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Objectives: To assess if baseline iron deficiency, with or without anemia, is associated with incident infections over 3 years among community-dwelling older adults.Design: Prospective secondary analysis of DO-HEALTH, a 3-year randomized, double-blind controlled trial.Setting And Participants: 2157 community-dwelling adults age 70+ from 5 European countries with good cognitive function and mobility and no major health events in the 5 years prior to enrollment Measurements: Incident infections, their severity and type were recorded every 3 months throughout the 3-year follow-up. Iron deficiency was defined as soluble transferrin receptor (sTfR) levels > 28.1 nmol/l and anemia as hemoglobin levels < 120 g/l for women and 130 g/l for men. We applied negative binomial mixed effects regression models with random effects for countries, and controlling for treatment allocation, age, sex, body mass index, polypharmacy, number of comorbidities, smoking status, living situation, alcohol intake, frailty status, and physical activity levels. A pre-defined stratified analysis was performed to explore if the associations between iron deficiency and infections were consistent by baseline anemia status.Results: In total, 2141 participants were included in the analyses (mean age 74.9 years, 61.5% of women, 26.8% with iron deficiency). Across all participants, baseline iron deficiency was not associated with incident overall infections, but was associated with a 63% greater rate of incident severe infections requiring hospitalization (incidence rate ratio [IRR] 1.63, 95% Confidence Interval [CI] 1.11–2.41, p=0.01). This association was more pronounced among the 2000 participants who did not have anemia at baseline (IRR=1.80, 95% CI 1.20–2.69, p=0.005).Conclusion: Based on this prospective study among generally healthy European community-dwelling older adults, iron deficiency was not associated with the incidence rate of overall infections but may increase the incidence of severe infections. Intervention studies are needed to prove the causality of this observation.

BACKGROUND Current guidelines favor transcatheter aortic valve implantation (TAVI) over surgical aortic valve replacement in patients with porcelain aorta (PAo). The clinical relevance of PAo in patients undergoing TAVI is however incompletely understood. The purpose of this study is to evaluate clinical outcome of patients with PAo undergoing TAVI. METHODS Consecutive patients undergoing TAVI were enrolled in a prospective single-center registry. Presence of PAo was evaluated by ECG-gated multi-slice computed tomography prior to the intervention. The primary endpoint was disabling stroke. RESULTS Among 2199 patients (mean age, 82.0������������6.3 years; 1135 females [51.6%]) undergoing TAVI between August 2007 and December 2019, 114 patients (5.2%) met VARC-2 criteria for PAo. Compared to individuals without PAo, patients with PAo were younger (79.4������������7.4 years vs. 82.1������������6.2 years; p�����

ERG is a transcription factor encoded on chromosome 21q22.2 with important roles in hematopoiesis and oncogenesis of prostate cancer. ERG amplification has been identified as one of the most common recurrent events in acute myeloid leukemia with complex karyotype (AML-CK). In this study, we uncover three different modes of ERG amplification in AML-CK. Importantly, we present evidence to show that ERG amplification is distinct from intrachromosomal amplification of chromosome 21 (iAMP21), a hallmark segmental amplification frequently encompassing RUNX1 and ERG in a subset of high-risk B-lymphoblastic leukemia. We also characterize the association with TP53 aberrations and other chromosomal aberrations, including chromothripsis. Lastly, we show that ERG amplification can initially emerge as subclonal events in low-grade myeloid neoplasms. These findings demonstrate that ERG amplification is a recurrent secondary driver event in AML and raise the tantalizing possibility of ERG as a therapeutic target.

