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[Background and objective] The benefits of exercise in atrial fibrillation (AF) are not clear yet. The aim was to assess the effects of exercise on functional capacity, quality of life, symptoms and adverse events in AF patients., [Methods] Pubmed, Web of Science, Science Direct and CENTRAL databases were searched to collect the literature concerning AF and exercise. Studies using an endurance and/or strength exercise of at least one-month duration were included. The meta-analysis was conducted using the random-effects method., [Results] 10 randomised controlled trials were selected. The analysis reported a significant improvement in the maximum exercise capacity (SMCR = 0.35; CI95% = 0.18, 0.51; p < .001) after exercise intervention. In patients with paroxysmal and persistent AF, exercise improved significantly VO2peak (SMCR = 0.387; CI95% = 0.214, 0.561; p < .001). Moreover, patients with permanent AF showed significant results in the 6-min walk test (SMCR = 0.74; CI95% = 0.31, 1.17; p < .001) and the resting heart rate (SMCR = −0.51; CI95% = −0.93, −0.10; p = .0015) thanks to exercise. Regarding quality of life, there was an improvement trend in the physical component score (SMCR = 0.13; CI95% = −0.05, 0.31; p = .17) and mental component score (SMCR = 0.09; CI95% = −0.09, 0.27; p = .35) in the exercise group. Nevertheless, pharmacological treatment tended to control the systolic blood pressure (SMCR = 0.13; CI95% = −0.03, 0.3; p = .11)., [Conclusion] Exercise has a beneficial role as an adjuvant treatment of AF., [Antecedentes y objetivo] Los beneficios del ejercicio físico en la fibrilación auricular (FA) todavía no están claros. El objetivo fue evaluar los efectos del ejercicio físico sobre la capacidad funcional, la calidad de vida, los síntomas y los episodios adversos en pacientes con FA., [Métodos] Se realizó una búsqueda en las bases de datos: Pubmed, Web of Science, Science Direct y CENTRAL para reunir la literatura relativa a FA y ejercicio. Los estudios incluidos utilizaron ejercicio aeróbico y/o fuerza de al menos un mes de duración. El metaanálisis fue elaborado mediante el método de efectos aleatorios., [Resultados] Se seleccionaron 10 ensayos controlados y aleatorizados. El análisis mostró mejoras significativas en la máxima capacidad de ejercicio (SMCR = 0,35; IC95% = 0,18, 0,51; p< 0,001) después del ejercicio. En pacientes con FA paroxística y persistente, el ejercicio mejoró significativamente el VO2pico (SMCR = 0,387; IC95% = 0,214, 0,561; p< 0,001). Además, pacientes con FA permanente mostraron resultados significativos en la prueba de marcha de 6 minutos (SMCR = 0,74; IC95% = 0,31, 1,17; p< 0,001) y en la frecuencia cardíaca en reposo (SMCR = -0,51; IC95% = -0,93, -0,10; p = 0,0015) gracias al ejercicio. A nivel de calidad de vida, hubo una tendencia de mejora en los resúmenes de los componentes físico (SMCR = 0,13; IC95% = -0,05, 0,31; p = 0,17) y mental (SMCR = 0,09; IC95% = -0,09, 0,27; p = 0,35) en el grupo ejercicio. Sin embargo, el tratamiento farmacológico tendió a regular mejor la presión arterial sistólica (SMCR = 0,13; IC95% = -0,03, 0,3; p = 0,11)., [Conclusión] El ejercicio físico tiene un papel beneficioso como tratamiento complementario de la FA.

Pembrolizumab is licensed for the treatment of pre-treated and PD-L1 positive non-small cell lung cancer (NSCLC), but response is heterogeneous. In this context, the Lung Immune Prognostic Index (LIPI) has been proposed as tool to prognosticate outcome.To investigate the real-world efficacy and safety of pembrolizumab in pre-treated NSCLC patients and the clinical utility of LIPI for patients' selection.Patients with pre-treated NSCLC and PD-L1 ≥ 1% treated with pembrolizumab were included in this retrospective series. The LIPI was used to classify patients in 3 prognostics subgroups according to the pre-treatment dNLR (derived neutrophil to lymphocyte ratio) and LDH in blood. The prognostic impact of the LIPI on progression free survival (PFS) and overall survival (OS) was evaluated with Cox regression. The combined effect of LIPI and other relevant prognostic factors was explored with multivariate regression.In total, 113 consecutive patients were included. Median (mPFS) and mOS was 4.3 (2.6-6.7) and 13.5 (10.3-17.7) months, respectively. Good-, intermediate-, and poor-LIPI was found in 54 (47.8%), 45 (39.8%), and 8 (7.1%) patients, respectively. Median PFS was 5.1 (2.8-9.1), 3.0 (2.5-6.8), and 1.4 (0.5-18.7) months, and mOS was 17.2 (12.0-26.4), 11.8 (8.4-17.1), and 3.7 (0.5-not calculable) months for good-, intermediate-, and poor-LIPI group, respectively. Patients with intermediate-LIPI and poor-LIPI had worse PFS versus good-LIPI, and statistically significant worse OS (p = 0.030 and p = 0.013, respectively). In the multivariate analysis, intermediate- versus good-LIPI (p = 0.190) was not independently associated to PFS or OS. Patients with both good-LIPI and high (≥ 50%) PD-L1 had better OS than all other subgroups defined by LIPI and PD-L1. Immune-related adverse events (irAEs) occurred in 47 (41.6%) patients (12.4% grade ≥ 3). In a time-varying analysis, irAEs were statistically associated with longer OS (HR 0.51, 0.31-0.84; p = 0.008).In our series, the outcome of pembrolizumab in pre-treated NSCLC is consistent with the registration trial. Lung Immune Prognostic Index is a readily available tool able to prognosticate outcome, also in PD-L1-high patients. The positive association between irAEs and OS might aid decision making.

This study aimed to assess how often overridden drug allergy alerts (ODAAs) lead to allergic adverse drug events (All-ADEs) and to evaluate the frequency with which drug allergy alerts (DAAs) were overridden and the reasons, as well as appropriateness of these overrides.A retrospective observational study of DAA generated between 2014 and 2016 was conducted. The corresponding DAA records were reviewed to determine the frequency of alert overrides. A chart review was performed on a subset of 194 ODAA (the first of every 3 chronologically ordered ODAA) to identify All-ADEs and to evaluate the override reasons and the appropriateness of these overrides.A total of 2044 DAAs were overridden (override rate of 44.8%). Most were triggered by a nonexact match (93.81%), when ordering nervous system (21.1%) and cardiovascular system (19.6%) drugs and were generated by physicians (72.7%). The main override reason was that the patient was already taking the drug or had previously tolerated the drug. Only 9.28% of ODAAs were inappropriately overridden. Six All-ADEs (3.09%) were identified and were due to anti-infective (1), antineoplastic (1), and iodinated-contrast (4) drug administration. Most All-ADEs were cutaneous and were mild. None was life-threatening or fatal. The All-ADEs rate was higher among inappropriately ODAA (15.79%, P = 0.013).Alert overrides are not exempt from clinical consequences, although few are associated with All-ADEs. It is necessary to identify the drugs involved in those reactions and to update allergy lists to generate only specific and important DAA and to avoid the negative consequences of overrides.

Hypertension-mediated organ damage frequently includes renal function decline in which several mechanisms are involved. The present review outlines the state of the art on extracellular vesicles in hypertension and hypertension-related renal damage. Emerging evidence indicates that extracellular vesicles, small vesicles secreted by most cell types and body fluids, are involved in cell-to-cell communication and are key players mediating biological processes such as inflammation, endothelial dysfunction or fibrosis, mechanisms present the onset and progression of hypertension-associated kidney disease. We address the potential use of extracellular vesicles as markers of hypertension-mediated kidney damage severity and their application as therapeutic agents in hypertension-associated renal damage. The capacity of exosomes to deliver a wide variety of cargos to the target cell efficiently makes them a potential drug delivery system for treatment of renal diseases.

The advent of PD-(L)1 and CTLA-4 immune check point inhibitors (CPIs) has dramatically changed the treatment landscape of advanced non-small-cell lung cancer (NSCLC). For up to a quarter of patients with advanced NSCLC, CPIs have the potential to induce durable responses with long-term survival outcomes. Since the approval of first-line pembrolizumab for patients whose tumors express a PD-L1 ≥ 50%, several pivotal first-line CPI-based phase 3 studies have been conducted investigating combination treatments combining CPIs with chemotherapy (ChT) or combining different CPIs with or without ChT. As a result, there has been an increase in front-line treatment options for advanced NSCLC, and treatment algorithms are changing very quickly. In fit patients with advanced NSCLC, combination treatments including CPI and ChT are considered the new standard of care with improved clinical outcomes. CPI combination treatments are well tolerated and quality of life also seems to be better when CPIs are implemented in the first-line setting. The aim of this review is to provide a summary of the recently published first-line phase 3 studies investigating CPIs as monotherapy or in combination with other CPIs or ChT in advanced NSCLC, and to suggest possible treatment algorithms.

