Forecasting with an N-dimensional Langevin equation and a neural-ordinary differential equation.

Accurate prediction of electricity day-ahead prices is essential in competitive electricity markets. Although stationary electricity-price forecasting techniques have received considerable attention, research on non-stationary methods is comparatively scarce, despite the common prevalence of non-stationary features in electricity markets. Specifically, existing non-stationary techniques will often aim to address individual non-stationary features in isolation, leaving aside the exploration of concurrent multiple non-stationary effects. Our overarching objective here is the formulation of a framework to systematically model and forecast non-stationary electricity-price time series, encompassing the broader scope of non-stationary behavior. For this purpose, we develop a data-driven model that combines an N-dimensional Langevin equation (LE) with a neural-ordinary differential equation (NODE). The LE captures fine-grained details of the electricity-price behavior in stationary regimes but is inadequate for non-stationary conditions. To overcome this inherent limitation, we adopt a NODE approach to learn, and at the same time predict, the difference between the actual electricity-price time series and the simulated price trajectories generated by the LE. By learning this difference, the NODE reconstructs the non-stationary components of the time series that the LE is not able to capture. We exemplify the effectiveness of our framework using the Spanish electricity day-ahead market as a prototypical case study. Our findings reveal that the NODE nicely complements the LE, providing a comprehensive strategy to tackle both stationary and non-stationary electricity-price behavior. The framework's dependability and robustness is demonstrated through different non-stationary scenarios by comparing it against a range of basic naïve methods.

Meaningful time-related aspects of alerts in Clinical Decision Support Systems. A unified framework.

Alerts are a common functionality of clinical decision support systems (CDSSs). Although they have proven to be useful in clinical practice, the alert burden can lead to alert fatigue and significantly reduce their usability and acceptance. Based on a literature review, we propose a unified framework consisting of a set of meaningful timestamps that allows the use of state-of-the-art measures for alert burden, such as alert dwell time, alert think time, and response time. In addition, it can be used to investigate other measures that could be relevant as regards dealing with this problem. Furthermore, we provide a case study concerning three different types of alerts to which the framework was successfully applied. We consider that our framework can easily be adapted to other CDSSs and that it could be useful for dealing with alert burden measurement thus contributing to its appropriate management.

Physics-informed Bayesian inference of external potentials in classical density-functional theory.

The swift progression and expansion of machine learning (ML) have not gone unnoticed within the realm of statistical mechanics. In particular, ML techniques have attracted attention by the classical density-functional theory (DFT) community, as they enable automatic discovery of free-energy functionals to determine the equilibrium-density profile of a many-particle system. Within classical DFT, the external potential accounts for the interaction of the many-particle system with an external field, thus, affecting the density distribution. In this context, we introduce a statistical-learning framework to infer the external potential exerted on a classical many-particle system. We combine a Bayesian inference approach with the classical DFT apparatus to reconstruct the external potential, yielding a probabilistic description of the external-potential functional form with inherent uncertainty quantification. Our framework is exemplified with a grand-canonical one-dimensional classical particle ensemble with excluded volume interactions in a confined geometry. The required training dataset is generated using a Monte Carlo (MC) simulation where the external potential is applied to the grand-canonical ensemble. The resulting particle coordinates from the MC simulation are fed into the learning framework to uncover the external potential. This eventually allows us to characterize the equilibrium density profile of the system by using the tools of DFT. Our approach benchmarks the inferred density against the exact one calculated through the DFT formulation with the true external potential. The proposed Bayesian procedure accurately infers the external potential and the density profile. We also highlight the external-potential uncertainty quantification conditioned on the amount of available simulated data. The seemingly simple case study introduced in this work might serve as a prototype for studying a wide variety of applications, including adsorption, wetting, and capillarity, to name a few.

Socioeconomic Inequalities in Alcohol and Tobacco Consumption: A National Ecological Study in Mexican Adolescents.

