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This phase 3, multiregional, randomized, double-blind, placebo-controlled study assessed the efficacy/safety profile of anacetrapib added to ongoing therapy with statin ± other lipid-modifying therapies in patients with hypercholesterolemia who were not at their low-density lipoprotein (LDL-C) goal (as per the National Cholesterol Education Program Adult Treatment Panel III guidelines) and in those with low high-density lipoprotein cholesterol (HDL-C). Patients on a stable dose of statin ± other lipid-modifying therapies and with LDL-C ≥70 to <115, ≥100 to <145, ≥130, or ≥160 mg/dl for very high, high, moderate, or low CHD risk or at LDL-C goal (per CHD risk category) with HDL-C ≤40 mg/dl were randomized in a ratio of 1:1 to anacetrapib 100 mg (n = 290) or placebo (n = 293) for 24 weeks, followed by a 12-week off-drug phase. The co-primary end points were % change from baseline in LDL-C and HDL-C and the safety profile of anacetrapib. Treatment with anacetrapib reduced LDL-C (BQ) by 37% (95% confidence interval −42.5, −31.0) and increased HDL-C by 118% (95% confidence interval 110.6, 125.7) relative to placebo (p <0.001 for both). Anacetrapib also reduced non-HDL-C, apolipoprotein B, and lipoprotein a and increased apolipoprotein AI versus placebo (p <0.001 for all). There were no clinically meaningful differences between the anacetrapib and placebo groups in the % patients who discontinued drug due to an adverse event or in abnormalities in liver enzymes, creatine kinase, blood pressure, electrolytes, or adjudicated cardiovascular events. Treatment with anacetrapib substantially reduced LDL-C and also increased HDL-C and was well tolerated over 24 weeks in statin-treated patients with hypercholesterolemia or low HDL-C.

Background Epidemiological studies suggest an association between air pollution and ventricular arrhythmias, with reactive oxygen species (ROS) playing a crucial role. However, the causal relationship and long-term effects remain uncertain, and the effectiveness of interventions aimed at reducing ROS requires further investigation. Here we aimed to evaluate the effects of a 3-weeks exposure to diesel exhaust particles (DEPs) on ventricular arrhythmogenesis, explore the underlying mechanisms, and assess the potential of cerium oxide nanoparticles (CeO 2 NP) as a ROS-detoxifying intervention. Results Sprague–Dawley rats underwent intratracheal instillation of saline without or with DEPs (7.5 g/Kg for 1–3 weeks). Ventricular arrhythmia inducibility was then assessed in isolated hearts using a protocol of programmed electrical stimulation. Cardiac hypertrophy, collagen content, inflammation and oxidative stress were analyzed using histology, Western blot, RT-qPCR, and measurement of malondialdehyde content. The potential protective effects of CeO 2 NP (0.5 mg/Kg/week, i.p.) were also tested. DEP exposure for 3 weeks increased the incidence and duration of sustained ventricular tachyarrhythmias (VTs), a finding that correlated with a moderate increase in interstitial collagen (from 3.11 ± 0.12% in controls to 4.80 ± 0.21% in DEP-exposed rats, p < 0.001), and an early upregulation in the expression of collagen and other fibrotic and inflammatory markers. These effects associated with prolonged QRS complex and enhanced malondialdehyde content (356.7 ± 21.2 vs. 455.3 ± 17.2 μmol/g tissue, p = 0.0066) after 3 weeks. CeO 2 NP treatment reduced oxidative stress and myocardial fibrosis, reversed electrocardiographic changes and attenuated DEP-induced pro-arrhythmic effects. Conclusions DEP exposure increases the incidence and duration of sustained VTs, collagen deposition and oxidative stress in rats. Treatment with CeO 2 NP attenuate these effects, arising as a potential novel strategy to mitigate the deleterious effects of air pollution.

