Efficacy and safety of biological treatment for inflammatory bowel disease in elderly patients: Results from a GETECCU cohort.

INTRODUCTION: Biological therapies used for the treatment of inflammatory bowel disease (IBD) have shown to be effective and safe, although these results were obtained from studies involving mostly a young population, who are generally included in clinical trials. The aim of our study was to determine the efficacy and safety of the different biological treatments in the elderly population. METHODS: Multicenter study was carried out in the GETECCU group. Patients diagnosed with IBD and aged over 65 years at the time of initiating biological therapy (infliximab, adalimumab, golimumab, ustekinumab or vedolizumab) were retrospectively included. Among the patients included, clinical response was assessed after drug induction (12 weeks of treatment) and at 52 weeks. Patients' colonoscopy data in week 52 were assessment, where available. Regarding complications, development of oncological events during follow-up and infectious processes occurring during biological treatment were collected (excluding bowel infection by cytomegalovirus). RESULTS: A total of 1090 patients were included. After induction, at approximately 12-14 weeks of treatment, 419 patients (39.6%) were in clinical remission, 502 patients (47.4%) had responded without remission and 137 patients (12.9%) had no response. At 52 weeks of treatment 442 patients (57.1%) had achieved clinical remission, 249 patients had responded without remission (32.2%) and 53 patients had no response to the treatment (6.8%). Before 52 weeks, 129 patients (14.8%) had discontinued treatment due to inefficacy, this being significantly higher (p<0.0001) for Golimumab - 9 patients (37.5%) - compared to the other biological treatments analyzed. With respect to tumor development, an oncological event was observed in 74 patients (6.9%): 30 patients (8%) on infliximab, 23 (7.14%) on adalimumab, 3 (11.1%) on golimumab, 10 (6.4%) on ustekinumab, and 8 (3.8%) on vedolizumab. The incidence was significantly lower (p=0.04) for the vedolizumab group compared to other treatments. As regards infections, these occurred in 160 patients during treatment (14.9%), with no differences between the different biologicals used (p=0.61): 61 patients (19.4%) on infliximab, 39 (12.5%) on adalimumab, 5 (17.8%) on golimumab, 22 (14.1%) on ustekinumab, and 34 (16.5%) on vedolizumab. CONCLUSIONS: Biological drug therapies have response rates in elderly patients similar to those described in the general population, Golimumab was the drug that was discontinued most frequently due to inefficacy. In our experience, tumor development was more frequent in patients who used anti-TNF therapies compared to other targets, although its incidence was generally low and that this is in line with younger patients based on previous literature.

Real-World Evidence of Tofacinitib in Ulcerative Colitis: Short-Term and Long-Term Effectiveness and Safety.

INTRODUCTION: The objective of this study was to assess the durability, short-term and long-term effectiveness, and safety of tofacitinib in ulcerative colitis (UC) in clinical practice. METHODS: This is a retrospective multicenter study including patients with UC who had received the first tofacitinib dose at least 8 weeks before the inclusion. Clinical effectiveness was based on partial Mayo score. RESULTS: A total of 408 patients were included. Of them, 184 (45%) withdrew tofacitinib during follow-up (mean = 18 months). The probability of maintaining tofacitinib was 67% at 6 m, 58% at 12 m, and 49% at 24 m. The main reason for tofacitinib withdrawal was primary nonresponse (44%). Older age at the start of tofacitinib and a higher severity of clinical activity were associated with tofacitinib withdrawal. The proportion of patients in remission was 38% at week 4, 45% at week 8, and 47% at week 16. Having moderate-to-severe vs mild disease activity at baseline and older age at tofacitinib start were associated with a lower and higher likelihood of remission at week 8, respectively. Of 171 patients in remission at week 8, 83 (49%) relapsed. The probability of maintaining response was 66% at 6 m and 54% at 12 m. There were 93 adverse events related to tofacitinib treatment (including 2 pulmonary thromboembolisms [in patients with risk factors] and 2 peripheral vascular thrombosis), and 29 led to tofacitinib discontinuation. DISCUSSION: Tofacitinib is effective in both short-term and long-term in patients with UC. The safety profile is similar to that previously reported.

Risk of partial school closure for COVID-19 by socio-economic level in the period 2020-22.

