Development of a standardized methodology for transfer learning with QSAR models: a purely data-driven approach for source task selection.

Transfer learning is a machine learning technique that works well with chemical endpoints, with several papers confirming its efficiency. Although effective, because the choice of source/assistant tasks is non-trivial, the application of this technique is severely limited by the domain knowledge of the modeller. Considering this limitation, we developed a purely data-driven approach for source task selection that abstracts the need for domain knowledge. To achieve this, we created a supervised learning setting in which transfer outcome (positive/negative) is the variable to be predicted, and a set of six transferability metrics, calculated based on information from target and source datasets, are the features for prediction. We used the ChEMBL database to generate 100,000 transfers using random pairing, and with these transfers, we trained and evaluated our transferability prediction model (TP-Model). Our TP-Model achieved a 135-fold increase in precision while achieving a sensitivity of 92%, demonstrating a clear superiority against random search. In addition, we observed that transfer learning could provide considerable performance increases when applicable, with an average Matthews Correlation Coefficient (MCC) increase of 0.19 when using a single source and an average MCC increase of 0.44 when using multiple sources.

Predictors of intubation in COVID-19 patients treated with out-of-ICU continuous positive airway pressure.

BACKGROUND: As delayed intubation may worsen the outcome of coronavirus disease 2019 (COVID-19) patients treated with continuous positive airway pressure (CPAP), we sought to determine COVID-specific early predictors of CPAP failure. METHODS: In this observational retrospective multicentre study, we included all COVID-19 patients treated with out-of-ICU CPAP, candidates for intubation in case of CPAP failure. From these patients, we collected demographic and clinical data. RESULTS: A total of 397 COVID-19 patients were treated with CPAP for respiratory failure, with the therapeutic goal of providing intubation in case of CPAP failure. Univariable analysis showed that, age, lactate dehydrogenase (LDH) and white cell counts were all significantly lower in patients with successful CPAP treatment compared to those failing it and undergoing subsequent intubation. The percentage changes between baseline and CPAP application in the ratio of partial pressure arterial oxygen (PaO2) and fraction of inspired oxygen (FiO2), PaO2, respiratory rate and ROX index were higher in patients experiencing successful CPAP compared to those failing it. FiO2 and male gender were also significantly associated with intubation. Multivariable analysis adjusting for age, gender, Charlson comorbidity index, percentage change in PaO2/FiO2 or PaO2 and FiO2 separately, lactate, white blood cell count, LDH and C-reactive protein levels led to an area under the curve of 0.818 and confirmed that age, LDH and percentage increase in PaO2/FiO2 are predictors of intubation. CONCLUSIONS: In COVID-19 patients requiring CPAP, age, LDH and percentage change in PaO2/FiO2 after starting CPAP are predictors of intubation.

Analytical techniques to recognize inclusion complexes formation involving monoterpenes and cyclodextrins: A study case with (-) borneol, a food ingredient.

Monoterpenes are non-polar secondary metabolites widely used by industry due to their excellent therapeutic, food-ingredient and cosmetic properties. However, their low solubility in water limits their use. In this sense, cyclodextrins (CDs) have been widely used to solve these technological challenges. Thus, this study aims to use (-)-borneol as a monoterpene model to prepare inclusion complexes between ß-CD and hydroxypropyl-ß-CD (HP-ß-CD) through different ways and characterize them in order to choose the best inclusion method to improve physicochemical properties of monoterpenes. To achieve this goal, the samples were prepared by physical mixture (PM), paste complex (PA) and freeze-drying complex (FD) and then, extensively characterized by thermal analysis, Fourier-transform infrared spectroscopy, scanning electron microscopy, size particle, X-ray diffraction and nuclear magnetic resonance. The physicochemical results showed that freeze-drying was more effective to form inclusion complexes between (-)-borneol with both CDs. This research highlights the importance of recognizing the best method to prepare inclusion complexes, including food additives as (-)-borneol, to achieve better results in food preparations.

[The use of RCGO triggers in the obstetric - gynecological procedures: the impact on the reduction of adeverse events. The experience of the Lombardia Region]. / L'utilizzo dei RCOG trigger in area ostetrica - ginecologica e la riduzione degli eventi avversi. L'esperienza della regione Lombardia.