BACKGROUND Definitions of periprocedural myocardial infarction (MI) differ with respect to biomarker threshold as well as ancillary criteria for myocardial ischemia and are limited in terms of validation. OBJECTIVES This study evaluated the frequency and impact of periprocedural MI by using various MI definitions among patients with chronic coronary syndrome (CCS) undergoing percutaneous coronary intervention (PCI). METHODS Between 2010 and 2018, periprocedural MIs were assessed according to the third and fourth Universal Definition of Myocardial Infarction (UDMI), Academic Research Consortium-2 (ARC-2), and Society for Cardiovascular Angiography and Interventions (SCAI) criteria based on high-sensitivity troponin in patients with CCS undergoing PCI enrolled into the Bern PCI registry. The primary endpoint was cardiac death at 1 year. RESULTS Among 4,404 patients with CCS, periprocedural MI defined by the third UDMI, fourth UDMI, ARC-2, and SCAI were observed in 18.0%, 14.9%, 2.0%, and 2.0% of patients, respectively. Among patients with periprocedural MI defined by the third UDMI, fourth UDMI, ARC-2, and SCAI, cardiac mortality at 1 year was 2.9%, 3.0%, 5.8%, and 10.0%. The ARC-2 (HR: 3.90; 95%��CI: 1.54-9.93) and SCAI (HR: 7.66; 95%��CI: 3.64-16.11) were more relevant compared with the third UDMI (HR: 1.76; 95%��CI: 1.04-3.00) and fourth UDMI (HR: 1.93; 95%��CI: 1.11-3.37) for cardiac death at 1 year. CONCLUSIONS Among patients with CCS undergoing PCI, periprocedural MI defined according to the ARC-2 and SCAI criteria was 7 to 9 times less frequent compared with the third and fourth UDMI. Periprocedural MI defined by using the��ARC-2 and SCAI were more prognostic for cardiac death at 1 year compared with the third and fourth UDMI. (CARDIOBASE Bern PCI Registry; NCT02241291).

BACKGROUND The role of direct oral anticoagulants as compared with vitamin K antagonists for atrial fibrillation after successful transcatheter aortic-valve replacement (TAVR) has not been well studied. METHODS We conducted a multicenter, prospective, randomized, open-label, adjudicator-masked trial comparing edoxaban with vitamin K antagonists in patients with prevalent or incident atrial fibrillation as the indication for oral anticoagulation after successful TAVR. The primary efficacy outcome was a composite of adverse events consisting of death from any cause, myocardial infarction, ischemic stroke, systemic thromboembolism, valve thrombosis, or major bleeding. The primary safety outcome was major bleeding. On the basis of a hierarchical testing plan, the primary efficacy and safety outcomes were tested sequentially for noninferiority, with noninferiority of edoxaban established if the upper boundary of the 95% confidence interval for the hazard ratio did not exceed 1.38. Superiority testing of edoxaban for efficacy would follow if noninferiority and superiority were established for major bleeding. RESULTS A total of 1426 patients were enrolled (713 in each group). The mean age of the patients was 82.1 years, and 47.5% of the patients were women. Almost all the patients had atrial fibrillation before TAVR. The rate of the composite primary efficacy outcome was 17.3 per 100 person-years in the edoxaban group and 16.5 per 100 person-years in the vitamin K antagonist group (hazard ratio, 1.05; 95% confidence interval [CI], 0.85 to 1.31; P���=���0.01 for noninferiority). Rates of major bleeding were 9.7 per 100 person-years and 7.0 per 100 person-years, respectively (hazard ratio, 1.40; 95% CI, 1.03 to 1.91; P���=���0.93 for noninferiority); the difference between groups was mainly due to more gastrointestinal bleeding with edoxaban. Rates of death from any cause or stroke were 10.0 per 100 person-years in the edoxaban group and 11.7 per 100 person-years in the vitamin K antagonist group (hazard ratio, 0.85; 95% CI, 0.66 to 1.11). CONCLUSIONS In patients with mainly prevalent atrial fibrillation who underwent successful TAVR, edoxaban was noninferior to vitamin K antagonists as determined by a hazard ratio margin of 38% for a composite primary outcome of adverse clinical events. The incidence of major bleeding was higher with edoxaban than with vitamin K antagonists. (Funded by Daiichi Sankyo; ENVISAGE-TAVI AF ClinicalTrials.gov number, NCT02943785.).

