Polymorphisms within the ARNT2 and CX3CR1 Genes Are Associated with the Risk of Developing Invasive Aspergillosis.

Invasive aspergillosis (IA) is a life-threatening infection that affects an increasing number of patients undergoing chemotherapy or allo-transplantation, and recent studies have shown that genetic factors contribute to disease susceptibility. In this two-stage, population-based, case-control study, we evaluated whether 7 potentially functional single nucleotide polymorphisms (SNPs) within the ARNT2 and CX3CR1 genes influence the risk of IA in high-risk hematological patients. We genotyped selected SNPs in a cohort of 500 hematological patients (103 of those had been diagnosed with proven or probable IA), and we evaluated their association with the risk of developing IA. The association of the most interesting markers of IA risk was then validated in a replication population, including 474 subjects (94 IA and 380 non-IA patients). Functional experiments were also performed to confirm the biological relevance of the most interesting markers. The meta-analysis of both populations showed that carriers of the ARNT2rs1374213G, CX3CR1rs7631529A, and CX3CR1rs9823718G alleles (where the RefSeq identifier appears as a subscript) had a significantly increased risk of developing IA according to a log-additive model (P value from the meta-analysis [PMeta] = 9.8 · 10-5, PMeta = 1.5 · 10-4, and PMeta =7.9 · 10-5, respectively). Haplotype analysis also confirmed the association of the CX3CR1 haplotype with AG CGG with an increased risk of IA (P = 4.0 · 10-4). Mechanistically, we observed that monocyte-derived macrophages (MDM) from subjects carrying the ARNTR2rs1374213G allele or the GG genotype showed a significantly impaired fungicidal activity but that MDM from carriers of the ARNT2rs1374213G and CX3CR1rs9823718G or CX3CR1rs7631529A alleles had deregulated immune responses to Aspergillus conidia. These results, together with those from expression quantitative trait locus (eQTL) data browsers showing a strong correlation of the CX3CR1rs9823718G allele with lower levels of CX3CR1 mRNA in whole peripheral blood (P = 2.46 · 10-7) and primary monocytes (P = 4.31 · 10-7), highlight the role of the ARNT2 and CX3CR1 loci in modulating and predicting IA risk and provide new insights into the host immune mechanisms involved in IA development.

Management of antiplatelet therapy in patients with coronary stents undergoing noncardiac surgery: association with adverse events.

BACKGROUND: Perioperative discontinuation of antiplatelet therapy (APT) in patients with coronary stents has been associated with major adverse cardiac events. Our aim was to analyse the perioperative management of APT in such patients and its relationship to the incidence of major adverse cardiac and cerebrovascular events (MACCE) and major bleeding events (MBE) in noncardiac surgery. METHODS: We completed a prospective multicentre observational study of patients with coronary stents undergoing noncardiac surgery in 11 hospitals in Spain. The main objectives were to record perioperative events and prospectively analyse the management of APT, and to assess whether the different preoperative APT regimens were associated with MACCE and MBE. RESULTS: Of 432 surgical procedures studied, 15% experienced a perioperative MACCE and 37% a MBE. Overall mortality was 3.0%. Presurgical APT was prescribed in 95% of procedures, and was preoperatively discontinued in 15%. Surgery was urgent or emergent in 22% of patients, 31% were ASA IV, and 38% had a Revised Cardiac Risk Index of IV. MACCE were related to recent myocardial infarction (P=0.038), chronic kidney disease (P<0.001), insulin-dependent diabetes (P=0.006) and no preoperative APT (P=0.018). MBE also increased MACCE risk (P<0.001). We found statin therapy (P=0.049) and obesity (P=0.016) to be protective factors for MACCE. CONCLUSIONS: Patients with coronary stents undergoing noncardiac surgery suffer a high incidence of perioperative adverse events, even with perioperative APT. Major adverse cardiac and cerebrovascular events are mainly related to previous medical conditions and perioperative major bleeingn events. Our findings should be treated with caution when applied to an elective surgery population. CLINICAL TRIAL REGISTRATION: NCT01171612.

Preoperative estimated glomerular filtration rate and the risk of major adverse cardiovascular and cerebrovascular events in non-cardiac surgery.