The last few weeks of pregnancy are critical to a baby's health because important organs, including the brain and lungs, are not completely developed until the end of pregnancy. The adverse events during labor and childbirth can have very serious physical, psychological and financial consequences for the child, the family, health professionals and the whole community. These events can be reduced through interventions aimed at improving the safety and quality of care, based on evidence-based knowledge, guidelines and practices that must be widely and effectively applied. This work reports the experience of the Lombardy Region on improvement actions in the obstetric and gynecological procedures for the reduction of adverse events and sentinel events through the monitoring and management of the RCGS trigger tool.

Cell-based multi-target QSAR model for design of virtual versatile inhibitors of liver cancer cell lines.

Liver cancers are one of the leading fatal diseases among malignant neoplasms. Current chemotherapeutic treatments used to fight these illnesses have become less efficient in terms of both efficacy and safety. Therefore, there is a great need of search for new anti-liver cancer agents and this can be accelerated by using computer-aided drug discovery approaches. In this work, we report the development of the first cell-based multi-target model based on quantitative structure-activity relationships (CBMT-QSAR) for the design and prediction of chemicals as anticancer agents against 17 liver cancer cell lines. While having a good quality and predictive power (accuracy higher than 80%) in the training and test sets, respectively, the CBMT-QSAR model was employed as a tool to directly extract suitable fragments from the physicochemical and structural interpretations of the molecular descriptors. Some of these desirable fragments were assembled, leading to the virtual design of eight molecules with drug-like properties, with six of them being predicted as versatile anticancer agents against the 17 liver cancer cell lines reported here.

Antidepressants and the risk of arrhythmia in elderly affected by a previous cardiovascular disease: a real-life investigation from Italy.

PURPOSE: The study aimed to fill existing knowledge gaps on the safety of antidepressant drugs (ADs) by estimating the risk of hospitalization for arrhythmia associated with use of selective serotonin reuptake inhibitors (SSRIs) and newer atypical ADs (NAAs) among elderly with previous cardiovascular (CV) events. METHODS: The cohort was composed by 199,569 individuals aged ≥ 65 years from five Italian healthcare territorial units who were discharged for cardiovascular outcomes in the years 2008-2010. The 17,277 patients who experienced hospital admission for arrhythmia during follow-up were included as cases. Odds of current ADs use among cases (i.e., 14 days before hospital admission) was compared with (i) odds of current use of 1:5 matched controls (between-patients case-control) and with (ii) odds of previous use during 1:5 matched control periods (within-patient case-crossover). The risk of arrhythmia associated with ADs current use was modelled fitting a conditional logistic regression. A set of sensitivity analyses was performed to account for sources of systematic uncertainty. RESULTS: Current users of SSRIs and NAAs were at increased risk of arrhythmia with case-control odds ratios (OR) of 1.37 (95% confidence interval, CI 1.18 to 1.58) and 1.41 (1.16 to 1.71) and case-crossover OR of 1.48 (1.20 to 1.81) and 1.72 (1.31 to 2.27). An increased risk of arrhythmia was associated with current use of trazodone (NAA) consistently in case-control and case-crossover designs. CONCLUSIONS: Evidence that current use of SSRIs and NAAs is associated to an increased risk of arrhythmia among elderly with CV disease was consistently supplied by two observational approaches.

Statin use and risk of new-onset diabetes: A meta-analysis of observational studies.

BACKGROUND AND AIMS: Meta-analyses of randomized control trials investigating the association between incident diabetes and statin use showed an increased risk of new-onset diabetes (NOD) from 9% to 13% associated with statins. However, short follow-up period, unpowered sample size, and lack of pre-specified diagnostic criteria for diabetes detection could be responsible of an underestimation of this risk. We conducted a meta-analysis of published observational studies to evaluate the association between statins use and risk of NOD. METHODS AND RESULTS: PubMed, EMBASE and MEDLINE databases were searched from inception to June 30, 2016 for cohort and case-control studies with risk of NOD in users vs nonusers, on ≥1000 subjects followed-up for ≥1 year. Two review authors assessed study eligibility and risk of bias and undertook data extraction independently. Pooled estimates were calculated by a random-effects model and between-study heterogeneity was tested and measured by I2 index. Furthermore, stratified analyses and the evaluation of publication bias were performed. Finally, the meta-analysis included 20 studies, 18 cohort and 2 case-control studies. Overall, NOD risk was higher in statin users than nonusers (RR 1.44; 95% CI 1.31-1.58). High between-study heterogeneity (I2 = 97%) was found. Estimates for all single statins showed a class effect, from rosuvastatin (RR 1.61; 1.30-1.98) to simvastatin (RR 1.38; 1.19-1.61). CONCLUSIONS: The present meta-analysis confirms and reinforces the evidence of a diabetogenic effect by statins utilization. These observations confirm the need of a rigorous monitoring of patients taking statins, in particular pre-diabetic patients or patients presenting with established risk factors for diabetes.