Alcohol and cigarettes are the psychoactive substances that adolescents use most frequently. When both addictions are combined, they carry the worst burden of disease globally. The objective of this study was to identify whether socioeconomic factors correlate with alcohol and tobacco consumption in Mexican adolescents aged 10 years or more and to establish the relationship in the consumption between the two substances. This ecological study utilized data describing alcohol and tobacco consumption among adolescents aged 10-16 years (n = 48,837 ≈ N = 11,621,100). Having ever consumed any alcohol-containing beverage constituted alcohol consumption. Smoking a cigarette within 30 days constituted cigarette consumption. For both variables, the state-level percentages reported in the survey were used. Diverse socioeconomic variables were collected from official sources. Data on the prevalence of tobacco use and alcohol consumption were entered into an Excel database estimated for each of the states of the Mexican Republic, as well as the socioeconomic variables. We performed the analysis using Stata 14. Consumption prevalence was 15.0% for alcohol and 4.2% for tobacco. Alcohol consumption was not correlated with any studied socioeconomic variable (p > 0.05). The prevalence of tobacco consumption among elementary school students correlated (p < 0.05) with the portion of the population living in private dwellings without sewage, drainage, or sanitation (r = 0.3853). The prevalence of tobacco consumption among middle-school adolescents correlated with the portion of the employed population that earned up to two minimum wages (r = 0.3960), the percentage in poverty by income 2008 (r = 0.4754) and 2010 (r = 0.4531), and the percentage in extreme poverty by income 2008 (r = 0.4612) and 2010 (r = 0.4291). Positive correlations were found between tobacco consumption and alcohol consumption among both elementary (r = 0.5762, p=0.0006) and middle-school children (r = 0.7016, p=0.0000). These results suggest that certain socioeconomic factors correlate with tobacco consumption but not alcohol consumption. A correlation between alcohol consumption and tobacco consumption was observed. The results can be used for developing interventions in adolescents.

Transcriptional organization and regulation of the Pseudomonas putida flagellar system.

A single region of the Pseudomonas putida genome, designated the flagellar cluster, includes 59 genes potentially involved in the biogenesis and function of the flagellar system. Here, we combine bioinformatics and in vivo gene expression analyses to clarify the transcriptional organization and regulation of the flagellar genes in the cluster. We have identified 11 flagellar operons and characterized 22 primary and internal promoter regions. Our results indicate that synthesis of the flagellar apparatus and core chemotaxis machinery is regulated by a three-tier cascade in which fleQ is a Class I gene, standing at the top of the transcriptional hierarchy. FleQ- and σ54 -dependent Class II genes encode most components of the flagellar structure, part of the chemotaxis machinery and multiple regulatory elements, including the flagellar σ factor FliA. FliA activation of Class III genes enables synthesis of the filament, one stator complex and completion of the chemotaxis apparatus. Accessory regulatory proteins and an intricate operon architecture add complexity to the regulation by providing feedback and feed-forward loops to the main circuit. Because of the high conservation of the gene arrangement and promoter motifs, we believe that the regulatory circuit presented here may also apply to other environmental pseudomonads.

PACAP modulates the transcription of TLR-1/TLR-5/MyD88 pathway genes and boosts antimicrobial defenses in Clarias gariepinus.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a multifunctional neuropeptide that belongs to the secretin/glucagon/GHRH/VIP superfamily. Some of these molecules have antimicrobial activity and they are capable of stimulating the immune system. The present work studied the antibacterial and immunostimulatory activity of PACAP-38 from African catfish Clarias gariepinus against the Gram-negative bacterium Pseudomonas aeruginosa in an in vivo test. PACAP-38 improved antimicrobial activity of skin mucus molecules against P. aeruginosa. The peptide modulates the gene expression profile of TLR-1, TLR-5, MyD88, IL-1ß, TNF-ɑ, IL-8, pardaxin, hepcidin and G/C-type lysozymes in skin, spleen and head kidney. The influenced exerted depended on the time after infection and tissue analyzed. This study provides the first evidence of a link between PACAP and antimicrobial peptides hepcidin and pardaxin. Our results suggest further use of PACAP as antimicrobial agent that could potentially be used to control disease in aquaculture.

