Unplanned intensive care admission leading to an adverse event:Incidence,preventability and feature analysis

Objective:To compare the characteristics of patients between adverse event(AE)group and non-AE group,and to assess the causes,preventability,and severity of AE.Methods:A retrospective triple-phase medical record study was conducted at a Spanish tertiary hospital.Data was collected over a 6-month period,including all patients with an unplanned intensive care admission.Demographic characteristics,APACHE栻,length of ICU stay,mortality were compare between AE and non-AE group causes,preventability and severity were analyzed in AE cases.Results:597 Patients were included in the study.The overall incidence of AEs was 17.3%(n=103),of which 83.5%were considered preventable.Mortality within the AE group was higher than in the non-AE group(23.3%vs.13.6%),making it 1.7 times more frequent in the AE group(95%CI:1.143-2.071).The primary cause of AE was associated with surgical procedures(43.7%).Of the AEs,18.4%were classified as mild,58.3%as moderate,and 23.3%as severe.Conclusions:The incidence of unplanned intensive care admissions due to AE is high and potentially preventable.This is concerning given the high mortality observed in patients admitted to the intensive care unit because of an AE,although direct causality cannot always be established.The findings emphasize the importance of patient safety and underscore the need for improved quality and management of care resources.They also indicate where efforts should be directed to enhance care risk management.

An update on iron physiology

Iron is an essential micronutrient, as it is required for adequate erythropoietic function, oxidative metabolism and cellular immune responses. Although the absorption of dietary iron (1-2 mg/d) is regulated tightly, it is just balanced with losses. Therefore, internal turnover of iron is essential to meet the requirements for erythropoiesis (20-30 mg/d). Increased iron requirements, limited external supply, and increased blood loss may lead to iron deficiency (ID) and iron-deficiency anemia. Hepcidin, which is made primarily in hepatocytes in response to liver iron levels, inflammation, hypoxia and anemia, is the main iron regulatory hormone. Once secreted into the circulation, hepcidin binds ferroportin on enterocytes and macrophages, which triggers its internalization and lysosomal degradation. Thus, in chronic inflammation, the excess of hepcidin decreases iron absorption and prevents iron recycling, which results in hypoferremia and iron-restricted erythropoiesis, despite normal iron stores (functional ID), and anemia of chronic disease (ACD), which can evolve to ACD plus true ID (ACD + ID). In contrast, low hepcidin expression may lead to iron overload, and vice versa. Laboratory tests provide evidence of iron depletion in the body, or reflect iron-deficient red cell production. The appropriate combination of these laboratory tests help to establish a correct diagnosis of ID status and anemia.

Are proton pump inhibitors a new antidiabetic drug? A cross sectional study

AIM: To investigate the effect of proton pump inhibitors (PPIs) on glycemic control (HbA1c) in type 2 diabetic patients. METHODS: A crosssectional study of consecutive in-patients admitted to hospital in any department during the fi rst semester of the year 2010 who had a recent HbA1c measurement. The study excluded those with a diagnosis of hyperglycemic decompensation, diabetic onset or pregnancy. It compared HbA1c levels of those taking PPIs and those not. RESULTS: A total of 97 patients were recruited. The average HbA1C level was 7.0% ± 1.2%. Overall PPI consumption was 55.7%. HbA1c was signif icantly lower in individuals who took PPIs: -0.6%, 95% CI: -0.12 to-0.83. People who used PPIs with some type of insulin therapy had a HbA1c reduction by -0.8%, 95% CI: -0.12 to -1.48. For the rest of subgroup analysis based on the antidiabetic drug used, PPI consumption always exhibited lower HbA1c levels. CONCLUSION: PPIs seems to be consistently associated with better glycemic control in type 2 diabetes. HbA1c reduction observed is similar to incretin-based therapies.