BACKGROUND: The objective was to analyse the risk of partial school closure by economic level in Barcelona city. METHODS: In this ecological study, the risk of partial school closure for the academic years 2020-21 and 2021-22 was estimated by dividing the total number of days that each child was in quarantine or isolation by the total number of days that each child was at risk to be in quarantine or isolation in the academic year. The association between partial school closure risk and mean income by district was estimated with the Spearman rho. RESULTS: The lower the mean income, the higher the risk of partial closure (Spearman rho = 0.83; P-value = 0.003) during the academic year 2020-21. Specifically, the children from the district with the lowest income had a six times greater risk of partial school closure compared with those from the highest-income district. This risk did not show a significant socioeconomic gradient in the academic year 2021-22. CONCLUSIONS: The risk of partial school closure presented an inverse socioeconomic gradient in the city of Barcelona according to average income by district in the academic year 2020-21. This distribution was not observed in the academic year 2021-22.

Increased COVID-19 Mortality in People With Previous Cerebrovascular Disease: A Population-Based Cohort Study.

BACKGROUND: The aim of the study was to determine the association between previous stroke and mortality after coronavirus disease 2019 (COVID-19) according to sex, age groups, and stroke subtypes. METHODS: Prospective population-based cohort study including all COVID-19 positive cases between February 1 and July 31, 2020. Comorbidities and mortality were extracted using linked health administration databases. Previous stroke included transient ischemic attack, ischemic stroke, hemorrhagic stroke, spontaneous subarachnoid hemorrhage, and combined stroke for cases with more than one category. Other comorbidities were obesity, diabetes, hypertension, ischemic heart disease, atrial fibrillation, heart failure, chronic obstructive pulmonary disease, chronic kidney disease, cirrhosis, dementia, individual socioeconomic index, and deprivation index. Cases were followed up until December 31, 2020. Primary outcome was mortality of any cause after COVID-19 positivity. Cox proportional regression analysis adjusted for comorbidities was used. Stratified analyses were performed for sex and age (<60, 60-79, and ≥80 years). RESULTS: There were 91 629 COVID-19 cases. Previous strokes were 5752 (6.27%), of which 3887 (67.57%) were ischemic, 1237 (21.50%) transient ischemic attack, 255 (4.43%) combined, 203 (3.53%) hemorrhagic, and 170 (2.96%) subarachnoid hemorrhage. There were 9512 deaths (10.38%). Mortality was associated with previous stroke (hazard ratio [HR]=1.12 [95% CI, 1.06-1.18]; P<0.001), in both sexes separately (men=1.13 [1.05-1.22]; P=0.001; women=1.09 [1.01-1.18]; P=0.023), in people <60 years (HR=2.97 [1.97-4.48]; P<0.001) and 60 to 79 years (HR=1.32 [1.19-1.48]; P<0.001) but not in people ≥80 years (HR=1.02 [0.96-1.09]; P=0.437). Ischemic (HR=1.11 [1.05-1.18]; P=0.001), hemorrhagic (HR=1.53 [1.20-1.96]; P=0.001) and combined (HR=1.31 [1.05-1.63]; P=0.016) strokes were associated but not transient ischemic attack. Subarachnoid hemorrhage was associated only in people <60 years (HR=5.73 [1.82-18.06]; P=0.003). CONCLUSIONS: Previous stroke was associated with a higher mortality in people younger than 80 years. The association occurred for both ischemic and hemorrhagic stroke but not for transient ischemic attack. These data might help healthcare authorities to establish prioritization strategies for COVID-19 vaccination.

Caregivers' Profiles Based on the Canadian Occupational Performance Measure for the Adoption of Assistive Technologies.

The COPM (Canadian Occupational Performance Measure) is a tool that is based on the identification of self-perceived performance and satisfaction problems in the performance of occupations, allowing the creation of a hierarchy in the order of the interventions to be carried out, and speeding up the identification of the necessary AT (Assistive Technologies). Given the importance of the caregiver's perception about their own performance in the design of AT, this research examines the caregiver's profile through the COPM. A sample of 40 caregivers volunteered to participate in the study. A cluster analysis was carried out on the COPM scores. Two caregiver profiles were found in relation to the COPM measure, one with low scores on performance and satisfaction and another with high scores on both of these two variables. The main predictor was found to be the self-perception of performance. The structure was replicated through a hierarchical cluster analysis, where the role of caregivers was of interest. These results are relevant on both a theoretical and practical level.

