Prior drug allergies are associated with worse outcome in patients with idiosyncratic drug-induced liver injury: A machine learning approach for risk stratification.

The impact of prior drug allergies (PDA) on the clinical features and outcomes of patients who develop idiosyncratic drug-induced liver injury (DILI) is largely unknown. We aimed to assess the clinical presentation and outcomes of DILI patients based on the presence or absence of PDA and explore the association between culprit drugs responsible for DILI and allergy. We analysed a well-vetted cohort of DILI cases enrolled from the Spanish DILI Registry. Bootstrap-enhanced least absolute shrinkage operator procedure was used in variable selection, and a multivariable logistic model was fitted to predict poor outcomes in DILI. Of 912 cases with a first episode of DILI, 61 (6.7%) had documented PDA. Patients with PDA were older (p = 0.009), had higher aspartate aminotransferase (AST) levels (p = 0.047), lower platelet count (p = 0.011) and higher liver-related mortality than those without a history of drug allergies (11% vs. 1.6%, p < 0.001). Penicillin was the most common drug associated with PDA in DILI patients (32%). A model including PDA, nR-based type of liver injury, female sex, AST, total bilirubin, and platelet count showed an excellent performance in predicting poor outcome in patients from the Spanish DILI Registry (area under the ROC curve [AUC] 0.887; 95% confidence interval [CI] 0.794 - 0.981) and the LATINDILI Network (AUC 0.932; 95% CI 0.884 - 0.981). Patients with suspected DILI should be screened for PDA as they would require a close monitoring for early detection of worsening clinical course.

COVID-19 and common mental health symptoms in the early phase of the pandemic: An umbrella review of the evidence.

BACKGROUND: There remains uncertainty about the impact of the Coronavirus Disease 2019 (COVID-19) pandemic on mental health. This umbrella review provides a comprehensive overview of the association between the pandemic and common mental disorders. We qualitatively summarized evidence from reviews with meta-analyses of individual study-data in the general population, healthcare workers, and specific at-risk populations. METHODS AND FINDINGS: A systematic search was carried out in 5 databases for peer-reviewed systematic reviews with meta-analyses of prevalence of depression, anxiety, and post-traumatic stress disorder (PTSD) symptoms during the pandemic published between December 31, 2019 until August 12, 2022. We identified 123 reviews of which 7 provided standardized mean differences (SMDs) either from longitudinal pre- to during pandemic study-data or from cross-sectional study-data compared to matched pre-pandemic data. Methodological quality rated with the Assessment of Multiple Systematic Reviews checklist scores (AMSTAR 2) instrument was generally low to moderate. Small but significant increases of depression, anxiety, and/or general mental health symptoms were reported in the general population, in people with preexisting physical health conditions, and in children (3 reviews; SMDs ranged from 0.11 to 0.28). Mental health and depression symptoms significantly increased during periods of social restrictions (1 review; SMDs of 0.41 and 0.83, respectively) but anxiety symptoms did not (SMD: 0.26). Increases of depression symptoms were generally larger and longer-lasting during the pandemic (3 reviews; SMDs depression ranged from 0.16 to 0.23) than those of anxiety (2 reviews: SMDs 0.12 and 0.18). Females showed a significantly larger increase in anxiety symptoms than males (1 review: SMD 0.15). In healthcare workers, people with preexisting mental disorders, any patient group, children and adolescents, and in students, no significant differences from pre- to during pandemic were found (2 reviews; SMD's ranging from -0.16 to 0.48). In 116 reviews pooled cross-sectional prevalence rates of depression, anxiety, and PTSD symptoms ranged from 9% to 48% across populations. Although heterogeneity between studies was high and largely unexplained, assessment tools and cut-offs used, age, sex or gender, and COVID-19 exposure factors were found to be moderators in some reviews. The major limitations are the inability to quantify and explain the high heterogeneity across reviews included and the shortage of within-person data from multiple longitudinal studies. CONCLUSIONS: A small but consistent deterioration of mental health and particularly depression during early pandemic and during social restrictions has been found in the general population and in people with chronic somatic disorders. Also, associations between mental health and the pandemic were stronger in females and younger age groups than in others. Explanatory individual-level, COVID-19 exposure, and time-course factors were scarce and showed inconsistencies across reviews. For policy and research, repeated assessments of mental health in population panels including vulnerable individuals are recommended to respond to current and future health crises.

