Hypersensitivity to Non-Steroidal Anti-Inflammatory Drugs on a pediatric Portuguese cohort.

Summary: Background. Non-steroidal anti-inflammatory drugs (NSAID)/analgesics (paracetamol) are among the most common causes of drug hypersensitivity reactions in children, with a reported prevalence of around 0.3% in the pediatric population. Paracetamol and ibuprofen are the most commonly reported culprits in the pediatric population. Our objective was to describe the allergy workup to NSAID/paracetamol of a pediatric population monitored in an allergy outpatient clinic. Methods. Retrospective observational study by consulting the medical records of patients evaluated in a pediatric outpatient clinic with history of NSAID/paracetamol, between January 2016 to August 2022. Results. A total of 43 patients have been evaluated for NSAID/paracetamol suspected allergy: 53.5% females, mean age of 9.8 ± 5.1 years, 47.7% atopic. The drugs reported as culprits were: ibuprofen (75.6%), paracetamol (17.8%), metamizole (4.4%) and naproxen (2.2%) and clinical manifestations were mainly urticaria/angioedema and maculopapular exanthema. Skin tests were performed in 7 patients: paracetamol (n = 5) and metamizole (n = 2), which were all negative. Fourty-six drug provocation tests were performed: 28 with the culprit drug and 18 with an alternative one; only 2 were positive (ibuprofen - culprit NSAID group): one immediate periorbital angioedema and one delayed lip edema with oropharyngeal tightness. Conclusions. The investigation of allergy to NSAID/paracetamol in children remains a challenge. In our population, ibuprofen was the most common NSAID reported. There were only 2 (4.3%) mild reactions on DPT. We could allow the use of the culprit NSAID/analgesic in 11 patients and an alternative one in 9 patients. This study highlights the importance of DPT in children for a correct diagnosis of NSAID hypersensitivity and selection of an alternative drug.

Hybrid Methacrylated Gelatin and Hyaluronic Acid Hydrogel Scaffolds. Preparation and Systematic Characterization for Prospective Tissue Engineering Applications.

Hyaluronic acid (HA) and gelatin (Gel) are major components of the extracellular matrix of different tissues, and thus are largely appealing for the construction of hybrid hydrogels to combine the favorable characteristics of each biopolymer, such as the gel adhesiveness of Gel and the better mechanical strength of HA, respectively. However, despite previous studies conducted so far, the relationship between composition and scaffold structure and physico-chemical properties has not been completely and systematically established. In this work, pure and hybrid hydrogels of methacroyl-modified HA (HAMA) and Gel (GelMA) were prepared by UV photopolymerization and an extensive characterization was done to elucidate such correlations. Methacrylation degrees of ca. 40% and 11% for GelMA and HAMA, respectively, were obtained, which allows to improve the hydrogels' mechanical properties. Hybrid GelMA/HAMA hydrogels were stiffer, with elastic modulus up to ca. 30 kPa, and porous (up to 91%) compared with pure GelMA ones at similar GelMA concentrations thanks to the interaction between HAMA and GelMA chains in the polymeric matrix. The progressive presence of HAMA gave rise to scaffolds with more disorganized, stiffer, and less porous structures owing to the net increase of mass in the hydrogel compositions. HAMA also made hybrid hydrogels more swellable and resistant to collagenase biodegradation. Hence, the suitable choice of polymeric composition allows to regulate the hydrogels´ physical properties to look for the most optimal characteristics required for the intended tissue engineering application.

Effectiveness of a chat-bot for the adult population to quit smoking: protocol of a pragmatic clinical trial in primary care (Dejal@).

