Active eosinophils regulate host defence and immune responses in colitis.

In the past decade, single-cell transcriptomics has helped to uncover new cell types and states and led to the construction of a cellular compendium of health and disease. Despite this progress, some difficult-to-sequence cells remain absent from tissue atlases. Eosinophils-elusive granulocytes that are implicated in a plethora of human pathologies1-5-are among these uncharted cell types. The heterogeneity of eosinophils and the gene programs that underpin their pleiotropic functions remain poorly understood. Here we provide a comprehensive single-cell transcriptomic profiling of mouse eosinophils. We identify an active and a basal population of intestinal eosinophils, which differ in their transcriptome, surface proteome and spatial localization. By means of a genome-wide CRISPR inhibition screen and functional assays, we reveal a mechanism by which interleukin-33 (IL-33) and interferon-γ (IFNγ) induce the accumulation of active eosinophils in the inflamed colon. Active eosinophils are endowed with bactericidal and T cell regulatory activity, and express the co-stimulatory molecules CD80 and PD-L1. Notably, active eosinophils are enriched in the lamina propria of a small cohort of patients with inflammatory bowel disease, and are closely associated with CD4+ T cells. Our findings provide insights into the biology of eosinophils and highlight the crucial contribution of this cell type to intestinal homeostasis, immune regulation and host defence. Furthermore, we lay a framework for the characterization of eosinophils in human gastrointestinal diseases.

Mitonuclear epistasis involving TP63 and haplogroup Uk: Risk of rapid progression of knee OA in patients from the OAI.

OBJECTIVE: To investigate genetic interactions between mitochondrial deoxyribonucleic acid (mtDNA) haplogroups and nuclear single nucleotide polymorphisms (nSNPs) to analyze their impact on the development of the rapid progression of knee osteoarthritis (OA). DESIGN: A total of 1095 subjects from the Osteoarthritis Initiative, with a follow-up time of at least 48-months, were included. Appropriate statistical approaches were performed, including generalized estimating equations adjusting for age, gender, body mass index, contralateral knee OA, Western Ontario and McMaster Universities Osteoarthritis Index pain, previous injury in target knee and the presence of the mtDNA variant m.16519C. Additional genomic data consisted in the genotyping of Caucasian mtDNA haplogroups and eight nSNPs previously associated with the risk of knee OA in robust genome-wide association studies. RESULTS: The simultaneous presence of the G allele of rs12107036 at TP63 and the haplogroup Uk significantly increases the risk of a rapid progression of knee OA (odds ratio = 1.670; 95% confidence interval [CI]: 1.031-2.706; adjusted p-value = 0.027). The assessment of the population attributable fraction showed that the highest proportion of rapid progressors was under the simultaneous presence of the G allele of rs12107036 and the haplogroup Uk (23.4%) (95%CI: 7.89-38.9; p-value < 0.05). The area under the curve of the cross-validation model (0.730) was very similar to the obtained for the predictive model (0.735). A nomogram was constructed to help clinicians to perform clinical trials or epidemiologic studies. CONCLUSIONS: This study demonstrates the existence of a mitonuclear epistasis in OA, providing new mechanisms by which nuclear and mitochondrial variation influence the susceptibility to develop different OA phenotypes.

Long term clinical outcome of sirolimus drug coated balloons in large coronary vessels.