Risk of SARS-CoV-2 infection, severe COVID-19 illness and COVID-19 mortality in people with pre-existing mental disorders: an umbrella review.

INTRODUCTION: The COVID-19 pandemic has posed a serious health risk, especially in vulnerable populations. Even before the pandemic, people with mental disorders had worse physical health outcomes compared to the general population. This umbrella review investigated whether having a pre-pandemic mental disorder was associated with worse physical health outcomes due to the COVID-19 pandemic. METHODS: Following a pre-registered protocol available on the Open Science Framework platform, we searched Ovid MEDLINE All, Embase (Ovid), PsycINFO (Ovid), CINAHL, and Web of Science up to the 6th of October 2021 for systematic reviews on the impact of COVID-19 on people with pre-existing mental disorders. The following outcomes were considered: risk of contracting the SARS-CoV-2 infection, risk of severe illness, COVID-19 related mortality risk, risk of long-term physical symptoms after COVID-19. For meta-analyses, we considered adjusted odds ratio (OR) as effect size measure. Screening, data extraction and quality assessment with the AMSTAR 2 tool have been done in parallel and duplicate. RESULTS: We included five meta-analyses and four narrative reviews. The meta-analyses reported that people with any mental disorder had an increased risk of SARS-CoV-2 infection (OR: 1.71, 95% CI 1.09-2.69), severe illness course (OR from 1.32 to 1.77, 95%CI between 1.19-1.46 and 1.29-2.42, respectively) and COVID-19 related mortality (OR from 1.38 to 1.52, 95%CI between 1.15-1.65 and 1.20-1.93, respectively) as compared to the general population. People with anxiety disorders had an increased risk of SAR-CoV-2 infection, but not increased mortality. People with mood and schizophrenia spectrum disorders had an increased COVID-19 related mortality but without evidence of increased risk of severe COVID-19 illness. Narrative reviews were consistent with findings from the meta-analyses. DISCUSSION AND CONCLUSIONS: As compared to the general population, there is strong evidence showing that people with pre-existing mental disorders suffered from worse physical health outcomes due to the COVID-19 pandemic and may therefore be considered a risk group similar to people with underlying physical conditions. Factors likely involved include living accommodations with barriers to social distancing, cardiovascular comorbidities, psychotropic medications and difficulties in accessing high-intensity medical care.

Activation of NLRP3 Inflammasome in Liver of Long Evans Lactating Rats and Its Perinatal Effects in the Offspring after Bisphenol F Exposure.

The liver is the organ responsible for the metabolism and detoxification of BPF, the BPA analogue that is replacing it in plastic-based products. It is not known whether BPF can trigger inflammatory responses via the NLRP3 inflammasome, which plays a major role in the development of liver disease. The aim of this study was to evaluate nitrosative stress species (RNS) and NLRP3 inflammasome activation in the liver of lactating dams after BPF exposure. Moreover, it was studied whether this effect could also be observed in the liver of female and male offspring at postnatal day 6 (PND6). 36 Long Evans rats were randomly distributed according to oral treatment into three groups: Control, BPF-low dose (LBPF; 0.0365 mg/kg b.w./day) group and BPF-high dose (HBPF; 3.65 mg/kg b.w./day) group. The levels of nitrosative stress-inducing proteins (eNOS, iNOS, HO-1d), NLRP3 inflammasome components (NLRP3, PyCARD, CASP1) and proinflammatory cytokines (IL-1ß, IL-18, IFN-γ and TNF-α) were measured by gene and protein expression in the liver of lactating dams and in female and male PND6 offspring. Lactating dams treated with LBPF showed a significant increase in iNOS and HO-1d, activation of NLRP3 components (NLRP3, PyCARD, CASP1) and promoted the release of proinflammatory cytokines such as IL-1ß, IL-18, IFN-γ and TNF-α. Similar effects were found in female and male PND6 offspring after perinatal exposure. LBPF oral administration and perinatal exposure caused an increase of nitrosative stress markers and proinflammatory cytokines. Also, NLRP3 inflammasome activation was significantly increased in in the liver of lactating dams and PND6 offspring.

Herbal and Dietary Supplements-Induced Liver Injury in Latin America: Experience From the LATINDILI Network.