Mannose-binding lectin (MBL)-associated serine protease-2 (MASP-2) is an indispensable enzyme for the activation of the lectin pathway of complement. Its deficiency is classified as a primary immunodeficiency associated to pyogenic bacterial infections, inflammatory lung disease, and autoimmunity. In Europeans, MASP-2 deficiency, due to homozygosity for c.359A > G (p.D120G), occurs in 7 to 14/10,000 individuals. We analyzed the presence of the p.D120G mutation in adults (increasing the sample size of our previous studies) and children. Different groups of patients (1495 adults hospitalized with community-acquired pneumonia, 186 adults with systemic lupus erythematosus, 103 pediatric patients with invasive pneumococcal disease) and control individuals (1119 healthy adult volunteers, 520 adult patients without history of relevant infectious diseases, and a pediatric control group of 311 individuals) were studied. Besides our previously reported MASP-2-deficient healthy adults, we found a new p.D120G homozygous individual from the pediatric control group. We also reviewed p.D120G homozygous individuals reported so far: a total of eleven patients with a highly heterogeneous range of disorders and nine healthy controls (including our four MASP-2-deficient individuals) have been identified by chance in association studies. Individuals with complete deficiencies of several pattern recognition molecules of the lectin pathway (MBL, collectin-10 and collectin-11, and ficolin-3) as well as of MASP-1 and MASP-3 have also been reviewed. Cumulative evidence suggests that MASP-2, and even other components of the LP, are largely redundant in human defenses and that individuals with MASP-2 deficiency do not seem to be particularly prone to infectious or autoimmune diseases.

Purpose Conflicting results about the role of genetic variability at IL6 , particularly the -174 G/C single nucleotide polymorphism (SNP), in sepsis have been reported. We studied the genetic variability at IL6 in patients with community-acquired pneumonia (CAP) and pneumococcal CAP (P-CAP). Methods This was a multicenter, prospective observational study. IL6 -174 was analyzed in 1,227 white Spanish patients with CAP (306 with P-CAP). IL6 1753 C/G ( N  = 750), 2954 G/C ( N  = 845), and haplotypes defined by these SNPs were also studied. Results In CAP patients the genotype -174 GG were associated with protection against acute respiratory distress syndrome (ARDS) ( p  = 0.008, OR = 0.4, 95% CI 0.2–0.8). No other significant associations were observed. However, in patients with P-CAP multivariate analysis adjusted for age, gender, co-morbidity, hospital of origin, and severity (pneumonia severity index, PSI) showed that the IL6 -174 GG genotype was protective against the development of ARDS ( p  = 0.002, OR = 0.25, 95% CI 0.07–0.79), septic shock ( p  = 0.006, OR = 0.46, 95% CI 0.18–0.79), and multiple organ dysfunction syndrome ( p  = 0.02, OR = 0.53, 95% CI 0.27–0.89). P-CAP patients homozygous for IL6 -174 G also showed a higher survival in a logistic regression analysis adjusted for age, gender, co-morbidity, hospital of origin, and PSI ( p  = 0.048, OR = 0.27, 95% CI 0.07–0.98). Conclusions Our results indicate that the IL-6 -174 GG genotype is associated with lower severity and mortality in patients with P-CAP. This effect was higher than that observed in patients with CAP irrespective of the causal pathogen involved. Our results highlight the importance of the causal pathogen in genetic epidemiological studies in sepsis.

Background/Objectives: Prostate cancer (PC) is the most prevalent cancer in men in Spain. Clinical management depends on the stage/tumor response to therapy/therapy availability. Given the limited national data, we analyzed real-world prevalence and management patterns. Methods: This was an observational, retrospective study using electronic medical records from public primary care centers/hospitals in Spain (BIG-PAC® database), between 1 June 2014, and 31 December 2021. Adult PC-diagnosed patients were classified into localized PC with no compromised lymph nodes and no metastasis (N0/M0), locally advanced PC with compromised lymph nodes, no metastasis (N1/M0), metastatic hormone-sensitive PC (mHSPC), non-metastatic castration-resistant PC (nmCRPC), and metastatic castration-resistant PC (mCRPC, categorized by treatment line). Progression across stages was recorded. All analyses were descriptive and exploratory. Results: A total of 19,224 patients met the inclusion criteria. The five-year PC prevalence was 590 cases/100,000 males; localized PC was the most prevalent form of cancer (PC[N0/M0]: 473/100,000; PC[N1/M0]: 78/100,000), followed by mCRPC (16/100,000), mHSPC (14/100,000), and nmCRPC (8/100,000). We further analyzed 5583 patients with progression. Surgery was performed in 61.7% PC (N1/M0), while radiotherapy was used in 24.3%. Taxanes were used in 52.4% of the mHSPC patients. First prescription options for mCRPC L1 and L2 were androgen receptor pathway inhibitors (55.9% and 49.7%); 44.9% of mCRPC L3 and 83.3% of L4+ (≥4 treatment lines) patients used taxanes. Analgesics were common in mHSPC, nmCRPC, and mCRPC patients. Few mHSPC patients died without progression (11.6%); 90.2% and 56.2% of the mCRPC patients received first- and second-line treatments, respectively. During follow-up, 2436 patients died. Cardiovascular comorbidities increased with stage. Conclusions: PC management in Spain varies substantially by disease stage. Advanced disease was associated with higher comorbidity burden and reduced survival in mHSPC and mCRPC patients, despite multiple available treatments.