BACKGROUND: Studies evaluating the safety and efficacy of drug coating balloons (DCB) for the treatment of lesions in large coronary vessel are limited. AIMS: Our study aimed to evaluate the performance of a sirolimus DCB in large coronary arteries. METHODS: We analyzed all the procedures included in the EASTBOURNE Registry (NCT03085823) enrolling patients with a clinical indication to percutaneous coronary intervention performed by a sirolimus DCB according to investigator judgment. In the present analysis, a cut-off of 2.75 mm was used to define large coronary arteries. Primary endpoint of the study was clinically driven target lesion revascularization (TLR) at 24 months whereas secondary endpoint included procedural success, myocardial infarction (MI), cardiac death and total mortality. RESULTS: Among the 2123 patients and 2440 lesions enrolled in the EASTBOURNE study between 2016 and 2020, 757 patients/810 lesions fulfilled the criteria for the present analysis. Mean reference vessel diameter was 3.2 ± 0.3 mm with mean lesion length of 22 ± 7 mm. Procedural success was high (96%) and at 2-year follow up the device showed a good efficacy with a TLR rate of 9%. There were 34 deaths (4.5%), 30 MIs (4%) and 8 BARC type 3-5 bleedings (1.1%). In-stent restenosis (629 lesions) and de novo lesions (181) were associated with 11% and 4% rates of TLR at 2 years, respectively (p = 0.003). CONCLUSIONS: Clinical performance of a sirolimus DCB in large coronary artery vessels shows promising signals at 2-year follow up, both in de novo and in-stent restenosis lesions.

Usefulness of risk scores and predictors of atrial fibrillation recurrence after elective electrical cardioversion.

INTRODUCTION: Electrical cardioversion (ECV) is a frequently used procedure for restoring sinus rhythm in atrial fibrillation (AF); however, the rate of recurrence is high. The identification of patients at high risk of recurrence could influence the decision-making process. The present study evaluates the predictive value of risk scores in atrial fibrillation recurrence after elective electrical cardioversion. METHODS: Unicentric, observational, and prospective study of adult patients who have undergone an elective ECV as rhythm control strategy between July 2017 and September 2022. RESULTS: From the 283 analyzed patients (mean age 63.95 ± 10.76212, 74.9% male); 99 had paroxysmal AF (35%) and 159 (59%) presented AF recurrence during a follow-up of 6 months. In patients with post-ECV AF recurrence, the period of time from diagnosis until the performance of the procedure was longer (393 ± 891 vs. 195 ± 527, p = .02). No paroxysmal AF (71.3% vs. 57.8%, p = .02) and LA dilatation with >40 mL/m2 (35.9% vs. 23.3%, p = .02) volumes were more frequent within these patients. AF recurrence was more frequent in patients who had previous ECV (HR = 1.32; 95% CI: 1.12-2.35; p = .01) and more than 1 shock to recover sinus rhythm (HR = 1.62; 95% CI: 1.07-1.63; p = .01). The SLAC, ALARMEc, ATLAS, and CAAP-AF scores were statistically significant, although with a moderate predictive capacity for post-ECV recurrence. CONCLUSIONS: Risk scores analyzed showed a modest value predicting AF recurrence after ECV. Previous ECV, and greater difficulty in restoring SR were independent predictors of recurrence.

A meta-analysis and a functional study support the influence of mtDNA variant m.16519C on the risk of rapid progression of knee osteoarthritis.

OBJECTIVES: To identify mitochondrial DNA (mtDNA) genetic variants associated with the risk of rapid progression of knee osteoarthritis (OA) and to characterise their functional significance using a cellular model of transmitochondrial cybrids. METHODS: Three prospective cohorts contributed participants. The osteoarthritis initiative (OAI) included 1095 subjects, the Cohort Hip and Cohort Knee included 373 and 326 came from the PROspective Cohort of Osteoarthritis from A Coruña. mtDNA variants were screened in an initial subset of 450 subjects from the OAI by in-depth sequencing of mtDNA. A meta-analysis of the three cohorts was performed. A model of cybrids was constructed to study the functional consequences of harbouring the risk mtDNA variant by assessing: mtDNA copy number, mitochondrial biosynthesis, mitochondrial fission and fusion, mitochondrial reactive oxygen species (ROS), oxidative stress, autophagy and a whole transcriptome analysis by RNA-sequencing. RESULTS: mtDNA variant m.16519C is over-represented in rapid progressors (combined OR 1.546; 95% CI 1.163 to 2.054; p=0.0027). Cybrids with this variant show increased mtDNA copy number and decreased mitochondrial biosynthesis; they produce higher amounts of mitochondrial ROS, are less resistant to oxidative stress, show a lower expression of the mitochondrial fission-related gene fission mitochondrial 1 and an impairment of autophagic flux. In addition, its presence modulates the transcriptome of cybrids, especially in terms of inflammation, where interleukin 6 emerges as one of the most differentially expressed genes. CONCLUSIONS: The presence of the mtDNA variant m.16519C increases the risk of rapid progression of knee OA. Among the most modulated biological processes associated with this variant, inflammation and negative regulation of cellular process stand out. The design of therapies based on the maintenance of mitochondrial function is recommended.