Background Incorporating in the Intensive Care Unit (ICU) a clinical pharmacist who performs interventions on antimicrobials may be cost-effective. Objectives To evaluate the clinical and economic impact of clinical pharmacist interventions on antimicrobials in an ICU. To identify drug related problems and medication errors detected by the pharmacist. Methods A retrospective observational study was performed to analyze drug related problems, medication errors and clinical pharmacist interventions related to antimicrobials in adults admitted to an ICU in a 5-month period. The economic impact of pharmacist interventions was estimated considering difference in cost derived from antimicrobial treatment, adverse drug events and clinical pharmacist time. Results A total of 212 drug related problems were detected in 114 patients, 18 being medication errors. Clinical pharmacist developed one intervention for each problem identified. 204 interventions (96.2%) were considered important with improved patient care and 7 (3.3%) very important. No negative impact of any intervention was identified. Physicians accepted 97.6% of the interventions. A potential saving of 10,905 € was estimated as a result of pharmacist interventions and 4.8 € were avoided per euro invested in a clinical pharmacist. Conclusions A clinical pharmacist performing interventions on antimicrobials in the ICU has a positive impact on patient care and decreases costs.

Circulating tumor DNA (ctDNA) is tumor-derived fragmented DNA in the bloodstream that has come from primary or metastatic cancer sites. Neoplasm-specific genetic and epigenetic abnormalities are increasingly being identified through liquid biopsy: a novel, minimally invasive technique used to isolate and analyze ctDNA in the peripheral circulation. Liquid biopsy and other emerging ctDNA technologies represent a paradigm shift in cancer diagnostics because they allow for the detection of minimal residual disease in patients with early-stage disease, improve risk stratification, capture tumor heterogeneity and genomic evolution, and enhance ctDNA-guided adjuvant and palliative cancer therapy. Moreover, ctDNA can be used to monitor the tumor response to neoadjuvant and postoperative therapy in patients with metastatic disease. Using clearance of ctDNA as an endpoint for escalation/de-escalation of adjuvant chemotherapy for patients considered to have high-risk disease has become an important area of research. The possibility of using ctDNA as a surrogate for treatment response–including for overall survival, progression-free survival, and disease-free survival–is an attractive concept; this surrogate will arguably reduce study duration and expedite the development of new therapies. In this review, we summarize the current evidence on the applications of ctDNA for the diagnosis and management of gastrointestinal tumors. Gastrointestinal cancers–including tumors of the esophagus, stomach, colon, liver, and pancreas–account for one-quarter of global cancer diagnoses and contribute to more than one-third of cancer-related deaths. Given the prevalence of gastrointestinal malignancies, ctDNA technology represents a powerful tool to reduce the global burden of disease.

Background and objective: Drug allergy alert systems (DAAS), have been considered an effective strategy to reduce preventable adverse drug events (ADEs), improving patient’s safety. To date, no review has been conducted analyzing characteristics of DAAS in the hospital setting. Therefore, the aim of this study is to identify, describe and summarize the DAAS used in hospitals. The secondary objectives are to analyse drug allergy alerts (DAA) characteristics, the override rate (OvR) and the clinical consequences of alert overrides. Methods: Searches were conducted in Medline and Cochrane Library to identify studies describing DAAS. Systems characteristics, generated alerts, DAA, OvR, and its clinical consequences were extracted and analyzed. Results: Twenty-eight articles were included in the review. Seventeen different electronic DAAS were identified, of which 53% were commercially available. Systems differed in drug allergy information and rules for generating alerts. DAA were generally interruptive, triggered by non-exact match at drug prescribing and when ignored, an override reason was mandatory. The OvR ranged from 43.7% to 97%. The main override reason given by pro- viders was that ‘patient had previously tolerated or had taken the drug without allergic reaction’. Clinical consequences of overriding DAA were only analyzed in four studies, with an ADE incidence between 0% and 6%. Conclusions: Different DAAS are used in hospitals with some degree of heterogeneity. Accurate and updated drug allergy information is important to generate only high value alerts. A regular review of DAAS and a standard- ization of alert rules, alert information and override reasons are necessary to optimize systems. Future studies should evaluate the impact of the DAAS aspects on preventing ADEs.

The addition of a fourth year to the hospital pharmacy residency program has allowed trainees to rotate through various inpatient clinical units where they can, under the supervision of a specialist pharmacist, work shoulder to shoulder with other healthcare providers to ensure that patients receive the care they need. In addition to sharing their pharmacotherapeutic and pharmacokinetic knowledge (among others) with their colleagues, hospital pharmacists can and should contribute with their expertise in the areas of drug evaluation, selection and positioning. As no other healthcare professional masters like a pharmacist the intricacies of treatment efficacy or effectiveness, or of therapeutic safety, conveying this knowledge is yet another of the many clinical activities a hospital pharmacist must perform as a member of a multidisciplinary team, while assisting fellow-team members in deciding what medications are best suited to each patient. Both the public authorities and the pharmaceutical profession as a whole should make sure the pharmacist's role is rightfully valued and given the recognition it deserves.La especialidad de Farmacia Hospitalaria incorporó con el cuarto año de su programa formativo una parte importante de rotación por unidades clínicas de hospitalización en las que el farmacéutico en formación, acompañado de farmacéuticos especialistas, tiene la oportunidad de trabajar conjuntamente con otros profesionales en la atención directa al paciente. Además de contribuir a esta atención con sus conocimientos de farmacoterapia y farmacocinética, el farmacéutico de hospital puede y debe aportar al equipo su liderazgo en evaluación, selección y posicionamiento de medicamentos. Ningún profesional conoce como él los aspectos relativos a la eficacia o efectividad, seguridad y eficiencia de los tratamientos, y estos conocimientos constituyen una actividad clínica más de las que debe desempeñar en los equipos multidisciplinares, ayudando a la toma de decisiones sobre medicamentos en cada paciente. Es necesario que tanto desde los organismos públicos como desde nuestra propia profesión se ponga en valor este papel y que se potencie de forma adecuada.

Small Rab GTPases, the largest group of small monomeric GTPases, regulate vesicle trafficking in cells, which are integral to many cellular processes. Their role in neurological diseases, such as cancer and inflammation have been extensively studied, but their implication in kidney disease has not been researched in depth. Rab3a and its effector Rabphillin-3A (Rph3A) expression have been demonstrated to be present in the podocytes of normal kidneys of mice rats and humans, around vesicles contained in the foot processes, and they are overexpressed in diseases with proteinuria. In addition, the Rab3A knockout mice model induced profound cytoskeletal changes in podocytes of high glucose fed animals. Likewise, RphA interference in the Drosophila model produced structural and functional damage in nephrocytes with reduction in filtration capacities and nephrocyte number. Changes in the structure of cardiac fiber in the same RphA-interference model, open the question if Rab3A dysfunction would produce simultaneous damage in the heart and kidney cells, an attractive field that will require attention in the future.

Cancer cells adapt their metabolic activities to support growth and proliferation. However, increased activity of metabolic enzymes is not usually considered an initiating event in the malignant process. Here, we investigate the possible role of the enzyme serine hydroxymethyltransferase-2 (SHMT2) in lymphoma initiation. SHMT2 localizes to the most frequent region of copy number gains at chromosome 12q14.1 in lymphoma. Elevated expression of SHMT2 cooperates with BCL2 in lymphoma development; loss or inhibition of SHMT2 impairs lymphoma cell survival. SHMT2 catalyzes the conversion of serine to glycine and produces an activated one-carbon unit that can be used to support S-adenosyl methionine synthesis. SHMT2 induces changes in DNA and histone methylation patterns leading to promoter silencing of previously uncharacterized mutational genes, such as SASH1 and PTPRM. Together, our findings reveal that amplification of SHMT2 in cooperation with BCL2 is sufficient in the initiation of lymphomagenesis through epigenetic tumor suppressor silencing. Parsa et al. report a mechanism of lymphoma initiation involving cooperation of BCL2 and increased activity of the metabolic enzyme SHMT2, which imparts changes in DNA and histone methylation.