Objective This study aimed to examine the factor structure, reliability, inter-rater agreement and convergent validity of the child and parent Italian versions of the paediatric quality of life inventory multidimensional fatigue scale (PedsQL-MFS) in paediatric inpatients with obesity and one of their parents. Methods 100 pairs of children/adolescents (64% female, mean age = 15.34) with obesity and one of their parents completed the PedsQL-MFS and the Child Behaviour Checklist (CBCL) or the Youth Self Report. Results Conirmatory Factor Analysis indicated that the three correlated irst-order factors model corresponding to the published subscales demonstrated acceptable it and achieved strict invariance across parent and child informants. Bifactor Analysis supported the multidimensionality and the reliability of the total and subscale scores as multidimensional composites. Parent–child agreement was low with latent means higher for parent reports. PedsQL-MFS total scores were strongly correlated with Somatic Complaints scores on the CBCL, and moderately associated with anxiety, depression, social problems and school problems. Conclusions Total scores of the child and parent Italian versions of the PedsQL-MFS demonstrated good reliability and convergent validity in paediatric inpatients with obesity and their parents, and are complementary rather than interchangeable. &nbsp

Objective Transplantation of minor salivary glands (MSGs) to the conjunctiva is a treatment option for patients suffering from dry eye disease. As there is not enough information about labial and buccal MSGs in dogs, the aim of this study was to provide evidence of the presence of these glands and to investigate their spatial arrangement and excretory ducts. Methods The oral mucosa of the lower lip of 4 dogs and the whole lower jaw of 1 dog were used for histological and microCT analysis. Presence, number, volumes and the tissue depth of MSGs were assessed. Results Histological analysis showed that compact tubulo‐acinar glands were located in the submucosal connective tissue. MicroCT images revealed that 9 to 21 MSGs were arranged in a single row at the level of the dental alveolae. The volume of the MSGs increased from rostral to caudal and the total volume of glandular tissue per animal ranged from 35.01 mm3 to 549.43 mm3. The mean tissue depth of MSGs ranged from 0.57 mm to 1.37 mm (upper surface of glands) and between 1.43 mm and 3.09 mm (lower surface of the glands). Excretory ducts left the dorsal part of the glands and ran in dorso‐rostral direction. Conclusions The location, number and volume of the labial and buccal MSGs in the dog could be detected and described using microCT scans and histology. The present results can provide valuable information for future transplantation of labial MSGs as therapeutic measure against keratoconjunctivitis sicca.

BACKGROUND Dragonfly and damselfly larvae have been considered as possible biocontrol agents against young instars of mosquito vectors in urban environments. Yet our knowledge about adult odonate predation against mosquito adults is scarce. We quantified daily and annual predation rates, consumption rates and prey preferences of adult Hetaerina vulnerata male damselflies in an urban park. A focus on predation of mosquito species was provided, quantified their arbovirus (dengue, chikungunya and Zika) infection rates and biting activity. RESULTS Foraging times of H. vulnerata overlapped with those of the maximum activity of hematophagous mosquitoes. The most consumed preys were Diptera and Hymenoptera and, in lower quantities, Hemiptera, Coleoptera, Trichoptera, Psocoptera and Neuroptera. Of note, 7% of the diet was represented by hematophagous dipterans, with 2.4% being Aedes aegypti and Aedes albopictus. Prey abundance in the diet coincided with that of the same species in the environment. The arboviral infection rate (dengue, chikungunya and Zika) was 1.6% for A. aegypti and A. albopictus. The total biting rate of these mosquito vectors was 16 bites per person per day, while the annual rate of infectious bites was 93.4. CONCLUSION Although 2.4% for both Aedes species seems a low consumption, considering the presence of 12 odonate species at the park, it can be argued that adult odonates may play a relevant role as mosquito vector regulators, therefore impacting the spread of mosquito-borne diseases. Our study outlines the need for further research on the topic of the possible role of adult odonates for mosquito biocontrol. © 2021 Society of Chemical Industry.