Can healthcare utilization data reliably capture cases of chronic respiratory diseases? a cross-sectional investigation in Italy.

BACKGROUND: Healthcare utilization data are increasingly used for chronic disease surveillance. Nevertheless, no standard criteria for estimating prevalence of high-impact diseases, such as chronic obstructive pulmonary disease (COPD) and asthma, are available. In this study an algorithm for recognizing COPD/asthma cases from HCU data is developed and implemented in the HCU databases of the Italian Lombardy Region (about 10 million residents). The impact of diagnostic misclassification for reliably estimating prevalence was also assessed. METHODS: Disease-specificdrug codes, hospital discharges together with co-payment exemptions when available, and a combination of them according with patient's age, were used to create the proposed algorithm. Identified cases were considered for prevalence estimation. An external validation study was also performed in order to evaluate systematic uncertainty of prevalence estimates. RESULTS: Raw prevalence of COPD and asthma in 2010 was 3.6 and 3.3% respectively. According to external validation, sensitivity values were 53% for COPD and 39% for asthma. Adjusted prevalence estimates were respectively 6.8 and 8.5% for COPD (among person aged 40 years or older) and asthma (among person aged 40 years or younger). CONCLUSIONS: COPD and asthma prevalence may be estimated from HCU data, albeit with high systematic uncertainty. Validation is recommended in this setting.

Use of antidepressants and the risk of cardiovascular and cerebrovascular disease: a meta-analysis of observational studies.

PURPOSE: This study aims to systematically review studies quantifying the associations between antidepressants (ADs) use and the risk of cardiovascular (CV) outcomes. METHODS: Medline was searched to October 2015 for full text articles in English. Prospective cohort and case-control studies were admitted if they investigated the relationship between current use of ADs as a whole, tricyclic antidepressants (TCAs) or selective serotonin reuptake inhibitors (SSRIs), and the onset CV events. Summary relative risks (RRs) with confidence intervals (CIs) were calculated using random-effects or fixed-effects models. RESULTS: A total of 99,367 incident cases of CV outcomes who met inclusion criteria were identified from 22 observational studies. Compared with no users of ADs, use of SSRIs was associated with an increased risk of cerebrovascular disease (RRs, 1.24; 95% CI, 1.15 to 1.34), while the use of TCA was associated with an increased risk of acute heart disease (RRs, 1.29; 95% CI, 1.09 to 1.54). CONCLUSIONS: The results of this meta-analysis have to be taken with caution because even though an increased risk of cerebrovascular and acute heart disease was observed respectively in SSRIs and TCA users, the estimates are characterized by a high between study heterogeneity. Moreover, it was not possible to distinguish between the effects of ADs and depression itself. Further well-designed studies are required to confirm this association.

Sphingosine-1-phosphate restores endothelial barrier integrity in ovarian hyperstimulation syndrome.