Meta-analysis of erosive hand osteoarthritis identifies four common variants that associate with relatively large effect.

OBJECTIVES: Erosive hand osteoarthritis (EHOA) is a severe subset of hand osteoarthritis (OA). It is unclear if EHOA is genetically different from other forms of OA. Sequence variants at ten loci have been associated with hand OA but none with EHOA. METHODS: We performed meta-analysis of EHOA in 1484 cases and 550 680 controls, from 5 populations. To identify causal genes, we performed eQTL and plasma pQTL analyses, and developed one zebrafish mutant. We analysed associations of variants with other traits and estimated shared genetics between EHOA and other traits. RESULTS: Four common sequence variants associated with EHOA, all with relatively high effect. Rs17013495 (SPP1/MEPE, OR=1.40, p=8.4×10-14) and rs11243284 (6p24.3, OR=1.35, p=4.2×10-11) have not been associated with OA, whereas rs11631127 (ALDH1A2, OR=1.46, p=7.1×10-18), and rs1800801 (MGP, OR=1.37, p=3.6×10-13) have previously been associated with hand OA. The association of rs1800801 (MGP) was consistent with a recessive mode of inheritance in contrast to its additive association with hand OA (OR homozygotes vs non-carriers=2.01, 95% CI 1.71 to 2.37). All four variants associated nominally with finger OA, although with substantially lower effect. We found shared genetic components between EHOA and other OA measures, grip strength, urate levels and gout, but not rheumatoid arthritis. We identified ALDH1A2, MGP and BMP6 as causal genes for EHOA, with loss-of-function Bmp6 zebrafish mutants displaying EHOA-like phenotypes. CONCLUSIONS: We report on significant genetic associations with EHOA. The results support the view of EHOA as a form of severe hand OA and partly separate it from OA in larger joints.

ß-Turn Induction by a Diastereopure Azepane-Derived Quaternary Amino Acid.

ß-Turns are one of the most common secondary structures found in proteins. In the interest of developing novel ß-turn inducers, a diastereopure azepane-derived quaternary amino acid has been incorporated into a library of simplified tetrapeptide models in order to assess the effect of the azepane position and peptide sequence on the stabilization of ß-turns. The conformational analysis of these peptides by molecular modeling, NMR spectroscopy, and X-ray crystallography showed that this azepane amino acid is an effective ß-turn inducer when incorporated at the i + 1 position. Moreover, the analysis of the supramolecular self-assembly of one of the ß-turn-containing peptide models in the solid state reveals that it forms a supramolecular helical arrangement while maintaining the ß-turn structure. The results here presented provide the basis for the use of this azepane quaternary amino acid as a strong ß-turn inducer in the search for novel peptide-based bioactive molecules, catalysts, and biomaterials.

[Invasive mucormycosis during COVID-19 infection. Report of two cases]. / Mucormicosis invasora en pacientes con COVID-19: reporte de 2 casos.

COVID-19 disease is associated with a significant number of opportunistic infections, including invasive fungal infections such as mucormycosis. The prevalence of the latter is rare, estimated to be between 0.005 and 1.7 per million inhabitants. Risk factors include hematological diseases, Diabetes Mellitus with poor metabolic control, solid organ transplantation, neutropenia, and prolonged administration of systemic corticosteroids. We report two males aged 60 and 75 years with pulmonary and tracheobronchial invasive mucormycosis, respectively. Both patients had a deficient metabolic control of their diabetes as a predisposing risk factor added to severe COVID-19 infection. High suspicion and early diagnosis are essential for prompt treatment, especially considering the associated high morbidity and mortality of this fungal infection.