BACKGROUND Coronary access after transcatheter aortic valve replacement (TAVR) can be challenging and complicate percutaneous coronary intervention (PCI). AIMS We aimed to investigate the incidence, characteristics, and predictors of unplanned PCI after TAVR. METHODS In a single-centre registry, TAVR candidates were systematically screened for concomitant coronary artery disease (CAD) through the use of coronary angiography prior to TAVR. Rates of unplanned PCI were prospectively collected and independently adjudicated. RESULTS Among 3,015 patients undergoing TAVR between August 2007 and December 2020, 67 patients (2.2%) underwent unplanned PCI after TAVR. The indication for unplanned PCI was acute coronary syndrome in more than half of the cases. Patients with unplanned PCI were younger (80.2±6.5 years vs 81.9±6.4 years; p=0.028) and more likely to be male (75% vs 50%; p

Importance Noncardiac surgery after transcatheter aortic valve implantation (TAVI) is a clinical challenge with concerns about safety and optimal management. Objectives To evaluate perioperative risk of adverse events associated with noncardiac surgery after TAVI by timing of surgery, type of surgery, and TAVI valve performance. Design, Setting, and Participants This cohort study was conducted using data from a prospective TAVI registry of patients at the tertiary care University Hospital in Bern, Switzerland. All patients undergoing noncardiac surgery after TAVI were identified. Data were analyzed from November through December 2021. Exposures Timing, clinical urgency, and risk category of noncardiac surgery were assessed among patients who had undergone TAVI and subsequent noncardiac surgery. Main Outcomes and Measures A composite of death, stroke, myocardial infarction, and major or life-threatening bleeding within 30 days after noncardiac surgery. Results Among 2238 patients undergoing TAVI between 2013 and 2020, 300 patients (mean [SD] age, 81.8 [6.6] years; 144 [48.0%] women) underwent elective (160 patients) or urgent (140 patients) noncardiac surgery after TAVI and were included in the analysis. Of these individuals, 63 patients (21.0%) had noncardiac surgery within 30 days of TAVI. Procedures were categorized into low-risk (21 patients), intermediate-risk (190 patients), and high-risk (89 patients) surgery. Composite end points occurred within 30 days of surgery among 58 patients (Kaplan-Meier estimate, 19.7%; 95% CI, 15.6%-24.7%). There were no significant differences in baseline demographics between patients with the 30-day composite end point and 242 patients without this end point, including mean (SD) age (81.3 [7.1] years vs 81.9 [6.5] years; P = .28) and sex (25 [43.1%] women vs 119 [49.2%] women; P = .37). Timing (ie, ≤30 days from TAVI to noncardiac surgery), urgency, and risk category of surgery were not associated with increased risk of the end point. Moderate or severe prosthesis-patient mismatch (adjusted hazard ratio [aHR], 2.33; 95% CI, 1.37-3.95; P = .002) and moderate or severe paravalvular regurgitation (aHR, 3.61; 95% CI 1.25-10.41; P = .02) were independently associated with increased risk of the end point. Conclusions and Relevance These findings suggest that noncardiac surgery may be performed early after successful TAVI. Suboptimal device performance, such as prosthesis-patient mismatch and paravalvular regurgitation, was associated with increased risk of adverse outcomes after noncardiac surgery.

Advanced in vitro kidney models are of great importance to the study of renal physiology and disease. Kidney tubuloids can be established from primary cells derived from adult kidney tissue or urine. Tubuloids are three-dimensional multicellular structures that recapitulate tubular function and have been used to study infectious, malignant, metabolic, and genetic diseases. For tubuloids to more closely represent the in vivo kidney, they can be integrated into an organ-on-a-chip system that has a more physiological tubular architecture and allows flow and interaction with vasculature or epithelial and mesenchymal cells from other organs. Here, we describe a detailed protocol for establishing tubuloid cultures from tissue and urine (1-3 weeks), as well as for generating and characterizing tubuloid cell-derived three-dimensional tubular structures in a perfused microfluidic multi-chip platform (7 d). The combination of the two systems yields a powerful in vitro tool that better recapitulates the complexity of the kidney tubule with donor-specific properties.

