Background Recent research shows that both pediatric and adult patients with eosinophilic esophagitis (EoE) experience esophageal remodeling marked by increased collagen deposition in which TGF-β ...plays an important role. However, limited data are available on the intensity and reversibility of fibrous remodeling in adults with EoE. Objective We sought to analyze differences in collagen deposition in the lamina propria (LP) and profibrogenic cytokine gene expression along with other changes induced by prolonged treatment with fluticasone propionate in adults with EoE. Methods Ten adults given consecutive diagnoses of EoE were studied prospectively. Deep esophageal biopsy specimens were obtained before and after 1 year of treatment with fluticasone propionate. Collagen deposition in the LP was assessed in tissue sections with the aid of the Masson trichrome technique. IL5 , TGFB1 , fibroblast growth factor 9 (FGF9) , and CCL18 gene expression was quantified through real-time PCR. EoE results were compared among samples from 10 adult patients with gastroesophageal reflux disease and 10 control subjects with healthy esophagi. Results Patients with EoE showed a significant increase in subepithelial collagen deposition; this correlated positively with eosinophil density in the LP and the patient’s age. Prolonged steroid treatment induced a nonsignificant reduction in subepithelial fibrosis, which remained significantly higher than in control subjects. Profibrogenic cytokine gene expression also increased in patients with EoE, with IL5 ( P < .001), FGF9 ( P = .005), and CCL18 ( P = .008) all significantly upregulated. After 1 year of treatment, a reduction was observed in gene expression; for CCL18 expression, this decrease was statistically significant ( P < .001). Conclusions Esophageal remodeling is associated with upregulated gene expression of profibrogenic cytokines in adults with EoE. Prolonged treatment with fluticasone propionate leads to a nonsignificant reduction in subepithelial collagen deposition accompanied by downregulation of profibrogenic cytokine gene expression, with that of CCL18 being especially significant.
Abstract
Background
Drug–drug interactions (DDIs) that involve antiretrovirals (ARVs) tend to cause harm if unrecognized, especially in the context of comorbidity and polypharmacy.
Methods
A linkage ...was established between the drug dispensing registry of Madrid and the Liverpool human immunodeficiency virus (HIV) DDI database (January 2017–June 2017). Polypharmacy was defined as the use of ≥5 non-HIV medications, and DDIs were classified by a traffic-light ranking for severity.
Results
A total of 22 945 people living with HIV (PLWH) and 6 613 506 individuals without HIV had received medications. ARV regimens were predominantly based on integrase inhibitors (51.96%). Polypharmacy was higher in PLWH (32.94%) than individuals without HIV (22.16%; P < .001); this difference was consistently observed across all age strata except for individuals ≥75 years. Polypharmacy was more common in women than men in both PLWH and individuals without HIV. The prevalence of contraindicated combinations involving ARVs was 3.18%. Comedications containing corticosteroids, quetiapine, or antithrombotic agents were associated with the highest risk for red-flag DDI, and the use of raltegravir- or dolutegravir-based antiretroviral therapy was associated with an adjusted odds ratio of 0.72 (95% confidence interval, .60–.88; P = .001) for red-flag DDI.
Conclusions
Polypharmacy was more frequent among PLWH across all age groups except those aged ≥75 years and was more common in women. The detection of contraindicated medications in PLWH suggests a likely disconnect between hospital and community prescriptions. Switching to alternative unboosted integrase regimens should be considered for patients with risk of harm from DDIs.
Polypharmacy was more frequent among people living with human immunodeficiency virus (PLWH) than individuals without HIV. The prevalence of red-flag drug–drug interactions among PLWH was 3.18% and mostly involved the combination of protease inhibitors and corticosteroids, quetiapine, or antithrombotics.