Is osteoarthritis a mitochondrial disease? What is the evidence.

PROPOSE OF REVIEW: To summarize the evidence that suggests that osteoarthritis (OA) is a mitochondrial disease. RECENT FINDINGS: Mitochondrial dysfunction together with mtDNA damage could contribute to cartilage degradation via several processes such as: (1) increased apoptosis; (2) decreased autophagy; (3) enhanced inflammatory response; (4) telomere shortening and increased senescence chondrocytes; (5) decreased mitochondrial biogenesis and mitophagy; (6) increased cartilage catabolism; (7) increased mitochondrial fusion leading to further reactive oxygen species production; and (8) impaired metabolic flexibility. SUMMARY: Mitochondria play an important role in some events involved in the pathogenesis of OA, such as energy production, the generation of reactive oxygen and nitrogen species, apoptosis, authophagy, senescence and inflammation. The regulation of these processes in the cartilage is at least partially controlled by retrograde regulation from mitochondria and mitochondrial genetic variation. Retrograde regulation through mitochondrial haplogroups exerts a signaling control over the nuclear epigenome, which leads to the modulation of nuclear genes, cellular functions and development of OA. All these data suggest that OA could be considered a mitochondrial disease as well as other complex chronic disease as cancer, cardiovascular and neurologic diseases.

Single nucleotide polymorphism genes and mitochondrial DNA haplogroups as biomarkers for early prediction of knee osteoarthritis structural progressors: use of supervised machine learning classifiers.

BACKGROUND: Knee osteoarthritis is the most prevalent chronic musculoskeletal debilitating disease. Current treatments are only symptomatic, and to improve this, we need a robust prediction model to stratify patients at an early stage according to the risk of joint structure disease progression. Some genetic factors, including single nucleotide polymorphism (SNP) genes and mitochondrial (mt)DNA haplogroups/clusters, have been linked to this disease. For the first time, we aim to determine, by using machine learning, whether some SNP genes and mtDNA haplogroups/clusters alone or combined could predict early knee osteoarthritis structural progressors. METHODS: Participants (901) were first classified for the probability of being structural progressors. Genotyping included SNP genes TP63, FTO, GNL3, DUS4L, GDF5, SUPT3H, MCF2L, and TGFA; mtDNA haplogroups H, J, T, Uk, and others; and clusters HV, TJ, KU, and C-others. They were considered for prediction with major risk factors of osteoarthritis, namely, age and body mass index (BMI). Seven supervised machine learning methodologies were evaluated. The support vector machine was used to generate gender-based models. The best input combination was assessed using sensitivity and synergy analyses. Validation was performed using tenfold cross-validation and an external cohort (TASOAC). RESULTS: From 277 models, two were defined. Both used age and BMI in addition for the first one of the SNP genes TP63, DUS4L, GDF5, and FTO with an accuracy of 85.0%; the second profits from the association of mtDNA haplogroups and SNP genes FTO and SUPT3H with 82.5% accuracy. The highest impact was associated with the haplogroup H, the presence of CT alleles for rs8044769 at FTO, and the absence of AA for rs10948172 at SUPT3H. Validation accuracy with the cross-validation (about 95%) and the external cohort (90.5%, 85.7%, respectively) was excellent for both models. CONCLUSIONS: This study introduces a novel source of decision support in precision medicine in which, for the first time, two models were developed consisting of (i) age, BMI, TP63, DUS4L, GDF5, and FTO and (ii) the optimum one as it has one less variable: age, BMI, mtDNA haplogroup, FTO, and SUPT3H. Such a framework is translational and would benefit patients at risk of structural progressive knee osteoarthritis.