BACKGROUND: Chronic kidney disease is an independent predictor of perioperative cardiovascular morbidity and mortality. We analysed the preoperative estimated glomerular filtration rate (eGFR) as a risk factor for perioperative major adverse cardiovascular and cerebrovascular events (MACCE) in non-cardiac surgery. METHODS: In a post hoc analysis of the ANESCARDIOCAT database, patients were classified into six stages of eGFR calculated with the abbreviated Modification of Diet in Renal Disease Study and the Chronic Kidney Disease Epidemiology Collaboration equations: >90 (1), 60-89.9 (2), 45-59.9 (3a), 30-44.9 (3b), 15-29.9 (4), and <15 (5) ml min(-1) 1.73 m(-2). We analysed differences in MACCE, length of hospital stay, and all-cause mortality between eGFR stages. RESULTS: The eGFR was available in 2323 patients. Perioperative MACCE occurred in 4.5% of patients and cardiac-related mortality was 0.5%. Five hundred and forty-three (23.4%) patients had an eGFR of <60 ml min(-1) 1.73 m(-2) and 127 (5.4%) had an eGFR below 45 ml min(-1) 1.73 m(-2). Logistic regression analysis showed that MACCE increased with eGFR impairment (P<0.001), with a marked increase from stage 3b onwards (odds ratio 1.8 vs 3.9 in 3a and 3b, respectively, P=0.047). All-cause mortality was not related to eGFR (P=0.071), but increased substantially between stages 3b and 4. The length of stay correlated with eGFR (P<0.001). CONCLUSIONS: Perioperative MACCE increase with declining eGFR, primarily when <45 ml min(-1) 1.73 m(-2). We recommend the use of preoperative eGFR for cardiovascular risk assessment.

COVID-19 thromboprophylaxis. New evidence.

Recent publications have questioned the efficacy of using therapeutic or intermediate doses of low molecular weight heparin (LMWH) in COVID-19 patients, especially in the most severe patients. In order to update these recommendations, a non-systematic review has been carried out in the main medical databases. A total of 14 randomized clinical trials, 14 meta-analyses and the recommendations of 12 scientific societies were selected, stratified according to the type of patient (outpatient, hospitalized, admitted to critical care or post-discharge). The efficacy of LMWH and other therapeutic approaches (rivaroxaban, apixaban, sulodexide, acetylsalicylic acid and P2Y12 inhibitors) has been analyzed. The findings recommend using standard doses of LMWH as thromboprophylaxis in critically hospitalized COVID-19 patients and therapeutic doses in non-critically hospitalized patients if the risk of bleeding is low. In outpatients and those discharged from the hospital, LMWH could be used at a prophylactic dose if there are thrombotic risk factors, and the bleeding risk is low. It is not recommended to associate antiplatelet agents with LMWH unless previously indicated.

[CLINICAL IMPACT OF THE SUSPENSION OF THE ERAS PROTOCOL ON PATIENTS UNDERGOING RADICAL CYSTECTOMY DURING THE COVID-19 PANDEMIC.] / IMPACTO CLÍNICO DE NO APLICAR EL PROTOCOLO ERAS EN LOS PACIENTES SOMETIDOS A CISTECTOMÍA DURANTE LA PANDEMIA COVID-19.

INTRODUCTION: During the beginning of the COVID-19 pandemic in our center, neither prehabilitation nor multimodal rehabilitation could be applied due to the excessive patient load on the health system and to reduce SARS-CoV-2 transmission. The objective of our study was to analyze the evolution, complications, and survival up to one year of patients who underwent radical cystectomy in our hospital from March 1st to May 31st, 2020 (period of the first wave COVID-19 pandemic in Spain). We also compared the results with cystectomized patients outside the pandemic period and with application of the ERAS (Enhanced Recovery After Surgery) protocol. MATERIAL AND METHODS: Single-center, retrospective cohort study of patients scheduled for radical cystectomy from March 1st,2020 to May 31st, 2020. They were matched with previously operated patients using a 1:2 propensity matching score. The matching variables were demographic data, preoperative and intraoperative clinical conditions. RESULTS: A total of 23 radical cystectomies with urinary diversion were performed in the period described. In none of the cases the prehabilitation or the follow-up of our ERAS protocol could be applied, and this was the only difference we found between the 2 groups. Although the minimally invasive approach was more frequent in the pandemic group, the difference was not statistically significant. Three patients were diagnosed with COVID-19 during their admission, presenting severe respiratory complications and high in-hospital mortality. Apart from respiratory complications secondary to SARS-CoV-2, we also found statistically significant differences in other postoperative complications. The hospital stay increased by 3 days in the pandemic group. CONCLUSIONS: Patients who underwent radical cystectomy at our center during the first wave of the COVID-19 pandemic had a higher number and severity of respiratory and non-respiratory complications. Discontinuation of the ERAS protocol was the main difference in treatment between groups.