Despite being a cardinal experimental model, the induction of cirrhosis in rats by repeated exposure to carbon tetrachloride (CCl4) has low reproducibility. Here, we compared two models of cirrhosis ...induced by orogastric administration of CCl4 once (CCl4-1xWk) or twice a week (CCl4-2xWk) for 12 weeks in male Sprague-Dawley rats. Control rats received water instead of CCl4. Both CCl4 protocols similarly attenuated body weight gain (p < 0.01 vs. Control). Although both CCl4 protocols increased hepatic fibrosis, portal hypertension and splenomegaly, the magnitude of these alterations was higher and more consistent in CCl4-2xWk rats. Importantly, two CCl4-1xWk rats did not develop cirrhosis versus a 100% yield of cirrhosis in CCl4-2xWk rats. The CCl4-2xWk protocol consistently induced liver atrophy together with hematological, biochemical and coagulation abnormalities characteristic of advanced cirrhosis that were absent in CCl4-1xWk rats. Ascites occurred in 20% and 80% of rats in theCCl4-1xWk and CCl4-2xWk groups (p < 0.01). All rats showed normal renal function, arterial blood gases and stable systemic hemodynamics. The total dose of CCl4 and mortality rate were similar in both protocols. The CCl4-2xWk protocol, therefore, was highly reproducible and effective for the induction of experimental cirrhosis within a confined time, representing a valuable advance for liver research.
Abstract
Background
We studied the association of obesity-related single-nucleotide polymorphisms (OR-SNPs) with weight gain after antiretroviral therapy (ART) in people with human immunodeficiency ...virus (HIV; PWH).
Methods
Participants were ART-naive PWH from the Spanish HIV Research Cohort who started ART from 2014 onward and had blood/DNA deposited in the cohort Biobank. The primary outcome was change in weight at 96 weeks after starting ART. We genotyped 14 OR-SNPs from a meta-analysis of genome-wide association studies of body mass index (BMI) loci. Changes over time in weight and BMI were studied using adjusted linear mixed models.
Results
A total of 1021 PWH were included. The mean weight gain over 96 weeks was 2.90 (95% confidence interval, 2.54–3.26) kg. Factors associated with higher weight gain were female sex, birth in sub-Saharan Africa, prior AIDS, CD4+ <200 cells/µL, HIV-RNA >100 000 copies/mL, negative hepatitis C virus serology, and use of tenofovir alafenamide. A significant association was found between ZC3H4 rs3810291 GG genotype and BCDIN3D/FAIM2 rs7138803 GG genotype polymorphisms and weight and BMI increase. The estimated adjusted mean (standard error SE) of weight gain was 4.26 (0.56) kg in ZC3H4 rs3810291 GG carriers and 2.66 (0.19) kg in AA/AG carriers (P = .007). Likewise the estimated weight gain at 96 weeks was 3.35 (0.29) kg in BCDIN3D/FAIM2 rs7138803 GG carriers and 2.51 (0.24) kg in AG/AA carriers (P = .020).
Conclusions
Genetic factors may play a role in weight gain after ART initiation. Further work is needed to replicate our findings and understand how the identified SNPs lead to higher weight gain in this context.
We studied the association of obesity-related SNPs with weight and BMI increase at 96 weeks after ART initiation in treatment-naïve patients. A significant association was found between ZC3H4 rs3810291 GG and BCDIN3D/FAIM2 rs7138803 GG genotypes with weight and BMI increase.
BACKGROUND:Children are at higher risk of tuberculosis (TB) dissemination and extrapulmonary disease, contributing greatly to TB-associated morbidity and long-term sequelae. However, there are very ...few studies that assess the impact and clinical spectrum of pediatric extrapulmonary TB (EPTB) in low-prevalence regions.
METHODS:Children <18 years of age diagnosed with TB in Madrid region (2005–2013) were reviewed. We compared the epidemiology, clinical characteristics and the performance of diagnostic tests in childhood extrapulmonary and pulmonary disease. We performed a multivariate logistic regression to identify factors associated with EPTB.