STUDY QUESTION: Are follicular fluid (FF) sphingosine-1-phosphate (S1P) levels in patients at risk of developing ovarian hyperstimulation syndrome (OHSS) altered and in part responsible for the high vascular permeability observed in these patients. STUDY ANSWER: FF S1P levels are lower in FF from patients at risk of OHSS and treatment with S1P may reduce vascular permeability in these patients. WHAT IS KNOWN ALREADY: Although advances have been made in the diagnosis, and management of OHSS and in basic knowledge of its development, complete prevention has proven difficult. STUDY DESIGN, SIZE, DURATION: A total of 40 FF aspirates were collected from patients undergoing ART. The women (aged 25-39 years old) were classified into a control group (n = 20) or a group at risk of OHSS (n = 20). The EA.hy926 endothelial cell line was used to assess the efffects of FF from patients at risk of OHSS with or without the addition of S1P. An animal model that develops OHSS in immature Sprague-Dawley rats were also used. PARTICIPANTS/MATERIALS, SETTING, METHODS: Migration assays, confocal microscopy analysis of actin filaments, immunoblotting and quail chorioallantoic membrane (CAM) assays of in-vivo angiogenesis were performed and statistical comparisons between groups were made. MAIN RESULTS AND THE ROLE OF CHANCE: The S1P concentration was significantly lower in FF from patients at risk of OHSS (P = 0.03). The addition of S1P to this FF decreased cell migration (P < 0.05) and prevented VE-cadherin phosphorylation in endothelial cells (P < 0.05). S1P in the FF from patients at risk of OHSS increased the levels of VE-cadherin (P < 0.05), N-cadherin (P < 0.05) and ß-catenin (P < 0.05), and partially reversed actin redistribution in endothelial cells. The addition of S1P in FF from patients at risk of OHSS also decreased the levels of vascular endothelial growth factor (VEGF121; P < 0.01) and S1P lyase (SPL; P < 0.05) and increased the levels of S1PR1 (P < 0.05) in endothelial cells. In CAMs incubated with FF from patients at risk of OHSS with S1P, the number of vessel branch points decreased while the periendothelial cell coverage increased. Additionally, in a rat OHSS model, we demonstrated that vascular permeability and VEGF121 and its receptor KDR expression were increased in the OHSS group compared to the control group and that S1P administration decreased these parameters. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: The results of this study were generated from an in-vitro system. This model reflects the microvasculature in vivo. Even though the ideal model would be the use of human endothelial cells from the ovary, it is obviously not possible to carry out this kind of approach in ovaries of patients from ART. More studies will be necessary to delineate the effects of S1P in the pathogenesis of OHSS. Hence, clinical studies are needed in order to choose the most appropriate method of prevention and management. WIDER IMPLICATIONS OF THE FINDINGS: The use of bioactive sphingolipid metabolites may contribute to finding better and safer therapeutic strategies for the treatment of OHSS and other human diseases that display aberrant vascular leakage. STUDY FUNDING/COMPETING INTERESTS: This work was supported by grants ANPCyT (PICT 2012-897), CONICET (PIP 5471), Roemmers and Baron Foundation, Argentina. The authors declare no conflict of interest.

Design, synthesis, molecular docking and biological evaluation of thiophen-2-iminothiazolidine derivatives for use against Trypanosoma cruzi.

In this study, we designed and synthesized a series of thiophen-2-iminothiazolidine derivatives from thiophen-2-thioureic with good anti-Trypanosoma cruzi activity. Several of the final compounds displayed remarkable trypanocidal activity. The ability of the new compounds to inhibit the activity of the enzyme cruzain, the major cysteine protease of T. cruzi, was also explored. The compounds 3b, 4b, 8b and 8c were the most active derivatives against amastigote form, with significant IC50 values between 9.7 and 6.03µM. The 8c derivative showed the highest potency against cruzain (IC50=2.4µM). Molecular docking study showed that this compound can interact with subsites S1 and S2 simultaneously, and the negative values for the theoretical energy binding (Eb=-7.39kcal·mol(-1)) indicates interaction (via dipole-dipole) between the hybridized sulfur sp(3) atom at the thiazolidine ring and Gly66. Finally, the results suggest that the thiophen-2-iminothiazolidines synthesized are important lead compounds for the continuing battle against Chagas disease.

Extracellular histones reduce survival and angiogenic responses of late outgrowth progenitor and mature endothelial cells.