Growth hormone secretagogue peptide-6 enhances oreochromicins transcription and antimicrobial activity in tilapia (Oreochromis sp.).

Growth Hormone-Releasing Peptide 6 (GHRP-6) (His-(D-Trp)-Ala-Trp-(D-Phe)-Lys-NH2) is an agonist of the growth hormone secretagogue receptor. GHRP-6 mimics the effect of ghrelin. The present study focuses on the immunomodulatory effects of GHRP-6 in tilapia with and without the presence of Pseudomonas aeruginosa infection. GHRP-6 up-regulated the transcription levels of three piscidin-like antimicrobial peptides (Oreochromicins I, II, and III) and granzyme in a tissue-dependent manner. Antimicrobial activity stimulation in serum (lysozyme and anti-protease activity) was also confirmed. Besides, GHRP-6 enhanced the in vitro antimicrobial activity against P. aeruginosa in tilapia gills mucus and serum samples and decreased the bacterial load in vivo after infection with this Gram-negative bacterium. Our results evidenced, for the first time, a direct link between a growth hormone secretagogue ghrelin mimetic in fish and the enhancement of antimicrobial peptides transcription, which suggests that this secretagogue is capable to lead the activation of microbicidal activity in tilapia. Thus, these results open new possibilities for GHRP-6 application in aquaculture to stimulate the teleost immune system as an alternative treatment against opportunistic bacteria.

Monoclonal antibody against Nile tilapia (Oreochromis niloticus) IgM heavy chain: A valuable tool for detection and quantification of IgM and IgM+ cells.

Nile tilapia (Oreochromis niloticus) is a freshwater fish, which is extensively cultivated worldwide and constitutes one of the model species for the study of fish immunology. Monoclonal antibodies are very advantageous molecular tools for studying teleost immune system. Specifically, monoclonal antibodies that react with immunoglobulins are used successfully in the study of the humoral immune response of several fish species. In the present study, we produced and characterized a monoclonal antibody against tilapia IgM heavy chain using a peptide-based strategy. The peptide sequence was selected from the surface-exposed region between CH3-CH4 domains. The specificity of the polyclonal serum and the hybridoma culture supernatant obtained by immunization with the peptide conjugated to keyhole limpet hemocyanin were evaluated by western blotting, both showing reactivity against tilapia serum IgM. The purified mAb was able to recognize secreted IgM by western blotting and ELISA and membrane IgM by flow cytometry. We also demonstrated that the antibody doesn't cross-react with a recombinant IgT fragment. This tool allowed us to study for the first time the stimulation of mucosal immunity after Pituitary Adenylate Cyclase Activating Polypeptide administration. Overall, the results demonstrated the utility of this mAb to characterize humoral immune response in O. niloticus.

Catalytic inhibition of KDM1A in Ewing sarcoma is insufficient as a therapeutic strategy.

BACKGROUND: Ewing sarcoma and desmoplastic small round cell tumors (DSRCT) are rare and clinically aggressive sarcomas usually characterized by oncogenic fusion proteins involving EWS. Emerging studies of Ewing sarcoma have demonstrated EWS-FLI1-driven chromatin remodeling as a key aspect of tumorigenicity. In particular, the lysine-specific demethylase KDM1A/LSD1 is linked to transcriptional regulation of target genes orchestrated by the EWS portion of the fusion protein interacting with repressive chromatin-remodeling complexes. Consistent with this model, depletion of KDM1A supports it is a molecular therapeutic target in Ewing sarcoma cells, but effective drugs need to be identified. PROCEDURE: A comprehensive phenotypic analysis of the effects of catalytic KDM1A inhibitors ORY-1001 and GSK2879552, including clinically relevant doses, was carried out in 2D and 3D spheroid models of Ewing sarcoma and DSRCT. RESULTS: Catalytic inhibition of KDM1A did not affect cell viability in 2D and 3D assays and had no impact on invasion in a 3D assay. CONCLUSIONS: Overall, evidence presented here does not support inhibition of KDM1A catalytic demethylase activity as an effective therapeutic strategy for Ewing sarcoma or DSRCT. However, roles of KDM1A beyond its demethylase activity should be considered for these sarcomas.