A guide to diagnosis of iron deficiency and iron deficiency anemia in digestive diseases

Iron deficiency （ID）, with or without anemia, is often caused by digestive diseases and should always be investigated, except in very specific situations, as its causes could be serious diseases, such as cancer. Diagnosis of ID is not always easy. Low serum levels of ferritin or transferrin saturation, imply a situation of absolute or functional ID. It is sometimes difficult to differentiate ID anemia from anemia of chronic diseases, which can coexist. In this case, other parameters, such as soluble transferrin receptor activity can be very useful. After an initial evaluation by clinical history, urine analysis, and serological tests for celiac disease, gastroscopy and colonoscopy are the key diagnostic tools for investigating the origin of ID, and will detect the most important and prevalent diseases. If both tests are normal and anemia is not severe, treatment with oral iron can be indicated, along with stopping any treatment with non-steroidal anti-inflammatory drugs. In the absence of response to oral iron, or if the anemia is severe or clinical suspicion of important disease persists, we must insist on diagnostic evaluation. Repeat endoscopic studies should be considered in many cases and if both still show normal results, investigating the small bowel must be considered. The main techniques in this case are capsule endoscopy, followed by

Analysis of the postoperative hemostatic profile of colorectal cancer patients subjected to liver metastasis resection surgery

BACKGROUND Liver resection surgery has advanced greatly in recent years,and the adoption of fasttrack programs has yielded good results.Combination anesthesia (general anesthesia associated to epidural analgesia) is an anesthetic-analgesic strategy commonly used for the perioperative management of patients undergoing surgery of this kind,though there is controversy regarding the coagulation alterations it may cause and which can favor the development of spinal hematomas.AIM To study the postoperative course of liver resection surgery,an analysis was made of the outcomes of liver resection surgery due to colorectal cancer metastases in our centre in terms of morbiditymortality and hospital stay according to the anesthetic technique used (general vs combination anesthesia).METHODS A prospective study was made of 61 colorectal cancer patients undergoing surgery due to liver metastases under general and combination anesthesia between January 2014 and October 2015.The patient characteristics,intraoperative variables,postoperative complications,evolution of hemostatic parameters,and stay in intensive care and in hospital were analyzed.RESULTS A total of 61 patients were included in two homogeneous groups: general anesthesia (n = 30) and combination anesthesia (general anesthesia associated to epidural analgesia)(n = 31).All patients had normal coagulation values before surgery.The international normalized ratio (INR) in both the general and combination anesthesia groups reached maximum values at 2448 h (mean 1.37 and 1.45 vs 1.39 and 1.41,respectively),followed by a gradual decrease.There was less intraoperative bleeding in the combination anesthesia group (769 mL) than in the general anesthesia group (1200 mL)(P < 0.05).Of the 61 patients,38.8% in the general anesthesia group experienced some respiratory complication vs 6.6% in the combination anesthesia group (P < 0.001).The time to gastrointestinal tolerance was significantly correlated to the type of anesthesia,though not so the stay in critical care or the time to hospital discharge.CONCLUSION Epidural analgesia in liver resection surgery was seen to be safe,with good results in terms of pain control and respiratory complications,and with no associated increase in complications secondary to altered hemostasis.

Intravenous iron in inflammatory bowel disease

The prevalence of anemia across studies on patients with inflammatory bowel disease (IBD) is high (30%). Both iron defi ciency (ID) and anemia of chronic disease contribute most to the development of anemia in IBD. The prevalence of ID is even higher (45%). Anemia and ID negatively impact the patient's quality of life. Therefore, together with an adequate control of disease activity, iron replacement therapy should start as soon as anemia or ID is detected to attain a normal hemoglobin (Hb) and iron status. Many patients will respond to oral iron, but compliance may be poor, whereas intravenous (IV) compounds are safe, provide a faster Hb increase and iron store repletion, and presents a lower rate of treatment discontinuation. Absolute indications for IV iron treatment should include severe anemia, intolerance or inappropriate response to oral iron, severe intestinal disease activity, or use of an erythropoietic stimulating agent. Four different products are principally used in clinical practice, which differ in their pharmacokinetic properties and safety profi les: iron gluconate and iron sucrose (lower single doses), and iron dextran and ferric carboxymaltose (higher single doses). After the initial resolution of anemia and the repletion of iron stores, the patient's hematological and iron parameters should be carefully and periodically monitored, and maintenance iron treatment should be provided as required. New IV preparations that allow for giving 1000-1500 mg in a single session, thus facilitating patient management,provide an excellent tool to prevent or treat anemia and ID in this patient population, which in turn avoids allogeneic blood transfusion and improves their quality of life.