Urinary albumin excretion (UAE) is a marker of cardiovascular risk and renal damage in hypertension. MicroRNAs (miRNAs) packaged into exosomes function as paracrine effectors in cell communication and the kidney is not exempt. This study aimed to state an exosomal miRNA profile/signature associated to hypertension with increased UAE and the impact of profibrotic TGF-β1 (transforming growth factor β1) on exosomes miRNA release. Therefore, exosomes samples from patients with hypertension with/without UAE were isolated and characterized. Three individual and unique small RNA libraries from each subject were prepared (total plasma, urinary, and plasma-derived exosomes) for next-generation sequencing profiling. Differentially expressed miRNAs were over-represented in Kyoto Encyclopedia of Genes and Genomes pathways, and selected miRNAs were validated by real-time quantitative polymerase chain reaction in a confirmation cohort. Thus, a signature of 29 dysregulated circulating miRNAs was identified in UAE hypertensive subjects, regulating 21 pathways. Moreover, changes in the levels of 4 exosomes-miRNAs were validated in a confirmation cohort and found associated with albuminuria. In particular miR-26a, major regulator of TGF-β signaling, was found downregulated in both type of exosomes when compared with healthy controls and to hypertension normoalbuminurics ( P

Background Small-cell lung cancer (SCLC) is an aggressive disease with high metastatic potential and poor prognosis. Due to its low prevalence, epidemiological and clinical information of SCLC patients retrieved from lung cancer registries is scarce. Patients and methods This was an observational multicenter study that enrolled patients with lung cancer and thoracic tumors, recruited from August 2016 to January 2020 at 50 Spanish hospitals. Demographic and clinical data, treatment patterns and survival of SCLC patients included in the Thoracic Tumor Registry (TTR) were analyzed. Results With a total of 956 cases, the age of 64.7 ± 9.1 years, 78.6% were men, 60.6% smokers, and ECOG PS 0, 1 or ≥ 2 in 23.1%, 53.0% and 23.8% of cases, respectively. Twenty percent of patients had brain metastases at the diagnosis. First-line chemotherapy (CT), mainly carboplatin or cisplatin plus etoposide was administered to >90% of patients. In total, 36.0% and 13.8% of patients received a second and third line of CT, respectively. Median overall survival was 9.5 months (95% CI 8.8–10.2 months), with an estimated rate of 70.3% (95% CI 67.2–73.4%), 38.9% (95% CI 35.4–42.4%), and 14.8% (95% CI 11.8–17.8%) at 6, 12 and 24 months respectively. Median progression-free survival was 6.3 months. Higher mortality and progression rates were significantly associated with male sex, older age, smoking habit, and ECOG PS 1–2. Long-term survival (> 2 years) was confirmed in 6.6% of patients, showing a positive correlation with better ECOG PS, poor smoking and absence of certain metastases at diagnosis. Conclusion This study provides an updated overview of the clinical situation and treatment landscape of ES-SCLC in Spain. Our results might assist oncologists to improve current clinical practice towards a better prognosis for these patients.

The mechanistic target of rapamycin complex 1 (mTORC1) integrates cellular nutrient signaling and hormonal cues to control metabolism. We have previously shown that constitutive nutrient signaling to mTORC1 by means of genetic activation of RagA (expression of GTP-locked RagA, or RagAGTP) in mice resulted in a fatal energetic crisis at birth. Herein, we rescue neonatal lethality in RagAGTP mice and find morphometric and metabolic alterations that span glucose, lipid, ketone, bile acid and amino acid homeostasis in adults, and a median lifespan of nine months. Proteomic and metabolomic analyses of livers from RagAGTP mice reveal a failed metabolic adaptation to fasting due to a global impairment in PPARα transcriptional program. These metabolic defects are partially recapitulated by restricting activation of RagA to hepatocytes, and revert by pharmacological inhibition of mTORC1. Constitutive hepatic nutrient signaling does not cause hepatocellular damage and carcinomas, unlike genetic activation of growth factor signaling upstream of mTORC1. In summary, RagA signaling dictates dynamic responses to feeding-fasting cycles to tune metabolism so as to match the nutritional state., The mechanistic target of rapamycin complex 1 (mTORC1) integrates nutrient and hormonal signals to control metabolism. Here the authors investigate the effects of constitutive nutrient signaling through genetic activation of RagA in adult mice and show that constitutive nutrient signaling regulates the response to feeding-fasting cycles and does not drive liver cancer.

Sirtuins have become important players in renal damage in hypertension and diabetes, but their value as biomarkers is poorly assessed. The aims of the study were to evaluate the levels of sirtuin1 (SIRT1), and two miRNAs that regulate SIRT1 expression in hypertensive patients with incipient renal damage with and without diabetes. We quantified urinary SIRT1 and claudin 1 (CLDN1) mRNA and miR34-a and miR-200a levels by quantitative real-time polymerase chain reaction (RT-qPCR) from patients and in cultured podocytes treated with high glucose and angiotensin II. Western blot and fluorescence analyses were also performed. We found decreased SIRT1 levels in patients with increased urinary albumin excretion (UAE), the lowest with diabetes presence, and a strong association with UAE, discriminating incipient renal damage. In vitro experiments also showed SIRT1 overall decreases in podocyte cultures under treatment conditions. In urine samples, miR-34a was reduced and miR-200a increased, both related to UAE levels. However, both miRNAs were generally increased in podocyte cultures under high glucose and angiotensin-II treatment. These results show a significant urinary SIRT1 decrease in albuminuric hypertensive patients, strongly associated with albuminuria, suggesting that SIRT1 could be a potential and non-invasive method to assess incipient renal damage in hypertensive patients.

Small-cell lung cancer (SCLC) is an aggressive and rapidly growing disease with poor prognosis. Despite intense efforts to improve clinical outcomes, platinum/etoposide chemotherapy has remained the most effective regimen for first-line extensive disease SCLC for decades. The addition of immune checkpoint inhibitors, and specifically programmed death-ligand 1 inhibitors, to standard platinum/etoposide, significantly improves survival and represents a promising advance in this field. However, identification of a predictive biomarker to refine patient selection is an area of unmet need. Further understanding of tumour immunity and mechanism of resistance is required to design novel strategies that improve survival. In this review, we describe recent developments and future directions on first-line immune checkpoint blockade for extensive disease-SCLC., Highlights • The addition of PD-L1 inhibitors but not CTLA-4 inhibitors to platinum/etoposide improves survival in first line SCLC. • A small proportion of patients derive long-term survival benefit which highlights the relevance of tumour heterogeneity. • At present, maintenance therapy with immune checkpoint inhibitors following platinum/etoposide can't be recommended. • Predictive biomarkers to aid patient selection for immune checkpoint inhibitors in SCLC remain an area of unmet need. • Upcoming trials will evaluate PD-L1 inhibitors plus chemotherapy in combination with drugs that promote tumour immunity.

Kidney injury in hypertension and diabetes entails, among in other structures, damage in a key cell of the glomerular filtration barrier, the podocyte. Podocytes are polarized and highly differentiated cells in which vesicular transport, partly driven by Rab GTPases, is a relevant process. The aim of the present study was to analyze Rab GTPases of the Rab-Rabphilin system in human immortalized podocytes and the impact of high glucose and angiotensin II. Furthermore, alterations of the system in urine cell pellets from patients with hypertension and diabetes were studied. Apoptosis was analyzed in podocytes, and mRNA level quantification, Western blot analysis, and immunofluorescence were developed to quantify podocyte-specific molecules and Rab-Rabphilin components (Rab3A, Rab27A, and Rabphilin3A). Quantitative RT-PCR was performed on urinary cell pellet from patients. The results showed that differentiated cells had reduced protein levels of the Rab-rabphillin system compared with undifferentiated cells. After glucose overload and angiotensin II treatment, apoptosis was increased and podocyte-specific proteins were reduced. Rab3A and Rab27A protein levels were increased under glucose overload, and Rabphilin3A decreased. Furthermore, this system exhibited higher levels under stress conditions in a manner of angiotensin II dose and time treatment. Immunofluorescence imaging indicated different expression patterns of podocyte markers and Rab27A under treatments. Finally, Rab3A and Rab27A were increased in patient urine pellets and showed a direct relationship with albuminuria. Collectively, these results suggest that the Rab-Rabphilin system could be involved in the alterations observed in injured podocytes and that a mechanism may be activated to reduce damage through the vesicular transport enhancement directed by this system.

Urinary exosomes, especially microRNAs (miRNAs) packaged within, are ideal sources of renal damage markers. We investigated the association between exosomal miR-146a, (anti-inflammatory regulator) and disease activity, proteinuria and systemic lupus erythematosus (SLE) flares over a 36-month follow-up period. We isolated urinary exosomes from 41 SLE patients, 27 with lupus nephritis (LN) and 20 healthy controls, and exosomal miR-146a, quantified by the real-time quantitative polymerase chain reaction (RT-qPCR), was correlated with histological features in 13 renal biopsies. We also analysed the association between the exosomal miR-146a and TRAF6 axis. Exosomal miR-146a showed an inverse association with circulating C3 and C4 complement components, proteinuria, and with histological features such as chronicity index. This marker was able to identify LN with an AUC of 0.82 (p = 0.001). Basal exosomal miR-146a was associated with disease activity and proteinuria changes and was an independent marker of 36-month follow-up flares (OR 7.08, p = 0.02). Pathway analysis identified IRAK1 and TRAF6 as miR-146a target genes. Finally, in vitro experiments suggested that miR-146a exerts a protective effect through negative regulation of inflammation by suppressing IRAK1 and TRAF6. Urinary exosomal miR-146a levels are correlated with lupus activity, proteinuria and histological features, discriminating patients with LN and being a good baseline marker of SLE flares. We have identified a relevant biological miR-146a-TRAF6 axis association in LN renal fibrosis progression.