Supplemental Digital Content is available in the text., Background: Female sex is an independent risk factor for stroke and systemic embolic events in patients with atrial fibrillation. This study aimed to examine the efficacy and safety profile of edoxaban in women versus men. Methods: The ENGAGE AF-TIMI 48 trial (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) randomly assigned 21 105 patients (8040 women) with atrial fibrillation and CHADS2 score ≥2 either to a higher-dose edoxaban regimen, a lower-dose edoxaban regimen, or warfarin. The primary end points of the trial were the composite of stroke or systemic embolic events (efficacy), and International Society on Thrombosis and Haemostasis–defined major bleeding (safety). Results: In comparison with men, women were older, had lower body weight, were more likely to have hypertension and renal dysfunction, but less likely to smoke, drink alcohol, or have diabetes or coronary artery disease. Pretreatment endogenous factor Xa activity was significantly higher in women than in men (92.5% versus 86.1%, P

Cyclophosphamide (CYC) is an alkylating agent with immunosuppressive effect by inhibiting DNA synthesis and producing apoptosis used in many autoimmune diseases, including multiple sclerosis (MS). Here, we analyze the efficacy of CYC treatment in relapsing-remitting (RRMS) and active secondary progressive MS (SPMS) in our center with a monthly scheme. Patients with MS treated with CYC and a follow up of at least 36 months were eligible for inclusion. All participants had received a standard CYC regimen. The EDSS score mean annualized relapse rate (ARR) and progression index (PI) were measured as efficacy outcomes at 12, 24, and 36 months. Outcomes were also analyzed comparing disease course and activity. A total of 16 patients were included (50% male, 18.75% RRMS and 81.25% SPMS). EDSS remained stable along the follow-up period, with 62.5% improving or maintaining the same EDSS score at 12 months. PI decreased 14% and 21% at 12 and 24–36 months of follow-up, respectively. ARR decreased 20% after 12 months, 19% after 24 months, and 30.23% after 36 months. Median differences in ARR were higher in patients with high relapse activity (0.60 vs 0.07, p = 0.001) and malignant course (0.60 vs 0.17, p = 0.027). PI also differed with higher mean differences in patients with high relapse activity (0.70 vs 0.03, p = 0.016) and malignant course (1.17 vs 0.03, p = 0.003). CYC continues to be a valid therapeutic option, especially in regions with limited access to high-efficiency therapies particularly in patients with high relapsing activity and malignant course.

The ACROBAT pilot trial of early cryoprecipitate for severe postpartum haemorrhage used deferred consent procedures. Pretrial discussions with a patient and public involvement group found mixed views towards deferred consent. This study aimed to build an understanding of how the deferred consent procedures worked in practice, to inform plans for a full-scale trial.Qualitative interview study within a cluster-randomised pilot trial, involving four London maternity services.Individual interviews were conducted postnatally with 10 women who had received blood transfusion for severe postpartum haemorrhage and had consented to the trial. We also interviewed four 'recruiters'-two research midwives and two clinical trials practitioners who conducted trial recruitment.Consent procedures in the ACROBAT pilot trial were generally acceptable and the intervention was viewed as low risk, but most women did not remember much about the consent conversation. As per trial protocol, recruiters sought to consent women before hospital discharge, but this time pressure had to be balanced against the need to ensure women were not approached when distressed or very unwell. Extra efforts had to be made to communicate trial information to women due to the exhaustion of their recovery and competing demands for their attention. Participant information was further complicated by explanations about the cluster design and change in transfusion process, even though the consent sought was for access to medical data.Our findings indicate that deferred consent procedures raise similar concerns as taking consent when emergency obstetric research is occurring-that is, the risk that participants may conflate research with clinical care, and that their ability to process trial information may be impacted by the stressful nature of recovery and newborn care. A future trial may support more meaningful informed consent by extending the window of consent discussion and ensuring trial information is minimal and easy to understand.ISRCTN12146519.