BACKGROUND: Herbal and dietary supplements (HDS) consumption, a growing cause of hepatotoxicity, is a common practice among Latin-American populations. OBJECTIVES: To evaluate clinical, laboratory features and outcome in HDS-hepatotoxicity included in the Latin America-Drug Induced Liver Injury (LATINDILI) Network. METHODS: A total of 29 adjudicated cases of HDS hepatotoxicity reported to the LATINDILI Network from October 2011 through December 2019 were compared with 322 DILI cases due to conventional drugs and 16 due to anabolic steroids as well as with other series of HDS-hepatotoxicity. RESULTS: From 367 DILI cases, 8% were attributed to HDS. An increasing trend in HDS-hepatotoxicity was noted over time (p = .04). Camellia sinensis, Herbalife® products, and Garcinia cambogia, mostly used for weight loss, were the most frequently adjudicated causative agents. Mean age was 45 years (66% female). Median time to onset was 31 days. Patients presented typically with hepatocellular injury (83%) and jaundice (66%). Five cases (17%) developed acute liver failure. Compared to conventional medications and anabolic steroids, HDS hepatotoxicity cases had the highest levels of aspartate and alanine transaminase (p = .008 and p = .021, respectively), had more re-exposure events to the culprit HDS (14% vs 3% vs 0%; p = .026), and had more severe and fatal/liver transplantation outcomes (21% vs 12% vs 13%; p = .005). Compared to other DILI cohorts, less HDS hepatotoxicity cases in Latin America were hospitalized (41%). CONCLUSIONS: HDS-hepatotoxicity in Latin-America affects mainly young women, manifests mostly with hepatocellular injury and is associated with higher frequency of accidental re-exposure. HDS hepatotoxicity is more serious with a higher chance of death/liver transplantation than DILI related to conventional drugs.

Lysyl-tRNA synthetase as a drug target in malaria and cryptosporidiosis.

Malaria and cryptosporidiosis, caused by apicomplexan parasites, remain major drivers of global child mortality. New drugs for the treatment of malaria and cryptosporidiosis, in particular, are of high priority; however, there are few chemically validated targets. The natural product cladosporin is active against blood- and liver-stage Plasmodium falciparum and Cryptosporidium parvum in cell-culture studies. Target deconvolution in P. falciparum has shown that cladosporin inhibits lysyl-tRNA synthetase (PfKRS1). Here, we report the identification of a series of selective inhibitors of apicomplexan KRSs. Following a biochemical screen, a small-molecule hit was identified and then optimized by using a structure-based approach, supported by structures of both PfKRS1 and C. parvum KRS (CpKRS). In vivo proof of concept was established in an SCID mouse model of malaria, after oral administration (ED90 = 1.5 mg/kg, once a day for 4 d). Furthermore, we successfully identified an opportunity for pathogen hopping based on the structural homology between PfKRS1 and CpKRS. This series of compounds inhibit CpKRS and C. parvum and Cryptosporidium hominis in culture, and our lead compound shows oral efficacy in two cryptosporidiosis mouse models. X-ray crystallography and molecular dynamics simulations have provided a model to rationalize the selectivity of our compounds for PfKRS1 and CpKRS vs. (human) HsKRS. Our work validates apicomplexan KRSs as promising targets for the development of drugs for malaria and cryptosporidiosis.

Preclinical candidate for the treatment of visceral leishmaniasis that acts through proteasome inhibition.

Visceral leishmaniasis (VL), caused by the protozoan parasites Leishmania donovani and Leishmania infantum, is one of the major parasitic diseases worldwide. There is an urgent need for new drugs to treat VL, because current therapies are unfit for purpose in a resource-poor setting. Here, we describe the development of a preclinical drug candidate, GSK3494245/DDD01305143/compound 8, with potential to treat this neglected tropical disease. The compound series was discovered by repurposing hits from a screen against the related parasite Trypanosoma cruzi Subsequent optimization of the chemical series resulted in the development of a potent cidal compound with activity against a range of clinically relevant L. donovani and L. infantum isolates. Compound 8 demonstrates promising pharmacokinetic properties and impressive in vivo efficacy in our mouse model of infection comparable with those of the current oral antileishmanial miltefosine. Detailed mode of action studies confirm that this compound acts principally by inhibition of the chymotrypsin-like activity catalyzed by the ß5 subunit of the L. donovani proteasome. High-resolution cryo-EM structures of apo and compound 8-bound Leishmania tarentolae 20S proteasome reveal a previously undiscovered inhibitor site that lies between the ß4 and ß5 proteasome subunits. This induced pocket exploits ß4 residues that are divergent between humans and kinetoplastid parasites and is consistent with all of our experimental and mutagenesis data. As a result of these comprehensive studies and due to a favorable developability and safety profile, compound 8 is being advanced toward human clinical trials.