BACKGROUND The proper dosage of antibiotics is a key element in the effective treatment of infection, especially in critically ill patients. This study aimed to evaluate the efficacy of optimized meropenem regimens based on pharmacokinetic/pharmacodynamic criteria in patients admitted to the intensive care unit. METHODS This observational, naturalistic, retrospective, unicentric cohort study was performed between May 2011 and December 2017. The clinical and bacteriologic responses of 77 control intensive care unit patients receiving meropenem were compared with those of 77 propensity score-balanced patients who received meropenem dose adjusted by therapeutic drug monitoring. The primary end point of clinical response was a reduction at the end of treatment of at least 80% of the maximum procalcitonin (PCT) value recorded during the meropenem treatment. RESULTS The primary end point was met by 55 patients (71.4%) in the adjusted group compared with 41 (53.3%) patients in the control group (mean difference 18.1%, P = 0.02). Fifty-one patients (66.2%) in the adjusted group required a meropenem dose adjustment, being necessary in 46 of them (90.2%) to decrease the dose. The reduction of PCT was the greatest in the adjusted group compared with the unadjusted group (93% versus 85%, P = 0.004); a greater percentage of patients reached a PCT level < 0.5 ng/mL (63.6% versus 41.6%, P = 0.006), and there was a trend toward an improved bacteriologic response (relative risk = 1.27; 95% confidence interval: 0.92-1.56). There were no differences in early mortality or safety between groups. CONCLUSIONS Adjustment of meropenem therapy by monitoring is a useful strategy for improving meropenem effectiveness in the treatment of infection in critically ill patients, with no impact on safety.

On March 11, 2020, the Director-General of the World Health Organization (WHO) declared the disease caused by SARS-CoV-2 (COVID-19) as a pandemic. The spread and evolution of the pandemic is overwhelming the healthcare systems of dozens of countries and has led to a myriad of opinion papers, contingency plans, case series and emerging trials. Covering all this literature is complex. Briefly and synthetically, in line with the previous recommendations of the Working Groups, the Spanish Society of Intensive, Critical Medicine and Coronary Units (SEMICYUC) has prepared this series of basic recommendations for patient care in the context of the pandemic.

BACKGROUND Levetiracetam (LEV) is a second-generation antiepileptic drug extensively used in therapeutics. The aim of this study was to evaluate the influence that sex, age, and weight exert on LEV pharmacokinetics in clinical practice. METHODS We conducted a 6-year retrospective observational study. Patients were classified in subgroups according to sex, weight (normal range, overweight, and obese), and age (young adult: 16-30 years old, middle-aged adult: 31-50 years old, advanced adult: 51-64 years old, and elderly adult: ≥65 years old). We compared LEV apparent oral clearance (LEV CL/F) between the subgroups. RESULTS A total of 238 LEV basal serum concentrations (LEV C0) corresponding to 156 patients were identified. Significant differences were observed in LEV CL/F between males and females when LEV CL/F was expressed as L/h [mean (SD): 4.79 (1.84) L/h in males versus 4.13 (1.64) L/h in females; P < 0.001]. These differences were not significant when LEV CL/F was normalized by weight [mean (SD): 60.64 (24.90) mL/h/kg in males versus 64.10 (28.87) mL/h/kg in females; n.s.]. Weight in females was 17% lower compared with males. A progressive reduction in LEV CL/F was observed with increasing age, in a proportion that was similar to the decline in renal function. The elderly patients presented 30% lower LEV CL/F (mL/h/kg) and 43% lower creatinine clearance (CCr) in comparison with adults. No statistically significant differences were observed in LEV CL/F calculated in L/h between weight subgroups. However, when LEV CL/F was expressed in mL/h/kg, a progressive reduction was observed [normal weight: 72.21 (28.97); overweight: 57.84 (25.38); obese: 49.45 (14.50); P < 0.001]. A significant and positive correlation between CCr and LEV CL/F was observed, confirming the important role of the renal function in LEV CL/F. The CCr increased in each sex group when weight increased; however, LEV CL/F (L/h) remained constant. CONCLUSIONS Sex, age, and weight affect LEV pharmacokinetics, having an impact on the individual dosage regimen needed to achieve the therapeutic objective. Sex is a conditioning factor of LEV CL/F, although its influence is principally due to the weight. LEV CL/F decreases with advancing age, proportionally to the decline in renal function. It is confirmed that LEV dosage per body weight is not required, and prescribing higher doses of LEV in obese patients is not justified. These data suggest that routine LEV therapeutic drug monitoring in the elderly patients, patients with renal dysfunction, and obese patients is indicated.

Orofacial granulomatosis is a nonspecific term that contains a wide variety of granulomatous entities, which share a clinical and histopathological presentation. It manifests as persistent or recurrent orofacial swelling, amongst other findings. Idiopathic orofacial granulomatosis, characterized by an absence of systemic granulomatous disease, is a diagnosis of exclusion. The main differential diagnosis is Crohn's disease. Its pathogenesis is unknown, however, it seems to be immune-mediated. Patch-test sensitivity to multiple allergens is well documented. Currently, therapeutic options consider restrictive diets, topical, intralesional, and systemic agents. First-line therapy is currently a matter of debate. We present a review of the value of diet therapy in this syndrome, along with two illustrative cases.

[Objective]: Patients included in MAINRITSAN2 trial received either an individually tailored or a fixed-schedule therapy with rituximab as maintenance treatment of antineutrophil cytoplasm antibody associated vasculitides. The aim of this study was to compare the real-world costs of both arms. [Method]: We performed a cost-minimization analysis over an 18-month time period, estimating direct costs –drug acquisition, preparation, administration and monitoring costs– from the health system perspective. We conducted a number of additional sensitivity analyses with different assumptions for unit costs, with further scenarios including the interquartile range of the tailored-infusion group results, different number of monitoring visits for fixed-schedule regimen and different number of reported severe adverse events. A cost-effectiveness analysis was conducted as a sensitivity analysis using the absolute difference in the relapse rate and its confidence interval. Results: The individually tailored maintenance therapy with rituximab was shown to be a cost-saving treatment compared to the fixed-schedule therapy (6,049 euros vs. 7,850 euros). Savings resulted primarily from lower drug acquisition costs (2,861 vs. 4,768 euros) and lower preparation and administration costs (892 vs. 1,486 euros), due to the lower number of infusions per patient in the tailored-infusion regimen. The tailoredinfusion regimen presented higher monitoring costs (2,296 vs. 1,596 euros). This result was replicated in all assumptions considered in the sensitivity analysis of cost-minimization approach. [Conclusions]: From the perspective of the health system, the tailoredtherapy regimen seems to be the preferable option in terms of direct costs. Further studies assessing all the effects and costs associated to vasculitides maintenance treatment with rituximab are needed to support clinical management and healthcare planning. [Objetivo]: Los pacientes incluidos en el ensayo MAINRITSAN2 recibieron una pauta individualizada o un esquema fijo de rituximab como tratamiento de mantenimiento para la vasculitis asociada con anticuerpos contra el citoplasma de los neutrófilos. El objetivo de este estudio es comparar los costes reales de ambos esquemas de tratamiento. [Método]: Se llevó a cabo un análisis de minimización de costes sobre un periodo de 18 meses, estimando los costes directos —adquisición del fármaco, preparación, administración y costes de monitorización— desde la perspectiva del sistema de salud. Se realizaron varios análisis de sensibilidad con diferentes supuestos para los costes unitarios, añadiendo escenarios que incluían el rango intercuartílico de los resultados en el grupo de la pauta individualizada, diferente número de visitas de control para el grupo que seguía el esquema fijo y distinto número de eventos adversos registrados. Se realizó un análisis de coste-efectividad como parte del análisis de sensibilidad usando la diferencia absoluta en la tasa de recaída y su intervalo de confianza. [Resultados]: El esquema de tratamiento con la pauta individualizada demostró una reducción del coste en comparación con el esquema de dosis fijas (6.049 versus 7.850 euros). El ahorro se debió principalmente a un menor coste en la adquisición del fármaco (2.861 versus 4.768 euros) y a menos costes de preparación y administración (892 versus 1.486 euros), debido al menor número de infusiones por paciente en el brazo del esquema individualizado. Este esquema individualizado presentó mayores costes de monitorización (2.296 versus 1.596 euros). Este resultado se repitió en todos los supuestos considerados en el análisis de sensibilidad desde el enfoque de minimización de costes. [Conclusiones]: Desde la perspectiva del sistema de salud, la pauta individualizada parece ser la opción preferible en términos de costes directos. No obstante, son necesarios más estudios que evalúen todos los efectos y costes asociados al tratamiento de mantenimiento con rituximab de la vasculitis por anticuerpo anticitoplasma de neutrófilo para respaldar el manejo clínico y la asistencia sanitaria.

