Three study decades on irrigation performance and salt concentrations and loads in the irrigation return flows of La Violada irrigation district (Spain)

30 Pags., 3 Tabls., 9 Figs. The definitive version is available at: http://www.sciencedirect.com/science/journal/01678809Irrigation district salt balances identify the main sources and sinks of salts and quantify salt loads in irrigation return flows. Salt balances were performed in La Violada Irrigation District during the 80s (1982–1984), 90s (1995–1998) and 00s (2006–2008) decades. Total Dissolved Solids (TDS) and loads in irrigation return flows were related with changes in irrigation performance and infrastructures during these decades. TDS increased linearly to increases in Irrigation Consumptive Use Coefficient (ICUC) (P 66%, and decreased exponentially for values above and below these thresholds, respectively. Therefore, the key management strategy to reduce salt discharge to downstream areas is to decrease drainage volumes by improving irrigation management.This work was sponsored by the Spanish Ministry of Science and Education project AGL2006-11860/AGR, the European Regional Development Fund (FEDER) and the European Union project INCO CT-2005-015031.Peer reviewe

Development and validation of a Score for Preoperative Prediction of Obstructive Sleep Apnea (SPOSA) and its perioperative outcomes

Background Postoperative respiratory complications (PRCs) are associated with significant morbidity, mortality, and hospital costs. Obstructive sleep apnea (OSA), often undiagnosed in the surgical population, may be a contributing factor. Thus, we aimed to develop and validate a score for preoperative prediction of OSA (SPOSA) based on data available in electronic medical records preoperatively. Methods OSA was defined as the occurrence of an OSA diagnostic code preceded by a polysomnography procedure. A priori defined variables were analyzed by multivariable logistic regression analysis to develop our score. Score validity was assessed by investigating the score’s ability to predict non-invasive ventilation. We then assessed the effect of high OSA risk, as defined by SPOSA, on PRCs within seven postoperative days and in-hospital mortality. Results A total of 108,781 surgical patients at Partners HealthCare hospitals (2007–2014) were studied. Predictors of OSA included BMI >25 kg*m−2 and comorbidities, including pulmonary hypertension, hypertension, and diabetes. The score yielded an area under the curve of 0.82. Non-invasive ventilation was significantly associated with high OSA risk (OR 1.44, 95% CI 1.22–1.69). Using a dichotomized endpoint, 26,968 (24.8%) patients were identified as high risk for OSA and 7.9% of these patients experienced PRCs. OSA risk was significantly associated with PRCs (OR 1.30, 95% CI 1.19–1.43). Conclusion SPOSA identifies patients at high risk for OSA using electronic medical record-derived data. High risk of OSA is associated with the occurrence of PRCs

Beharrlichkeit und Bürde fehlgeschlagener Paradigmen in der Arzneimittelentwicklung: eine explorative Analyse der VEGF-Inhibition bei Brustkrebs