Control of cardiovascular risk factors with tailored recommendations: A randomized controlled trial.

This study analyzed the efficacy of tailored recommendations to control cardiovascular risk factors at 1-year follow-up in a population-based randomized controlled trial in individuals aged 35-74 years with no history of cardiovascular disease at baseline. Total, low-density lipoprotein (LDL), and high-density lipoprotein cholesterol and systolic and diastolic blood pressure (BP) were measured at baseline and at 1-year follow-up. The primary outcome was the quantitative change in total cholesterol. To estimate the differences within and between groups, McNemar and Student t-tests were applied according to an intention-to-treat strategy. We enrolled 955 individuals [52.3% women; mean age, 50 years (standard deviation 10)]. Finally, 1 participant in each group presented a cardiovascular event and 768 were reexamined at 1-year follow-up. Intervention and control groups showed significant increases in total cholesterol [5.49 (standard deviation 1.02) to 5.56 (1.06) mmol/L and 5.34 (0.94) to 5.43 (0.93) mmol/L, respectively]. Men in the intervention group showed significant decreases in systolic and diastolic BP [117.2 (14.6) to 115.6 mmHg (14.1) and 77.9 (9.7) to 76.5 mmHg (9.7), respectively]; no changes were found in the rates of total cholesterol <5.2 mmol/L and LDL cholesterol <3.0 mmol/L. In the control group, both values were significantly decreased (43.5 to 36.4% and 26.4 to 20.8%, respectively) in men. In the stratified analysis, women showed no differences in any of the outcomes. In conclusion, an intervention with tailored recommendations increased mean total cholesterol values. The intervention effect was higher in men who maintained blood lipids at optimal levels and had decreased BP values.

Parvovirus B19 Myocarditis: Looking Beyond the Heart.

Human parvovirus B19 represents the most common etiology of myocarditis in the pediatric population. Although it usually causes a benign exanthematic viral infection, parvovirus B19 may also present as disseminated disease with tropism for the myocardium, causing heart failure with high mortality. We present the case of a 2-year-old patient with fulminating acute myocarditis in whom the histological, immunophenotypic, and microbiological findings in necropsy showed multiorgan involvement caused by parvovirus B19. The autopsy revealed changes due to infection with parvovirus B19 as well as hypoxic-ischemic and secondary autoimmune changes. Medullary aplasia was observed, transmural lymphocyte myocarditis, lymphocytosis in the dermis with endothelial cells positive for parvovirus B19 in immunohistochemistry, cholestatic hepatitis due to ischemia and autoimmune hepatitis, lymphadenitis, and signs of hemophagocytosis. We also found hypoxic-ischemic encephalopathy.

Impact of COVID-19 outbreak by income: hitting hardest the most deprived.

BACKGROUND: The impact of the 2019 coronavirus disease (COVID-19) has many facets. This ecological study analysed age-standardized incidence rates by economic level in Barcelona. METHODS: We evaluated confirmed cases of COVID-19 in Barcelona (Spain) between 26 February 2020 and 19 April 2020. Districts were classified according to most recent (2017) mean income data. The reference for estimating age-standardized cumulative incidence rates was the 2018 European population. The association between incidence rate and mean income by district was estimated with the Spearman rho. RESULTS: The lower the mean income, the higher the COVID-19 incidence (Spearman rho = 0.83; P value = 0.003). Districts with the lowest mean income had the highest incidence of COVID-19 per 10 000 inhabitants; in contrast, those with the highest income had the lowest incidence. Specifically, the district with the lowest income had 2.5 times greater incidence of the disease, compared with the highest-income district [70 (95% confidence interval 66-73) versus 28 (25-31), respectively]. CONCLUSIONS: The incidence of COVID-19 showed an inverse socioeconomic gradient by mean income in the 10 districts of the city of Barcelona. Beyond healthcare for people with the disease, attention must focus on a health strategy for the whole population, particularly in the most deprived areas.

Acetylcholinesterase Inhibition of Diversely Functionalized Quinolinones for Alzheimer's Disease Therapy.