UNLABELLED: ESSENTIALS: Extracellular histones are highly augmented in sites of neovessel formation, such as regeneration tissues. We studied histone effect on survival and angiogenic activity of mature and progenitor endothelial cells. Extracellular histones trigger apoptosis and pyroptosis and reduce angiogenesis in vivo and in vitro. Histone blockade can be useful as a therapeutic strategy to improve angiogenesis and tissue regeneration. BACKGROUND: Extracellular histones are highly augmented in sites of neovessel formation, like regeneration tissues. Their cytotoxic effect has been studied in endothelial cells, although the mechanism involved and their action on endothelial colony-forming cells (ECFCs) remain unknown. OBJECTIVE: To study the effect of histones on ECFC survival and angiogenic functions and compare it with mature endothelial cells. METHODS AND RESULTS: Nuclear morphology analysis showed that each human recombinant histone triggered both apoptotic-like and necrotic-like cell deaths in both mature and progenitor endothelial cells. While H1 and H2A exerted a weak toxicity, H2B, H3 and H4 were the most powerful. The percentage of apoptosis correlated with the percentage of ECFCs exhibiting caspase-3 activation and was zeroed by the pan-caspase inhibitor Z-VAD-FMK. Necrotic-like cell death was also suppressed by this compound and the caspase-1 inhibitor Ac-YVAD-CMK, indicating that histones triggered ECFC pyroptosis. All histones, at non-cytotoxic concentrations, reduced migration and H2B, H3 and H4 induced cell cycle arrest and impaired tubulogenesis via p38 activation. Neutrophil-derived histones exerted similar effects. In vivo blood vessel formation in the quail chorioallantoic membrane was also reduced by H2B, H3 and H4. Their cytotoxic and antiangiogenic effects were suppressed by unfractioned and low-molecular-weight heparins and the combination of TLR2 and TLR4 blocking antibodies. CONCLUSIONS: Histones trigger both apoptosis and pyroptosis of ECFCs and inhibit their angiogenic functions. Their cytotoxic and antiangiogenic effects are similar in mature endothelial cells and disappear after heparin addition or TLR2/TLR4 blockade, suggesting both as therapeutic strategies to improve tissue regeneration.

Risk of cardiac valvulopathy with use of bisphosphonates: a population-based, multi-country case-control study.

UNLABELLED: Analyses of healthcare data from 30 million individuals in three countries showed that current use of bisphosphonates may be associated with a small increased risk of cardiac valvulopathy (vs. those not exposed within the previous year), although confounding cannot be entirely ruled out. The observed tendency for decreased valvulopathy risk with cumulative duration of bisphosphonate use >6 months may even indicate a protective effect with prolonged use. Further studies are still needed to evaluate whether bisphosphonates increase or decrease the risk of valvulopathy. INTRODUCTION: A signal of cardiac valve disorders with use of bisphosphonates was identified in the literature and EudraVigilance database, which contains reports of suspected adverse drug reactions from worldwide sources. The aim of this study was to evaluate the association using population-based healthcare data. METHODS: This was a case-control study among users of bisphosphonates and other drugs for osteoporosis in six healthcare databases covering over 30 million individuals in Italy, Netherlands and the UK from 1996 to 2012. Prescriptions/dispensations were used to assess drug exposure. Newly diagnosed cases of cardiac valvulopathy were identified via disease codes/free-text search. Controls were matched to each case by age, sex, database and index date. Adjusted odds ratios (ORs) were estimated using conditional logistic regression for the pooled data and meta-analysis of individual database risk estimates. RESULTS: A small but statistically significant association was found between exposure to bisphosphonates as a class and risk of valvulopathy. Overall risk was 18 % higher (95 % CI 12-23 %) in those currently exposed to any bisphosphonate (mainly alendronate and risedronate) vs. those not exposed within the previous year. Risk of valve regurgitation was 14 % higher (95 % CI 7-22 %). Decreased valvulopathy risk was observed with longer cumulative duration of bisphosphonate use, compared to use of less than 6 months. Meta-analyses of database-specific estimates confirmed results from pooled analyses. CONCLUSIONS: The observed increased risks of cardiac valvulopathy with bisphosphonate use, although statistically significant, were quite small and unlikely to be clinically significant. Further studies are still needed to evaluate whether bisphosphonates increase or decrease the risk of valvulopathy and to investigate possible mechanisms for the association.

In-silico analyses of natural products on leishmania enzyme targets.

Natural products are compounds that are isolated from plants, provide a variety of lead structures for the development of new drugs by the pharmaceutical industry. The interest in these substances increases because of their beneficial effects on human health, which include antiviral, antiallergic, antiplatelet, anti-inflammatory, antitumor, antioxidant, and antiparasitic activities. Leishmaniasis is the infection caused by protozoa of the genus Leishmania, which affects mainly people who live in poor countries, and can cause chronic fever, liver problems, anemia, and other blood problems. Current chemotherapies against the disease cause side effects, and are ineffective. There are no vaccines, and new chemotherapeutic agents for the treatment of leishmaniasis are greatly needed. This work reports on some of the enzymatic targets studied in the development of new drugs using natural products as inhibitors for the treatment of leishmaniasis. We applied ligand-based-virtual screening using Random Forest, associated with structure-based-virtual screening (docking), of a small dataset of 683 flavonoids and derivatives from an in-house data bank to select structures with potential inhibitory activity against pyruvate kinase, an important enzyme in Leishmania mexicana's energy production chemistry. The computer-aided drug design studies revealed good results against Leishmaniasis for flavones.