Clinical impact of the suspension of the ERAS protocol on patients undergoing radical cystectomy during the COVID-19 pandemic.

INTRODUCTION: During the beginning of the COVID-19 pandemic in our center, neither prehabilitation nor multimodal rehabilitation could be applied due to the excessive patient load on the health system and to reduce SARS-CoV-2 transmission. The objective of our study was to analyze the evolution, complications, and survival up to one year of patients who underwent radical cystectomy in our hospital from March 1st to May 31st, 2020 (period of the first wave COVID-19 pandemic in Spain). We also compared the results with cystectomized patients outside the pandemic period and with application of the ERAS (Enhanced Recovery After Surgery) protocol. MATERIAL AND METHODS: Single-center, retrospective cohort study of patients scheduled for radical cystectomy from March 1st, 2020 to May 31st, 2020. They were matched with previously operated patients using a 1:2 propensity matching score. The matching variables were demographic data, preoperative and intraoperative clinical conditions. RESULTS: A total of 23 radical cystectomies with urinary diversion were performed in the period described. In none of the cases the prehabilitation or the follow-up of our ERAS protocol could be applied, and this was the only difference we found between the 2 groups. Although the minimally invasive approach was more frequent in the pandemic group, the difference was not statistically significant. Three patients were diagnosed with COVID-19 during their admission, presenting severe respiratory complications and high in-hospital mortality. Apart from respiratory complications secondary to SARS-CoV-2, we also found statistically significant differences in other postoperative complications. The hospital stay increased by 3 days in the pandemic group. CONCLUSIONS: Patients who underwent radical cystectomy at our center during the first wave of the COVID-19 pandemic had a higher number and severity of respiratory and non-respiratory complications. Discontinuation of the ERAS protocol was the main difference in treatment between groups.

Recommendations on the use of azole antifungals in hematology-oncology patients.

The administration of antifungals for therapeutic and, especially, prophylactic purposes is virtually a constant in patients requiring hematology-oncology treatment. Any attempt to prevent or treat Aspergillus or Mucor infections requires the administration of some drugs in the azole group, which include voriconazole, posaconazole and isavuconazole, noted for their activity against these pathogens. One very relevant aspect is the potential risk of interaction when associated with one of the antineoplastic drugs used to treat hematologic tumors, with serious complications. In this regard, acalabrutinib, bortezomib, bosutinib, carfilzomib, cyclophosphamide, cyclosporine A, dasatinib, duvelisib, gilteritinib, glasdegib, ibrutinib, imatinib, nilotinib, ponatinib, prednisone, ruxolitinib, tacrolimus, all-transretinoic acid, arsenic trioxide, venetoclax, or any of the vinca alkaloids, are very clear examples of risk, in some cases because their clearance is reduced and in others because of increased risk of QTc prolongation, which is particularly evident when the drug of choice is voriconazole or posaconazole.

Real-world evidence from a European cohort study of patients with treatment resistant depression: Healthcare resource utilization.