In this communication, we report the synthesis and cholinesterase (ChE)/monoamine oxidase (MAO) inhibition of 19 quinolinones (QN1-19) and 13 dihydroquinolinones (DQN1-13) designed as potential multitarget small molecules (MSM) for Alzheimer's disease therapy. Contrary to our expectations, none of them showed significant human recombinant MAO inhibition, but compounds QN8, QN9, and DQN7 displayed promising human recombinant acetylcholinesterase (hrAChE) and butyrylcholinesterase (hrBuChE) inhibition. In particular, molecule QN8 was found to be a potent and quite selective non-competitive inhibitor of hrAChE (IC50 = 0.29 µM), with Ki value in nanomolar range (79 nM). Pertinent docking analysis confirmed this result, suggesting that this ligand is an interesting hit for further investigation.

Early smoking-onset age and risk of cardiovascular disease and mortality.

Early smoking onset age (SOA) is a public health concern with scant empirical evidence of its role in health outcomes. The study had two aims: i) to assess whether an early SOA was associated with the risk of fatal and non-fatal CVD and all-cause and CVD mortality and ii) to explore the linear and non-linear association between SOA and the outcomes of interest. Data from 4499 current or former smokers, recruited from 1995 to 2005, aged 25 to 79 years, and with a median 7.02 years of follow-up, were obtained from the REGICOR population-based cohort. In the present analysis, performed in 2018, the independent variable was SOA and the dependent variables were CVD events, CVD mortality, and all-cause mortality. Penalized smoothing spline methods were used to assess the linear and non-linear association. During follow-up, 361 deaths and 210 CVD events were recorded. A significant non-linear component was identified in the association between SOA and CVD outcomes with a cut-off point at 12 years: In the group aged ≤12 years, each year of delay in SOA was inversely associated with CVD risk (HR = 0.71; 95%CI = 0.53-0.96) and CVD mortality (HR = 0.58; 95%CI = 0.37-0.90). No association was observed in the older SOA group. A linear association was observed between SOA and all-cause mortality, and each year of delay was associated with 4% lower risk of mortality (HR = 0.96; 95%CI = 0.93-0.98). The associations were adjusted for lifelong exposure to tobacco and cardiovascular risk factors. These results reinforce the value of preventing tobacco use among teenagers and adolescents.

Interaction between cardiovascular risk factors and body mass index and 10-year incidence of cardiovascular disease, cancer death, and overall mortality.

The effect of above-normal body mass index (BMI) on health outcomes is controversial because it is difficult to distinguish from the effect due to BMI-associated cardiovascular risk factors. The objective was to analyze the impact on 10-year incidence of cardiovascular disease, cancer deaths and overall mortality of the interaction between cardiovascular risk factors and BMI. We conducted a pooled analysis of individual data from 12 Spanish population cohorts with 10-year follow-up. Participants had no previous history of cardiovascular diseases and were 35-79years old at basal examination. Body mass index was measured at baseline being the outcome measures ten-year cardiovascular disease, cancer and overall mortality. Multivariable analyses were adjusted for potential confounders, considering the significant interactions with cardiovascular risk factors. We included 54,446 individuals (46.5% with overweight and 27.8% with obesity). After considering the significant interactions, the 10-year risk of cardiovascular disease was significantly increased in women with overweight and obesity [Hazard Ratio=2.34 (95% confidence interval: 1.19-4.61) and 5.65 (1.54-20.73), respectively]. Overweight and obesity significantly increased the risk of cancer death in women [3.98 (1.53-10.37) and 11.61 (1.93-69.72)]. Finally, obese men had an increased risk of cancer death and overall mortality [1.62 (1.03-2.54) and 1.34 (1.01-1.76), respectively]. In conclusion, overweight and obesity significantly increased the risk of cancer death and of fatal and non-fatal cardiovascular disease in women; whereas obese men had a significantly higher risk of death for all causes and for cancer. Cardiovascular risk factors may act as effect modifiers in these associations.

Synthesis and biological evaluation of aryl-oxadiazoles as inhibitors of Mycobacterium tuberculosis.

Despite increased research efforts to find new treatments for tuberculosis in recent decades, compounds with novel mechanisms of action are still required. We previously identified a series of novel aryl-oxadiazoles with anti-tubercular activity specific for bacteria using butyrate as a carbon source. We explored the structure activity relationship of this series. Structural modifications were performed in all domains to improve potency and physico-chemical properties. A number of compounds displayed sub-micromolar activity against M. tuberculosis utilizing butyrate, but not glucose as the carbon source. Compounds showed no or low cytotoxicity against eukaryotic cells. Three compounds were profiled in mouse pharmacokinetic studies. Plasma clearance was low to moderate but oral exposure suggested solubility-limited drug absorption in addition to first pass metabolism. The presence of a basic nitrogen in the linker slightly increased solubility, and salt formation optimized aqueous solubility. Our findings suggest that the 1,3,4-oxadiazoles are useful tools and warrant further investigation.