BACKGROUND Volleyball is a complex intermittent sport characterized by short explosive technical movements, many of which involve vertical jumping. The assessment of mechanical jumping variables in relation to both injury prevention and performance enhancement through the use of wearable technologies is becoming a new training tool among professional volleyball players. METHODS The present study aimed to assess the vertical jumping mechanics before and after a controlled load (volume and intensity) of a routine volleyball training session among male professional players. Twelve male elite professional volleyball players (23.7 ± 4.9 years, 198.1 ± 6.2 cm, 92.2 ± 10.3 kg) of national and international level belonging to the same Brazilian first league team were recruited. Biomechanical analysis of vertical unilateral countermovement jump (CMJ) and bilateral CMJ tests were performed before and after a routine training session of these players at their usual training court. An inertial orientation sensor placed at the third lumbar vertebra was employed for biomechanical data collection. RESULTS In relation to the unilateral CMJ, a 10% decrease (p = 0.02) in the vertical ground reaction force after training compared to pre-training values was observed. However, no significant differences were observed in the remaining outcomes. Regarding the bilateral CMJ, no significant differences were observed in all assessed outcomes. CONCLUSIONS Our findings showed no evidence of fatigue after a controlled regular in season volleyball training session in professional players. In addition, this volleyball training session induced a significant reduction in the vertical ground reaction force during unilateral CMJ in volleyball players.

The mechanisms by which prenatal immune activation increase the risk for neuropsychiatric disorders are unclear. Here, we generated developmental cortical interneurons (cINs)-which are known to be affected in schizophrenia (SCZ) when matured-from induced pluripotent stem cells (iPSCs) derived from healthy controls (HCs) and individuals with SCZ and co-cultured them with or without activated microglia. Co-culture with activated microglia disturbed metabolic pathways, as indicated by unbiased transcriptome analyses, and impaired mitochondrial function, arborization, synapse formation and synaptic GABA release. Deficits in mitochondrial function and arborization were reversed by alpha lipoic acid and acetyl-L-carnitine treatments, which boost mitochondrial function. Notably, activated-microglia-conditioned medium altered metabolism in cINs and iPSCs from HCs but not in iPSCs from individuals with SCZ or in glutamatergic neurons. After removal of activated-microglia-conditioned medium, SCZ cINs but not HC cINs showed prolonged metabolic deficits, which suggests that there is an interaction between SCZ genetic backgrounds and environmental risk factors.

BACKGROUND Abnormal invasive hemodynamics after transcatheter aortic valve replacement (TAVR) is associated with poor survival; however, the mechanism is unknown. HYPOTHESIS Diastolic dysfunction will modify the association between invasive hemodynamics postTAVR and mortality. METHODS Patients with echocardiographic assessment of diastolic function and postTAVR invasive hemodynamic assessment were eligible for the present analysis. Diastology was classified as normal or abnormal (Stages 1 to 3). The aorto-ventricular index (AVi) was calculated as the difference between the aortic diastolic and the left ventricular end-diastolic pressure divided by the heart rate. AVi was categorized as abnormal (AVi

Introduction Chronic asthma is a heterogeneous disease, and increased eosinophils have been shown to predict increased asthma exacerbations, especially in adults. Recent recommendations suggest the need for supplemental PPV‐23 vaccination in older children with chronic asthma. Methods To investigate differences in preschool asthma, our case‐cohort study comprised of 127 children, mean age 47 months (32‐65), with a history of asthma exacerbations requiring more than three courses of systemic steroid bursts and more than six antibiotics courses in the previous year. Results At baseline, mean antibody titer response to Streptococcus pneumoniae was decreased at 2.6 ± 2 out of 14 serotypes, despite prior complete pneumococcal conjugate vaccine (PCV) vaccinations. All children were readministered pneumococcal vaccinations with PCV‐13 booster and/or PPSV‐23. Mean postvaccination pneumococcal vaccine (PV) titer response was 16 ± 5 out of 23 serotypes. After contacting 91 parents/caretakers, 75 responded with less frequency of corticosteroids and antibiotic use for asthma exacerbations after PV. This group had baseline eosinophil counts of 211 ± 36/µL, while those without improvement were significantly higher at 371 ± 123/µL,*P .05) between the two groups from other baseline measures including demography or atopic status. Conclusions This subset of children with exacerbation‐prone asthma had poor antibody titer response to Streptococcus pneumoniae, even with prior complete PCV‐13 immunization. Identification of low antibody responses to PV serotypes may provide a targeted therapeutic approach to reduce wheezing exacerbations in a precise asthma phenotype in children.