[Optimizing blood pressure control through telemedicine in Primary Care in Spain (Iniciativa Óptima): Results from a Delphi study]. / Optimización del control telemático de la presión arterial en atención primaria en España (Iniciativa Óptima): resultados de un estudio Delphi.

AIM: Members of the working groups on hypertension or cardiovascular disease of the Spanish Societies of Primary Care Physicians (PCPs) [SEMERGEN], Family and Community Medicine [semFYC] and General and Family Physicians [SEMG], conducted a Delphi study to validate with a panel of PCPs with expertise in hypertension several recommendations to optimize teleconsultation in hypertensive patients. MATERIALS AND METHODS: Delphi study based on an online questionnaire with 59 recommendations based on the available evidence and the clinical experience of the authors. RESULTS: 118 PCPs participated in two rounds of the questionnaire (98.3% of the invited physicians), reaching consensus in 53/62 statements (85%). The Primary Care team must proactively select the hypertensive patients suitable for telematic consultation and contact them to set up an appointment. Telematic consultation must begin explaining the reason and aims pursued, continuing with anamnesis, which must explore signs and symptoms of disease worsening, current treatments and level of adherence. In patients with a home blood pressure measurement (HBPM) ≤135/85mmHg, it is recommended to schedule a new telematic appointment in 3-6months. On the contrary, asymptomatic patients with a HBPM ≥135/85mmHg should undergo ambulatory blood pressure monitoring, treatment modification or, in case of warning signs or symptoms, referral to a face-to-face visit or to emergency department. CONCLUSIONS: Teleconsultation can complement face-to-face consultation, constituting an additional tool for the appropriate follow-up of hypertensive patients.

A novel multiple-stage antimalarial agent that inhibits protein synthesis.

There is an urgent need for new drugs to treat malaria, with broad therapeutic potential and novel modes of action, to widen the scope of treatment and to overcome emerging drug resistance. Here we describe the discovery of DDD107498, a compound with a potent and novel spectrum of antimalarial activity against multiple life-cycle stages of the Plasmodium parasite, with good pharmacokinetic properties and an acceptable safety profile. DDD107498 demonstrates potential to address a variety of clinical needs, including single-dose treatment, transmission blocking and chemoprotection. DDD107498 was developed from a screening programme against blood-stage malaria parasites; its molecular target has been identified as translation elongation factor 2 (eEF2), which is responsible for the GTP-dependent translocation of the ribosome along messenger RNA, and is essential for protein synthesis. This discovery of eEF2 as a viable antimalarial drug target opens up new possibilities for drug discovery.

Profile of herbal and dietary supplements induced liver injury in Latin America: A systematic review of published reports.

Hepatotoxicity related to HDS is a growing global health issue. We have undertaken a systematic review of published case reports and case series from LA from 1976 to 2020 to describe the clinical features of HDS related hepatotoxicity in this region. We search in PubMed, Web of Science, Scopus and specific LA databases according to PRISMA guidelines. Only HILI cases published in LA that met criteria for DILI definition were included. Duplicate records or reports that lacked relevant data that precluded establishing causality were excluded. Finally, 17 records (23 cases) were included in this review. Centella asiatica, Carthamus tinctorius, and Herbalife® were the most reported HDS culprit products, the main reason for HDS consumption was weight loss. The clinical characteristics of HDS hepatotoxicity in our study were compared to those of other studies in the USA, Europe and China showing a similar signature with predominance of young females, hepatocellular damage, a high rate of ALF and mortality, more frequent inadvertent re-challenge and chronic damage. This study underscores the challenge in causality assessment when multi-ingredients HDS are taken and the need for consistent publication practice when reporting hepatotoxicity cases due to HDS, to foster HDS liver safety particularly in LA.

Cross-national prevalence and factors associated with suicide ideation and attempts in older and young-and-middle age people.