Benzo- and thienobenzo- diazepines: multi-target drugs for CNS disorders.

Benzodiazepines (BZ or BZD) are a class of gabaminergic psychoactive chemicals used in hypnotics, sedation, in the treatment of anxiety, and in other CNS disorders. These drugs include alprazolam (Xanax), diazepam (Valium), clonazepam (Klonopin), and others. There are two distinct types of pharmacological binding sites for benzodiazepines in the brain (BZ1 and BZ2), these sites are on GABA-A receptors, and are classified as short, intermediate, or long-acting. From the thienobenzodiazepine class (TBZ), Olanzapine (2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine) (Zyprexa) was used as an example to demonstrate the antagonism of this class of compounds for multiples receptors including: dopamine D1-D5, α-adrenoreceptor, histamine H1, muscarinic M1-M5 and 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3 and 5-HT6 receptors. Olanzapine is an atypical antipsychotic agent, structurally related to clozapine, and extensively used for the treatment of schizophrenia, bipolar disorder-associated mania, and the behavioral symptoms of Alzheimer's disease. The functional blockade of these multiple receptors contributes to the wide range of its pharmacologic and therapeutic activities, having relatively few side effects when compared to other antipsychotics agents. Thienobenzodiazepines (such as Olanzapine) are characterized as multi- receptor- targeted- acting- agents. This mini-review discusses these 2 drug classes that act on the central nervous system, the main active compounds used, and the various receptors with which they interact. In addition, we propose 12 olanzapine analogues, and generated Random Forest models, from a data set obtained from the ChEMBL database, to classify the structures as active or inactive against 5 dopamine receptors (D1, D2, D3, D4, D5 and D6), and dopamine transporter.

Assessment of immature platelet fraction and immature reticulocyte fraction as predictors of engraftment after hematopoietic stem cell transplantation.

INTRODUCTION: Engraftment is a critical milestone of the hematopoietic stem cell transplantation (HSCT) process. The immature platelet fraction (IPF) and immature reticulocyte fraction (IRF) are considered early indicators of bone marrow recovery. The objective of this study was to assess these parameters as predictors of HSCT engraftment. METHODS: Neutrophil and platelet engraftment were defined as the first of three consecutive days with an absolute neutrophil count >0.5 × 10(9) /L or platelet count >20 × 10(9) /L, respectively. The IRF cutoff was 12%. Two IPF cutoffs were used: >6.2% and >10%. RESULTS: The study sample comprised 44 patients, of whom 24 had undergone autologous HSCT and 20 had undergone allogeneic HSCT. Absolute neutrophil counts >0.5 × 10(9) /L were preceded by IRF >12% in 86% of patients (38 of 44). Platelet counts >20 × 10(9) /L were preceded by an IPF >6.2% in 90% of patients (37 of 41) and by an IPF >10% in 63% of patients (26 of 41). CONCLUSION: The results show that IRF and IPF are engraftment predictors. Peak in IPF was observed before rise in platelet count, while IRF rises before absolute neutrophil count (ANC) and persists increased. This indicates that IRF and IPF can be considered as new tools for hematopoietic assessment after HSCT.

Alcohol consumption and site-specific cancer risk: a comprehensive dose-response meta-analysis.

BACKGROUND: Alcohol is a risk factor for cancer of the oral cavity, pharynx, oesophagus, colorectum, liver, larynx and female breast, whereas its impact on other cancers remains controversial. METHODS: We investigated the effect of alcohol on 23 cancer types through a meta-analytic approach. We used dose-response meta-regression models and investigated potential sources of heterogeneity. RESULTS: A total of 572 studies, including 486 538 cancer cases, were identified. Relative risks (RRs) for heavy drinkers compared with nondrinkers and occasional drinkers were 5.13 for oral and pharyngeal cancer, 4.95 for oesophageal squamous cell carcinoma, 1.44 for colorectal, 2.65 for laryngeal and 1.61 for breast cancer; for those neoplasms there was a clear dose-risk relationship. Heavy drinkers also had a significantly higher risk of cancer of the stomach (RR 1.21), liver (2.07), gallbladder (2.64), pancreas (1.19) and lung (1.15). There was indication of a positive association between alcohol consumption and risk of melanoma and prostate cancer. Alcohol consumption and risk of Hodgkin's and Non-Hodgkin's lymphomas were inversely associated. CONCLUSIONS: Alcohol increases risk of cancer of oral cavity and pharynx, oesophagus, colorectum, liver, larynx and female breast. There is accumulating evidence that alcohol drinking is associated with some other cancers such as pancreas and prostate cancer and melanoma.

