

Mesoporous bioactive glasses (MBGs) are promising materials for regenerative medicine, due to their favorable properties including bioactivity and degradability. These key properties, but also their surface area, pore structure and pore volume are strongly dependent on synthesis parameters and glass stoichiometry. However, to date no systematic study on MBG properties covering a broad range of possible compositions exists. Here, 24 MBG compositions in the SiO2-CaO-P2O5 system were synthesized by varying SiO2 (60-90 mol %), CaO and P2O5 content (both 0 to 40 mol-%), while other synthesis parameters were kept constant. Mesopore characteristics, degradability and bioactivity were analysed. The results showed that, within the tested range of compositions, mesopore formation required a molar SiO2 content above 60% but was independent of CaO and P2O5 content. While mesopore size did not depend on glass stoichiometry, mesopore arrangement was influenced by the SiO2 content. Specific surface area and pore volume were slightly altered by the SiO2 content. All materials were degradable; however, degradation as well as bioactivity, i.e. the ability to form a CaP mineral on the surface, depended on stoichiometry. Major differences were found in early surface reactions in simulated body fluid: where some MBGs induced direct hydroxyapatite crystallization, high release of calcium in others resulted in calcite formation. In summary, degradation and bioactivity, both key parameters of MBGs, can be controlled by glass stoichiometry over a broad range while leaving the unique structural parameters of MBGs relatively unaffected. This allows targeted selection of material compositions for specific regenerative medicine applications.

Impact of investigator initiated trials and industry sponsored trials on medical practice (IMPACT): rationale and study design.

BACKGROUND: The German Research Foundation (DFG) and the Federal Ministry of Education and Research (BMBF) initiated large research programs to foster high quality clinical research in the academic area. These investigator initiated trials (IITs) cover important areas of medical research and often go beyond the scope of industry sponsored trials (ISTs). The purpose of this project was to understand to what extent results of randomized controlled IITs and ISTs have an impact on medical practice, measured by their availability for decisions in healthcare and their implementation in clinical practice. We aimed to determine study characteristics influencing a trial's impact such as type of sponsor and place of conduct. In this article, we describe the rationale and design of this project and present the characteristics of the trials included in our study cohort. METHODS: The research impact of the following sub-cohorts was compared: German IITs (funded by DFG and BMBF or by other German non-commercial organizations), international IITs (without German contribution), German ISTs, and international ISTs. Trials included were drawn from the DFG-/BMBF-Websites, the German Clinical Trials Register, and from ClinicalTrials.gov . Research impact was measured as follows: 1) proportion of published trials, 2) time to publication, 3) proportion of publications appropriately indexed in biomedical databases, 4) proportion of openly accessible publications, 5) broadness of publication's target group, 6) citation of publications by systematic reviews or meta-analyses, and 7) appearance of publications or citing systematic reviews or meta-analyses in clinical practice guidelines. We also aimed to identify study characteristics associated with the impact of trials. RESULTS: We included 691 trials: 120 German IITs, 200 International IITs, 171 German ISTs and 200 International ISTs. The median number of participants was 150, 30% were international trials and 70% national trials, 48% drug-trials and 52% non-drug trials. Overall, 72% of the trials had one pre-defined primary endpoint, 28% two or more (max. 36). CONCLUSIONS: The results of this project deepen our understanding of the impact of biomedical research on clinical practice and healthcare policy, add important insights for the efficient allocation of scarce research resources and may facilitate providing accountability to the different stakeholders involved.

Understanding the global hydrological droughts of 2003-2016 and their relationships with teleconnections.