BACKGROUND: Treatment resistant depression (TRD) is diagnosed when patients experiencing a major depressive episode fail to respond to ≥2 treatments. Along with substantial indirect costs, patients with TRD have higher healthcare resource utilization (HCRU) than other patients with depression. However, research on the economic impact of this HCRU, and differences according to response to treatment, is lacking. METHODS: This multicenter, observational study documented HCRU among patients with TRD in European clinical practice initiating new antidepressant treatments. Data regarding access to outpatient consultations and other healthcare resources for the first 6 months, collected using a questionnaire, were analyzed qualitatively according to response and remission status. The economic impact of HCRU, estimated using European costing data, was analyzed quantitatively. RESULTS: Among 411 patients, average HCRU was higher in non-responders, attending five times more general practitioner (GP) consultations and spending longer in hospital (1.7 versus 1.1 days) than responders. Greater differences were observed according to remission status, with non-remitters attending seven times more GP consultations and spending approximately three times longer in hospital (1.7 versus 0.6 days) than remitters. Consequently, the estimated economic impacts of non-responders and non-remitters were significantly greater than those of responders and remitters, respectively. LIMITATIONS: Key limitations are small cohort size, absence of control groups and generalizability to different healthcare systems. CONCLUSION: Patients with TRD, particularly those not achieving remission, have considerable HCRU, with associated economic impact. The costs of unmet TRD treatment needs are thus substantial, and treatment success is fundamental to reduce individual needs and societal costs.

[Risk factors for postoperative acute kidney injury in a cohort of 2378 patients from 59 hospitals]. / Factores de riesgo de insuficiencia renal aguda postoperatoria. Análisis en una cohorte de 2.378 pacientes de 59 hospitales.

OBJECTIVES: To assess risk factors for postoperative acute kidney injury (AKI) in adults with normal renal function hospitalized for major surgery. To analyze mortality and length of hospital stay in patients who develop postoperative AKI. PATIENTS AND METHODS: Data for analysis were drawn from the 2006 ARISCAT study. The dependent variable was postoperative AKI defined as a decline in renal function demonstrated by a rise in plasma creatinine level to twice the baseline measurement or a 50% reduction in the glomerular filtration rate. Bivariate and multivariate analyses were used to identify preoperative and intraoperative risk factors. RESULTS: We analyzed 2378 of the ARISCAT cases, which had been enrolled from 59 participating hospitals; 25 patients (1.1%) developed AKI. Analysis identified 5 risk factors: age, peripheral arterial disease, type of surgical incision, blood loss, and infusion of colloids. The area under the receiver operating characteristic curve was 0.88% (95% confidence interval, 0.79%-0.69%). Duration of hospital stay was longer for patients with postoperative AKI (21.8 days, vs 5.5 days for other patients; P=.007). Mortality was higher in patients with AKI at 30 days (36% vs 0.9%) and at 3 months (48% vs 1.7%). CONCLUSIONS: The incidence of postoperative AKI was slightly over 1%. Knowledge of postoperative AKI risk factors can facilitate the planning of surgical interventions and anesthesia to reduce subsequent morbidity and mortality and length of hospital stay.

Real-world evidence from a European cohort study of patients with treatment resistant depression: Baseline patient characteristics.

BACKGROUND: Treatment resistant depression (TRD; failure to respond to ≥2 treatments) affects ~20% of patients with major depressive disorder (MDD). Real-world data could help describe patient characteristics and TRD disease burden, to assess the unmet needs of TRD patients in Europe. METHODS: This observational study collected data from adults with moderate to severe TRD initiating a new treatment for depression, according to local standards of care. At baseline, socio-demographic characteristics, medical history, prior and current treatments were recorded. Disease severity, health-related quality of life (HRQoL), functionality and productivity were assessed. RESULTS: Overall, 411 eligible patients were enrolled across seven European countries. Mean (standard deviation [SD]) patient age was 51.0 (10.8) years; 62.3% were female. Long-term sick leave was reported by 19.0% of patients; 30.2% were unemployed. The mean (SD) duration of the current episode was 2.6 (3.9) years. At baseline, mean (SD) HRQoL scores for EuroQoL 5-dimension 5-level (UK tariff) and EQ-Visual Analog Scale were 0.41 (0.25) and 41.1 (18.7), respectively. The Work Productivity and Activity Impairment questionnaire demonstrated mean (SD) absenteeism of 57.0% (44.9%) and presenteeism of 54.7% (29.5%); mean (SD) overall work impairment was 60.5% (29.9%). LIMITATIONS: Key limitations are small cohort size, absence of a control group and generalizability to countries with different healthcare models. CONCLUSIONS: TRD patients had a high disease burden, low HRQoL and reduced function and productivity, with a substantial proportion unable to work. This demonstrates an unmet treatment need in TRD patients that, if addressed, could reduce the heavy personal and societal burden.