A functional variant that affects exon-skipping and protein expression of SP140 as genetic mechanism predisposing to multiple sclerosis.

Several variants in strong linkage disequilibrium (LD) at the SP140 locus have been associated with multiple sclerosis (MS), Crohn's disease (CD) and chronic lymphocytic leukemia (CLL). To determine the causal polymorphism, we have integrated high-density data sets of expression quantitative trait loci (eQTL), using GEUVADIS RNA sequences and 1000 Genomes genotypes, with MS-risk variants of the high-density Immunochip array performed by the International Multiple Sclerosis Genetic Consortium (IMSGC). The variants most associated with MS were also correlated with a decreased expression of the full-length RNA isoform of SP140 and an increase of an isoform lacking exon 7. By exon splicing assay, we have demonstrated that the rs28445040 variant was the causal factor for skipping of exon 7. Western blots of peripheral blood mononuclear cells from MS patients showed a significant allele-dependent reduction of the SP140 protein expression. To confirm the association of this functional variant with MS and to compare it with the best-associated variant previously reported by GWAS (rs10201872), a case-control study including 4384 MS patients and 3197 controls was performed. Both variants, in strong LD (r(2) = 0.93), were found similarly associated with MS [P-values, odds ratios: 1.9E-9, OR = 1.35 (1.22-1.49) and 4.9E-10, OR = 1.37 (1.24-1.51), respectively]. In conclusion, our data uncover the causal variant for the SP140 locus and the molecular mechanism associated with MS risk. In addition, this study and others previously reported strongly suggest that this functional variant may be shared with other immune-mediated diseases as CD and CLL.

Impact of implementing electronic clinical practice guidelines for the diagnosis, control and treatment of cardiovascular risk factors: A pre-post controlled study.

OBJECTIVE: To evaluate the impact of computerized clinical practice guidelines on the management, diagnosis, treatment, control, and follow-up of the main cardiovascular risk factors: hypertension, hypercholesterolaemia, and type 2 diabetes mellitus. DESIGN: Pre-post controlled study. SETTING: Catalonia, autonomous community located in north-eastern Spain. PARTICIPANTS: Individuals aged 35-74 years assigned to general practitioners of the Catalan Health Institute. INTERVENTION: The intervention group consisted of individuals whose general practitioners had accessed the computerized clinical practice guidelines at least twice a day, while the control group consisted of individuals whose general practitioner had never accessed the computerized clinical practice guidelines platform. MAIN OUTCOMES: The Chi-squared test was used to detect significant differences in the follow-up, control, and treatment variables for all three disorders (hypertension, hypercholesterolaemia, and type 2 diabetes mellitus) between individuals assigned to users and non-users of the computerized clinical practice guidelines, respectively. RESULTS: A total of 189,067 patients were included in this study, with a mean age of 56 years (standard deviation 12), and 55.5% of whom were women. Significant differences were observed in hypertension management, treatment and control; type 2 diabetes mellitus management, treatment and diagnoses, and the management and control of hypercholesterolaemia in both sexes. CONCLUSIONS: Computerized clinical practice guidelines are an effective tool for the control and follow-up of patients diagnosed with hypertension, type 2 diabetes mellitus, and hypercholesterolaemia. The usefulness of computerized clinical practice guidelines to diagnose and adequately treat individuals with these disorders remains unclear.

Estimation of Inorganic Arsenic Exposure in Populations With Frequent Seafood Intake: Evidence From MESA and NHANES.