Droughts often evolve gradually and cover large areas, and therefore, affect many people and activities. This motivates developing techniques to integrate different satellite observations, to cover large areas, and understand spatial and temporal variability of droughts. In this study, we apply probabilistic techniques to generate satellite derived meteorological, hydrological, and hydro-meteorological drought indices for the world's 156 major river basins covering 2003-2016. The data includes Terrestrial Water Storage (TWS) estimates from the Gravity Recovery And Climate Experiment (GRACE) mission, along with soil moisture, precipitation, and evapotranspiration reanalysis. Different drought characteristics of trends, occurrences, areal-extent, and frequencies corresponding to 3-, 6-, 12-, and 24-month timescales are extracted from these indices. Drought evolution within selected basins of Africa, America, and Asia is interpreted. Canonical Correlation Analysis (CCA) is then applied to find the relationship between global hydro-meteorological droughts and satellite derived Sea Surface Temperature (SST) changes. This relationship is then used to extract regions, where droughts and teleconnections are strongly interrelated. Our numerical results indicate that the 3- to 6-month hydrological droughts occur more frequently than the other timescales. Longer memory of water storage changes (than water fluxes) has found to be the reason of detecting extended hydrological droughts in regions such as the Middle East and Northern Africa. Through CCA, we show that the El Niño Southern Oscillation (ENSO) has major impact on the magnitude and evolution of hydrological droughts in regions such as the northern parts of Asia and most parts of the Australian continent between 2006 and 2011, as well as droughts in the Amazon basin, South Asia, and North Africa between 2010 and 2012. The Indian ocean Dipole (IOD) and North Atlantic Oscillation (NAO) are found to have regional influence on the evolution of hydrological droughts.

Discovery of a novel thermostable Zn2+ -dependent alcohol dehydrogenase from Chloroflexus aurantiacus through conserved domains mining.

AIMS: The purpose of the study was to demonstrate feasibility of the Conserved Domains Database (CDD) for identification of novel biocatalysts with desirable properties from a class of well-characterized biocatalysts. METHODS AND RESULTS: The thermostable ADH from Sulfolobus solfataricus with a broad substrate range was applied as a template for the search for novel thermostable ADHs via CDD. From the resulting hits, a putative ADH gene from the thermophilic organism Chloroflexus aurantiacus was cloned and expressed in Escherichia coli. The resulting enzyme was purified and characterized. With a temperature activity optimum of 70°C and a broad substrate spectrum especially for diketones, a versatile new biocatalyst was obtained. CONCLUSIONS: Database-based mining in CDD is a suitable approach to obtain novel biocatalysts with desirable properties. Thereby, the available diversity of similar but not equal enzymes within this class can be increased. SIGNIFICANCE AND IMPACT OF THE STUDY: For industrial applications, there is a demand for larger diversity of similar well-characterized enzymes in order to test them for a given process (biodiversity screening). For fundamental science, the comparison of enzymes with similar function but different sequence can provide insight into structure function relationships or the evolution of enzymes. This study gives a good example on how this demand can be efficiently met.

Strontium-modified premixed calcium phosphate cements for the therapy of osteoporotic bone defects.

In this study a premixed strontium-containing calcium phosphate bone cement for the application in osteoporotic bone defects has been developed and characterised regarding its material and in vitro properties as well as minimally invasive applicability in balloon kyphoplasty. Strontium was introduced into the cement by substitution of one precursor component, CaCO3, with its strontium analogue, SrCO3. Using a biocompatible oil phase as carrier liquid, a cement paste that only set upon contact with aqueous environment was obtained. Strontium modification resulted in an increased strength of set cements and radiographic contrast; and the cements released biologically relevant doses of Sr2+-ions that were shown to enhance osteoprogenitor cell proliferation and osteogenic differentiation. Finally, applicability of strontium-containing cement pastes in balloon kyphoplasty was demonstrated in a human cadaver spine procedure. The cement developed in this study may therefore be well suited for minimally invasive, osteoporosis-related bone defect treatment. STATEMENT OF SIGNIFICANCE: Strontium-releasing calcium phosphate bone cements are promising materials for the clinical regeneration of osteoporosis-related bone defects since they have been shown to stimulate bone formation and at the same time limit osteoclastic bone resorption. Today clinical practice favours minimally invasive surgical techniques, e.g. for vertebral fracture treatment, posing special demands on such cements. We have therefore developed a premixed, strontium-releasing bone cement with enhanced mechanical properties and high radiographic visibility that releases biologically relevant strontium concentrations and thus stimulates cells of the osteogenic lineage. In a pilot experiment we also exemplify its excellent suitability for minimally invasive balloon kyphoplasty procedures.

Neurosteroidogenesis and progesterone anti-inflammatory/neuroprotective effects.