Glutathione metabolism is essential for self-renewal and chemoresistance of pancreatic cancer stem cells

BACKGROUND Cellular metabolism regulates stemness in health and disease.A reduced redox state is essential for self-renewal of normal and cancer stem cells(CSCs).However,while stem cells rely on glycolysis,different CSCs,including pancreatic CSCs,favor mitochondrial metabolism as their dominant energy-producing pathway.This suggests that powerful antioxidant networks must be in place to detoxify mitochondrial reactive oxygen species(ROS)and maintain stemness in oxidative CSCs.Since glutathione metabolism is critical for normal stem cell function and CSCs from breast,liver and gastric cancer show increased glutathione content,we hypothesized that pancreatic CSCs also rely on this pathway for ROS detoxification.AIM To investigate the role of glutathione metabolism in pancreatic CSCs.METHODS Primary pancreatic cancer cells of patient-derived xenografts(PDXs)were cultured in adherent or CSC-enriching sphere conditions to determine the role of glutathione metabolism in stemness.Real-time polymerase chain reaction(PCR)was used to validate RNAseq results involving glutathione metabolism genes in adherent vs spheres,as well as the expression of pluripotency-related genes following treatment.Public TCGA and GTEx RNAseq data from pancreatic cancer vs normal tissue samples were analyzed using the webserver GEPIA2.The glutathione-sensitive fluorescent probe monochlorobimane was used to determine glutathione content by fluorimetry or flow cytometry.Pharmacological inhibitors of glutathione synthesis and recycling[buthionine-sulfoximine(BSO)and 6-Aminonicotinamide(6-AN),respectively]were used to investigate the impact of glutathione depletion on CSC-enriched cultures.Staining with propidium iodide(cell cycle),Annexin-V(apoptosis)and CD133(CSC content)were determined by flow cytometry.Self-renewal was assessed by sphere formation assay and response to gemcitabine treatment was used as a readout for chemoresistance.RESULTS Analysis of our previously published RNAseq dataset E-MTAB-3808 revealed upregulation of genes involved in the KEGG(Kyoto Encyclopedia of Genes and Genomes)Pathway Glutathione Metabolism in CSC-enriched cultures compared to their differentiated counterparts.Consistently,in pancreatic cancer patient samples the expression of most of these up-regulated genes positively correlated with a stemness signature defined by NANOG,KLF4,SOX2 and OCT4 expression(P<10-5).Moreover,3 of the upregulated genes(MGST1,GPX8,GCCT)were associated with reduced disease-free survival in patients[Hazard ratio(HR)2.2-2.5;P=0.03-0.0054],suggesting a critical role for this pathway in pancreatic cancer progression.CSC-enriched sphere cultures also showed increased expression of different glutathione metabolism-related genes,as well as enhanced glutathione content in its reduced form(GSH).Glutathione depletion with BSO induced cell cycle arrest and apoptosis in spheres,and diminished the expression of stemness genes.Moreover,treatment with either BSO or the glutathione recycling inhibitor 6-AN inhibited self-renewal and the expression of the CSC marker CD133.GSH content in spheres positively correlated with intrinsic resistance to gemcitabine treatment in different PDXs r=0.96,P=5.8×1011).Additionally,CD133+cells accumulated GSH in response to gemcitabine,which was abrogated by BSO treatment(P<0.05).Combined treatment with BSO and gemcitabine-induced apoptosis in CD133+cells to levels comparable to CD133-cells and significantly diminished self-renewal(P<0.05),suggesting that chemoresistance of CSCs is partially dependent on GSH metabolism.CONCLUSION Our data suggest that pancreatic CSCs depend on glutathione metabolism.Pharmacological targeting of this pathway showed that high GSH content is essential to maintain CSC functionality in terms of self-renewal and chemoresistance.