Hollow organs such as the lungs pose a considerable challenge for post-mortem imaging in preclinical research owing to their extremely low contrast and high structural complexity. The aim of our study was to enhance the contrast of tuberculosis lesions for their stratification by 3D x-ray&-based virtual slicing. Organ samples were taken from five control and five tuberculosis-infected mice. Micro-Computed Tomography (CT) scans of the subjects were acquired in vivo (without contrast agent) and post-mortem (with contrast agent). The proposed contrast-enhancing technique consists of x-ray contrast agent uptake (silver nitrate and iodine) by immersion. To create the histology ground-truth, the CT scan of the paraffin block guided the sectioning towards specific planes of interest. The digitalized histological slides reveal the presence, extent, and appearance of the contrast agents in lung structures and organized aggregates of immune cells. These findings correlate with the contrast-enhanced micro-CT slice. The abnormal densities in the lungs due to tuberculosis disease are concentrated in the right tail of the lung intensity histograms. The increase in the width of the right tail (~376%) indicates a contrast enhancement of the details of the abnormal densities. Postmortem contrast agents enhance the x-ray attenuation in tuberculosis lesions to allow 3D visualization by polychromatic x-ray CT, providing an advantageous tool for virtual slicing of whole lungs. The proposed contrast-enhancing technique combined with computational methods and the diverse micro-CT modalities will open the doors to the stratification of lesion types associated with infectious diseases. The research leading to these results received funding from the Innovative Medicines Initiative (www.imi.europa.eu) Joint Undertaking under grant agreement no. 115337, whose resources comprise funding from the European Union Seventh Framework Programme (FP7/2007–2013) and EFPIA companies in kind contribution. This work was partially funded by projects RTC-2015-3772-1, TEC2015-73064-EXP and TEC2016-78052-R from the Spanish Ministry of Economy, TOPUS S2013/MIT-3024 project from the regional government of Madrid and by the Department of Health, UK. This study (was supported by the Instituto de Salud Carlos III (Plan Estatal de I + D + i 2013–2016) and co-financed by the European Social Fund (ESF) “ESF investing in your future”. The authors thank Dr.Guembe from CIMA-Universidad de Navarra for preparing and staining the tissue sections, and to Dr. Guerrero-Aspizua and Prof. Conti of the Department of Bioengineering, Universidad Carlos III de Madrid for the pathology evaluation.

Background: the standard treatment for locally advanced rectal cancer is neoadjuvant chemo-radiotherapy, surgery and adjuvant chemotherapy. Only 50% of patients receive the adjuvant treatment due to the surgical complications and toxicity of radiotherapy. Recently, neoadjuvant chemotherapy has been investigated in the locally advanced rectal cancer setting, with the aim of guaranteeing an uninterrupted systemic treatment. The objective of the present study was to assess the safety and efficacy of neoadjuvant chemotherapy in locally advanced rectal cancer. Methods and patients: patients treated with neoadjuvant chemotherapy and surgery were identified from a prospective database of patients with rectal cancer (cII-III). The primary outcomes were the assessment of the number of R0 resections, the degree of pathologic response, patterns of recurrence and overall and disease-free survival. Treatment schedule: patients received 6-8 cycles of oxaliplatin and fluoropyrimides based chemotherapy. Results: twenty-seven patients who received neoadjuvant chemotherapy were identified. Twenty-six anterior resections and one Hartmann intervention were performed. An R0 resection was performed in 27 (100%) patients and no involvement of the circumferential margin was observed. Complete pathologic response (ypT0N0) was confirmed in four (14.8%) patients. The median follow-up was 35 months (range: 10-81) and four distant recurrences were recorded. Overall and disease-free survival at five years was 85% and 84.7%, respectively. Twenty-seven (100%) patients received all the cycles of chemotherapy, with a mean of six cycles (range 5-8) per patient. Conclusions: neoadjuvant chemotherapy is a promising alternative in the locally advanced rectal cancer setting and further phase III clinical trials are clearly warranted.

The purpose of the study was to analyze the effectiveness of adding nebulized antibiotics to systemic antimicrobials in critically ill patients with respiratory tract infections (pneumonia or tracheobronchitis) and the effect on renal function. A retrospective observational cohort study including critically ill patients with respiratory tract infections during a 2-year period was conducted. Intervention group included patients that received nebulized and systemic antimicrobials. Patients in the control group received only systemic antimicrobials. Clinical resolution was the primary endpoint. Secondary outcomes included change in fever, inflammatory parameters, and creatinine clearance; length of hospital stay, systemic therapy, and mechanical ventilation; hospital readmission; and mortality. Regression models were performed to estimate the effect of nebulized antibiotics on outcome variables adjusted by potential confounders. A total of 136 patients were included (93 in control group and 43 in intervention group). The intervention group had higher odds of clinical resolution (adjusted odds ratio (OR): 7.1; 95% confidence interval (95% CI): 1.2, 43.3). Nebulized antibiotic therapy was independently associated with reduction in procalcitonin (adjusted OR: 12.4; 95% CI: 1.4, 109.7). There were no significant differences in the rest of the secondary outcomes or in creatinine clearance reduction. Adding nebulized antibiotics for the management of respiratory tract infections has a positive impact on clinical resolution without increasing the risk of renal toxicity. Electronic supplementary material The online version of this article (10.1007/s10096-019-03733-6) contains supplementary material, which is available to authorized users.

Purpose A case of severe bilateral sensorineural hearing loss associated with oral morphine is reported. Summary A 52-year-old Spanish man was admitted to the intensive care unit with a Glasgow Coma Scale score of 3, a fever, and sudden hearing loss with tinnitus in both ears. His medical history included type 2 diabetes mellitus, depression, sleep disorder, and hypertension. The patient also had pyelonephritis in 2011 and pulmonary embolism in 2014, requiring the placement of an inferior vena cava filter and chronic anticoagulation. His hearing loss appeared after the initiation of oral morphine, specifically on the eighth day of treatment, with increasing dosages of up to 120 mg daily. We did not find any other possible causes of the hearing loss. Ototoxicity is an adverse reaction of ibuprofen and acetaminophen, but the patient received only three doses of ibuprofen 600 mg and did not require acetaminophen. The patient’s other medications did not have ototoxicity as an adverse reaction, and the patient confirmed not to have received any salicylate product. Brain magnetic resonance imaging discarded other possible causes of hearing loss. Our patient’s hearing loss did not resolve after opioid discontinuation, and the use of hearing aids was necessary. According to the Naranjo et al. adverse drug reaction probability scale, this event would be classified as “probable.” Conclusion A 52-year-old man developed tinnitus and hearing loss after receiving high doses of oral morphine sulfate. His hearing loss did not fully resolve after the discontinuation of morphine, and he required the use of hearing aids.

Amelogenesis imperfecta (AI) is a group of enamel development disorders that alter the structure and chemical composition of the tissue. There is great variability in the clinical presentation; according to Witkop, AI can be categorized into 14 subtypes, which makes its diagnosis extremely complex. Objective: This study aimed to describe and determine the frequency of clinical and radiographic features and inheritance patterns found in 41 Chilean families diagnosed with diverse types of AI. Material and Methods: We analyzed the clinical records, photographs, pedigrees and radiographs of 121 individuals recruited between 2003 and 2016. All of the information was included in a database that was analyzed using the application Stata 14. Results: The 72 affected individuals had average age of 16 years, and no sex association with the presence of AI was found. The most frequent clinical subtypes were as follows: 43% hypomature, 25% hypoplastic, 21% hypomature/hypoplastic, 7% hypocalcified and 4% hypocalcified/hypoplastic. The number of severely affected teeth was 22, which occurred in the patients with hypocalcified and hypocalcified/hypoplasic AI who presented the highest number of damaged teeth. Caries and periodontal disease were found in 47 and 32% of the patients, respectively. Malocclusions were observed in 43% of the individuals with AI, with open bite being the most frequent. Radiographically, the thickness of the enamel decreased in 51% of the patients, and 80% showed decreased radiopacity of the enamel compared to that of dentin. Autosomal dominant inheritance pattern was found in 37% of the families with hypoplastic AI, and autosomal recessive pattern was present in 56% of the other clinical subtypes, but more frequently in those affected with hypomature and hypocalcified AI. Conclusion: Of the five clinical subtypes, autosomal recessive hypomature, autosomal dominant hypoplastic and autosomal recessive hypomature/hypoplastic AI were the most prevalent subtypes in this group.