BACKGROUND: The wide scale and severity of consequences of tobacco use, benefits derived from cessation, low rates of intervention by healthcare professionals, and new opportunities stemming from novel communications technologies are the main factors motivating this project. Thus, the purpose of this study is to assess the effectiveness of an intervention that helps people cease smoking and increase their nicotine abstinence rates in the long term via a chat-bot, compared to usual practice, utilizing a chemical validation at 6 months. METHODS: Design: Randomized, controlled, multicentric, pragmatic clinical trial, with a 6-month follow-up. SETTING: Healthcare centers in the public healthcare system of the Community of Madrid (Madrid Regional Health Service). PARTICIPANTS: Smokers > 18 years of age who attend a healthcare center and accept help to quit smoking in the following month. N = 460 smokers (230 per arm) who will be recruited prior to randomization. Intervention group: use of a chat-bot with evidence-based contents to help quit smoking. CONTROL GROUP: Usual treatment (according to the protocol for tobacco cessation by the Madrid Regional Health Service Main variable: Continuous nicotine withdrawal with chemical validation (carbon monoxide in exhaled air). Intention-to-treat analysis. Difference between groups in continuous abstinence rates at 6 months with their corresponding 95% confidence interval. A logistic regression model will be built to adjust for confounding factors. RESULTS: First expected results in January 2020. DISCUSSION: Providing science-based evidence on the effectiveness of clinical interventions via information technologies, without the physical presence of a professional, is essential. In addition to being more efficient, the characteristics of these interventions can improve effectiveness, accessibility, and adherence to treatment. From an ethics perspective, this new type of intervention must be backed by scientific evidence to circumvent pressures from the market or particular interests, improve patient safety, and follow the standards of correct practices for clinical interventions. TRIAL REGISTRATION: ClinicalTrials.gov, reference number NCT03445507.

Non-healing post-surgical fistulae: treatment with image-guided percutaneous injection of cyanoacrylic glue.

OBJECTIVES: To present the results of our experience with cyanoacrylic glue percutaneous injection to treat post-surgical non-healing enteric fistulae after failure of standard treatments. METHODS: Eighteen patients (14 males; age range 33-84, mean 69 years) were treated for a non-healing post-surgical enteric fistula after failure of standard treatments. Under computed tomography and/or fluoroscopic guidance, a mixture of cyanoacrylic glue (Glubran 2, GEM, Viareggio, Italy) and ethiodized oil was injected at the site of the fistula. Fistula was considered healed when no material was drained by the percutaneous drainage and a subsequent computed tomography confirmed the disappearance of any fluid collection. RESULTS: In all cases, it was possible to reach the site of the fistula using a percutaneous access. A median of 1 injection (range 1-5) was performed. Fistula healing was achieved in 16/18 (89 %) patients. One patient died for other reasons before fistula healing. Median time for fistula healing was 0 days (mean 8, range 0-58 days). No complications occurred. Reoperation was needed in one patient. CONCLUSIONS: Percutaneous injection of cyanoacrylic glue is feasible, safe, and effective to treat non-healing post-surgical enteric fistulae. It may represent a further option to avoid surgical reoperation in frail patients.

Discriminatory value of alanine aminotransferase for diabetes prediction: the Insulin Resistance Atherosclerosis Study.

AIMS: To examine the incremental usefulness of adding alanine aminotransferase to established risk factors for predicting future diabetes. METHODS: The study population of the Insulin Resistance Atherosclerosis Study included 724 people aged 40-69 years. We excluded people who had excessive alcohol intake or were treated with lipid-lowering agents. Incident diabetes was assessed after a mean follow-up period of 5.2 years. RESULTS: Alanine aminotransferase had a non-linear relationship with incident diabetes (Wald chi-squared test, P < 0.001; P for linearity = 0.005) independent of demographic variables, family history of diabetes, BMI and fasting glucose; therefore, we used Youden's J statistic to dichotomize alanine aminotransferase [threshold ≥ 0.43 µkat/L ( ≥ 26 IU/l)]. Dichotomized alanine aminotransferase increased the area under the receiver-operating characteristic curve (0.805 vs. 0.823; P = 0.007) of a model that included demographic variables, family history of diabetes, BMI and fasting glucose as independent variables. The net reclassification improvement was 9.6% (95% CI 1.8-17.4; P = 0.016), and the integrated discrimination improvement was 0.031 (95% CI 0.011-0.050; P = 0.002). Dichotomized alanine aminotransferase reclassified a net of 9.6% of individuals more appropriately. CONCLUSIONS: Alanine aminotransferase may be useful for classifying individuals who are at risk of future diabetes after accounting for the effect of other risk factors, including family history, adiposity and plasma glucose.