Lipid droplets as metabolic determinants for stemness and chemoresistance in cancer

Previously regarded as simple fat storage particles,new evidence suggests thatlipid droplets(LDs)are dynamic and functional organelles involved in keycellular processes such as membrane biosynthesis,lipid metabolism,cellsignalling and inflammation.Indeed,an increased LD content is one of the mostapparent features resulting from lipid metabolism reprogramming necessary tosupport the basic functions of cancer cells.LDs have been associated to differentcellular processes involved in cancer progression and aggressiveness,such astumorigenicity,invasion and metastasis,as well as chemoresistance.Interestingly,all of these processes are controlled by a subpopulation of highly aggressivetumoral cells named cancer stem cells(CSCs),suggesting that LDs may befundamental elements for stemness in cancer.Considering the key role of CSCs onchemoresistance and disease relapse,main factors of therapy failure,the design ofnovel therapeutic approaches targeting these cells may be the only chance forlong-term survival in cancer patients.In this sense,their biology and functionalproperties render LDs excellent candidates for target discovery and design ofcombined therapeutic strategies.In this review,we summarise the currentknowledge identifying LDs and CSCs as main contributors to cancer aggressiveness,metastasis and chemoresistance.

阻塞性睡眠呼吸暂停综合征男性患者持续正压通气治疗对心血管系统远期预后的疗效观察

Background: The effect of obstructive sleep apnoea-hypopnoea as a cardiovascular risk factor and the potential protective effect of its treatment with continuous positive airway pressure (CPAP) is unclear. We did an observational study to compare incidence of fatal and non-fatal cardiovascular events in simple snorers, patients with untreated obstructive sleep apnoea-hypopnoea, patients treated with CPAP, and healthy men recruited from the general population. Methods: We recruited men with obstructive sleep apnoea-hypopnoea or simple snorers from a sleep clinic, and a population-based sample of healthy men, matched for age and body-mass index with the patients with untreated severe obstructive sleep apnoea-hypopnoea. The presence and severity of the disorder was determined with full polysomnography, and the apnoea-hypopnoea index (AHI) was calculated as the average number of apnoeas and hypopnoeas per hour of sleep. Participants were followed-up at least once per year for a mean of 10.1 years (SD 1.6) and CPAP compliance was checked with the built-in meter. Endpoints were fatal cardiovascular events (death from myocardial infarction or stroke) and non-fatal cardiovascular events (non-fatal myocardial infarction, non-fatal stroke, coronary artery bypass surgery, and percutaneous transluminal coronary angiography). Findings: 264 healthy men, 377 simple snorers, 403 with untreated mild-moderate obstructive sleep apnoea-hypopnoea, 235 with untreated severe disease, and 372 with the disease and treated with CPAP were included in the analysis. Patients with untreated severe disease had a higher incidence of fatal cardiovascular events (1.06 per 100 person-years) and non-fatal cardiovascular events (2.13 per 100 person-years) than did untreated patients with mild-moderate disease (0.55, p=0.02 and 0.89, p < 0.0001), simple snorers (0.34, p=0.0006 and 0.58, p < 0.0001), patients treated with CPAP (0.35, p=0.0008 and 0.64, p < 0.0001), and healthy participants (0.3, p=0.0012 and 0.45, p < 0.0001). Multivariate analysis, adjusted for potential confounders, showed that untreated severe obstructive sleep apnoea-hypopnoea significantly increased the risk of fatal (odds ratio 2.87, 95%CI 1.17-7.51) and non-fatal (3.17, 1.12-7.51) cardiovascular events compared with healthy participants. Interpretation: In men, severe obstructive sleep apnoea-hypopnoea significantly increases the risk of fatal and non-fatal cardiovascular events. CPAP treatment reduces this risk.