Real-world evidence from a European cohort study of patients with treatment resistant depression: Treatment patterns and clinical outcomes.

BACKGROUND: Treatment resistant depression (TRD) characterizes a subgroup of 10-30% of patients with major depressive disorder, and is associated with considerable morbidity and mortality. A consensus treatment for TRD does not exist, which often leads to wide variations in treatment strategies. Real-world studies on treatment patterns and outcomes in TRD patients in Europe are lacking and could help elucidate current treatment strategies and their efficacy. METHODS: This non-interventional cohort study of patients with TRD (defined as treatment failure on ≥2 oral antidepressants given at adequate dose and duration) with moderate to severe depression collected real-world data on treatment patterns and outcomes in several European countries. Patients were started on a new treatment for depression according to routine clinical practice. RESULTS: Among 411 patients enrolled, after 6 months, only 16.7% achieved remission and 73.5% showed no response. At Month 12, while 19.2% achieved remission and 69.2% showed no response, 33.3% of those in remission at Month 6 were no longer in remission. Pharmacological treatments employed were heterogenous; 54 different drugs were recorded at baseline, and the top 5 treatment types according to drug classes accounted for 40.0% of patients. Even though remission rates were very low, at Month 12, 60.0% of patients had not changed treatment since enrolment. CONCLUSIONS: The heterogeneity of treatments highlights a lack of consensus. Moreover, despite low response rates, patients often remained on treatments for substantial periods of time. These data further support existence of an unmet treatment need for TRD patients in Europe.

Effect of Two Unique Nanoparticle Formulations on the Efficacy of a Broadly Protective Vaccine Against Pseudomonas Aeruginosa.

Pseudomonas aeruginosa is an opportunistic pathogen responsible for a wide range of infections in humans. In addition to its innate antibiotic resistance, P. aeruginosa is very effective in acquiring resistance resulting in the emergence of multi-drug resistance strains and a licensed vaccine is not yet available. We have previously demonstrated the protective efficacy of a novel antigen PaF (Pa Fusion), a fusion of the type III secretion system (T3SS) needle tip protein, PcrV, and the first of two translocator proteins, PopB. PaF was modified to provide a self-adjuvanting activity by fusing the A1 subunit of the heat-labile enterotoxin from Enterotoxigenic E. coli to its N-terminus to give L-PaF. In addition to providing protection against 04 and 06 serotypes of P. aeruginosa, L-PaF elicited opsonophagocytic killing and stimulated IL-17A secretion, which have been predicted to be required for a successful vaccine. While monomeric recombinant subunit vaccines can be protective in mice, this protection often does not transfer to humans where multimeric formulations perform better. Here, we use two unique formulations, an oil-in-water (o/w) emulsion and a chitosan particle, as well as the addition of a unique TLR4 agonist, BECC438 (a detoxified lipid A analogue designated Bacterial Enzymatic Combinatorial Chemistry 438), as an initial step in optimizing L-PaF for use in humans. The o/w emulsion together with BECC438 provided the best protective efficacy, which correlated with high levels of opsonophagocytic killing and IL-17A secretion, thereby reducing the lung burden among all the vaccinated groups tested.

SEDAR-SEMICYUC consensus recommendations on the management of haemostasis disorders in severely ill patients with COVID-19 infection. / Recomendaciones de consenso SEDAR-SEMICYUC sobre el manejo de las alteraciones de la hemostasia en los pacientes graves con infección por COVID-19.

The infection by the coronavirus SARS-CoV-2, which causes the disease called COVID-19, mainly causes alterations in the respiratory system. In severely ill patients, the disease often evolves into an acute respiratory distress syndrome that can predispose patients to a state of hypercoagulability, with thrombosis at both venous and arterial levels. This predisposition presents a multifactorial physiopathology, related to hypoxia as well as to the severe inflammatory process linked to this pathology, including the additional thrombotic factors present in many of the patients. In view of the need to optimise the management of hypercoagulability, the working groups of the Scientific Societies of Anaesthesiology-Resuscitation and Pain Therapy (SEDAR) and of Intensive, Critical Care Medicine and Coronary Units (SEMICYUC) have developed a consensus to establish guidelines for actions to be taken against alterations in haemostasis observed in severely ill patients with COVID-19. These recommendations include prophylaxis of venous thromboembolic disease in these patients, and in the peripartum, management of patients on long-term antiplatelet or anticoagulant treatment, bleeding complications in the course of the disease, and the interpretation of general alterations in haemostasis.