RESULTS:During the study period, 93 of 526 pediatric TB cases had EPTB (17.7%). The most common site was lymphatic TB (34.5%). The source case was not identified in most extrapulmonary cases, contrary to pulmonary TB (28% vs. 63.3%; P < 0.001). The tuberculin-skin-test induration was smaller in EPTB cases (<5 mm 22% vs. 5%; P < 0.001), but the sensitivity of interferon-gamma-release-assays was similar (76.9% vs. 79.4%). Children with EPTB presented higher rate of bacteriologic confirmation (66% vs. 49.4%; P < 0.01), and higher incidence of multidrug resistant TB (8.2% vs. 1.6%; P = 0.03). Complications were present in 40.2% extrapulmonary cases. EPTB was associated with the childʼs foreign origin odds ratio (OR) 2.3 (1.1–5.3), immune disorders OR 5.8 (1.9–17.1) and drug resistance OR 2.4 (1.1–5.4).
CONCLUSIONS:In our low-prevalence region, childhood EPTB was linked to immigrant status, immune disorders and drug resistance, and presented high rate of complications. Our study underscores the relevance of improved diagnostic tools and systematic TB screening in high risk populations.
Background. Sustained virological response (SVR) after therapy with interferon plus ribavirin reduces liver-related complications and mortality in patients coinfected with human immunodeficiency ...virus (HIV) and hepatitis C virus (HCV). We assessed the effect of SVR on HIV progression and mortality not related to liver disease. Methods. An observational cohort study including consecutive HIV/HCV-coinfected patients treated with interferon plus ribavirin between 2000 and 2008 in 19 centers in Spain. Results. Of 1599 patients, 626 (39%) had an SVR. After a median follow-up of approximately 5 years, we confirmed that failure to achieve an SVR was associated with an increased risk of liver-related events and liver-related death. We also observed higher rates of the following events in nonresponders than in responders: AIDS-defining conditions (rate per 100 person years, 0.84 95% confidence interval (CI), .59–1.10 vs 0.29 .10–.48; P = .003), non—liver-related deaths (0.65 .42–.87 vs 0.16 .02–.30; P = .002), and non—liver-related, non—AIDS-related deaths (0.55 .34–.75 vs 0.16 .02–.30; P = .002). Cox regression analysis showed that the adjusted hazard ratios of new AIDS-defining conditions, non—liver-related deaths, and non—liver-related, non—AIDS-related deaths for nonresponders compared with responders were 1.90 (95% CI, .89–4.10; P = .095), 3.19 (1.21–8.40; P = .019), and 2.85 (1.07–7.60; P = .036), respectively. Conclusions. Our findings suggest that eradication of HCV after therapy with interferon plus ribavirin in HIV/HCV-coinfected patients is associated not only with a reduction in liver-related events but also with a reduction in HIV progression and mortality not related to liver disease.
Extremely variable prevalence rates of atherogenic dyslipidaemia (AD) in type 2 diabetes (T2DM) subjects have been reported. The primary aim was to assess AD prevalence in Spanish T2DM subjects. ...Secondary objectives were to evaluate the differential clinical characteristics between T2DM subjects with and without AD, to describe lipid profile evolution and use of lipid-lowering treatment in clinical practice by the Spanish Lipid Units. Data was obtained from the National Registry of Dyslipidaemias of the Spanish Atherosclerosis Society, from a multicentric sub-study focused on AD prevalence in T2DM subjects (PREDISAT study). The inclusion criteria were subjects diagnosed of T2DM with age ≥18 years old. A total of 385 T2DM subjects with a mean age of 61 years and 246 (64%) men were included. The mean follow-up was 22 ± 7.4 months. At baseline, 41.3% of the T2DM subjects presented AD, this percentage decreasing to 34.8% with therapeutic intervention. AD prevalence varied in different age groups and appeared to be more prevalent in younger T2DM subjects. Those with AD had a more atherogenic lipid profile at baseline, with higher total cholesterol, triglyceride and non-(high-density lipoprotein) HDL cholesterol levels at baseline, together with lower HDL cholesterol concentrations, without achieving lipid subfraction goals during follow-up. Although almost 90% of the AD subjects were under lipid-lowering treatment, most were receiving only one drug, being statins the most used treatmentA high AD prevalence in T2DM subjects was observed, being age a determinant factor, with a modest decline during follow-up. Although almost 90% of the AD subjects were under lipid-lowering drugs, most were only receiving monotherapy with statins.