The sum of urinary inorganic arsenic (iAs) and methylated arsenic (monomethylarsonate and dimethylarsinate (DMA)) species is the main biomarker of iAs exposure. Assessing iAs exposure, however, is difficult in populations with moderate-to-high seafood intakes. In the present study, we used subsamples from the Multi-Ethnic Study of Atherosclerosis (2000-2002) (n = 310) and the 2003-2006 National Health and Nutrition Examination Survey (n = 1,175). We calibrated urinary concentrations of non-seafood-derived iAs, DMA, and methylarsonate, as well as the sum of inorganic and methylated arsenic species, in the Multi-Ethnic Study of Atherosclerosis and of DMA in the National Health and Nutrition Examination Survey by regressing their original concentrations by arsenobetaine and extracting model residuals. To confirm that calibrated biomarkers reflected iAs exposure but not seafood intake, we compared urinary arsenic concentrations by levels of seafood and rice intakes. Self-reported seafood intakes, estimated n-3 polyunsaturated fatty acid levels, and measured n-3 polyunsaturated fatty acid levels were positively associated with the original urinary arsenic biomarkers. Using the calibrated arsenic biomarkers, we found a marked attenuation of the associations with self-reported seafood intake and estimated or measured n-3 fatty acids, whereas associations with self-reported rice intake remained similar. Our residual-based method provides estimates of iAs exposure and metabolism for each participant that no longer reflect seafood intake and can facilitate research about low-to-moderate levels of iAs exposure in populations with high seafood intakes.

Oxadiazoles Have Butyrate-Specific Conditional Activity against Mycobacterium tuberculosis.

Mycobacterium tuberculosis is a global pathogen of huge importance which can adapt to several host niche environments in which carbon source availability is likely to vary. We developed and ran a phenotypic screen using butyrate as the sole carbon source to be more reflective of the host lung environment. We screened a library of ∼87,000 small compounds and identified compounds which demonstrated good antitubercular activity against M. tuberculosis grown with butyrate but not with glucose as the carbon source. Among the hits, we identified an oxadiazole series (six compounds) which had specific activity against M. tuberculosis but which lacked cytotoxicity against mammalian cells.

A Novel Nociceptin Receptor Antagonist LY2940094 Inhibits Excessive Feeding Behavior in Rodents: A Possible Mechanism for the Treatment of Binge Eating Disorder.

Nociceptin/orphanin FQ (N/OFQ), a 17 amino acid peptide, is the endogenous ligand of the ORL1/nociceptin-opioid-peptide (NOP) receptor. N/OFQ appears to regulate a variety of physiologic functions including stimulating feeding behavior. Recently, a new class of thienospiro-piperidine-based NOP antagonists was described. One of these molecules, LY2940094 has been identified as a potent and selective NOP antagonist that exhibited activity in the central nervous system. Herein, we examined the effects of LY2940094 on feeding in a variety of behavioral models. Fasting-induced feeding was inhibited by LY2940094 in mice, an effect that was absent in NOP receptor knockout mice. Moreover, NOP receptor knockout mice exhibited a baseline phenotype of reduced fasting-induced feeding, relative to wild-type littermate controls. In lean rats, LY2940094 inhibited the overconsumption of a palatable high-energy diet, reducing caloric intake to control chow levels. In dietary-induced obese rats, LY2940094 inhibited feeding and body weight regain induced by a 30% daily caloric restriction. Last, in dietary-induced obese mice, LY2940094 decreased 24-hour intake of a high-energy diet made freely available. These are the first data demonstrating that a systemically administered NOP receptor antagonist can reduce feeding behavior and body weight in rodents. Moreover, the hypophagic effect of LY2940094 is NOP receptor dependent and not due to off-target or aversive effects. Thus, LY2940094 may be useful in treating disorders of appetitive behavior such as binge eating disorder, food choice, and overeating, which lead to obesity and its associated medical complications and morbidity.

A Novel, Orally Bioavailable Nociceptin Receptor Antagonist, LY2940094, Reduces Ethanol Self-Administration and Ethanol Seeking in Animal Models.