Interventional radiology treatment for pulmonary embolism

Venous thromboembolism(VTE) is an illness that has a potentially life-threatening condition that affects a large percentage of the global population. VTE with pulmonary embolism(PE) is the third leading cause of death after myocardial infarction and stroke. In the first three months after an acute PE, there is an estimated 15% mortality among submassive PE, and 68% mortality in massive PE. Current guidelines suggest fibrinolytic therapy regarding the clinical severity, however some studies suggest a more aggressive treatment approach. This review will summarize the available endovascular treatments and the different techniques with its indications and outcomes.

Tenofovir vs lamivudine plus adefovir in chronic hepatitis B:TENOSIMP-B study

AIM To demonstrate the non-inferiority(15% non-inferiority limit) of monotherapy with tenofovir disoproxil fumarate(TDF) vs the combination of lamivudine(LAM) plus adefovir dipivoxil(ADV) in the maintenance of virologic response in patients with chronic hepatitis B(CHB) and prior failure with LAM.METHODS This study was a Phase IV prospective, randomized, open, controlled study with 2 parallel groups(TDF and LAM+ADV) of adult patients with hepatitis B e antigen(HBe Ag)-negative CHB, prior failure with LAM, on treatment with LAM+ADV for at least 6 mo, without prior resistance to ADV and with an undetectable viral load at the start of the study, in 14 Spanish hospitals. The follow-up time for each patient was 48 wk after randomization, with quarterly visits in which the viral load, biochemical and serological parameters, adverse effects, adherence to treatment and consumption of hospital resources were analysed.RESULTS Forty-six patients were evaluated [median age: 55.4 years(30.2-75.2); 84.8% male], including 22 patients with TDF and 24 with LAM+ADV. During study development, hepatitis B virus DNA(HBV-DNA) remained undetectable, all patients remained HBe Ag negative, and hepatitis B surface antigen(HBs Ag) positive. Alanine aminotransferase(ALT) values at the end of the study were similar in the 2 groups(25.1± 7.65, TDF vs 24.22 ± 8.38, LAM+ADV, P = 0.646). No significant changes were observed in creatinine or serum phosphorus values in either group. No significant differences between the 2 groups were noted in the identification of adverse effects(AEs)(53.8%, TDF vs 37.5%, LAM+ADV, P = 0.170), and none of the AEs which occurred were serious. Treatment adherence was 95.5% and 83.3% in the TDF and the LAM+ADV groups, respectively(P = 0.488). The costs associated with hospital resource consumption were significantly lower with the TDF treatment than the LAM+ADV treatment(€4943 ± 1059 vs €5811 ± 1538, respectively, P < 0.001).CONCLUSION TDF monotherapy proved to be safe and not inferior to the LAM+ADV combination therapy in maintaining virologic response in patients with CHB and previous LAM failure. In addition, the use of TDF generated a significant savings in hospital costs.

Metabolic determinants of stemness in medulloblastoma

Medulloblastomas(MBs)are the most prevalent brain tumours in children.They are classified as grade IV,the highest in malignancy,with about 30%metastatic tumours at the time of diagnosis.Cancer stem cells(CSCs)are a small subset of tumour cells that can initiate and support tumour growth.In MB,CSCs contribute to tumour initiation,metastasis,and therapy resistance.Metabolic differences among the different MB groups have started to emerge.Sonic hedgehog tumours show enriched lipid and nucleic acid metabolism pathways,whereas Group 3 MBs upregulate glycolysis,gluconeogenesis,glutamine anabolism,and glutathione-mediated anti-oxidant pathways.Such differences impact the clinical behaviour of MB tumours and can be exploited therapeutically.In this review,we summarise the existing knowledge about metabolic rewiring in MB,with a particular focus on MB-CSCs.Finally,we highlight some of the emerging metabolism-based therapeutic strategies for MB.