Nomogram based on baseline clinicopathological characteristics for predicting bladder cancer-specific survival to neoadjuvant chemotherapy in muscle-invasive bladder cancer.

PURPOSE: To develop a risk score based on a prognostic model and a nomogram integrating baseline clinicopathological variables to predict bladder cancer-specific survival (BCSS) to neoadjuvant chemotherapy (NAC) in muscle-invasive bladder cancer (MIBC) patients. METHODS: We retrospectively identified a consecutive sample of 247 MIBC patients treated with cisplatin-based NAC-plus-cystectomy in two Spanish hospitals between 2000 and 2019. Age at MIBC diagnosis, sex, histology, lymphovascular invasion, previous non-MIBC, hydronephrosis, and clinical TNM were included in the initial Cox regression model. A risk score was computed based on the final prognostic model and a nomogram was used to estimate BCSS at 2 and 5 years. RESULTS: Median age was 66 years; 89% were males; 83% had pure urothelial carcinoma; 16.2% had previous non-MIBC. Clinical stage was T2N0, T3-4aN0, and Tx-4N + in 24%, 57%, and 19% of patients, respectively. Complete pathological response was seen in 29.4% and downstaging to non-MIBC (ypT1, ypTa, ypTis) in 12.5% of patients. Overall 5-year BCSS was 59%. Four prognostic factors were identified: variant histology, previous non-MIBC, female sex and hydronephrosis. By adding the points attributed to each of these factors, we categorized patients in three groups: low-risk (0 points); intermediate-risk (1-9 points); high-risk (≥ 10 points). Five-year BCSS was 72%, 53%, and 15%, respectively (p < 0.0001). CONCLUSION: We developed a nomogram and risk score based on four baseline clinicopathological characteristics to predict BCSS to NAC-plus-cystectomy in MIBC patients. If validated in prospective studies, this nomogram can be useful for selecting patients likely to benefit from NAC.

[Effectiveness of a multidimensional therapeutic program for aged people attending senior centers]. / Efectividad a mediano plazo de un programa multidimensional en personas mayores en centros diurnos en Chile.

BACKGROUND: It is imperative to have effective programs to improve or maintain the health of aged people. AIM: To evaluate the effectiveness of an intervention based on a multidimensional program in Senior centers in Chile five months after its implementation, in the domains of physical and mental health, functionality and quality of life in aged people. MATERIAL AND METHODS: Sixty participants older than 60 years completed a multidimensional program for one month that included interventions of guided physical exercises, in addition to educational and social activities. They were evaluated at baseline and one and five months after the intervention. RESULTS: After the first and fifth months, significant improvements were observed in the five times sit to stand test (5TSTS) and gait speed (WST), in addition, significant improvements were observed in literacy measured by the Short Assessment of Health Literacy for Spanish-speaking Adults (SAHLSA). At the fifth month, slight improvements were observed in the Yesavage and short Falls efficacy scales, Barthel index, Unipodal Station and EuroQol five-dimensional quality of life tests. CONCLUSIONS: A multidimensional program for aged people lasting one month, improved the physical health dimension and literacy by the fifth month of evaluation.

Mitochondrial DNA from osteoarthritic patients drives functional impairment of mitochondrial activity: a study on transmitochondrial cybrids.

With the redefinition of osteoarthritis (OA) and the understanding that the joint behaves as an organ, OA is now considered a systemic illness with a low grade of chronic inflammation. Mitochondrial dysfunction is well documented in OA and has the capacity to alter chondrocyte and synoviocyte function. Transmitochondrial cybrids are suggested as a useful cellular model to study mitochondrial biology in vitro, as they carry different mitochondrial variants with the same nuclear background. The aim of this work was to study mitochondrial and metabolic function of cybrids with mitochondrial DNA from healthy (N) and OA donors. In this work, the authors demonstrate that cybrids from OA patients behave differently from cybrids from N donors in several mitochondrial parameters. Furthermore, OA cybrids behave similarly to OA chondrocytes. These results enhance our understanding of the role of mitochondria in the degeneration process of OA and present cybrids as a useful model to study OA pathogenesis.