The use of illicit drugs as self-medication in the treatment of cluster headache: Results from an Italian online survey.

BACKGROUND: Cluster headache (CH) patients often receive unsatisfactory treatment and may explore illicit substances as alternatives. We aimed to explore this use of illicit drugs for CH treatment. METHODS: We invited CH patients from an Internet-based self-help group to complete a questionnaire regarding their therapeutic use of illicit substances. RESULTS: Of the 54 respondents, 29 were classified as chronic and 39 were drug-resistant cases. Fifty patients had previously tried subcutaneous sumatriptan, 40 had tried O2, and 48 had tried at least one prophylactic treatment. All 54 patients specified that they were dissatisfied with conventional treatments. Thirty-four patients had used cannabinoids, 13 cocaine, 8 heroin, 18 psilocybin, 12 lysergic acid amide (LSA), and 4 lysergic acid diethylamide (LSD). DISCUSSION: Some patients with intractable CH decided to try illicit drugs concomitantly with cessation of medical care. Most of these patients found suggestions for illicit drug use on the Internet. Many patients seemed to underestimate the judicial consequences of, and had an overestimated confidence in the safety of, such illicit treatments. Physicians are often not informed by patients of their choice to use illicit drugs. This leads to questions regarding the true nature of the physician-patient relationship among dissatisfied CH patients.

Antifungal activities of three different Lactobacillus species and their production of antifungal carboxylic acids in wheat sourdough.

This study was undertaken to assess the antifungal performance of three different Lactobacillus species.Experiments were conducted in vitro and in situ to extend the shelf life of wheat bread. Standard sourdough analyses were performed characterising acidity and carbohydrate levels. Overall, the strains showed good inhibition in vitro against the indicator mould Fusarium culmorum TMW4.2043. Sourdough bread fermented with Lactobacillus amylovorus DSM19280 performed best in the in situ shelf life experiment. An average shelf life extension of six more mould-free days was reached when compared to the non-acidified control bread. A range of antifungal-active acids like 3-phenyllactic acid, 4-hydroxyphenyllactic acid and 2-hydroxyisocaproic acid in quantities between 0.1 and 360 mg/kg were present in the freeze-dried sourdoughs. Their concentration differed greatly amongst the species.However, a higher concentration of these compounds could not completely justify the growth inhibition of environmental moulds. In particular, although Lb. reuteri R29 produced the highest total concentration of these active compounds in the sourdough, its addition to bread did not result in a longest shelf life. Nevertheless, when the artificial compounds were spiked into a chemically acidified dough, it succeeded in a longer shelf life (+25 %) than achieved only by acidifying the dough. This provides evidence of their contribution to the antifungal activity and their synergy in concentration levels far below their single minimal inhibition concentrations under acidic conditions.

Preparation of antioxidant active films based on chitosan: diffusivity study of α-tocopherol into food simulants.

New active films based on chitosan and polycaprolactone blends and containing α-tocopherol were designed for food packaging applications. Mechanical properties, stability against temperature and swelling degree in 50 % ethanol (v/v) were evaluated. Migration kinetics of α-tocopherol from the developed films into butter and food simulants [50 % ethanol (v/v), 95 % ethanol (v/v), and isooctane] at different temperatures were studied. α-Tocopherol was quantified in the food simulants by means of high performance liquid chromatography with diode-array detection at 292 nm. The proposed method exhibited a good sensitivity with a limit of detection of 0.1 mg/L. The kinetics release of α-tocopherol was characterized by determining the partition and the diffusion coefficients by using a mathematical modeling based on Fick's Second Law. The diffusion coefficients obtained ranged between 1.03 × 10(-13) and 2.24 × 10(-12) cm(2)/s for 95 % ethanol (v/v) at 4 and 20 °C, respectively. Developed films maintained the antioxidant activity for more than 20 days.