The influence of emotional stress on Doppler-derived aortic peak velocity in boxer dogs.

BACKGROUND: Subaortic stenosis (SAS) is a common congenital heart disease in Boxers. Doppler-derived aortic peak velocity (AoPV) is a diagnostic criterion for the disease. OBJECTIVES: To investigate the influence of emotional stress during echocardiographic examination on AoPV in normal and SAS-affected Boxers. To evaluate the effects of aortic root diameters on AoPV in normal Boxers. DOGS: Two hundred and fifteen normal and 19 SAS-affected Boxers. METHODS: The AoPV was recorded at the beginning of echocardiographic examination (T0), and when the emotional stress of the dog was assumed to decrease based on behavioral parameters and heart rate (T1). AoPV0-AoPV1 was calculated. In normal dogs, stroke volume index was calculated at T0 and T1. Aortic root diameters were measured and their relationship with AoPV and AoPV0-AoPV1 was evaluated. RESULTS: In normal dogs, AoPV was higher at T0 (median, 1.95 m/s; range, 1.60-2.50 m/s) than at T1 (median, 1.76 m/s; range, 1.40-2.20 m/s; P < .0001; reduction 9.2%). The stroke volume index at T0 also was greater than at T1 (P < .0001). Weak negative correlations were detected between aortic root size and aortic velocities. In SAS-affected dogs, AoPV0 was higher than AoPV1 (P < .0001; reduction 7.3%). CONCLUSION AND CLINICAL IMPORTANCE: Aortic peak velocity was affected by emotional stress during echocardiographic examination both in SAS-affected and normal Boxers. In normal Boxers, aortic root size weakly affected AoPVs, but did not affect AoPV0-AoPV1. Stroke volume seems to play a major role in stress-related AoPV increases in normal Boxers. Emotional stress should be taken into account when screening for SAS in the Boxer breed.

Alcohol drinking and cutaneous melanoma risk: a systematic review and dose-risk meta-analysis.

It has been suggested that alcohol intake increases sunburn severity, a major risk factor for cutaneous melanoma (CM). Several epidemiological studies have investigated the relationship between alcohol consumption and CM, but the evidence is inconsistent. Therefore, we aimed to quantify this relationship better, using a meta-analytical approach. The dose-risk relationship was also modelled through a class of flexible nonlinear meta-regression random effects models. The present meta-analysis included 16 studies (14 case-control and two cohort investigations) with a total of 6251 cases of CM. The pooled relative risk (RR) for any alcohol drinking compared with no/occasional drinking was 1·20 [95% confidence interval (CI) 1·06-1·37]. The risk estimate was similar in case-control (RR 1·20, 95% CI 1·01-1·44) and cohort studies (RR 1·26, 95% CI 1·19-1·35). The pooled RR was 1·10 (95% CI 0·96-1·26) for light alcohol drinking (≤ 1 drink per day) and 1·18 (95% CI 1·01-1·40) for moderate-to-heavy drinking. The pooled RR from 10 studies adjusting for sun exposure was 1·15 (95% CI 0·94-1·41), while the RR from six unadjusted studies was 1·27 (95% CI 1·20-1·35). No evidence of publication bias was detected. This meta-analysis of published data reveals that alcohol consumption is positively associated with the risk of CM. However, caution in interpreting these results is required, as residual confounding by sun exposure cannot be ruled out.

Acute abdominal aortic thrombosis caused by paroxysmal atrial fibrillation.

Acute abdominal aortic thrombosis is a rare and potential fatal event, which occurs in adult subjects. We present the case of a 72-year-old-man, who referred to the emergency Department of our hospital because of persistent severe abdominal and perineal pain. Doppler ultrasounds and computerized tomography angiography revealed the acute thrombosis of the abdominal aorta. Immediate revascularization through aortic thrombo-endoarterectomy resolved the disease.