Progesterone shows anti-inflammatory and promyelinating effects in mice with experimental autoimmune encephalomyelitis (EAE), a commonly used model for multiple sclerosis (MS). Because neurosteroids have been implicated as protective factors for MS and EAE, we analysed the expression of neurosteroidogenic enzymes in the compromised spinal cord of EAE mice. EAE was induced in female C57Bl6 mice, which were then killed on day 16 after induction. Progesterone was given by pellet implantation 1 week before EAE induction. Untreated EAE mice showed decreased mRNAs for the steroidogenic acute regulatory protein (Star), voltage-dependent anion channel (VDAC), cholesterol side-chain cleavage (P450scc), 5α-reductase, 3α-hydroxysteroid dehydrogenase (3α-HSOR) and aromatase, whereas changes of 3ß-hydroxysteroid dehydrogenase (3ß-HSD) were not significant. mRNA translocator protein (18 kDa) (TSPO) was elevated, concomitantly with a reactive microgliosis. EAE mice also showed abnormal mitochondrial ultrastructure in axons and neuronal bodies, as well as reduced expression of fission and fusion protein mRNAs. Progesterone pretreatment before EAE induction increased Star, VDAC, P450scc, 5α-reductase type I, 3α-HSOR and aromatase mRNAs and did not modify 3ß-HSD. TSPO mRNA was decreased, possibly as a result of reversal of microgliosis. Progesterone pretreatment also improved mitochondrial ultrastructure and increased fission/fusion protein mRNAs. These mitochondrial effects may be part of the progesterone recovery of neurosteroidogenesis. The enzymes 3ß-HSD, 3α-HSOR and 5α-reductase are also responsible for the formation of androgens. Because MS patients and EAE rodents show changes of central androgen levels, it is likely that, together with progestins and oestrogens, neuroandrogens afford neuroprotection for EAE and MS. The data reviewed suggest that enhanced synthesis of neurosteroids contributes in an auto/paracrine manner to reinforce the neuroprotective and anti-inflammatory effects of exogenous progesterone given to EAE mice.

Sex differences in brain mitochondrial metabolism: influence of endogenous steroids and stroke.

Steroids are neuroprotective and a growing body of evidence indicates that mitochondria are a potential target of their effects. The mitochondria are the site of cellular energy synthesis, regulate oxidative stress and play a key role in cell death after brain injury and neurodegenerative diseases. After providing a summary of the literature on the general functions of mitochondria and the effects of sex steroid administrations on mitochondrial metabolism, we summarise and discuss our recent findings concerning sex differences in brain mitochondrial function under physiological and pathological conditions. To analyse the influence of endogenous sex steroids, the oxidative phosphorylation system, mitochondrial oxidative stress and brain steroid levels were compared between male and female mice, either intact or gonadectomised. The results obtained show that females have higher a mitochondrial respiration and lower oxidative stress compared to males and also that these differences were suppressed by ovariectomy but not orchidectomy. We have also shown that the decrease in brain mitochondrial respiration induced by ischaemia/reperfusion is different according to sex. In both sexes, treatment with progesterone reduced the ischaemia/reperfusion-induced mitochondrial alterations. Our findings indicate sex differences in brain mitochondrial function under physiological conditions, as well as after stroke, and identify mitochondria as a target of the neuroprotective properties of progesterone. Thus, it is necessary to investigate sex specificity in brain physiopathological mechanisms, especially when mitochondria impairment is involved.

Student outbreak response teams: lessons learned from a decade of collaboration.

OBJECTIVES: Student response teams within colleges of public health effectively address important concerns for two stakeholders. For universities, students learn the fundamentals of field epidemiology and provide popular training and networking opportunities. For health departments, students serve as surge capacity as trained workforce available during outbreak investigations and potentially for routine tasks. STUDY DESIGN: This paper describes the interaction between a student response team and several health departments utilizing specific examples to demonstrate the various roles and activities students can fulfill. Lessons learned from both University team leaders and the various health departments are also included. METHODS: The program evolved over time, beginning with a needs assessment of local health departments and a determination of student training needs, collection, and confidential transmission of data, and interviewing techniques. Over the last decade students have worked on outbreak investigations, case-control studies, program evaluations, and in-field responses. RESULTS: Since 2005, over 200 public health graduate students have contributed more than 1800 h investigating 62 separate disease outbreaks in Arizona. In addition, over the past four years students also worked an additional 2500 h to assist county health departments in routine enteric investigations, specifically for Campylobacter and Salmonella. Best practices and lessons learned found that communication, preplanning and a willingness to collaborate increased the learning opportunities for students and ability for health departments to increase their capacity both during an emergency and for routine work. CONCLUSIONS: Establishment of a student response team (1) trains students in field experiences; (2) creates trained surge capacity for health departments; (3) increases collaboration between schools of public health and state/local health departments; (4) establishes a way to share funding with a local health department; and (5) increases the number of students being placed in health departments for projects, internships, and jobs following graduation.