Predicting the development of the metabolically healthy obese phenotype.

OBJECTIVE: The metabolically healthy (MHO) and unhealthy obese (MUHO) differ in terms of cardiovascular risk. However, little is known about predicting the development of these phenotypes and the future stability of the MHO phenotype. Therefore, we examined these two issues in the San Antonio Heart Study. DESIGN: Longitudinal, population-based study of cardiometabolic risk factors among Mexican Americans and non-Hispanic whites in San Antonio. SUBJECTS: The study sample included 2368 participants with neither MUHO nor diabetes at baseline. Median follow-up was 7.8 years. MHO was defined as obesity with ⩽1 metabolic abnormality; MUHO, as obesity with ⩾2 abnormalities. RESULTS: At baseline, 1595 and 498 individuals were non-obese with ⩽1 and ⩾2 metabolic abnormalities, respectively, and 275 were MHO. Among non-obese individuals, independent predictors of incident MHO (odds ratio (OR) for 1 s.d. change (95% confidence interval)) included body mass index (8.12 (5.66-11.7)), triglycerides (0.52 (0.39-0.68)) and high-density lipoprotein cholesterol (HDL-C) (1.41 (1.11-1.81)), whereas independent predictors of incident MUHO included body mass index (5.97 (4.58-7.77)) and triglycerides (1.26 (1.05-1.51)). Among participants with ⩽1 metabolic abnormality, obesity was associated with greater odds of developing multiple metabolic abnormalities (OR 2.26 (1.74-2.95)). CONCLUSIONS: Triglycerides and HDL-C may be useful for predicting progression to MHO. MHO may not be a stable condition, because it confers an increased risk of developing multiple metabolic abnormalities.

Migraine improvement during short lasting ketogenesis: a proof-of-concept study.

BACKGROUND AND PURPOSE: Ketogenesis is a physiological phenomenon due to starvation or a ketogenic diet (KD), a drastic restricted carbohydrate dietary regimen that induces lipid metabolism and ketone body synthesis. Two patients whose migraines disappeared only during, and not outside, cycles of very-low-calorie KD performed to reduce their weight were recently observed. To confirm our observation, in a dietitian clinical setting two parallel groups of migraineurs, one receiving a 1-month very-low-calorie KD prescription followed by a 5-month standard low-calorie diet (SD) and the other a 6-month SD, were followed. METHODS: Ninety-six overweight female migraineurs were enrolled in a diet clinic and blindly received a KD (n = 45) or an SD (n = 51) prescription. Mean monthly attack frequency, number of days with headaches and tablet intake were assessed before and 1, 2, 3 and 6 months after diet initiation. RESULTS: In the KD group, the baseline attack frequency (2.9 attacks per month), number of days with headaches (5.11 days per month) and tablet intake (4.91 doses per month) were significantly reduced after the first month of diet (respectively 0.71, 0.91, 0.51; overall, KD versus baseline, P < 0.0001). During the transition period (first versus second month), the KD group showed a transient worsening of each clinical headache variable (respectively 2.60, 3.60, 3.07), despite being improved compared with baseline, with continuous improvement up to month 6 (respectively 2.16, 2.78, 3.71). In the SD group, significant decreases in the number of days with headaches and tablet intake were observed only from month 3 (P < 0.0001), and in attack frequency at month 6 (P < 0.0001). CONCLUSIONS: The underlying mechanisms of KD efficacy could be related to its ability to enhance mitochondrial energy metabolism and counteract neural inflammation.