Impact of expert knowledge on the detection of patients at risk of antimicrobial therapy failure by clinical decision support systems.

Antimicrobial Susceptibility Tests (ASTs) are performed in hospitals to detect whether an infectious agent is resistant or susceptible to a set of antimicrobials. When AST results are available, the evaluation of the patient's antimicrobial therapy is a critical task to ensure its effectiveness against the found microorganism. Since not all the available antimicrobials can be tested in ASTs, clinicians rely on their expert knowledge to complement AST results and prescribe the most appropriate antimicrobials for each infection. Our goal is to help physicians in this task by improving the detection of antimicrobial therapies at risk of failure by Clinical Decision Support Systems (CDSSs). With this aim, we have incorporated the EUCAST expert rules in antimicrobial susceptibility testing into a CDSS to improve the results of ASTs. In order to achieve this, we have combined both ontologies and production rules. Furthermore, we have evaluated the impact of EUCAST expert rules on the detection of antimicrobial therapies at risk of failure. We performed a retrospective study with one year of clinical data, obtaining a total of 148 alerts from which 62 (41.9%) were based on the additional expert knowledge. Furthermore, the evaluation of the clinical relevance of 27 alerts resulted in 8 of them (29.7%) being clinically relevant. Of these, 6 were based on expert knowledge. Finally, an alarm fatigue study suggests that waiting between 48 and 72 h from the reception of the AST results can significantly reduce the number of alerts that are unnecessary in our CDSS because they are already being addressed in the hospital's daily workflow. In conclusion, we demonstrate that the incorporation of expert knowledge improves the capabilities of CDSSs as regards detecting the risk of antimicrobial therapy failure, which may improve the institutional outcomes in antimicrobial stewardship.

Effectiveness of Two Targeted Temperature Management Methods After Pediatric Postcardiac Arrest: A Multicenter International Study.

OBJECTIVES: It is currently recommended that after return of spontaneous circulation following cardiac arrest, fever should be prevented using TTM through a servo-controlled system. This technology is not yet available in many global settings, where manual physical measures without servo-control is the only option. Our aim was to compare feasibility, safety and quality assurance of servo-controlled system versus no servo-controlled system cooling, TTM protocols for cooling, maintenance and rewarming following return of spontaneous circulation after cardiac arrest in children. DESIGN: Prospective, multicenter, nonrandomized, study. SETTING: PICUs of 20 hospitals in South America, Spain, and Italy, 2012-2014. PATIENTS: Under 18 years old with a cardiac arrest longer than 2 minutes, in coma and surviving to PICU admission requiring mechanical ventilation were included. METHODS: TTM to 32-34°C was performed by prospectively designed protocol across 20 centers, with either servo-controlled system or no servo-controlled system methods, depending on servo-controlled system availability. We analyzed clinical data, cardiac arrest, temperature, mechanical ventilation duration, length of hospitalization, complications, survival, and neurologic outcomes at 6 months. PRIMARY OUTCOME: feasibility, safety and quality assurance of the cooling technique and secondary outcome: survival and Pediatric Cerebral Performance Category at 6 months. MEASUREMENTS AND MAIN RESULTS: Seventy patients were recruited, 51 of 70 TTM (72.8%) with servo-controlled system. TTM induction, maintenance, and rewarming were feasible in both groups. Servo-controlled system was more effective than no servo-controlled system in maintaining TTM (69 vs 60%; p = 0.004). Servo-controlled system had fewer temperatures above 38.1°C during the 5 days of TTM (0.1% vs 2.9%; p < 0.001). No differences in mortality, complications, length of mechanical ventilation and of stay, or neurologic sequelae were found between the two groups. CONCLUSIONS: TTM protocol (for cooling, maintenance and rewarming) following return of spontaneous circulation after cardiac arrest in children was feasible and safe with both servo-controlled system and no servo-controlled system techniques. Achieving, maintaining, and rewarming within protocol targets were more effective with servo-controlled system versus no servo-controlled system techniques.