Are we giving azathioprine too much time?

Azathioprine is currently the key drug in the maintenance treatment of inflammatory bowel diseases. However, there are still some practical issues to be resolved: one is how long we must maintain the drug. Given that inflammatory bowel diseases are to date chronic, non-curable conditions, treatment should be indefinite and only the loss of efficacy or the appearance of serious side effects may cause withdrawal. As regards to efficacy and their maintenance over time, evidence supports the continuous usefulness of the drug in the long term: in fact its withdrawal very substantially increases the risk of relapse. About side effects, azathioprine is a relatively well tolerated drug and even indefinite use seems safe. The main theoretical risks of prolonged use would be the myelotoxicity, hepatotoxicity, and the development of cancer. In fact, serious bone marrow suppression or serious liver damage are uncommon, and can be minimized with proper use of the drug. Recent metanalysis suggests that the risk of lymphoma is real, but the individual risk is rather low, and decision analysis suggests a favorable benefit/risk ratio in the long term. Therefore, in patients with inflammatory bowel diseases in whom azathioprine is effective and well tolerated, the drug should not be stopped. This recommendation concerns the use of azathioprine as a single maintenance drug, and is not necessarily applicable to patients receiving concomitant biological therapy.

Is the Current Diagnosis of Schizophrenia Useful or Harmful?

In recent decades, evidence has appeared in various scientific fields—genetic, psychopharmacological, neuro-psychological, etc.—which makes it difficult to maintain the positive and negative syndrome of schizophrenia under one and the same diagnosis. On the other hand, there are social and legal reasons recommending the conception of these two syndromes as different entities. In this paper, we conduct appropriate bibliographical researches to reveal these evidences. We discuss these findings and conclude proposing the split of positive and negative syndromes of schizophrenia in two different disorders.

Twelve-month efficacy and safety of the conversion to everolimus in maintenance heart transplant recipients

AIM: To determine the clinical reasons for conversion to everolimus(EVL) and long-term outcomes in heart transplant(HT) recipients.METHODS: A retrospective 12-mo study has been carried out in 14 Spanish centres to assess the efficacy and safety of conversion to EVL in maintenance HT recipients.RESULTS: Two hundred and twenty-two patients were included(mean age: 53 ± 10.5 years; mean time from HT: 8.1 ± 4.5 years). The most common reasons for conversion were nephrotoxicity(30%), chronic allograft vasculopathy(20%) and neoplasms(17%). The doses and mean levels of EVL at baseline(conversion to EVL) and after one year were 1.3 ± 0.3 and 1.2 ± 0.6 mg/d and 6.4 ± 3.4 and 5.6 ± 2.5 ng/mL, respectively. The percentage of patients receiving calcineurin inhibitors(CNIs) at baseline and on the final visit was 95% and 65%, respectively. The doses and mean levels of CNIs decreased between baseline and month 12 from 142.2 ± 51.6 to 98.0 ± 39.4 mg/d(P < 0.001) and from 126.1 ± 50.9 to 89.2 ± 47.7 ng/mL(P < 0.001), respectively, for cyclosporine, and from 2.9 ± 1.8 to 2.6 ± 1.9 mg/d and from 8.3 ± 4.0 to 6.5 ± 2.7 ng/mL(P = 0.011) for tacrolimus. In the subgroup of patients converted because of nephrotoxicity, creatinine clearance increased from 34.9 ± 10.1 to 40.4 ± 14.4 mL/min(P < 0.001). There were 37 episodes of acute rejection in 24 patients(11%). The most frequent adverse events were oedemas(12%), infections(9%) and gastrointestinal problems(6%). EVL was suspended in 44 patients(20%). Since the database was closed at the end of the study, no further followup data is available.CONCLUSION: Conversion to EVL in maintenance HT recipients allowed minimisation or suspension of the CNIs, with improved kidney function in the patients with nephrotoxicity, after 12 mo.