Associations of coffee consumption with markers of liver injury in the insulin resistance atherosclerosis study.

BACKGROUND: Coffee consumption has been associated with reduced risk of developing type 2 diabetes mellitus (T2DM) however, the mechanism for this association has yet to be elucidated. Non-alcoholic fatty liver disease (NAFLD) characterizes and predicts T2DM yet the relationship of coffee with this disorder remains unclear. Our aim was to investigate the associations of coffee with markers of liver injury in 1005 multi-ethnic, non-diabetic adults in the Insulin Resistance Atherosclerosis Study. METHODS: Dietary intake was assessed using a validated 114-item food frequency questionnaire. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and fetuin-A were determined in fasting blood samples and the validated NAFLD liver fat score was calculated. Multivariate linear regression assessed the contribution of coffee to variation in markers of liver injury. RESULTS: Caffeinated coffee showed significant inverse associations with ALT (ß = -0.08, p = 0.0111), AST (ß = -0.05, p = 0.0155) and NAFLD liver fat score (ß = -0.05, p = 0.0293) but not with fetuin-A (ß = 0.04, p = 0.17). When the highest alcohol consumers were excluded, these associations remained (ALT ß = -0.11, p = 0.0037; AST ß = -0.05, p = 0.0330; NAFLD liver fat score ß = -0.06, p = 0.0298). With additional adjustment for insulin sensitivity, the relationship with ALT remained significant (ALT ß = -0.08, p = 0.0400; AST ß = -0.03, p = 0.20; NAFLD liver fat score ß = -0.03, p = 0.27). There were no significant associations of decaffeinated coffee with liver markers. CONCLUSIONS: These analyses indicate a beneficial impact of caffeinated coffee on liver morphology and/or function, and suggest that this relationship may mediate the well-established inverse association of coffee with risk of T2DM.

Dynamic changes in thalamic microstructure of migraine without aura patients: a diffusion tensor magnetic resonance imaging study.

BACKGROUND AND PURPOSE: The thalamus seems to be profoundly involved in the cyclical recurrence of migraine clinical and neurophysiological features. Here possible structural changes in the thalamus of migraineurs were searched for by means of diffusion tensor (DT) magnetic resonance imaging (MRI). This MRI technique provides quantitative data on water molecule motion as a marker of tissue microstructure. METHODS: Twenty-four untreated migraine without aura (MO) patients underwent DT-MRI scans (3-T Siemens Gyroscan) during (n = 10) and between attacks (n = 14) and were compared with a group of 15 healthy volunteers (HVs). Fractional anisotropy (FA) and mean diffusivity (MD) were examined. RESULTS: During the interictal phase MO patients had a significantly higher FA and slightly lower MD values in bilateral thalami compared with HVs. During attacks, all MRI quantitative measurements in migraineurs were similar to those found in HVs. Right thalamic FA was positively correlated with the number of days since the last migraine attack in pooled patient data (r = 0.626, P = 0.003). CONCLUSIONS: These higher thalamic FA values noted during the interictal period which normalized during an attack are probably related to plastic peri-ictal modifications in regional branching and crossing of fibres. Whether these changes could be considered as the anatomical counterpart of the cyclical functional fluctuations previously observed in the neurophysiology of migraine remains to be determined.

Prolonged colonic manometry in children with defecatory disorders.