BACKGROUND A variety of local and systemic processes caused exogenous and endogenous pigmentation of the oral mucosa. Solitary melanotic pigmentation is rare, hence the scarce number of studies in children and adolescents. METHODS Clinical and histopathologic features of 10 Latin American children with solitary pigmented lesions of the oral mucosa were reviewed. RESULTS The area most affected was the gingiva, followed by the palate. All lesions were flat and

Objective The aim of this study was to determine the efficacy of a chamomile (Matricaria chamomilla) and linseed (Linum usitatissimum) saliva substitute in the relief of xerostomia in older participants. Background In elders, xerostomia is a permanent and progressive condition that significantly affects their quality of life. The treatment for progressive xerostomia is currently restricted to palliative measures, and saliva substitutes are indicated. A lack of evidence on the effectiveness of the saliva substitutes in the relief of symptoms of xerostomia has been reported. Materials and methods Seventy-four elderly participants presenting xerostomia of diverse origin were selected. Herbal saliva substitute and carboxymethyl cellulose conventional saliva substitute were tested using a double-blind, randomised, cross-sectional clinical trial. Results Every participant of the study exhibited dry mouth sensation. A sensation of thick saliva was described in 59.5% of the participants. The need for liquid intake to swallow food, the sensation of difficulty in swallowing and the burning sensation in the tongue were observed in 54.1, 56.8 and 27.0% of the participants, respectively. The most prevalent diseases were hypertension, depressive symptoms and arthritis. Results of the clinical tests showed that the herbal saliva substitute produced a greater relief of dry mouth symptoms, thick saliva sensation and the sensation of difficulty in swallowing than the conventional substitute (Wilcoxon test p < 0.05). Conclusions New chamomile- and linseed-based saliva substitute was effective in relieving xerostomia symptoms in older participants of this study.

Herein, we report a case of post-transfusion purpura after the reversal of anticoagulation for surgical purposes in a 66-year old ethnic Asian man who was undergoing long-term warfarin therapy for antiphospholipid syndrome. The patient experienced a sudden decrease in platelet count, from 308,000 per μL from the day of admission to 38,000 per μL the following day. Follow-up testing revealed unremarkable red blood cell (RBC) morphology, no evidence of platelet clumping, and negative heparin-induced antibody test results. Platelet antibody testing revealed anti-HPA15a antibodies.

Objetivo: determinar la incidencia de toxicidad hematológica por linezolid. Estudiar la influencia del aclaramiento renal en su aparición y la efectividad de la piridoxina en su prevención. Método: estudio observacional retrospectivo de todos los pacientes tratados con linezolid en un hospital universitario en seis meses. Se consideró toxicidad hematológica a la disminución del 25% de la hemoglobina, del 25% de las plaquetas y/o del 50% de neutrófilos al final respecto al inicio del tratamiento. Se comparó en los pacientes con y sin fallo renal (aclaramiento de creatinina inferior a 50 mL/min), con más o menos de 30 mL/min, y con o sin piridoxina, la incidencia de toxicidad hematológica mediante Chi-Cuadrado y la disminución en el porcentaje de variables analíticas hematológicas mediante U Mann-Whitney. Resultados: se evaluaron 38 pacientes. Dieciséis (42%) presentaron toxicidad hematológica (2 por disminución de hemoglobina, 9 de plaquetas y 8 de neutrófilos). En 2 pacientes (5%) se suspendió el tratamiento por plaquetopenia. La incidencia de toxicidad fue similar en pacientes con y sin insuficiencia renal, 42% vs. 42%, p = 0,970, con más o menos de 30 mL/min, 67% vs. 40%, p = 0,369, con piridoxina o sin ella, 47,8% vs. 33%, p = 0,376. Los pacientes con fallo renal presentaron una reducción significativamente mayor de plaquetas, p = 0,0185. Conclusiones: un 42% de los pacientes presentó toxicidad hematológica, más frecuentemente disminución de plaquetas y neutrófilos. Esta no fue significativamente mayor en los pacientes con fallo renal, ni en aquellos sin piridoxina. Se halló mayor reducción de plaquetas en los pacientes con insuficiencia renal. Objective: to determine the incidence of linezolid-induced haematological toxicity and study the influence of renal clearance on its appearance and the preventive effect of pyridoxine. Methods: a retrospective observational study was conducted. Every patient treated with linezolid in a university hospital during 6 months was included. Haematological toxicity was defined as a decrease of 25% in hemoglobin, of 25% in platelets and/or 50% in neutrophils from baseline. The incidence of haematological toxicity and the percentage decrease in analytical variables were compared in patients with and without renal failure (creatinine clearance lower than 50 mL/min), using the 30 mL/min threshold, and with or without pyridoxine; using Chi -Square and U Mann-Whitney tests, respectively. Results: thirty-eight patients were evaluated. Sixteen (42%) presented haematological toxicity (2 due to a decrease in haemoglobin, 9 in platelets and 8 in neutrophils). Two patients (5%) discontinued treatment due to thrombocytopenia. Toxicity incidence was similar in patients with and without renal failure, 42% vs 42%, p = 0.970, with more or less than 30 ml/min, 67% vs 40%, p = 0.369, or with or without pyridoxine, 47.8% vs 33%, p = 0.376. Patients with renal failure had a significantly greater reduction in platelet count, p = 0.0185. Conclusion: forty-two percent of patients had haematological toxicity, being more frequent platelets and neutrophils reduction. This was not significantly higher in patients with renal failure or in those without pyridoxine. Greater reduction in platelet count was observed in patients with renal failure.

Background The association between dilated cardiomyopathy (DCM) and low thyroid hormone (TH) levels has been previously described. In these patients abnormal thyroid function is significantly related to impaired left ventricular (LV) function and increased risk of death. Although TH was originally thought to be produced exclusively by the thyroid gland, we recently reported TH biosynthesis in the human ischemic heart. Objectives Based on these findings, we evaluated whether the genes required for TH production are also altered in patients with DCM. Methods Twenty-three LV tissue samples were obtained from patients with DCM (n = 13) undergoing heart transplantation and control donors (n = 10), and used for RNA sequencing analysis. The number of LV DCM samples was increased to 23 to determine total T4 and T3 tissue levels by ELISA. Results We found that all components of TH biosynthesis are expressed in human dilated heart tissue. Expression of genes encoding thyroperoxidase (-2.57-fold, P < 0.05) and dual oxidase 2 (2.64-fold, P < 0.01), the main enzymatic system of TH production, was significantlyaltered in patients with DCM and significantly associated with LV remodeling parameters. Thyroxine (T4) cardiac tissue levels were significantly increased (P < 0.01), whilst triiodothyronine (T3) levels were significantly diminished (P < 0.05) in the patients. Conclusions Expression of TH biosynthesis machinery in the heart and total tissue levels of T4 and T3, are altered in patients with DCM. Given the relevance of TH in cardiac pathology, our results provide a basis for new gene-based therapeutic strategies for treating DCM.

The purpose of this paper was to review the literature regarding the clinical and economic impact of pharmacist interventions (PIs) related to antimicrobials in the hospital setting. A PubMed literature search from January 2003 to March 2016 was conducted using the terms pharmacist* or clinical pharmacist* combined with antimicrobial* or antibiotic* or anti-infective*. Comparative studies that assessed the clinical and/or economic impact of PIs on antimicrobials in the hospital setting were reviewed. Outcomes were classified as: treatment-related outcomes (TROs), clinical outcomes (COs), cost and microbiological outcomes (MOs). Acceptance of pharmacist recommendations by physicians was collected. PIs were grouped into patient-specific recommendations (PSRs), policy, and education. Studies' risk of bias was analyzed using Cochrane's tool. Twenty-three studies were evaluated. All of them had high risk of bias. The design in most cases was uncontrolled before and after. PSRs were included in every study; five also included policy and four education. Significant impact of PI was found in 14 of the 18 studies (77.8%) that evaluated costs, 15 of the 20 studies (75.0%) that assessed TROs, 12 of the 22 studies (54.5%) that analyzed COs, and one of the two studies (50.0%) that evaluated MOs. None of the studies found significant negative impact of PIs. It could not be concluded that adding other strategies to PSRs would improve results. Acceptance of recommendations varied from 70 to 97.5%. Pharmacists improve TROs and COs, and decrease costs. Additional research with a lower risk of bias is unlikely to change this conclusion. Future research should focus on identifying the most efficient interventions.

Aims Ischaemic cardiomyopathy (ICM) leads to impaired contraction and ventricular dysfunction, causing high rates of morbidity and mortality. Epigenomics allows the identification of epigenetic signatures in human diseases. We analyse the differential epigenetic patterns of the ASB gene family in ICM patients and relate these alterations to their haemodynamic and functional status. Methods and results Epigenomic analysis was carried out using 16 left ventricular (LV) tissue samples, eight from ICM patients undergoing heart transplantation and eight from control (CNT) subjects without cardiac disease. We increased the sample size up to 13 ICM and 10 CNT for RNA sequencing and to 14 ICM for pyrosequencing analyses. We found a hypermethylated profile (cg11189868) in the ASB1 gene that showed a differential methylation of 0.26Δβ (P = 0.016). This result was validated by a pyrosequencing technique (0.23Δβ, P = 0.048). Notably, the methylation pattern was strongly related to LV ejection fraction (r = −0.849, P = 0.008), stroke volume (r = −0.929, P = 0.001), and end‐systolic and diastolic LV diameters (r = −0.743, P = 0.035 for both). ASB1 showed a down‐regulation in messenger RNA levels (−1.2‐fold, P = 0.039). Conclusions Our findings link a specific ASB1 methylation pattern to LV structure and performance in end‐stage ICM, opening new therapeutic opportunities and providing new insights regarding which is the functionally relevant genome in the ischaemic failing myocardium.