GOECP/SEOR radiotherapy guidelines for thymic epithelial tumours

Thymic epithelial tumours(TET)are rare,heterogeneous neoplasms that range from resectable indolent tumours to aggressive thymic carcinomas with a strong tendency to metastasize.The pathological diagnosis is complex,in part due to the management of TETs is scant and mainly based on non-randomised studies and retrospective series.Consequently,the clinical management of TETs tends to be highly heterogenous,which makes it difficult to improve the evidence level.The role of technological advances in the field of radiotherapy and new systemic therapies in the treatment of TETs has received little attention to date.In the present clinical guidelines,developed by the GOECP/SEOR,we review recent developments in the diagnosis and classification of TETs.We also present a consensus-based therapeutic strategy for each disease stage that takes into consideration the best available evidence.These guidelines focus primarily on the role of radiotherapy,including recent advances,in the management of TETs.The main aim of this document is to promote the standardisation of clinical practice and lay the foundations for future studies to clarify the main unresolved questions related to the optimal management of TET.

Relation between Gastrointestinal Adverse Effects in Gaucher Disease Patients and Intestinal Disaccharidases Activity Evaluated by Methane Hydrogen Breath Test

The aim of this paper is to study the disaccharidase profile in GD （Gaucher disease） patients treated or not with miglustat and compare it with a healthy control group. Miglustat is an iminosugar used as substrate inhibitor in the therapy of some lysosomal disorders, its main side effects resembling carbohydrate maldigestion symptoms and cause more than 50% of medication discontinuation among GD patients. In-vitro studies have revealed that miglustat can act as an inhibitor of some digestive enzymes. An exploratory non-interventional study was designed to compare the disaccharidase profile assessed by MHBT （methane hydrogen breath test） and to analyze the correlation with the reported gastrointestinal symptoms in GD patients （40） and healthy subjects （20）. MHBT was performed following the ingestion of lactose, sucrose and maltose on different days. Each participant completed two detailed surveys about dietary habits, medications and gastrointestinal symptoms previous and during the test. Twenty-one GD were receiving miglustat, 10 （47.6%） of them reported gastrointestinal side effects, and 7/10 （70%） recorded a positive MHBT （lactose 5, maltose 2, and sucrose 1）. In 6/19 （31.6%） patients that never been exposed to miglustat and 7/20 （35%） controls a positive MHBT were detected. The comparison of the malabsorption phenotype between GD patients exposed and not exposed to miglustat （p = 0.028） and control group （p 〈 0.04） showed high statistical significance for the group of patients treated with miglustat. These results suggest that miglustat therapy induces persistent changes in digestive enzyme activity in GD patients.

Prospective application of a bleeding and ischemic risks-adjusted antithrombotic protocol in elderly patients revascularized with everolimus-eluting stents:EPIC05-Sierra75 study

OBJECTIVES Elderly patients show a higher incidence of ischemic and bleeding events after percutaneous transluminal coron-ary intervention(PCI).We sought to investigate outcomes in elderly patients treated with antithrombotic strategy guided by bleeding and ischemic risks after revascularization with last generation everolimus-eluting stent(EES).METHODS Prospective multicenter registry including patients over 75 years revascularized with EES and antithrombotic ther-apy guided by clinical presentation,PCI complexity and PRECISE DAPT score.Co-primary safety endpoints were:(1)composite of cardiac death,myocardial infarction and stent thrombosis and;(2)bleeding(BARC 2-5).Primary efficacy endpoint was target lesion revascularization.A matched group of patients revascularized with current drug-eluting stents and no such tailored antith-rombotic therapy was used as control.RESULTS Finally,1064 patients were included in SIERRA-75 cohort,80.8±4.2 years,36.6%women,71%acute coronary syn-dromes(ACS)and 53.6%complex PCI.Co-primary safety endpoint of major adverse cardiovascular events was met in 6.2%,co-primary safety endpoint of bleeding in 7.8%and primary efficacy endpoint of TKLR in 1.5%.The multivariable adjusted model showed no significant association of the prescribed short/long dual antiplatelet therapy(DAPT)durations with any endpoint suggesting a well tailored therapy.No stent thrombosis reported in the subgroup with 1-3 months DAPT duration.As compared to control group,bleeding BARC 2-5 was significantly lower in SIERRA-75 group(7.4%vs.10.2%,P=0.04)as well as the net safety-efficacy endpoint(14.3%vs.18.5%,P=0.02).CONCLUSIONS In elderly population,the application of this risks-adjusted antithrombotic protocol after revascularization with last generation EES seems to be associated with an improved prognosis in terms of ischemic and bleeding outcomes.