OBJECTIVES: Colonic manometry is a test used in the evaluation of children with defecation disorders unresponsive to conventional treatment. The most commonly reported protocol in pediatrics consists of a study that lasts approximately 4 hours. Given the wide physiological variations in colonic motility throughout the day, longer observation may detect clinically relevant information. The aim of the present study was to compare prolonged colonic manometry studies in children referred for colonic manometry with the more traditional short water-perfused technology. METHODS: Colonic manometry studies of 19 children (8 boys, mean age 9.4 ± 0.9, range 3.9-16.3) with severe defecation disorders were analyzed. First, a "standard test" was performed with at least 1-hour fasting, 1-hour postprandial, and 1-hour postbisacodyl provocation recording. Afterwards, recordings continued until the next day. RESULTS: In 2 of the 19 children, prolonged recording gave us extra information. In 1 patient with functional nonretentive fecal incontinence who demonstrated no abnormalities in the short recording, 2 long clusters of high-amplitude contractions were noted in the prolonged study, possibly contributing to the fecal incontinence. In another patient evaluated after failing use of antegrade enemas through a cecostomy, short recordings showed colonic activity only in the most proximal part of the colon, whereas the prolonged study showed normal motility over a larger portion of the colon. CONCLUSIONS: Prolonged colonic measurement provides more information regarding colonic motor function and allows detection of motor events missed by the standard shorter manometry study.

Effects of the acupoints PC 6 Neiguan and LR 3 Taichong on cerebral blood flow in normal subjects and in migraine patients.

Acupuncture has been proven to be effective in the treatment of various cardiovascular disorders; it acts both on the peripheral flow and on the cerebral flow. Our study aimed to evaluate the effects of the insertion of PC 6 Neiguan and LR 3 Taichong acupoints on the cerebral blood flow (CBF) in the middle cerebral artery (MCA). These effects were measured in a group of patients suffering from migraine without aura (Group M) and in a healthy control group (Group C). In the study, we included 16 patients suffering from migraine without aura, classified according to the criteria of the International Headache Society, and 14 healthy subjects as a control group. The subjects took part in the study on two different days, and on each day, the effect of a single acupoint was evaluated. Transcranial Doppler was used to measure the blood flow velocity (BFV) in the MCA. Our study showed that the stimulation of PC 6 Neiguan in both groups results in a significant and longlasting reduction in the average BFV in the MCA. After pricking LR 3 Taichong, instead, the average BFV undergoes a very sudden and marked increase; subsequently, it decreases and tends to stabilize at a slightly higher level compared with the baseline, recorded before needle insertion. Our data seem to suggest that these two acupoints have very different effects on CBF. The insertion of PC 6 Neiguan probably triggers a vasodilation in MCA, while the pricking of LR 3 Taichong determines a rapid and marked vasoconstriction.

When should we use partially hydrolysed formulae for frequent gastrointestinal symptoms and allergy prevention?

UNLABELLED: Experts reviewed the literature to determine whether partially whey hydrolysed formulas (HF) offer benefits in the dietary management of frequent gastrointestinal symptoms and allergy prevention. Compared with standard cow's milk-based formulas, partially whey HF confer a limited protective effect against allergic disease in high-risk infants, particularly atopic dermatitis, but not respiratory allergies. No randomised clinical trials have been published on partially whey HF in infants with colicky symptoms. The group did not find sufficient evidence to support the use of partially whey HF in regurgitation, although recent data suggest that a thickened partially whey HF may be more effective. Partially whey HF, fortified with prebiotics and/or probiotics, with high levels of sn-2 palmitate in the fat blend or without palm oil, provide some benefit in functional constipation. CONCLUSION: Overall, partially whey HF may offer a useful alternative to intact protein in the dietary management of common functional gastrointestinal symptoms.

Most but not all laboratories can detect the recently emerged Neisseria gonorrhoeae porA mutants - results from the QCMD 2013 N. gonorrhoeae external quality assessment programme.

We describe the results of the Quality Control for Molecular Diagnostics 2013 Neisseria gonorrhoeae external quality assessment programme that included an N. gonorrhoeae strain harbouring an N. meningitidis porA gene which causes false-negative results in molecular diagnostic assays targeting the gonococcal porA pseudogene. Enhanced awareness of the international transmission of such gonococcal strains is needed to avoid false-negative results in both in-house and commercial molecular diagnostic assays used in laboratories worldwide, but particularly in Europe.