DUART: durvalumab after radiotherapy in patients with unresectable, stage III NSCLC who are ineligible for chemotherapy.

Consolidation durvalumab is standard of care in patients with unresectable, stage III non-small-cell lung cancer (NSCLC) without disease progression following chemoradiotherapy (the 'PACIFIC regimen'). However, many patients with poor performance status, older age or comorbidities may be ineligible for chemotherapy due to expected high toxicity. These patients typically receive radiotherapy alone, with poor survival outcomes. Based on the PACIFIC trial data, and the strong biological rationale for combining radiotherapy with anti-programmed cell death ligand-1 therapy, durvalumab following radiotherapy could provide additional survival benefit versus radiotherapy alone. Here, we describe the DUART trial, a Phase II, open-label, single-arm study assessing the safety and tolerability of durvalumab following radiotherapy in patients with unresectable, stage III NSCLC who are ineligible for chemotherapy (ClinicalTrials.gov Identifier: NCT04249362).

Lay abstract The current standard treatment for patients with stage III non-small-cell lung cancer whose cancer cannot be removed by surgery is chemotherapy plus radiotherapy; if their disease gets no worse after this, patients also receive durvalumab ­ altogether this is known as the 'PACIFIC regimen'. However, some patients who are older or who have existing health conditions cannot tolerate chemotherapy, so instead of the PACIFIC regimen they receive radiotherapy only. The DUART study described here is an ongoing, Phase II clinical trial looking at the safety and tolerability of durvalumab after radiotherapy in patients with stage III non-small-cell lung cancer who are unsuitable for chemotherapy and whose cancer cannot be removed by surgery. Clinical Trial Registration: NCT04249362.

A Heterogeneous Hardware Accelerator for Image Classification in Embedded Systems.

Convolutional neural networks (CNN) have been extensively employed for image classification due to their high accuracy. However, inference is a computationally-intensive process that often requires hardware acceleration to operate in real time. For mobile devices, the power consumption of graphics processors (GPUs) is frequently prohibitive, and field-programmable gate arrays (FPGA) become a solution to perform inference at high speed. Although previous works have implemented CNN inference on FPGAs, their high utilization of on-chip memory and arithmetic resources complicate their application on resource-constrained edge devices. In this paper, we present a scalable, low power, low resource-utilization accelerator architecture for inference on the MobileNet V2 CNN. The architecture uses a heterogeneous system with an embedded processor as the main controller, external memory to store network data, and dedicated hardware implemented on reconfigurable logic with a scalable number of processing elements (PE). Implemented on a XCZU7EV FPGA running at 200 MHz and using four PEs, the accelerator infers with 87% top-5 accuracy and processes an image of 224×224 pixels in 220 ms. It consumes 7.35 W of power and uses less than 30% of the logic and arithmetic resources used by other MobileNet FPGA accelerators.

[Compliance with post-cesarean section thromboprophylaxis recommendations. A cross sectional study in 233 women]. / Adherencia a las recomendaciones de tromboprofilaxis post-cesárea: estudio de corte transversal.