A decision support system for antibiotic prescription based on local cumulative antibiograms.

BACKGROUND: Local cumulative antibiograms are useful tools with which to select appropriate empiric or directed therapies when treating infectious diseases at a hospital. However, data represented in traditional antibiograms are static, incomplete and not well adapted to decision-making. METHODS: We propose a decision support method for empiric antibiotic therapy based on the Number Needed to Fail (NNF) measure. NNF indicates the number of patients that would need to be treated with a specific antibiotic for one to be inadequately treated. We define two new measures, Accumulated Efficacy and Weighted Accumulated Efficacy in order to determine the efficacy of an antibiotic. We carried out two experiments: the first during which there was a suspicion of infection and the patient had empiric therapy, and the second by considering patients with confirmed infection and directed therapy. The study was performed with 15,799 cultures with 356,404 susceptibility tests carried out over a four-year period. RESULTS: The most efficient empiric antibiotics are Linezolid and Vancomycin for blood samples and Imipenem and Meropenem for urine samples. In both experiments, the efficacies of recommended antibiotics are all significantly greater than the efficacies of the antibiotics actually administered (P < 0.001). The highest efficacy is obtained when considering 2 years of antibiogram data and 80% of the cumulated prevalence of microorganisms. CONCLUSION: This extensive study on real empiric therapies shows that the proposed method is a valuable alternative to traditional antibiograms as regards developing clinical decision support systems for antimicrobial stewardship.

Testosterone treatment is not associated with increased risk of prostate cancer or worsening of lower urinary tract symptoms: prostate health outcomes in the Registry of Hypogonadism in Men.

OBJECTIVES: To evaluate the effects of testosterone-replacement therapy (TRT) on prostate health indicators in hypogonadal men, including rates of prostate cancer diagnoses, changes in prostate-specific antigen (PSA) levels and lower urinary tract symptoms (LUTS) over time. PATIENTS AND METHODS: The Registry of Hypogonadism in Men (RHYME) is a multi-national patient registry of treated and untreated, newly-diagnosed hypogonadal men (n = 999). Follow-up assessments were performed at 3-6, 12, 24, and 36 months. Baseline and follow-up data collection included medical history, physical examination, blood sampling, and patient questionnaires. Prostate biopsies underwent blinded independent adjudication for the presence and severity of prostate cancer; PSA and testosterone levels were measured via local and central laboratory assays; and LUTS severity was assessed via the International Prostate Symptom Score (IPSS). Incidence rates per 100 000 person-years were calculated. Longitudinal mixed models were used to assess effects of testosterone on PSA levels and IPSS. RESULTS: Of the 999 men with clinically diagnosed hypogonadism (HG), 750 (75%) initiated TRT, contributing 23 900 person-months of exposure. The mean testosterone levels increased from 8.3 to 15.4 nmol/L in treated men, compared to only a slight increase from 9.4 to 11.3 nmol/L in untreated men. In all, 55 biopsies were performed for suspected prostate cancer, and 12 non-cancer related biopsies were performed for other reasons. Overall, the proportion of positive biopsies was nearly identical in men on TRT (37.5%) compared to those not on TRT (37.0%) over the course of the study. There were no differences in PSA levels, total IPSS, or the IPSS obstructive sub-scale score by TRT status. Lower IPSS irritative sub-scale scores were reported in treated compared to untreated men. CONCLUSIONS: Results support prostate safety of TRT in newly diagnosed men with HG.

Quality of Life and Sexual Function Benefits of Long-Term Testosterone Treatment: Longitudinal Results From the Registry of Hypogonadism in Men (RHYME).