Combinatorial immune checkpoint blockade increases myocardial expression of NLRP-3 and secretion of H-FABP, NT-Pro-BNP, interleukin-1ß and interleukin-6: biochemical implications in cardio-immuno-oncology.

Background: Immune checkpoint blockade in monotherapy or combinatorial regimens with chemotherapy or radiotherapy have become an integral part of oncology in recent years. Monoclonal antibodies against CTLA-4 or PD-1 or PDL-1 are the most studied ICIs in randomized clinical trials, however, more recently, an anti-LAG3 (Lymphocyte activation gene-3) antibody, Relatlimab, has been approved by FDA in combination with Nivolumab for metastatic melanoma therapy. Moreover, Atezolizumab is actually under study in association with Ipilimumab for therapy of metastatic lung cancer. Myocarditis, vasculitis and endothelitis are rarely observed in these patients on monotherapy, however new combination therapies could expose patients to more adverse cardiovascular events. Methods: Human cardiomyocytes co-cultured with human peripheral blood lymphocytes (hPBMCs) were exposed to monotherapy and combinatorial ICIs (PD-L1 and CTLA-4 or PD-1 and LAG-3 blocking agents, at 100 nM) for 48 h. After treatments, cardiac cell lysis and secretion of biomarkers of cardiotoxicity (H-FABP, troponin-T, BNP, NT-Pro-BNP), NLRP3-inflammasome and Interleukin 1 and 6 were determined through colorimetric and enzymatic assays. Mitochondrial functions were studied in cardiomyocyte cell lysates through quantification of intracellular Ca++, ATP content and NADH:ubiquinone oxidoreductase core subunit S1 (Ndufs1) levels. Histone deacetylases type 4 (HDAC-4) protein levels were also determined in cardiomyocyte cell lysates to study potential epigenetic changes induced by immunotherapy regimens. Results: Both combinations of immune checkpoint inhibitors exert more potent cardiotoxic side effects compared to monotherapies against human cardiac cells co-cultured with human lymphocytes. LDH release from cardiac cells was 43% higher in PD-L1/CTLA-4 blocking agents, and 35.7% higher in PD-1/LAG-3 blocking agents compared to monotherapies. HDAC4 and intracellular Ca++ levels were increased, instead ATP content and Ndufs1 were reduced in myocardial cell lysates (p < 0.001 vs. untreated cells). Troponin-T, BNP, NT-Pro-BNP and H-FABP, were also strongly increased in combination therapy compared to monotherapy regimen. NLRP3 expression, IL-6 and IL-1ß levels were also increased by PDL-1/CTLA-4 and PD-1/LAG-3 combined blocking agents compared to untreated cells and monotherapies. Conclusions: Data of the present study, although in vitro, indicate that combinatorial immune checkpoint blockade, induce a pro- inflammatory phenotype, thus indicating that these therapies should be closely monitored by the multidisciplinary team consisting of oncologists, cardiologists and immunologists.

The association of alanine aminotransferase within the normal and mildly elevated range with lipoproteins and apolipoproteins: the Insulin Resistance Atherosclerosis Study.