Landmark prediction of nosocomial infection risk to disentangle short- and long-stay patients.

Length of stay is one of the key determinants for the risk of nosocomial infections. The distribution of this at-risk time is heavily skewed and depends on discharge or death. This study applied landmark competing risk prediction models to account for a large proportion of short-stay patients and a small proportion of long-stay patients.

Calcium phosphate bone cement/mesoporous bioactive glass composites for controlled growth factor delivery.

Calcium phosphate (CaP) bone cements are widely used for the treatment of bone defects and have been proposed to serve as a delivery platform for therapeutic drugs, proteins and growth factors into the defect region. However, they lack sufficient porosity to allow immediate bone ingrowth and thus foster rapid integration into the bone tissue. In this study we investigated a composite prepared from a hydroxyapatite forming bone cement and mesoporous bioactive glass (MBG) granules as a potential carrier for biologically active proteins. The mechanical properties of the composite were not compromised by up to 10 wt% MBG granule addition, which can be attributed to the strong interface between the cement matrix and MBG particles, however this modification induced a significant increase in porosity within 3 weeks ageing in an aqueous liquid. The release profiles of two proteins, lysozyme and the vascular endothelial growth factor (VEGF), could be controlled when they were loaded onto MBG granules that were subsequently embedded into the cement when compared to direct loading into the cement precursor. Both proteins were also demonstrated to maintain their biologic activity during embedding and release from the composite. These findings suggest the CaP bone cement/MBG composite developed in this study as a potential delivery platform for growth factors or other bioactive substances.

Relevance of osteoclast-specific enzyme activities in cell-based in vitro resorption assays.

Cell-based in vitro resorption assays are an important tool to simulate the in vivo biodegradation of resorbable bone graft materials and to predict their clinical performance. The present study analyses the activity of osteoclast-specific enzymes as potential surrogate measures for classical pit assay, which is not applicable on irregular structured materials. Osteoclasts derived from human peripheral blood mononuclear cells were cultivated on different surfaces: calcium phosphate bone cements (CPC), dentin discs, osteoblast-derived extracellular matrix (ECM) and tissue culture polystyrene as control. Pit formation on the resorbable materials was investigated and correlated with the activity of tartrate resistant acid phosphatase (TRAP), carbonic anhydrase II (CAII) and cathepsin K (CTSK). Furthermore, the relation between intra- and extracellular enzyme activities was examined for TRAP and CTSK during resorption of the different materials. Resorbed area of CPC correlated with intracellular TRAP activity and intracellular CAII activity. Highest resorption was detected at around pH 7.2. Resorbed area on dentin correlated with the extracellular CTSK activity and extracellular TRAP activity and was maximal at around pH 6.8. Osteoclasts cultivated on cell-derived mineralised ECM showed a good correlation between both extracellular TRAP and CTSK activity and the release of calcium ions. Based on these data a different regulation of TRAP and CTSK secretion is hypothesised for the resorption of inorganic calcium phosphate compared to the resorption of collagenous mineralised matrix.

[Development of Endothelial Cell Density after Penetrating Keratoplasty in Patients with Fuchs Dystrophy or Keratoconus - Comparison of Excimer Laser and Mechanical Trephination]. / Entwicklung der Endothelzelldichte nach perforierender Keratoplastik bei Patienten mit Fuchs-Dystrophie oder Keratokonus ­ Vergleich von Excimer-Laser- und mechanischer Trepanation.