The phosphorylated form of LRRK2, pS935 LRRK2, has been proposed as a target modulation biomarker for LRRK2 inhibitors. The primary aim of the study was to characterize and qualify this biomarker for therapeutic trials of LRRK2 inhibitors in Parkinson's disease (PD). To this end, analytically validated assays were used to monitor levels of pS935 LRRK2 and total LRRK2 in peripheral blood mononuclear cells (PBMCs) from the following donor groups: healthy controls, idiopathic PD, and G2019S carriers with and without PD. Neither analyte correlated with age, gender, or disease severity. While total LRRK2 levels were similar across the four groups, there was a significant reduction in pS935 LRRK2 levels in disease-manifesting G2019S carriers compared to idiopathic PD. In aggregate, these data indicate that phosphorylation of LRRK2 at S935 may reflect a state marker for G2019S LRRK2-driven PD, the underlying biology for which requires investigation in future studies. This study also provides critical foundational data to inform the integration of pS935 and total LRRK2 levels as biomarkers in therapeutic trials of LRRK2 kinase inhibitors.

Four 2‐month‐old foals were presented to an equine hospital with acute kidney injury caused by Leptospira interrogans infection. Clinical signs were nonspecific and included lethargy, fever, and unwillingness to nurse. The most important hematologic and clinicopathologic findings were azotemia, anemia, thrombocytopenia, hyponatremia, and hypochloremia. The diagnosis was based on urinary real‐time PCR, serology using a microscopic agglutination test, or both. The most important serovars involved were L. interrogans serogroup australis serovar Bratislava and Australis. Treatment consisted of IV fluid therapy and antimicrobial treatment. Renal replacement therapy with hemodiafiltration was performed in 1 of the foals. All foals survived to discharge. This report highlights the importance of early diagnosis and treatment in foals with acute kidney injury caused by L. interrogans infection.

BACKGROUND Increased left ventricular afterload resulting from severe aortic stenosis (AS) leads to progressive cardiac remodeling. Left atrial enlargement (LAE) is an early manifestation in a series of maladaptive changes and may affect clinical outcomes after valvular replacement therapy. The aim of this study is to determine the impact of LAE on clinical outcomes in symptomatic patients with severe AS undergoing transcatheter aortic valve implantation (TAVI). METHODS In a prospective single-center TAVI registry, we analyzed LA dimensions measured by echocardiography before intervention. Patients with atrial fibrillation or concomitant mitral valve disease were excluded. LAE was defined as indexed LA volume >34���ml/m2 . The primary endpoint was cardiovascular death (CVD) at 1 year. RESULTS Among 1663 patients undergoing TAVI between August 2007 and December 2016, 768 (46.2%) were eligible for the present analysis and 486 patients had LAE. The prevalence of LAE was higher in males (68.3%) as compared to females (58.8%). Patients with LAE were older (82.3��������6.7 years vs. 80.0��������6.4 years) and had a higher STS-PROM score (6.1��������4.7% vs. 4.7��������2.9%). After adjustment, patients with LAE had an increased risk of CVD at 1-year compared to patients with normal LA dimensions (49 [10.4%] vs. 8 [2.9%]; HRadj , 3.52; 95% CI, 1.66-7.44)]. In multivariable analysis, LAE was independently associated with an increased risk of CVD at 1-year (HRadj , 3.52; 95% CI, 1.66-7.44). CONCLUSIONS LAE secondary to AS was documented in a significant proportion of patients undergoing TAVI and was associated with a more than threefold increased risk of CVD at 1-year.