The aim of this study was to develop a user-friendly checklist for critical appraisal of indirect comparisons of drugs, considering clinical, methodological/statistical and quality aspects, mainly to be applied in drug evaluation in the decision-making context. After conducting a review of the literature, we used group consensus to establish the key points of the checklist, focusing mainly on indirect comparisons, but including topics related to network meta-analysis or multiple treatment comparisons. The coordinating group elaborated the first draft, which was reviewed by external experts, re-evaluated by the coordinating group and finally assessed by 23 drug evaluation experts trained in indirect comparisons, who applied the checklist to one study. The Kappa index of agreement was calculated and the final checklist was developed by group consensus including the external experts. The checklist has two parts. The first consists of three eliminatory key questions while the second includes 17 items: 5 regarding quality, 5 regarding clinical issues and 7 dealing with methodology/statistics. The median kappa values of the 23 evaluations were 0.83 (range 0.67-0.93), 0.61 (0.54-0.91) and 0.36 (0.22-1) with regard to quality, clinical aspects and methodology/statistics, respectively. A structured checklist was developed to facilitate critical appraisal of key issues in indirect comparisons, including comments for assessing the consequences of its application to drug evaluation in the decision-making context. Agreement between reviewers in clinical and quality items was good, but weaker in methodology/statistics ones.

Changes in cardiomyocyte cytoskeletal components, a crucial scaffold of cellular structure, have been found in heart failure (HF); however, the altered cytoskeletal network remains to be elucidated. This study investigated a new map of cytoskeleton-linked alterations that further explain the cardiomyocyte morphology and contraction disruption in HF. RNA-Sequencing (RNA-Seq) analysis was performed in 29 human LV tissue samples from ischemic cardiomyopathy (ICM; n=13) and dilated cardiomyopathy (DCM, n=10) patients undergoing cardiac transplantation and six healthy donors (control, CNT) and up to 16 ICM, 13 DCM and 7 CNT tissue samples for qRT-PCR. Gene Ontology analysis of RNA-Seq data demonstrated that cytoskeletal processes are altered in HF. We identified 60 differentially expressed cytoskeleton-related genes in ICM and 58 genes in DCM comparing with CNT, hierarchical clustering determined that shared cytoskeletal genes have a similar behavior in both pathologies. We further investigated MYLK4, RHOU, and ANKRD1 cytoskeletal components. qRT-PCR analysis revealed that MYLK4 was downregulated (-2.2-fold; P

Background: Abnormal thyroid hormone (TH) metabolism is significantly associated with impaired left ventricular (LV) function and death. Although THwas traditionally thought to be produced exclusively by the thyroid gland, an increasing number of studies report TH production in other tissues. Based on these findings, we evaluated whether the genes required for TH biosynthesis are expressed in the human heart, and whether their expression is altered in patients with ischemic cardiomyopathy (ICM) and is related to epigenetic variations. Methods: Twenty-three LV tissue sampleswere obtained fromICMpatients (n=13) undergoing heart transplantation and control donors (n=10) for RNA sequencing analysis. We increased the LV samples to 27 for the ELISA determination of total T4 and T3 tissue levels. For epigenomic studies, 850 K InfiniumMethylationEPIC BeadChip platform was performed. Results: Using RNA-sequencing, we displayed the expression levels of all components required for TH biosynthesis in human heart tissue. We observed significantly altered expression of genes encoding thyroperoxidase (TPO; -2.48-fold, P < 0.05) and dual oxidase 2 (2.83-fold, P < 0.05), themain enzymatic systemof TH production, and significant relationships between their altered expression and LV remodeling parameters. In addition, epigenetic analysis revealed a differential methylation pattern in TPO, and triiodothyronine tissue levels were significantly decreased (P < 0.01). Conclusions: These results showed that the human heart expresses the TH biosynthesismachinery, being altered its main enzymatic system in patients with ICM. Given the relevance of TH in cardiac pathology, our results provide a foundation for new therapeutic approaches based on TPO for treating ICM. (C) 2017 Published by Elsevier Ireland Ltd.

Somatic mutations in CREBBP occur frequently in B-cell lymphoma. Here, we show that loss of CREBBP facilitates the development of germinal center (GC)–derived lymphomas in mice. In both human and murine lymphomas, CREBBP loss-of-function resulted in focal depletion of enhancer H3K27 acetylation and aberrant transcriptional silencing of genes that regulate B-cell signaling and immune responses, including class II MHC. Mechanistically, CREBBP-regulated enhancers are counter-regulated by the BCL6 transcriptional repressor in a complex with SMRT and HDAC3, which we found to bind extensively to MHC class II loci. HDAC3 loss-of-function rescued repression of these enhancers and corresponding genes, including MHC class II, and more profoundly suppressed CREBBP-mutant lymphomas in vitro and in vivo. Hence, CREBBP loss-of-function contributes to lymphomagenesis by enabling unopposed suppression of enhancers by BCL6/SMRT/HDAC3 complexes, suggesting HDAC3-targeted therapy as a precision approach for CREBBP-mutant lymphomas. Significance: Our findings establish the tumor suppressor function of CREBBP in GC lymphomas in which CREBBP mutations disable acetylation and result in unopposed deacetylation by BCL6/SMRT/HDAC3 complexes at enhancers of B-cell signaling and immune response genes. Hence, inhibition of HDAC3 can restore the enhancer histone acetylation and may serve as a targeted therapy for CREBBP-mutant lymphomas. Cancer Discov; 7(1); 38–53. ©2016 AACR. See related commentary by Höpken, p. 14. This article is highlighted in the In This Issue feature, p. 1

BACKGROUND: The detection of heart transplant rejection by non-invasive methods remains a major challenge. Despite the well-known importance of the study of sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) in the heart, its role as a rejection marker has never been analyzed. Our objective in this study was to determine whether circulating SERCA2a could be a good marker of cardiac rejection. METHODS: We collected 127 consecutive endomyocardial biopsies (EMBs) and serum samples from adult heart transplant recipients (49 without allograft rejection and 78 with the diagnosis of biopsy allograft rejection, including 48 Grade 1R, 21 Grade 2R and 9 Grade 3R). Serum concentrations of SERCA2a were determined using a specific sandwich enzyme-linked immunosorbent assay. We also analyzed SERCA2a expression changes on EMBs using immunofluorescence. RESULTS: SERCA2a cardiac tissue and serum levels were decreased in patients with cardiac rejection (p < 0.0001). A receiver-operating characteristic analysis showed that SERCA2a strongly discriminated between patients with and without allograft rejection: normal grafts vs all rejecting grafts (AUC = 0.804); normal grafts vs Grade 1R (AUC = 0.751); normal grafts vs Grade 2R (AUC = 0.875); normal grafts vs Grade 3R (AUC = 0.922); normal grafts vs Grade 2R and 3R (AUC = 0.889), with p < 0.0001 for all comparisons. CONCLUSIONS: We demonstrated that changes in SERCA2a cardiac tissue and serum levels occur in cardiac allograft rejection. Our findings suggest that SERCA2a concentration assessment may be a relatively simple, non-invasive test for heart transplant rejection, showing a strong capability for detection that improves progressively as rejection grades increase. (C) 2017 The Authors. Published by Elsevier Inc.

An essential factor for the production of nitric oxide by nitric oxide synthase 1 (NOS1), major modulator of cardiac function, is the cofactor tetrahydrobiopterin (BH4). BH4 is regulated by GTP cyclohydrolase 1, the rate-limiting enzyme in BH4 biosynthesis which catalyses the formation of dihydroneopterin 3′triphosfate from GTP, producing BH4 after two further steps catalyzed by 6-pyruvoyltetrahydropterin synthase and sepiapterin reductase. However, there are other essential factors involved in the regulation of NOS1 activity, such as protein inhibitor of NOS1 (PIN), calmodulin, heat shock protein 90 and NOS interacting protein. All these molecules have never been analysed in human non-ischemic dilated hearts (DCM). In this study we demonstrated that the upregulation of cardiac NOS1 is not accompanied by increased NOS1 activity in DCM, partly due to the elevated PIN levels and not because of alterations in biopterin biosynthesis. Notably, the PIN concentration was significantly associated with impaired ventricular function, highlighting the importance of this NOS1 activity inhibitor in Ca2+ homeostasis. These results take a central role in the current list of targets for future studies focused on the complex cardiac dysfunction processes through more efficient harnessing of NOS1 signalling.

The role of nitric oxide synthase 1 (NOS1) as a major modulator of cardiac function has been extensively studied in experimental models; however, its role in human ischemic cardiomyopathy (ICM) has never been analysed. Thus, the objectives of this work are to study NOS1 and NOS-related counterparts involved in regulating physiological function of myocyte, to analyze NOS1 localisation, activity, dimerisation, and its relationship with systolic function in ICM. The study has been carried out on left ventricular tissue obtained from explanted human hearts. Here we demonstrate that the upregulation of cardiac NOS1 is not accompanied by an increase in NOS activity, due in part to the alterations found in molecules involved in the regulation of its activity. We observed partial translocation of NOS1 to the sarcolemma in ischemic hearts, and a direct relationship between its protein levels and systolic ventricular function. Our findings indicate that NOS1 may be significant in the pathophysiology of human ischemic heart disease with a preservative role in maintaining myocardial homeostasis.