Irritable bowel syndrome (IBS) is a disorder of brain-gut interaction characterised by abdominal pain and changes in bowel habits. In the diarrhoea subtype (IBS-D), altered epithelial barrier and mucosal immune activation are associated with clinical manifestations. We aimed to further evaluate plasma cells and epithelial integrity to gain understanding of IBS-D pathophysiology. One mucosal jejunal biopsy and one stool sample were obtained from healthy controls and IBS-D patients. Gastrointestinal symptoms, stress, and depression scores were recorded. In the jejunal mucosa, RNAseq and gene set enrichment analyses were performed. A morphometric analysis by electron microscopy quantified plasma cell activation and proximity to enteric nerves and glycocalyx thickness. Immunoglobulins concentration was assessed in the stool. IBS-D patients showed differential expression of humoral pathways compared to controls. Activation and proximity of plasma cells to nerves and IgG concentration were also higher in IBS-D. Glycocalyx thickness was lower in IBS-D compared to controls, and this reduction correlated with plasma cell activation, proximity to nerves, and clinical symptoms. These results support humoral activity and loss of epithelial integrity as important contributors to gut dysfunction and clinical manifestations in IBS-D. Additional studies are needed to identify the triggers of these alterations to better define IBS-D pathophysiology.

Epidemiological studies suggest an association between air pollution and ventricular arrhythmias, with reactive oxygen species (ROS) playing a crucial role. However, the causal relationship and long-term effects remain uncertain, and the effectiveness of interventions aimed at reducing ROS requires further investigation. To evaluate the effects of chronic exposure to diesel exhaust particles (DEPs) on ventricular arrhythmogenesis, explore the underlying mechanisms, and assess the potential of cerium oxide nanoparticles (CeO2NP) as a ROS-detoxifying intervention. Sprague-Dawley rats underwent intratracheal instillation of saline without or with DEPs (7.5 g/Kg for 1-3 weeks). Ventricular arrhythmia inducibility was then assessed in isolated hearts using a protocol of programmed electrical stimulation. Cardiac hypertrophy, collagen content, inflammation and oxidative stress were analyzed using histology, Western blot, RT-PCR, and measurement of malondialdehyde content. The potential protective effects of CeO2NP (0.5 mg/Kg/week, i.p.) were also tested. DEP exposure for 3 weeks increased the incidence and duration of sustained ventricular tachyarrhythmias (VTs), a finding that correlated with a moderate increase in interstitial collagen (from 3.11±0.12% in controls to 4.80±0.21% in DEP-exposed rats, p<0.001), and an early upregulation in the expression of collagen and other fibrotic and inflammatory markers. These effects associated with prolonged QRS complex and QTc intervals, and enhanced malondialdehyde content (356.7±21.2 vs. 455.3±17.2 μmol/g tissue, p=0.0066) after 3 weeks. CeO2NP treatment reduced oxidative stress and myocardial fibrosis, reversed electrocardiographic changes and attenuated DEP-induced pro-arrhythmic effects. DEP exposure increases the incidence and duration of sustained VTs, collagen deposition and oxidative stress in rats. Treatment with CeO2NP attenuate these effects, arising as a potential novel strategy to mitigate the deleterious effects of air pollution.

Despite the high sustained virological response rates achieved with current directly-acting antiviral agents (DAAs) against hepatitis C virus (HCV), around 2% to 5% of treated patients do not achieve a sustained viral response. Identification of amino acid substitutions associated with treatment failure requires analytical designs, such as subtype-specific ultra-deep sequencing methods for HCV characterization and patient management. With this procedure we have identified six highly represented amino acid substitutions (HRS) in NS5A and NS5B of HCV from 220 patients who failed therapy, that are not bona fide resistance-associated substitutions (RAS). They were present frequently in basal and post-treatment virus of patients who failed therapy to different DAA-based treatments. Contrary to several RAS, they belong to the acceptable subset of substitutions according to the PAM250 replacement matrix. Coherently, their mutant frequency, measured by the number of deep sequencing reads within the viral quasispecies that encode the relevant substitutions, ranged between 90% and 100% in most cases. Also, they have limited predicted disruptive effects on the three-dimensional structures of the proteins harboring them. Possible mechanisms of HRS origin and dominance, as well as their potential predictive value of treatment response are discussed. Competing Interest Statement The authors have declared no competing interest.