Background: Failures in cancer drug development impose heavy burdens on patients, researchers, industry, and funders. Burdens in targeted drug development could be mitigated if investigators efficiently integrated not only trial outcomes, but also evidence for underlying pathophysiological hypotheses of drugs tested. However, little is known about how clinical trials testing different drugs with the same targets learn from each other’s failures and successes. The goal of this project was: a) to map the total patient burden and benefit of trials testing one failed drug development paradigm that showed particular perseverance (Vascular Endothelial Growth Factor [VEGF]-inhibition in breast cancer), and b) to describe the production and uptake of evidence from related clinical trials and address why the research agenda persisted despite limited evidence. Methods: We searched in the Embase and MEDLINE databases on February 9, 2017 for clinical trials testing VEGF inhibitors against breast cancer. We measured risk using drug-related serious adverse events (SAEs) Grade 3 or higher, benefit by objective response rate (ORR) and survival advantage versus a comparator arm, as well as trial outcomes by whether studies met their primary endpoint with acceptable toxicity. We assessed citation bias by comparing the number of cited earlier reports with the number of overall citable earlier reports within the trial reports included. Results: Up to February 2017, the VEGF inhibition paradigm in breast cancer consisted of 146 trials of 19 drugs that enrolled 17,924 patients. 6,441 patients receiving a VEGF inhibitor experienced ORR (46% of intent-to-treat population, 95% confidence interval [CI]: 45.1% to 46.8%), 114 died from drug-related toxicities (0.64%, 95% CI: 0.53% to 0.77%), at least 5448 experienced Grade 3–4 SAEs (30.4%, 95% CI: 29.7% to 31.1%). No trial showed a survival advantage for any VEGF inhibitor. Risk and benefit remained stable over the course of the paradigm suggesting little treatment optimization. Trials cited on average 5.38 prior reports within the set (12.6% of those available). Patients in positive trials were 2.4 times more likely to be cited in the discussion sections of subsequent reports than patients in non-positive trials. Citation bias did not diminish over the course of the paradigm’s testing. Fifty-seven (39%) of the trials cited reports that tested a different VEGF inhibitor. Conclusion: The paradigm of VEGF inhibition in breast cancer posed substantial patient burdens and did not provide survival benefit. Citation bias and limited learning between trials of different drugs of the same class may have contributed to its perseverance.Hintergrund: Misserfolge bei der Entwicklung von Krebsmedikamenten belasten Patienten, Forschung, Industrie und Geldgeber erheblich. Diese Last könnte bei der Entwicklung von zielgerichteten Medikamenten reduziert werden, indem die Forschung nicht nur Studienergebnisse, sondern auch Erkenntnisse zu den pathophysiologischen Hypothesen der getesteten Arzneimittel effizient integriert. Es ist jedoch wenig darüber bekannt, wie klinische Studien, in denen verschiedene Medikamente mit dem gleichen Wirkmechanismus getestet werden, aus den Misserfolgen und Erfolgen von Studien der gleichen Klasse lernen. Das Ziel dieses Projekts war es: a) Patientenlast und -nutzen klinischer Studien einer gescheiterten Medikamentenklasse, die besondere Beharrlichkeit gezeigt hat (Vascular Endothelial Growth Factor [VEGF]-Inhibition bei Brustkrebs) zu quantifizieren b) die Produktion und Integration von Evidenz aus miteinander verwandten klinischen Studien zu beschreiben und zu erörtern, warum die Forschungsagenda trotz begrenzter Evidenz vorangetrieben wurde. Methoden: Am 9. Februar 2017 wurden die Datenbanken Embase und MEDLINE nach klinischen Studien durchsucht, die VEGF-Inhibitoren in Brustkrebs untersuchten. Patientenlast wurde anhand von Serious Adverse Events (SAEs) Grad 3 oder höher bestimmt, Patientennutzen anhand von Objective Response Rate (ORR) sowie Überlebensvorteil gegenüber einem Vergleichsarm. Studienerfolg wurde durch das Erreichen des primären Endpunktes bei akzeptabler Toxizität definiert. Zitationsbias wurde gemessen, indem die Anzahl der zitierten vorangegangenen Studien mit der Anzahl der insgesamt zitierfähigen Studien in dem eingeschlossenen Set verglichen wurden. Ergebnisse: Das Entwicklungsparadigma der VEGF-Inhibition bei Brustkrebs bestand bis Februar 2017 aus 146 Studien mit 19 Arzneimitteln die 17.924 Patienten einschlossen. 6441 Patienten, die einem VEGF-Inhibitor ausgesetzt wurden, zeigten Objective Response (46% der intent-to-treat population, 95% Konfidenzintervall [CI]: 45,1% bis 46,8%), 114 starben an arzneimittelbedingten Nebenwirkungen (0,64%, 95% CI: 0,53 % bis 0,77%) und mindestens 5448 erlitten medikamentenbedingte Nebenwirkungen Grad 3–4 (30,4%, 95% CI: 29,7% bis 31,1%). Keine Studie zeigte einen Überlebensvorteil für einen VEGF-Inhibitor. Risiko und Nutzen blieben im Verlauf des Entwicklungsparadigmas konstant, was darauf hindeutet, dass wenig Optimierung der Therapie stattfinden konnte. Studien zitierten durchschnittlich 5,38 frühere Studien innerhalb des Samples (12,6% der verfügbaren Studienberichte). Patienten in positiven Studien wurden in den Diskussionsabschnitten nachfolgender Studien 2,4-mal häufiger zitiert als Patienten in nicht-positiven Studien. Der Zitationsbias hat im Verlauf des Paradigmas nicht abgenommen. Siebenundfünfzig (39%) Studien zitierten frühere Studienberichte, in denen ein anderer VEGF-Inhibitor getestet wurde. Schlussfolgerung: Das Entwicklungsparadigma der VEGF-Inhibition bei Brustkrebs war mit einer erheblichen Patientenlast verbunden und zeigte keinen Überlebensvorteil für einen VEGF-inhibitor. Zitationsbias und eingeschränkter Erkenntnisgewinn aus Arzneimittelstudien mit anderen Substanzen derselben Klasse haben möglicherweise zu Beharrlichkeit des Paradigmas beigetragen