Objectives: To report prevalence estimates of 12-month suicide ideation and attempts in young-and-middle age adults and older people, as well as their respective associated factors.Methods: A total of 52,150 community-dwelling adults who completed the adapted version of the Composite International Diagnostic Interview-Depression Module were included from SAGE and COURAGE in Europe studies. The presence of 12-month suicide ideation and attempts was measured among the participants who screened positively in the Depression Module. Global and national prevalence estimates of 12-month suicide ideation and attempts were calculated according to the total sample. Logistic regression analyses were conducted to separately determine factors associated with suicidal ideation and with suicide attempts in young-and-middle age adults and older adults.Results: Higher estimates of 12-month suicidal ideation were found for high-income countries and people aged 65 years and older. Higher negative affect, higher disability, and presence of food insecurity were associated with 12-month suicidal ideation and suicide attempts for young-and-middle-adults and older adults. Higher isolation, being female, and greater number of chronic health conditions were also related to 12-month suicidal ideation in both age groups. Younger age was associated with 12-month suicidal ideation for older people, and with suicide attempts in the young-and-middle age group. Finally, higher income was related to lower rates of 12-month suicidal ideation for the young-and-middle age group.Conclusions: Older people are at increased risk of suicidal ideation globally and of suicide attempts in some countries. There were common and different factors related to suicide in adults and older adults.

Microcystin-RR: Occurrence, content in water and food and toxicological studies. A review.

Microcystins (MCs) are hepatotoxins, produced by various species of cyanobacteria, whose occurrence is increasing worldwide owing to climate change and anthropogenic activities. More than 100 variants have been reported, and among them MC-LR is the most extensively studied, but there are other MC congeners that deserve to be investigated. The need for data to characterize the toxicological profile of MC variants other than MC-LR has been identified in order to improve risk assessment in humans and wildlife. Accordingly, the aim of this study was to evaluate the information available in the scientific literature dealing with MC-RR, as this congener is the second most common cyanotoxin in the environment. The review focuses on aspects such as occurrence in water and food, and toxicity studies both in vitro and in vivo. It reveals that, although MC-RR is a real hazard with a high exposure potential in some countries, little is known yet about its specific toxicological properties that differ from those of MC-LR, and important aspects such as genotoxicity and chronic effects have not yet been sufficiently addressed.

Herbal and Dietary Supplement-Induced Liver Injuries in the Spanish DILI Registry.

BACKGROUND & AIMS: There have been increasing reports of liver injury associated with use of herbal and dietary supplements, likely due to easy access to these products and beliefs among consumers that they are safer or more effective than conventional medications. We aimed to evaluate clinical features and outcomes of patients with herbal and dietary supplement-induced liver injuries included in the Spanish DILI Registry. METHODS: We collected and analyzed data on demographic and clinical features, along with biochemical parameters, of 32 patients with herbal and dietary supplement-associated liver injury reported to the Spanish DILI registry from 1994 through 2016. We used analysis of variance to compare these data with those from cases of liver injury induced by conventional drugs or anabolic androgenic steroid-containing products. RESULTS: Herbal and dietary supplements were responsible for 4% (32 cases) of the 856 DILI cases in the registry; 20 cases of DILI (2%) were caused by anabolic androgenic steroids. Patients with herbal and dietary supplement-induced liver injury were a mean age of 48 years and 63% were female; they presented a mean level of alanine aminotransferase 37-fold the upper limit of normal, 28% had hypersensitivity features, and 78% had jaundice. Herbal and dietary supplement-induced liver injury progressed to acute liver failure in 6% of patients, compared with none of the cases of anabolic androgenic steroid-induced injury and 4% of cases of conventional drugs. Liver injury after repeat exposure to the same product that caused the first DILI episode occurred in 9% of patients with herbal and dietary supplement-induced liver injury vs none of the patients with anabolic androgenic steroid-induced injury and 6% of patients with liver injury from conventional drugs. CONCLUSION: In an analysis of cases of herbal and dietary supplement-induced liver injury in Spain, we found cases to be more frequent among young women than older patients or men, and to associate with hepatocellular injury and high levels of transaminases. Herbal and dietary supplement-induced liver injury is more severe than other types of DILI and re-exposure is more likely. Increasing awareness of the hepatoxic effects of herbal and dietary supplements could help physicians make earlier diagnoses and reduce the risk of serious liver damage.

Use of micronucleus and comet assay to evaluate evaluate the genotoxicity of oregano essential oil (Origanum vulgare l. Virens) in rats orally exposed for 90 days.