Introduction: Some studies report that atopic patients have a greater frequency of delayed-type sensitization than non-atopic patients. Objective: To determine the influence of the atopic condition on delayed sensitization to dental materials. Design: cross-sectional study. Methods: Forty (40) atopic subjects and forty (40) non-atopic subjects, of both sexes, between 20 and 65 years of age were included. The determination of delayed sensitization to dental materials was performed using patch test. An oral exam was also carried out to check for lesions of the oral mucosa. Results: 61.25% of the patients were positive for delayed-type sensitization to one or more allergens, being palladium chloride (21.25%), ammoniated mercury (20%), benzoyl peroxide (12.5%) and amalgam (10%) the most frequent. The frequency of sensitization was 67.5% in the group of atopic patients, compared to 55% in the non atopic group (p>0.05). The materials with the greatest difference of sensitization in atopic compared to non-atopic patients were ammoniated mercury, benzoyl peroxide, amalgam and Bisphenol A Dimethacrylate (BIS-GMA). Conclusion: The atopic condition is not related to a higher frequency of delayed sensitization to a battery of dental materials. Key words: Patch test, delayed-type sensitization, allergy contact, atopia, dental materials.

Background. Several European governments have recently mandated price cuts in drugs to reduce health care spending. However, such measures without supportive evidence may compromise patient care because manufacturers may withdraw current products or not launch new agents. A value-based pricing scheme may be a better approach for determining a fair drug price and may be a medium for negotiations between the key stakeholders. To demonstrate this approach, pharmacoeconomic (PE) modeling was used from the Spanish health care system perspective to estimate a value-based price for bevacizumab, a drug that provides a 1.4-month survival benefit to patients with metastatic colorectal cancer (mCRC). The threshold used for economic value was three times the Spanish per capita GDP, as recommended by the World Health Organization (WHO). Methods. A PE model was developed to simulate outcomes in mCRC patients receiving chemotherapy ± bevacizumab. Clinical data were obtained from randomized trials and costs from a Spanish hospital. Utility estimates were determined by interviewing 24 Spanish oncology nurses and pharmacists. A price per dose of bevacizumab was then estimated using a target threshold of €78,300 per quality-adjusted life year gained, which is three times the Spanish per capita GDP. Results. For a 1.4-month survival benefit, a price of €342 per dose would be considered cost effective from the Spanish public health care perspective. The price may be increased to €733 or €843 per dose if the drug were able to improve patient quality of life or enhance survival from 1.4 to 3 months. Conclusions. This study demonstrated that a value-based pricing approach using PE modeling and the WHO criteria for economic value is feasible and perhaps a better alternative to government mandated price cuts. The former approach would be a good starting point for opening dialog between European government payers and the pharmaceutical industry.

Amelogenesis imperfecta is a group of genetic conditions that affect the structure and clinical appearance of tooth enamel. The types (hypoplastic, hypocalcified, and hypomature) are correlated with defects in different stages of the process of enamel synthesis. Autosomal dominant, recessive, and X-linked types have been previously described. These disorders are considered clinically and genetically heterogeneous in etiology, involving a variety of genes, such as AMELX, ENAM, DLX3, FAM83H, MMP-20, KLK4, and WDR72. The mutations identified within these causal genes explain less than half of all cases of amelogenesis imperfecta. Most of the candidate and causal genes currently identified encode proteins involved in enamel synthesis. We think it is necessary to refocus the search for candidate genes using biochemical processes. This review provides theoretical evidence that the human SLC4A4 gene (sodium bicarbonate cotransporter) may be a new candidate gene.

Objective: This study compared the cost-effectiveness of ranibizumab with that of photodynamic therapy (PDT) in the treatment of predominantly classic choroidal neovascularization secondary to age-related macular degeneration (AMD) from the perspective of a third-party payer in a Spanish setting. Methods: We constructed a Markov model with 5 states defined by visual acuity (VA) in the better-seeing eye (Snellen scale), as follows: VA >20/40, ≤20/40 to >20/80, ≤20/80 to >20/200, ≤20/200 to >20/400, and ≤20/400. A death state was also included. We took transition probabilities, number of ranibizumab injections, and number of PDT treatments from the ANCHOR (Anti—Vascular Endothelial Growth Factor Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in Age-Related Macular Degeneration) trial. Utilities were taken from a published study of patients' preferences. We used unit costs from our hospital and drug costs from a national database. Resource utilization was determined by an ophthalmologist according to current clinical practice. We performed univariate, threshold, and probabilistic sensitivity analyses. Incremental costs (2007 €) and quality-adjusted life-years (QALYs), both discounted at a 3% annual rate, and incremental cost-effectiveness ratios (ICERs; €/QALY) were determined for the 2-year and life-expectancy time horizons. Results: Treating patients with varying degrees of visual impairment with ranibizumab instead of PDT, with a 2-year time horizon, was found to be €18,328 more costly and to confer 0.140 additional QALY (€131,275/QALY). This ICER was reduced to €39,398/ QALY for the longer life-expectancy time horizon. According to the probabilistic sensitivity analysis, PDT is the therapy of choice in all cases below the threshold of €30,000/QALY for the 2-year time horizon. Ranibizumab was the optimal intervention in 26% of cases in the longer lifetime horizon. When the initial VA was ≤20/400, the ICER increased to €255,477 over 2 years. When ranibizumab was administered on an as-needed basis, as in the PrONTO (Prospective Optical coherence tomography imaging of patients with Neovascular AMD Treated with intra-Ocular ranibizumab) trial, the ICERs were reduced to €29,566/QALY and €11,469/QALY in the 2-year and life-expectancy horizons, respectively. Conclusions: Based on these results, ranibizumab was not cost-effective when administered on a monthly basis. When administered as needed, ranibizumab was cost-effective compared with PDT for the treatment of AMD.

Background Intercalated disks are unique structures in cardiac tissue, in which adherens junctions, desmosomes, and GAP junctions co-localize, thereby facilitating cardiac muscle contraction and function. Protocadherins are involved in these junctions; however, their role in heart physiology is poorly understood. We aimed to analyze the transcriptomic profile of adhesion molecules in patients with ischemic cardiomyopathy (ICM) and relate the changes uncovered with the hemodynamic alterations and functional depression observed in these patients. Methods and Results Twenty-three left ventricular tissue samples from patients diagnosed with ICM (n = 13) undergoing heart transplantation and control donors (CNT, n = 10) were analyzed using RNA sequencing. Forty-two cell adhesion genes involved in cellular junctions were differentially expressed in ICM myocardium. Notably, the levels of protocadherin PCDHGA3 were related with the stroke volume (r = -0.826, P = 0.003), ejection fraction (r = -0.793, P = 0.004) and left ventricular end systolic and diastolic diameters (r = 0.867, P = 0.001; r = 0.781, P = 0.005, respectively). Conclusions Our results support the importance of intercalated disks molecular alterations, closely involved in the contractile function, highlighting its crucial significance and showing gene expression changes not previously described. Specifically, altered PCDHGA3 gene expression was strongly associated with reduced stroke volume and ventricular dysfunction in ICM, suggesting a relevant role in hemodynamic perturbations and cardiac performance for this unexplored protocadherin.

Background In dilated cardiomyopathy (DCM), cardiac failure is accompanied by profound alterations of extracellular matrix associated with the progression of cardiac dilation and left ventricular (LV) dysfunction. Recently, we reported alterations of non-fibrillar collagen expression in ischemic cardiomyopathy linked to fibrosis and cardiac remodeling. We suspect that expression changes in genes coding for non-fibrillar collagens may have a potential role in DCM development. Objectives This study sought to analyze changes in the expression profile of non-fibrillar collagen genes in patients with DCM and to examine relationships between cardiac remodeling parameters and the expression levels of these genes. Methods and Results Twenty-three human left ventricle tissue samples were obtained from DCM patients (n = 13) undergoing heart transplantation and control donors (n = 10) for RNA sequencing analysis. We found increased mRNA levels of six non-fibrillar collagen genes, such as COL4A5, COL9A1, COL21A1, and COL23A1 (P < 0.05 for all), not previously described in DCM. Protein levels of COL8A1 and COL16A1 (P < 0.05 for both), were correspondingly increased. We also identified TGF-beta 1 significantly upregulated and related to both COL8A1 and COL16A1. Interestingly, we found a significant relationship between LV mass index and the gene expression level of COL8A1 (r = 0.653, P < 0.05). Conclusions In our research, we identified new non-fibrillar collagens with altered expression in DCM, being COL8A1 overexpression directly related to LV mass index, suggesting that they may be involved in the progression of cardiac dilation and remodeling.