BACKGROUND: Cesarean section increases four times the risk of venous thromboembolism compared to vaginal delivery. The Royal College of Obstetricians and Gynecologists guidelines are used at our service. A written alert was designed to stratify patients at high, intermediate or low risk making a suggestion for thromboprophylaxis. AIM: To assess the compliance with the guidelines and to evaluate the impact of a written alert in the thromboprophylaxis compliance in women subjected to caesarean section. PATIENTS AND METHODS: Review of medical records of 233 women aged 19 to 32 years, subjected to a caesarean section in a Gynecology Service, between 2016-2017. RESULTS: Compliance with recommendations was observed in 29% of patients (68/233), 86% in the low-risk group, 26% in the intermediate risk group and 100% in the high risk group. In 41/233 (18%) of patients, a written alert was included in the medical record. Compliance with recommendations in the presence of the written alert was 61% (25/41 women) compared to 22% (43/192) in those lacking the alert (p < 0.01). In women whose emergency caesarean section was the only risk factor, the compliance with the recommendation was 8%, compared with 30% among those who had at least one thrombotic risk factor associated with caesarean section (p < 0.01). CONCLUSIONS: In this cross-sectional study, we observed a low compliance with thromboprophylaxis guidelines in cesarean women. We observed that the use of a written alert improved the compliance with thromboprophylaxis.

Discovery of an autoantibody signature for the early diagnosis of knee osteoarthritis: data from the Osteoarthritis Initiative.

OBJECTIVE: To find autoantibodies (AAbs) in serum that could be useful to predict incidence of radiographic knee osteoarthritis (KOA). DESIGN: A Nucleic-acid Programmable Protein Arrays (NAPPA) platform was used to screen AAbs against 2125 human proteins in sera at baseline from participants free of radiographic KOA belonging to the incidence and non-exposed subcohorts of the Osteoarthritis Initiative (OAI) who developed or not, radiographic KOA during a follow-up period of 96 months. NAPPA-ELISA were performed to analyse reactivity against methionine adenosyltransferase two beta (MAT2ß) and verify the results in 327 participants from the same subcohorts. The association of MAT2ß-AAb levels with KOA incidence was assessed by combining several robust biostatistics analysis (logistic regression, Receiver Operating Characteristic and Kaplan-Meier curves). The proposed prognostic model was replicated in samples from the progression subcohort of the OAI. RESULTS: In the screening phase, six AAbs were found significantly different at baseline in samples from incident compared with non-incident participants. In the verification phase, high levels of MAT2ß-AAb were significantly associated with the future incidence of KOA and with an earlier development of the disease. The incorporation of this AAb in a clinical model for the prognosis of incident radiographic KOA significantly improved the identification/classification of patients who will develop the disorder. The usefulness of the model to predict radiographic KOA was confirmed on a different OAI subcohort. CONCLUSIONS: The measurement of AAbs against MAT2ß in serum might be highly useful to improve the prediction of OA development, and also to estimate the time to incidence.

BRCA1 and BRCA2 mutations and clinical interpretation in 398 ovarian cancer patients: comparison with breast cancer variants in a similar population.

BACKGROUND: Ovarian cancer is the leading cause of death worldwide among gynecologic malignancies. The recent approval of inhibitors of poly (ADP-ribose) polymerase (iPARP) in the treatment of ovarian cancer in the presence of a BRCA1/2 mutation has sparked the analysis of women with such diagnosis, which can further benefit from the detection of carriers in the family. Germline sequence and large rearrangements for BRCA1/2 were tested in 398 consecutive epithelial ovarian cancer (EOC) patients. The aim of this study was to identify the frequency and spectrum of germline BRCA1/2 pathogenic alterations in a cohort of patients with ovarian serous carcinoma, with a view to adequately selecting patients for prevention through family counseling and correlating this frequency with platinum sensitivity as a guidance to identify patients eligible for iPARP in our population. RESULTS: A total of 96 patients carried a pathogenic germline mutation, accounting for an overall 24.1% mutation incidence. Among mutation carriers, BRCA1 showed 62.5% incidence, BRCA2 rendered 36.5%, and one patient exhibited a mutation in both genes. Three pathogenic mutations were recurrent mutations detected five, three, and four times and represented 12.5% of the mutated samples. Worth highlighting, a 50% mutation incidence was detected when breast and ovarian cancer coexisted in the same patient. Novel mutations amounted to 9.4% of the total mutations, as compared to 4.7% in breast cancer. Forty out of 60 BRCA1 mutations were beyond the ovarian cancer cluster region (OCCR), in stark contrast with 22 out of 36 BRCA2 mutations being inside the OCCR. Taken together, germline BRCA1/2 mutations in EOC patients showed a distinct mutational spectrum compared to our previously published data on breast cancer patients. CONCLUSIONS: In sum, our study provides novel data on ovarian BRCA1/2 mutation prevalence worldwide, enhances adequate patient selection for family counseling and prevention, and sheds light on the benefits of iPARP treatment.