Purpose The aim of this retrospective study was to compare the development of endothelial cell density (ECD) after penetrating keratoplasty (PKP) in patients with Fuchs dystrophy (FD), keratoconus (KC) or "other diagnoses" (OD), depending on the type of trephination. Patients and Methods In 104 eyes with Fuchs dystrophy, keratoconus or "other diagnoses", the ECD after PKP using either excimer laser (EXC) or mechanical trephination (MECH) was registered after 1.5, 6, 12, 18 and 24 months. With linear and exponential regression models, the endothelial cell loss (ECL) was determined as absolute and percentage cell loss per year. Results For the entire group of patients, ECD was significantly higher after EXC-PKP during the full range of follow-up (except 6 months). With a linear regression model, there was no significant difference in the absolute ECL per year (p = 0.084), but with an exponential regression model, there was a significant difference in the percentage ECL per year (p = 0.021) in favour of EXC trephination. For keratoconus (n = 33), except for the 24-month-follow-up (p = 0.035), ECD was not significantly different on the basis of EXC vs. MECH. With a linear regression model, there was a significant difference in the absolute ECL per year (p = 0.015) in favour of EXC-trephination, but with an exponential regression model there was no significant difference in the percentage ECL per year (p = 0.088) between the two types of threphination. In patients with FUCHS (n = 35) - except for the 6-week-follow-up (p = 0.024) - ECD was not significantly different for EXC vs. MECH. With linear/exponential regression model, the ECL per year was not significantly different in favour of any type of trephination (p = 0.287/p = 0.121). In patients with OD (n = 36), ECD was not significantly different for EXC vs. MECH. With a linear/exponential regression model, the ECL per year was not significantly different in favour of any type of trephination (p = 0.494/p = 0.787). Conclusion During the first 24 months after PKP, a significantly higher ECD and a significantly lower percentage of ECL per year was observed after EXC trephination for the entire group of patients. For the different diagnostic groups KC, FD and OD, no significant difference in ECD or ECL loss was noticed over a range of follow-up intervals. This may most likely be attributed to the small number of patients in the three subgroups.

A pooled analysis of on-the-road highway driving studies in actual traffic measuring standard deviation of lateral position (i.e., "weaving") while driving at a blood alcohol concentration of 0.5 g/L.

INTRODUCTION: The on-the-road highway driving test is generally regarded as a gold standard for assessing drug-induced driving impairment. The primary outcome measure is the standard deviation of lateral position (SDLP), a measure of road tracking error or "weaving". The test has been calibrated for incremental doses of alcohol almost 30 years ago in order to define the impact of drug-induced impairment in terms of blood alcohol concentration (BAC) equivalents. Drug-induced changes in SDLP exceeding 2.4 cm have been evaluated as clinically relevant ever since. The present analysis was conducted to assess the robustness of the alcohol effect in a range of on-the-road driving studies which have been conducted since the initial alcohol calibration study. METHODS: The present study pooled data of 182 participants from nine placebo-controlled crossover studies who performed the highway driving test, while their BAC was at or just below the legal limit for drivers (i.e., 0.5 g/L). RESULTS: Overall, mean SDLP increased with 2.5 cm (95% CI 2.0-2.9 cm). Equivalence testing showed that the clinical relevance criterion value of 2.4 cm fell well within the 95% CI in each individual study. Gender did not affect alcohol-induced changes in SDLP. DISCUSSION: These results demonstrate the robustness and validity of the clinical relevance criterion for SDLP as measured during on-the-road driving.

COMPOSE: Using temporal patterns for interpreting wearable sensor data with computer interpretable guidelines.

This paper describes a novel temporal logic-based framework for reasoning with continuous data collected from wearable sensors. The work is motivated by the Metabolic Syndrome, a cluster of conditions which are linked to obesity and unhealthy lifestyle. We assume that, by interpreting the physiological parameters of continuous monitoring, we can identify which patients have a higher risk of Metabolic Syndrome. We define temporal patterns for reasoning with continuous data and specify the coordination mechanisms for combining different sets of clinical guidelines that relate to this condition. The proposed solution is tested with data provided by twenty subjects, which used sensors for four days of continuous monitoring. The results are compared to the gold standard. The novelty of the framework stands in extending a temporal logic formalism, namely the Event Calculus, with temporal patterns. These patterns are helpful to specify the rules for reasoning with continuous data and in combining new knowledge into one consistent outcome that is tailored to the patient's profile. The overall approach opens new possibilities for delivering patient-tailored interventions and educational material before the patients present the symptoms of the disease.