Essential oils from Origanum spp. exhibit antioxidant and antimicrobial activities making them suitable for use as food additives. The incorporation of oregano essential oil in active food packaging is under study; however, it has been not authorized for this purpose thus far. In order to fulfill the requirements of the European Food Safety Authority (EFSA), the aim of the present study was to determine the genotoxic potential of oregano essential oil using both the micronucleus (MN) test and comet (standard and enzyme-modified) assays in Wistar rats treated with 50, 100, or 200 mg/kg body weight administered daily for 90 days. MN was performed in cells from the bone marrow and standard and enzyme-modified comet assays were conducted in stomach, liver and blood cells. The major compound detected in the analytical study of oregano essential oil from Origanum vulgare L. virens, was carvacrol (55.82%) followed by thymol (5.14%), as well as their precursors, γ-terpinene (16.39%), and ρ-cimne (4.71%). The results obtained in the genotoxicity assays indicated lack of effect in MN and standard comet assay under the conditions tested. Furthermore, no apparent oxidative damage was observed in the enzyme-modified comet assay in any of the tissues examined of rats exposed to oregano essential oil for 90 days. Therefore, this oregano essential oil appears to be safe in Wistar rats and might be considered as a potential active material in food packaging industry.

The role of unhealthy lifestyles in the incidence and persistence of depression: a longitudinal general population study in four emerging countries.

BACKGROUND: Unhealthy lifestyles and depression are highly interrelated: depression might elicit and exacerbate unhealthy lifestyles and people with unhealthy lifestyles are more likely to become depressed over time. However, few longitudinal evidence of these relationships has been collected in emerging countries. The present study aims i) to analyse whether people with unhealthy lifestyles are more likely to develop depression, and ii) to examine whether depressed people with unhealthy lifestyles are more likely to remain depressed. A total of 7908 participants from Ghana, India, Mexico and Russia were firstly evaluated in the World Health Organization's Study on Global AGEing and Adult Health (SAGE) Wave 0 (2002-2004) and re-evaluated in 2007-2010 (Wave 1). Data on tobacco use, alcohol drinking and physical activity, were collected. Logistic regressions models were employed to assess whether baseline unhealthy lifestyles were related to depression in Wave 1, among people without 12-month depression in Wave 0 and any previous lifetime diagnosis of depression, and to 12-month depression at both study waves (persistent depression). RESULTS: Baseline daily and non-daily smoking was associated with depression in Wave 1. Low physical activity and heavy alcohol drinking were associated with persistent depression. CONCLUSIONS: Unhealthy lifestyles and depression are also positively related in emerging countries. Smoking on a daily and non-daily basis was longitudinally related to depression. Depressed people with low physical activity and with heavy drinking patterns were more likely to become depressed over time. Several interpretations of these results are given. Further studies should check whether a reduction of these unhealthy lifestyles leads to lower depression rates and/or to a better clinical prognosis of depressed people.

Application of a novel regulatable Cre recombinase system to define the role of liver and gut metabolism in drug oral bioavailability.

The relative contribution of hepatic compared with intestinal oxidative metabolism is a crucial factor in drug oral bioavailability and therapeutic efficacy. Oxidative metabolism is mediated by the cytochrome P450 mono-oxygenase system to which cytochrome P450 reductase (POR) is the essential electron donor. In order to study the relative importance of these pathways in drug disposition, we have generated a novel mouse line where Cre recombinase is driven off the endogenous Cyp1a1 gene promoter; this line was then crossed on to a floxed POR mouse. A 40 mg/kg dose of the Cyp1a1 inducer 3-methylcholanthrene (3MC) eliminated POR expression in both liver and small intestine, whereas treatment at 4 mg/kg led to a more targeted deletion in the liver. Using this approach, we have studied the pharmacokinetics of three probe drugs--paroxetine, midazolam, nelfinavir--and show that intestinal metabolism is a determinant of oral bioavailability for the two latter compounds. The Endogenous Reductase Locus (ERL) mouse represents a significant advance on previous POR deletion models as it allows direct comparison of hepatic and intestinal effects on drug and xenobiotic clearance using lower doses of a single Cre inducing agent, and in addition minimizes any cytotoxic effects, which may compromise interpretation of the experimental data.

Molecular characterisation of a bio-based active packaging containing Origanum vulgare L. essential oil using pyrolysis gas chromatography-mass spectrometry.