BACKGROUND: The nociceptin/orphanin-FQ (or opioid receptor-like [ORL1]) receptor (NOP) is localized in the mesolimbic reward pathway and has been suggested to play a role in feeding, mood, stress, and addiction. Since its deorphanization in 1995, there has been a clear dichotomy in the literature regarding whether an agonist or antagonist would provide therapeutic benefit. Specifically, the literature reports indicate that NOP receptor antagonists produce efficacy in animal models of hyperphagia and antidepressant-like activity, whereas NOP agonists produce anxiolytic-like effects and dampen reward/addiction behaviors including ethanol consumption. METHODS: We characterize here the potent, orally bioavailable NOP antagonist, LY2940094, in rodent models of ethanol consumption, including ethanol self-administration, progressive ratio operant self-administration, stress-induced reinstatement of ethanol seeking, and in vivo microdialysis in the nucleus accumbens. RESULTS: LY2940094 dose dependently reduced homecage ethanol self-administration in Indiana alcohol-preferring (P) and Marchigian Sardinian alcohol-preferring (msP) rats, without affecting food/water intake or locomotor activity. Reduced ethanol intake in P rats did not show significant tolerance over 4 days of subchronic dosing. LY2940094 attenuated progressive ratio operant responding and break points for ethanol in P rats. Moreover, stress-induced reinstatement of ethanol seeking in msP rats was completely blocked by LY2940094. Furthermore, LY2940094 blocked ethanol-stimulated dopamine release in response to ethanol challenge (1.1 g/kg, intraperitoneally). CONCLUSIONS: Our findings demonstrate for the first time that blockade of NOP receptors attenuates ethanol self-administration and ethanol-motivated behaviors, stress-induced ethanol seeking, and ethanol-induced stimulation of brain reward pathways in lines of rats that exhibit excessive ethanol consumption. Results suggest that LY2940094 may have potential therapeutic utility in treating alcohol addiction.

Role of renal function in cardiovascular risk assessment: A retrospective cohort study in a population with low incidence of coronary heart disease.

BACKGROUND: Early-stage chronic kidney disease (CKD), a marker of cardiovascular risk, is susceptible to therapeutic intervention but need further study in populations with low incidence of coronary heart disease (CHD). Incorporating glomerular filtration rate (GFR) could improve cardiovascular risk prediction in these patients. OBJECTIVE: To determine if decreased GFR is associated with increased risk of cardiovascular morbidity and all-cause mortality and to analyse GFR effect on cardiovascular risk prediction in a population with low CHD incidence. METHODS: Retrospective, observational, population-based study of 1,081,865 adults (35-74years old). Main exposure variable: GFR. OUTCOMES: CHD, cerebrovascular disease, cardiovascular diseases, all-cause mortality. Association between GFR categories of CKD (G1-G5) and outcomes was tested with Cox survival models. G1 was defined as the reference category. Predictive value of GFR was evaluated by integrated discrimination improvement (IDI) and net reclassification improvement (NRI) indices. RESULTS: Beginning at stage-3a CKD, increased risk was observed for coronary (HR 1.27 (95%CI 1.14-1.43)), cerebrovascular (HR 1.19 (95%CI 1.06-1.34)), cardiovascular (HR 1.23 (95%CI 1.13-1.34)) and all-cause mortality risk (HR 1.17 (95%CI 1.07-1.27)). GFR did not increase discrimination and reclassification indices significantly for any outcome. CONCLUSION: In general population with low CHD incidence and stage-3 CKD, impaired GFR was associated with increased risk of all cardiovascular diseases studied and all-cause mortality, but adding GFR values did not improve cardiovascular risk calculation. Despite a four-fold higher rate of CHD incidence at GFR G3a compared to G1, this represents moderate cardiovascular risk in our context.

Derivation and validation of a set of 10-year cardiovascular risk predictive functions in Spain: the FRESCO Study.

OBJECTIVE: To derive and validate a set of functions to predict coronary heart disease (CHD) and stroke, and validate the Framingham-REGICOR function. METHOD: Pooled analysis of 11 population-based Spanish cohorts (1992-2005) with 50,408 eligible participants. Baseline smoking, diabetes, systolic blood pressure (SBP), lipid profile, and body mass index were recorded. A ten-year follow-up included re-examinations/telephone contact and cross-linkage with mortality registries. For each sex, two models were fitted for CHD, stroke, and both end-points combined: model A was adjusted for age, smoking, and body mass index and model B for age, smoking, diabetes, SBP, total and HDL cholesterol, and for hypertension treatment by SBP, and age by smoking and by SBP interactions. RESULTS: The 9.3-year median follow-up accumulated 2973 cardiovascular events. The C-statistic improved from model A to model B for CHD (0.66 to 0.71 for men; 0.70 to 0.74 for women) and the combined CHD-stroke end-points (0.68 to 0.71; 0.72 to 0.75, respectively), but not for stroke alone. Framingham-REGICOR had similar C-statistics but overestimated CHD risk. CONCLUSIONS: The new functions accurately estimate 10-year stroke and CHD risk in the adult population of a typical southern European country. The Framingham-REGICOR function provided similar CHD prediction but overestimated risk.