The dried blood spot (DBS) is increasingly used for the hepatitis C virus (HCV) screening. Our objective was to perform a meta-analysis of the methodology for HCV screening in DBS samples, ...particularly in the type of diagnostic assay used. We performed a meta-analysis of all eligible studies published to date (March 2018). The literature search revealed 26 studies: 21 for detection of anti-HCV antibodies and 10 for detection of HCV-RNA. Statistical analyses were performed using Meta-DiSc and STATA (MIDAS module). For detection of HCV antibodies, pooled diagnostic accuracy measures were as follows: sensitivity 96.1%, specificity 99.2%, positive likelihood ratio (PLR) 105, negative likelihood ratio (NLR) 0.04, diagnostic odds ratio (DOR) 2692.9, and summary receiver operating characteristic (SROC) 0.997 ± 0.001. For detection of HCV-RNA, the pooled diagnostic accuracy measures were as follows: sensitivity 97.8%, specificity 99.2%, PLR 44.8, NLR 0.04, DOR 1966.9, and SROC 0.996 ± 0.013. Similar values of pooled diagnostic accuracy measures were found according to the type of anti-HCV antibody detection assay (enzyme-linked immunosorbent assay, rapid diagnostic test, and chemiluminescence assays) and HCV-RNA detection assay (real-time polymerase chain reaction and transcription-mediated amplification). The analysis of external validity showed a high negative predicted value (NPV) for both approaches, but a low positive predicted value (PPV) when prevalence was < 10%, particularly in HCV-RNA tests. Finally, this meta-analysis is subject to limitations, especially publication bias and significant heterogeneity between studies. In conclusion, HCV screening in DBS samples has an outstanding diagnostic performance, with no relevant differences between the techniques used. However, external validity may be limited when the HCV prevalence is low.
BACKGROUNDIn intermediate-to-high-risk patients, major abdominal surgery is associated with a high incidence of postoperative complications, mainly pulmonary. Neuromuscular blocking drugs have been ...suggested as a contributing factor, but this remains unproven.
OBJECTIVETo define the relationship of neuromuscular blockade management (reversal) with postoperative pulmonary complications (PPCs).
DESIGNThe individualised PeRioperative Open-lung approach Versus standard protectivE ventilation in abdominal surgery study was a prospective, multicentre, four-arm, randomised controlled trial. This is a secondary analysis of the data.
SETTINGTwenty-one teaching hospitals in Spain. The study was conducted between 2 January 2015, and 18 May 2016.
PATIENTSAge more than 18 years with an intermediate-to-high risk for PPCs, scheduled for major abdominal surgery lasting more than 2 h. Exclusion criteria included pregnancy or breastfeeding, and moderate-to-severe organ diseases.
INTERVENTIONSThe mode of reversal of neuromuscular blockade determined two patient groupspharmacological reversal versus spontaneous recovery.
MAIN OUTCOME MEASURESThe primary outcome was a composite of PPCs during the first 30 postoperative days. The association between categorical variables and PPCs within 30 days was studied. Univariate and multivariable logistic regression modelling and propensity score analyses were performed.
RESULTSFrom the 923 patients included, 596 (64.6%) presented with PPCs within 30 days after surgery. Patients who developed these complications were older with a higher BMI, a lower pre-operative SpO2, a higher ASA physical status score and a higher incidence of arterial hypertension, diabetes mellitus or chronic obstructive pulmonary disease. Pharmacological neuromuscular blockade reversal was associated with a lower incidence of PPCs (odds ratio 0.62, 95% CI 0.47 to 0.82).
CONCLUSIONSpontaneous recovery of neuromuscular blockade was an independent risk factor for PPCs in patients with intermediate-to-high risk, undergoing abdominal surgery. We suggest this factor should be included in future studies on PPCs.
TRIAL REGISTRATIONclinicaltrials.gov identifierNCT02158923.
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