Efficacy and Safety of Loading Doses With P2Y12-Receptor Antagonists in Patients Without Dual Antiplatelet Therapy Undergoing Elective Coronary Intervention.

BACKGROUND: European Guidelines on Myocardial Revascularization recommend clopidogrel loading dose added to acetylsalicylic acid in elective percutaneous coronary interventions (PCIs). However, there is few evidence supporting this recommendation and other P2Y12 inhibitors have not been tested in these patients. PURPOSE: To evaluate the effectiveness and safety of different loading doses of clopidogrel and ticagrelor in patients without double antiplatelet therapy and stable coronary artery disease (SCAD) undergoing elective PCI. METHODS: Retrospective study of 147 consecutive patients with SCAD undergoing elective PCI. Loading P2Y12 inhibitor doses evaluated were: clopidogrel 600 mg, clopidogrel 300 mg, clopidogrel 150 mg, and ticagrelor 180 mg. We analyzed the occurrence of major adverse cardiovascular events and periprocedural myocardial infarction. RESULTS: One hundred twenty-five patients were treated with clopidogrel (16 with clopidogrel 150 mg, 7 with clopidogrel 300 mg, and 93 with clopidogrel 600 mg) and 21 with ticagrelor 180 mg at the catheterization laboratory. The ticagrelor group had a significantly lower postprocedural peak of troponin-I (0.7 ± 3.4 vs. 0.3 ± 0.7 ng/mL; P = 0.02). There were no differences between groups in terms of major bleeding and hemoglobin drop after PCI (0.6 ± 0.8 vs. 4 ± 0.6; P = 0.8). The median of follow-up was 17 months (interquartile range 9-32.7). At the end of follow-up, major adverse cardiovascular event rate was not different between groups. CONCLUSIONS: In patients without dual antiplatelet therapy undergoing elective PCI, the use of ticagrelor showed lower postprocedural myocardial injury without more bleeding complications.

Trace analysis of UV filters and musks in living fish by in vivo SPME-GC-MS.

A method was developed for the simultaneous determination of two groups of personal care products, namely UV filters (oxybenzone, 3-(4-methylbenzylidene)camphor, padimate-O, 2-ethylhexyl-4-methoxycinnamate, and octocrylene) and polycyclic aromatic musks (galaxolide and tonalide), in fish by in vivo solid-phase microextraction followed by gas chromatography-mass spectrometry. The in vivo method was validated by carrying out in vitro experiments; the method validation parameters were linearity (r2 > 0.98), interday precision (relative standard deviations < 35.50%), limits of detection and quantification ranging from 2 to 25 ng g-1 and 5 to 70 ng g-1, respectively. The calibrations in vivo and in vitro were determined using a pre-equilibrium sampling rate calibration method. In vivo sampling rate (Rs) was greater than that in vitro; therefore in vivo Rs was applied to the uptake and elimination tracing under controlled laboratory conditions to avoid quantitation error. All analytes were bioaccumulated in muscle tissue over the 5-day exposure in different grades depending on their molecular structure and physicochemical properties; the most absorbed compound was tonalide and the least absorbed compound was padimate-O. The elimination rate was initially high with a rapid decrease of the analyte concentrations for the first 24 h; thereafter, the rate of elimination tended to decrease which indicated that the target analytes were bioaccumulated. To our knowledge, this is the first time that UV filters have been analyzed with in vivo SPME-GC-MS. The proposed method is a simple, miniaturized, and non-lethal alternative for the determination of personal care products in living organisms. Graphical abstract.