BACKGROUND: The benefits and risks of long-term testosterone administration have been a topic of much scientific and regulatory interest in recent years. AIM: To assess long-term quality of life (QOL) and sexual function benefits of testosterone replacement therapy (TRT) prospectively in a diverse, multinational cohort of men with hypogonadism. METHODS: A multinational patient registry was used to assess long-term changes associated with TRT in middle-age and older men with hypogonadism. Comprehensive evaluations were conducted at 6, 12, 24, and 36 months after enrollment into the registry. OUTCOMES: QOL and sexual function were evaluated by validated measures, including the Aging Males' Symptom (AMS) Scale and the International Index of Erectile Function (IIEF). RESULTS: A total of 999 previously untreated men with hypogonadism were enrolled at 25 European centers, 750 of whom received TRT at at least one visit during the period of observation. Patients on TRT reported rapid and sustained improvements in QOL, with fewer sexual, psychological, and somatic symptoms. Modest improvements in QOL and sexual function, including erectile function, also were noted in RHYME patients not on TRT, although treated patients showed consistently greater benefit over time in all symptom domains compared with untreated patients. AMS total scores for patients on TRT were 32.8 (95% confidence interval = 31.3-34.4) compared with 36.6 (95% confidence interval = 34.8-38.5) for untreated patients (P < .001). Small but significant improvements in IIEF scores over time also were noted with TRT. Approximately 25% of treated and untreated men also used phosphodiesterase type 5 inhibitors, with notable differences in the frequency of phosphodiesterase type 5 inhibitor prescription use according to physician specialty and geographic site location. CLINICAL IMPLICATIONS: TRT-related benefits in QOL and sexual function are well maintained for up to 36 months after initiation of treatment. STRENGTHS AND LIMITATIONS: The major strengths are the large, diverse patient population being treated in multidisciplinary clinical settings. The major limitation is the frequency of switching from one formulation to another. CONCLUSION: Overall, we confirmed the broad and sustained benefits of TRT across major QOL dimensions, including sexual, somatic, and psychological health, which were sustained over 36 months in our treatment cohort. Rosen RC, Wu F, Behre H, et al. Quality of Life and Sexual Function Benefits Effects of Long-Term Testosterone Treatment: Longitudinal Results From the Registry of Hypogonadism in Men (RHYME). J Sex Med 2017;14:1104-1115.

Novel IFNγ homologue identified in Nile tilapia (Oreochromis niloticus) links with immune response in gills under different stimuli.

Interferon gamma (IFN-γ) has important roles in both innate and adaptive immune responses. This cytokine plays a very important role in defining Th1 immune response in all vertebrates. In the present study, we identified and isolated for the first time the gene coding for Nile tilapia (Oreochromis niloticus) IFNγ from spleen lymphocytes. The isolated tilapia IFNγ has between 24 and 62% of amino acid identity as compared to reported sequences for other teleost fishes. It has close phylogenetic relationships with IFNγ molecules belonging to the group of Perciforms and presents the typical structural characteristics of gamma interferon molecules. The tissue expression analysis showed that IFNγ is expressed constitutively in head kidney, skin, intestine, muscle and brain. Its expression was not detected in gills by conventional RT-PCR. However, under conditions of stimulation with Poly I:C and LPS, IFNγ expression was up-regulated in gills after 24 h post-stimulation. IFNγ expression was also induced in gills 24 h after Edwardsiella tarda infection suggesting its important role in immunity against intracellular bacteria. The recombinant protein produced in Escherichia coli induced Mx gene transcription in head kidney primary culture cells. These results are the first steps to characterize the role of tilapia IFNγ in the defense against pathogens in tilapia. Furthermore, the isolation of this molecule provides a new tool to characterize the cellular immune response to various stimuli in this organism.

PDE5A Polymorphisms Influence on Sildenafil Treatment Success.