Host immune genetic variations influence the risk of developing acute myeloid leukaemia: results from the NuCLEAR consortium.

The purpose of this study was to conduct a two-stage case control association study including 654 acute myeloid leukaemia (AML) patients and 3477 controls ascertained through the NuCLEAR consortium to evaluate the effect of 27 immune-related single nucleotide polymorphisms (SNPs) on AML risk. In a pooled analysis of cohort studies, we found that carriers of the IL13rs1295686A/A genotype had an increased risk of AML (PCorr = 0.0144) whereas carriers of the VEGFArs25648T allele had a decreased risk of developing the disease (PCorr = 0.00086). In addition, we found an association of the IL8rs2227307 SNP with a decreased risk of developing AML that remained marginally significant after multiple testing (PCorr = 0.072). Functional experiments suggested that the effect of the IL13rs1295686 SNP on AML risk might be explained by its role in regulating IL1Ra secretion that modulates AML blast proliferation. Likewise, the protective effect of the IL8rs2227307 SNP might be mediated by TLR2-mediated immune responses that affect AML blast viability, proliferation and chemorresistance. Despite the potential interest of these results, additional functional studies are still warranted to unravel the mechanisms by which these variants modulate the risk of AML. These findings suggested that IL13, VEGFA and IL8 SNPs play a role in modulating AML risk.

[Hypertension and anesthesia: consensus statement of the Catalan Associations of Anesthesiology and Hypertension]. / Documento de Consenso sobre Hipertensión Arterial y Anestesia de las Sociedades Catalanas de Anestesiología e Hipertensión Arterial.

The prevalence of hypertension is high in the surgical population. Differing practices and the absence of consensus among physicians involved in caring for hypertensive patients has made it one of the most frequent reasons for cancelling scheduled surgery. The aim of this consensus statement is to outline a practical approach to managing the hypertensive surgical patient. Hypertension is associated with increased risk of perioperative complications, particularly those related to systemic effects and notable fluctuations in blood pressure during surgery. Preoperative assessment should center on a search for signs and symptoms of target organ damage. The anesthesiologist should seek to reduce perioperative fluctuations in arterial pressure, particularly guarding against sustained hypotension. After surgery, antihypertensive medication should be resumed as soon as possible.

Gender differences in C-reactive protein and homocysteine modulation of cognitive performance and real-world functioning in bipolar disorder.

BACKGROUND: Cognitive and psychosocial impairment has been associated with increased levels of C-reactive protein (CRP) and homocysteine in bipolar disorder, but gender differences have seldom been studied. METHODS: Two hundred and twenty-four bipolar outpatients were included. Cognitive performance was assessed through the Screen for Cognitive Impairment in Psychiatry (SCIP). Psychosocial functioning was evaluated using the Functioning Assessment Short Test (FAST) and the General Assessment of Functioning (GAF). Homocysteine and CRP levels were determined. Separate analyses were performed by gender. Partial correlations were calculated to test for associations between biomarkers and cognitive and psychosocial functioning. Hierarchical multiple regression was used to assess factors predicting cognitive and psychosocial functioning. Covariates were: age, education, duration of illness, hospital admissions, depressive symptoms, tobacco consumption, and BMI. RESULTS: A better performance was noted in women in delayed verbal learning (p = 0.010), along with better occupational functioning (p = 0.027) and greater leisure time impairment (p = 0.034). In men, CRP and homocysteine levels were associated with psychosocial dysfunction (interpersonal relationships and financial functioning, respectively). In women, CRP levels correlated with cognitive performance (SCIP total raw score, immediate and delayed verbal learning, and verbal fluency). CRP was a predictor of cognitive performance in women only. LIMITATIONS: The choice of the cognitive scale and covariates and the lack of a control group may be the main limitations. CONCLUSIONS: A gender difference was found in biomarker modulation of cognition and psychosocial functioning. A gender-based approach to cognition and real-world functioning should be considered in bipolar disorder to ensure an optimal outcome.