AIMS/HYPOTHESIS: Markers of liver injury, such as alanine aminotransferase (ALT), have been associated with atherogenic lipoprotein changes. We examined the extent to which this association was explained by insulin resistance, adiposity, glucose tolerance and chronic inflammation. METHODS: In this analysis we included 824 non-diabetic participants (age 40-69 years) in the Insulin Resistance Atherosclerosis Study. No participants reported excessive alcohol intake or treatment with lipid-lowering medications. Lipoproteins and apolipoproteins were measured by conventional methods and lipoprotein heterogeneity by nuclear magnetic resonance (NMR) spectroscopy. RESULTS: ALT had a positive relationship with triacylglycerols, LDL-to-HDL-cholesterol ratio and apolipoprotein B (ApoB) after adjusting for demographic variables (p < 0.001 for all three relationships). ALT was also associated with the following NMR lipoproteins: positively with large VLDL (p < 0.001), intermediate-density lipoprotein (IDL) (p < 0.001) and small LDL subclass particles (p < 0.001), and VLDL particle size (p < 0.001); and negatively with large LDL subclass particles (p < 0.05) and LDL (p < 0.001) and HDL particle sizes (p < 0.01). ALT remained associated with IDL and small LDL subclass particles and ApoB after adjusting for glucose tolerance, adiposity, directly measured insulin sensitivity and C-reactive protein. CONCLUSIONS/INTERPRETATION: ALT is associated with a wide range of atherogenic lipoprotein changes, which are partially explained by insulin resistance, adiposity, glucose tolerance and chronic inflammation. Because of the significant variability in the relationship between ALT and liver fat, further studies are needed to assess the extent of the lipoprotein changes using a direct measure of liver fat.

The association of inflammatory and fibrinolytic proteins with 5 year change in insulin clearance: the Insulin Resistance Atherosclerosis Study (IRAS).

AIMS/HYPOTHESIS: Insulin clearance may decline as an early mechanism compensating for deteriorating insulin sensitivity. However, no previous studies have investigated the association between subclinical inflammation or impaired fibrinolysis and insulin clearance. We examined the association between plasminogen activator inhibitor (PAI)-1, C-reactive protein (CRP), TNF-α, leptin and fibrinogen and the progression of metabolic clearance rate of insulin (MCRI) over time. METHODS: We studied 784 non-diabetic white, Hispanic and African-American individuals in the Insulin Resistance Atherosclerosis Study (IRAS). Insulin sensitivity, acute insulin response and MCRI were determined from frequently sampled intravenous glucose tolerance tests at baseline and at 5-year follow-up. Inflammatory and fibrinolytic proteins were measured in fasting plasma at baseline. RESULTS: MCRI had declined significantly by 29% at the 5-year follow-up. We observed a significant association between higher plasma PAI-1 levels and the decline in MCRI in multivariable-adjusted regression models (ß = -0.045 [95% CI -0.081, -0.0091]). Higher plasma CRP and leptin levels were associated with a decline in MCRI in unadjusted models, but these associations were non-significant after adjusting for BMI and waist circumference (ß = -0.016 [95% CI -0.041, 0.0083] for CRP; ß = -0.044 [95% CI -0.10, 0.011] for leptin). A higher plasma TNF-α concentration was associated with a decline in MCRI in unadjusted (ß = -0.071 [95% CI -0.14, -0.00087]) but not in multivariable-adjusted (ß = -0.056 [95% CI -0.13, 0.017]) models. Plasma fibrinogen level was not associated with the change in MCRI. CONCLUSIONS/INTERPRETATION: We identified that higher plasma PAI-1 (but not CRP, TNF-α, leptin or fibrinogen) levels independently predicted the progressive decline of insulin clearance in the multiethnic cohort of the IRAS.

Association of common genetic variants with risperidone adverse events in a Spanish schizophrenic population.

Risperidone non-compliance is often high due to undesirable side effects, whose development is in part genetically determined. Studies with genetic variants involved in the pharmacokinetics and pharmacodynamics of risperidone have yielded inconsistent results. Thus, the aim of this study was to investigate the putative association of genetic markers with the occurrence of four frequently observed adverse events secondary to risperidone treatment: sleepiness, weight gain, extrapyramidal symptoms and sexual adverse events. A series of 111 schizophrenia inpatients were genotyped for genetic variants previously associated with or potentially involved in risperidone response. Presence of adverse events was the main variable and potential confounding factors were considered. Allele 16Gly of ADRB2 was significantly associated with a higher risk of sexual adverse events. There were other non-significant trends for DRD3 9Gly and SLC6A4 S alleles. Our results, although preliminary, provide new candidate variants of potential use in risperidone safety prediction.