Electrodynamic Model of the Heart to Detect Necrotic Areas in a Human Heart

To diagnose the conditions and diseases of the cardiovascular system is the main task of electrocardiology. The problem of the cardiovascular system diagnostics is caused by a complex multi-level mechanism of its functioning, and only experienced specialists are able to establish a correct diagnosis. Since the working heart is inaccessible to direct observations in real life, diagnostics of diseases is based on noninvasive methods such as electrocardiography. By assumption, weak "bursts" (micropotentials) of electrocardiographic signals in different areas are the precursors of dangerous arrhythmias. The amplitude of these signals on the body surface is insignificant and tends to be commensurate with the noise level of the measuring system. Advances in electrocardiography make it possible to generate a high resolution ECG signal and to detect the heart micropotentials. The method of modeling helps to understand causes of micropotentials in the ECG signal by selecting the model parameters. The model of the heart should allow generating a signal close to the high resolution ECG signal. The research aims to find a numerical model that allows solving the inverse problem of the heart tissue characteristics recovery using a high resolution ECG signal and CT data on the heart geometry. The proposed computer model and highly sensitive methods for the ECG measurement are the part of the hardware-software complex to detect dangerous precursors of cardiac arrhythmias

Phase transitions in biological membranes

Native membranes of biological cells display melting transitions of their lipids at a temperature of 10-20 degrees below body temperature. Such transitions can be observed in various bacterial cells, in nerves, in cancer cells, but also in lung surfactant. It seems as if the presence of transitions slightly below physiological temperature is a generic property of most cells. They are important because they influence many physical properties of the membranes. At the transition temperature, membranes display a larger permeability that is accompanied by ion-channel-like phenomena even in the complete absence of proteins. Membranes are softer, which implies that phenomena such as endocytosis and exocytosis are facilitated. Mechanical signal propagation phenomena related to nerve pulses are strongly enhanced. The position of transitions can be affected by changes in temperature, pressure, pH and salt concentration or by the presence of anesthetics. Thus, even at physiological temperature, these transitions are of relevance. There position and thereby the physical properties of the membrane can be controlled by changes in the intensive thermodynamic variables. Here, we review some of the experimental findings and the thermodynamics that describes the control of the membrane function.Comment: 23 pages, 15 figure

The influence of anesthetics, neurotransmitters and antibiotics on the relaxation processes in lipid membranes

In the proximity of melting transitions of artificial and biological membranes fluctuations in enthalpy, area, volume and concentration are enhanced. This results in domain formation, changes of the elastic constants, changes in permeability and slowing down of relaxation processes. In this study we used pressure perturbation calorimetry to investigate the relaxation time scale after a jump into the melting transition regime of artificial lipid membranes. This time corresponds to the characteristic rate of domain growth. The studies were performed on single-component large unilamellar and multilamellar vesicle systems with and without the addition of small molecules such as general anesthetics, neurotransmitters and antibiotics. These drugs interact with membranes and affect melting points and profiles. In all systems we found that heat capacity and relaxation times are related to each other in a simple manner. The maximum relaxation time depends on the cooperativity of the heat capacity profile and decreases with a broadening of the transition. For this reason the influence of a drug on the time scale of domain formation processes can be understood on the basis of their influence on the heat capacity profile. This allows estimations of the time scale of domain formation processes in biological membranes.Comment: 12 pages, 6 figure

On the Auschwitz Lie

In the November 1986 issue of the Michigan Law Review, Professor Eric Stein addressed the then-recent German legislation prohibiting the Auschwitz lie. The Auschwitz lie refers to contemporary attempts to deny the historical truth of the Holocaust. In the time since his article was published, Professor Stein has corresponded with several European scholars on the issues raised by the 1985 legislation. That correspondence, though brief, highlights the contentious aspects of Professor Stein\u27s analysis; it suggests that the issues of restricting historical speech, promoting national consciousness, attributing collective guilt, and identifying the role of courts in punishing historical lies remain troublesome to German intellectuals. Excerpts from Professor Stein\u27s correspondence follow