INTRODUCTION: Diabetes and cardiovascular disease are risk factors for erectile dysfunction (ED). Selective inhibitors of the type 5 phosphodiesterase are the first option for treating ED. However, it is unknown why there are patients with low response to this treatment. Polymorphisms in the PDE5A gene may influence the response to PDE5 inhibitors treatment. AIM: The aim of this study is to analyze the relationship between PDE5A polymorphisms, diabetes, and the efficacy of sildenafil treatment. METHODS: A Spanish prospective cohort of 170 Caucasian male patients diagnosed with ED and ischemic heart disease treated with angioplasty was studied. MAIN OUTCOME MEASURES: ED was evaluated according to the 5-item version of the International Index for Erectile Function before and after treatment with sildenafil 50 mg. The gene sequence of the PDE5A gene was analyzed for the presence of rs12646525 and rs3806808 polymorphisms. Glucose and glycosylated hemoglobin levels were measured in blood serum samples. The relationship between treatment response, genotype, and glycemic status was analyzed. RESULTS: Patients with G-allele of rs3806808 polymorphism showed a worse response to the treatment compared to TT-homozygote patients. Nondiabetic G-allele carriers showed a worse treatment response than TT-homozygotes patients. These differences were not seen in diabetic patients. There were no significant differences in treatment response according to the rs12646525 polymorphism in total population or according to the glycemic status. Logistic regression analysis showed that nondiabetic carriers of the major allele of both the rs12646525 and rs3806808 polymorphism had a significantly higher likelihood to respond to the treatment than diabetic patients carriers of the minor allele (P < .05). CONCLUSION: The response to sildenafil treatment depends on polymorphisms in the PDE5A gene and the glycemic status of the patients.

Testosterone treatment is not associated with increased risk of adverse cardiovascular events: results from the Registry of Hypogonadism in Men (RHYME).

AIMS: The aim of this study was to assess cardiovascular (CV) safety of testosterone replacement therapy (TRT) in a large, diverse cohort of European men with hypogonadism (HG). METHODS: The Registry of Hypogonadism in Men (RHYME) was designed as a multi-national, longitudinal disease registry of men diagnosed with hypogonadism (HG) at 25 clinical sites in six European countries. Data collection included a complete medical history, physical examination, blood sampling and patient questionnaires at multiple study visits over 2-3 years. Independent adjudication was performed on all mortalities and CV outcomes. RESULTS: Of 999 patients enrolled with clinically diagnosed HG, 750 (75%) initiated some form of TRT. Registry participants, including both treated and untreated patients, contributed 23 900 person-months (99.6% of the targeted) follow-up time. A total of 55 reported CV events occurred in 41 patients. Overall, five patients died of CV-related causes (3 on TRT, 2 untreated) and none of the deaths were adjudicated as treatment-related. The overall CV incidence rate was 1522 per 100 000 person-years. CV event rates for men receiving TRT were not statistically different from untreated men (P=.70). Regardless of treatment assignment, CV event rates were higher in older men and in those with increased CV risk factors or a prior history of CV events. CONCLUSIONS: Age and prior CV history, not TRT use, were predictors of new-onset CV events in this multi-national, prospective hypogonadism registry.

Effect of surgical approach on erectile function recovery following bilateral nerve-sparing radical prostatectomy: an evaluation utilising data from a randomised, double-blind, double-dummy multicentre trial of tadalafil vs placebo.