BACKGROUND: Environmental, economic and safety challenges motivate shift towards safer materials for food packaging. New bioactive packaging techniques, i.e. addition of essential plant oils (EOs), are gaining attention by creating barriers to protect products from spoilage. Analytical pyrolysis gas chromatography-mass spectrometry (Py-GC-MS) was used to fingerprint a bioactive polylactic acid (PLA) with polybutylene succinate (PBS) (950 g kg(-1) :50 g kg(-1) ) film extruded with variable quantities (0, 20, 50 and 100 g kg(-1) ) of Origanum vulgare EO. RESULTS: Main PLA:PBS pyrolysis products were lactide enantiomers and monomer units from the major PLA fraction and succinic acid anhydride from the PBS fraction. Oregano EO pyrolysis released cymene, terpinene and thymol/carvacrol peaks as diagnostic peaks for EO. In fact, linear correlation coefficients better than 0.950R(2) value (P < 0.001) were found between the chromatographic area of the diagnostic peaks and the amount of oregano EO in the bioplastic. CONCLUSION: The pyrolytic behaviour of a bio-based active package polymer including EO is studied in detail. Identified diagnostic compounds provide a tool to monitor the quantity of EO incorporated into the PLA:PBS polymeric matrix. Analytical pyrolysis is proposed as a rapid technique for the identification and quantification of additives within bio-based plastic matrices. © 2015 Society of Chemical Industry.

Modelling sustainable salt water management under deficit irrigation conditions for melon in Spain and Brazil.

BACKGROUND: In water scarcity areas the use of saline water for irrigation is a common practice. In this study, experimental data from two two-year melon tests were collected for the calibration (2004 'Yellow Melon' (YeMe) type) and validation (2002 YeMe, 2005 and 2006 'Piel de Sapo' (PiSa) type) processes in melon crop simulation under deficit irrigation conditions using salt water. The simulations were carried out for Castilla-La Mancha (Spain) and Ceará (Brazil) using the MOPECO model, which includes optimized regulated deficit irrigation (ORDI) methodology. The objective was to determine the most suitable irrigation strategy for both areas. RESULTS: Under fresh water conditions, ORDI may increase yield by up to 20% (PiSa) and 7% (YeMe) compared with constant deficit irrigation. Higher water deficit should be induced during the vegetative development and ripening stages. The rainfall between irrigation periods is able to leach the salts supplied by the irrigation water. CONCLUSION: The combination of ORDI with different strategies for managing saline water may increase water use efficiency. In these areas it may be of interest not to apply the leaching fraction (saving up to 67% of irrigation water). However, leaching of the soluble salts accumulated before starting the most sensitive periods may be suitable.

Risk factors for incidence and persistence of disability in chronic major depression and alcohol use disorders: longitudinal analyses of a population-based study.

BACKGROUND: Major depression and alcohol use disorders are risk factors for incidence of disability. However, it is still unclear whether a chronic course of these health conditions is also prospectively associated with incidence of disability. The aim of the present study was, first, to confirm whether chronic major depression (MD) and alcohol use disorders (AUD) are, respectively, risk factors for persistence and incidence of disability in the general population; and then to analyze the role of help-seeking behavior in the course of disability among respondents with chronic MD and chronic AUD. METHOD: Data from two assessments in the National Epidemiologic Survey on Alcohol and Related Conditions were analyzed. Disability was measured by eight domains of the Short Form 12 Health Survey version 2 (SF-12). Generalized estimating equations and logistic regression models were run to estimate risk factors for persistence and incidence of disability, respectively. RESULTS: Analyses conducted on data from the US general population showed that chronic MD was the strongest risk factor for incidence and persistence of disability in the social functioning, emotional role and mental health domains. Chronic AUD were risk factors for incidence and persistence of disability in the vitality, social functioning, and emotional role domains. Within the group of chronic MD, physical comorbidity and help-seeking were associated with persistent disability in most of the SF-12 domains. Help-seeking behavior was also associated with incidence of problems in the mental health domain for the depression group. Regarding the AUD group, comorbidity with physical health problems was a strong risk factor for persistence of disability in all SF-12 domains. Help-seeking behavior was not related to either persistence or incidence of disability in the chronic alcohol group. CONCLUSIONS: Chronic MD and chronic AUD are independent risk factors for persistence and incidence of disability in the US general population. People with chronic MD seek help for their problems when they experience persistent disability, whereas people with chronic AUD might not seek any help even if they are suffering from persistent disability.