Interindividual Age-Independent Differences in Human CX43 Impact Ventricular Arrhythmic Risk

Connexin 43 (CX43) is one of the major components of gap junctions, the structures responsible for the intercellular communication and transmission of the electrical impulse in the left ventricle. There is limited information on the histological changes of CX43 with age and their effect on electrophysiology, especially in humans. Here, we analyzed left ventricular biopsies from living donors starting at midlife to characterize age-related CX43 remodeling. We assessed its quantity, degree of lateralization, and spatial heterogeneity together with fibrotic deposition. We observed no significant age-related remodeling of CX43. Only spatial heterogeneity increased slightly with age, and this increase was better explained by biological age than by chronological age. Importantly, we found that CX43 features varied considerably among individuals in our population with no relevant relationship to age or fibrosis content, in contrast to animal species. We used our experimental results to feed computational models of human ventricular electrophysiology and to assess the effects of interindividual differences in specific features of CX43 and fibrosis on conduction velocity, action potential duration, and arrhythmogenicity. We found that larger amounts of fibrosis were associated with the highest arrhythmic risk, with this risk being increased when fibrosis deposition was combined with a reduction in CX43 amount and/or with an increase in CX43 spatial heterogeneity. These mechanisms underlying high arrhythmic risk in some individuals were not associated with age in our study population. In conclusion, our data rule out CX43 remodeling as an age-related arrhythmic substrate in the population beyond midlife, but highlight its potential as a proarrhythmic factor at the individual level, especially when combined with increased fibrosis.

Phase Ⅱ trial of CDK4/6 inhibitor palbociclib in advanced sarcoma based on mRNA expression of CDK4/CDKN2A

Cyclin-dependent kinases 4 and 6(CDK4/6)inhibitors demonstrated activity in terms of progression-free survival(PFS)in advanced dedifferentiated liposarcoma(DD-LPS),a sarcoma with CDK4 amplification.CDK4 overexpression is by far more common than amplification in sarcomas and it might be a rational target for CDK inhibitors.Preclinical investigators of this study found that CDK4 overexpression,while not of CDKN2A,was the most consistent predictive factor for palbociclib efficacy in sarcomas.Advanced adult-type soft-tissue sarcoma,excluding DD-LPS,or bone sarcoma patients,progressing after at least one systemic line,whose tumors overexpressed CDK4,but not CDKN2A at baseline biopsy,were accrued in this single-arm phase II trial(EudraCT number:2016-004039-19).With the main endpoint of a 6-month PFS rate,40%was considered promising in this population.Palbociclib was administered orally at 125 mg/day for 21 days in 28-day cycles.A total of 214 patients with 236 CDK4/CDKN2A determinations were assessed for prescreening,archival material(141),and screening,baseline biopsy(95).There were 28(29%)with favorable mRNA profiles from 95 screened patients at baseline.From 23 enrolled patients,21 evaluable,the 6-month PFS rate was 29%(95%CI 9–48),and there were 6 patients out of 21 with a PFS longer than 6 months.The median PFS and overall survival were 4.2(95%CI 3.6–4.8)and 12(95%CI 8.7–15.4)months,respectively.Translational research showed a significant correlation between CDK4 mRNA and protein expression.Palbociclib was active in a variety of sarcoma subtypes,selected by CDK4/CDKN2A,and deserves further investigation in the sarcoma context.