OBJECTIVES: To report pre-specified and exploratory results on the effect of different surgical approaches on erectile function (EF) after nerve-sparing radical prostatectomy (nsRP) obtained from the multicentre, randomised, double-blind, double-dummy REACTT trial of tadalafil (once a day [OaD] or on-demand [pro-re-nata, PRN]) vs placebo. PATIENTS AND METHODS: Patients aged <68 years with normal preoperative EF who underwent nsRP for localised prostate cancer (Gleason ≤7, prostate-specific antigen [PSA] <10 ng/mL) were randomised after nsRP 1:1:1 to 9-month double-blind treatment with tadalafil 5 mg OaD, tadalafil 20 mg PRN, or placebo, followed by 6-week drug-free washout, and 3-month open-label OaD treatment (all patients). Recovery of EF was defined as an International Index of Erectile Function (IIEF)-EF domain score of ≥22 and normal orgasmic function was defined based on IIEF Question 10. Both parameters were analysed at the end of washout using logistic regression including terms for treatment, country, visit, visit-by-treatment interaction, age group, nerve-sparing score (perfect = 2, non-perfect >2), and surgical approach (open surgery, robot-assisted laparoscopy, conventional laparoscopy, other). Time to EF recovery was analysed post hoc with a Cox proportional-hazards model including terms for treatment, age-group, country, surgical approach and surgery-by-treatment interaction. RESULTS: Of 422 patients treated, 189 underwent open surgery, 115 robot-assisted laparoscopy, 88 conventional laparoscopy and 30 surgery classified as 'other'. The odds of achieving EF recovery at the end of drug-free washout were about twice as high for the robot-assisted laparoscopy group compared with the open surgery group (odds ratio 2.42; 95% confidence interval [CI] 1.24, 4.72; P = 0.029). Patients who underwent robot-assisted laparoscopy were significantly more likely to recover during double-blind treatment compared with patients who underwent open surgery (hazard ratio 1.92; 95% CI 1.17, 3.15; P = 0.010). No favourable effect of conventional laparoscopy compared with open surgery could be seen. CONCLUSION: These results may provide further insights into the role of surgery on EF recovery after nsRP. However, the trial was not designed for these analyses and further prospective studies are needed.

Duration of erection: does it really matter? A randomized, double-blind clinical trial to assess the impact of vardenafil ODT on duration of erection and its correlation with patients' and partners' sexual quality of life and duration of intercourse: the VADEOPEN study.

INTRODUCTION: Stopwatch-assessed duration of erection has been proposed as an objective and reliable efficacy end point for erectile dysfunction (ED) treatments. AIM: The aim of this study is to assess vardenafil orodispersible tablets' (ODTs) efficacy in terms of duration of erection and (i) its correlation with other efficacy end points and male and female sexual quality of life (QoL) and (ii) its impact on intercourse duration. METHODS: Randomized, double-blind, placebo-controlled, multicenter study comparing the efficacy and safety of vardenafil ODT 10 mg on-demand over 12 weeks in 127 patients with ED was carried out. MAIN OUTCOME MEASURES: Primary efficacy end points were stopwatch-assessed duration of erection (min) at any attempt and when leading to successful intercourse, and the erectile function domain of the International Index of Erectile Function (EF-IIEF) score. Secondary end points were sexual encounter profile (SEP) 3 response rate and male sexual QoL. End points in participating women (N = 46) were stopwatch-assessed duration of intercourse and sexual QoL. RESULTS: At week 12/last observation carried forward, patients taking vardenafil ODT had longer duration of erections (at any attempt or leading to successful intercourse) vs. placebo (least square mean ± standard error 10.2 ± 0.9 minutes vs. 7.9 ± 1.0 minutes, and 10.4 ± 0.8 vs. 8.3 ± 1.0 minutes, respectively), and significant increases in EF-IIEF scores, the SEP-3 response, and all sexual QoL items. An increased duration of intercourse was also observed. Female sexual QoL improved significantly. Both duration end points strongly correlated with EF-IIEF scores, and the three end points correlated well with SEP-3 response. Correlation was good with sexual QoL scores in men and women and with duration of intercourse, with differences between treatment groups only for duration end points. Safety was similar in both groups. CONCLUSION: This study provides further evidence for the consistency and reliability of the stopwatch-assessed duration of erection as an efficacy end point for ED treatments, with "duration of erection leading to successful intercourse" showing better properties than duration at any attempt.

BioMINT: A Temporary Immersion System for Agave Micropropagation.

Agaves are cultivated in Mexico as a source of industrial products such as fibers, nutritional supplements, and alcoholic beverages. Due to the demand for plant material, its long-life cycle, and the need to avoid predation on its natural populations, in vitro micropropagation represents a good option for agaves. Plant tissue culture has been successfully used to micropropagate selected elite individuals from plants of various Agave species of economic interest. However, it is necessary to implement systems that lower production costs without losing the quality of the plantlets obtained. This chapter describes the BioMINT™ bioreactor as an alternative for the micropropagation of agaves in the different stages of the micropropagation process.