Recombinant adeno-associated viruses (AAVs) have emerged as promising vectors for human gene therapy, but some variants have induced severe toxicity in Rhesus monkeys and piglets following high-dose intravenous (IV) administration. To characterize biodistribution, transduction, and toxicity among common preclinical species, an AAV9 neurotropic variant expressing the survival motor neuron 1 (

Background Female sex was not included among the high bleeding risk (HBR) criteria by the Academic Research Consortium (ARC) as it remains unclear whether it constitutes an HBR condition after percutaneous coronary intervention. We investigated whether female sex associates with HBR and assessed the performance of ARC HBR criteria separately in women and men. Methods and Results Among all consecutive patients undergoing percutaneous coronary intervention between 2009 and 2018, bleeding occurrences up to 1 year were prospectively collected and centrally adjudicated. All but one of the originally defined ARC HBR criteria were assessed, and the ARC HBR score generated accordingly. Among 16 821 patients, 25.6% were women. Compared with men, women were older and had lower creatinine clearance and hemoglobin values. After adjustment, female sex was independently associated with access‐site (adjusted hazard ratio, 2.14; 95% CI, 1.22–3.74; P =0.008) but not with overall or non–access‐site 1‐year Bleeding Academic Research Consortium 3 or 5 bleeding. This association remained consistent when the femoral but not the radial approach was chosen. The ARC HBR score discrimination, using the original criteria, was lower among women than men (c‐index 0.644 versus 0.688; P =0.048), whereas a revised ARC HBR score, in which age, creatinine clearance, and hemoglobin were modeled as continuous rather than dichotomized variables, performed similarly in both sexes. Conclusions Female sex is an independent predictor for access‐site bleeding but not for overall bleeding events at 1 year after percutaneous coronary intervention. The ARC HBR framework shows an overall good performance in both sexes, yet is lower in women than men, attributable to dichotomization of age, creatinine clearance, and hemoglobin values, which are differently distributed between sexes. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02241291.

BackgroundRheumatic heart disease (RHD) accounts for the highest number of deaths from valvular heart disease globally. Yet, rheumatic aortic stenosis (AS) was excluded from landmark studies investigating the safety and efficacy of transcatheter aortic valve implantation (TAVI). We aimed to describe the clinical and anatomical characteristics of patients with rheumatic AS undergoing TAVI, and to compare procedural and clinical outcomes with patients undergoing TAVI for degenerative AS.MethodsIn a prospective TAVI registry, patients with rheumatic AS were identified based on International Classification of Diseases version 10 codes and/or a documented history of acute rheumatic fever and/or the World Heart Federation criteria for echocardiographic diagnosis of RHD, and were propensity score-matched in a 1:4 ratio to patients with degenerative AS.ResultsAmong 2329 patients undergoing TAVI, 105 (4.5%) had rheumatic AS. Compared with patients with degenerative AS, patients with rheumatic AS were more commonly female, older, had higher surgical risk and more commonly suffered from multivalvular heart disease. In the unmatched cohort, both technical success (85.7% vs 85.9%, p=0.887) and 1-year cardiovascular mortality (10.0% vs 8.6%; HR 1.16, 95% CI 0.61 to 2.18, p=0.656) were comparable between patients with rheumatic and degenerative AS. In contrast, patients with rheumatic AS had lower rates of 30-day and 1-year cardiovascular mortality compared with matched patients with degenerative AS (1.9% vs 8.9%, adjusted HR (HRadj) 0.18, 95% CI 0.04 to 0.80, p=0.024; and 10.0% vs 20.3%, HRadj0.44, 95% CI 0.24 to 0.84, p=0.012, respectively).ConclusionTAVI may be a safe and effective treatment strategy for selected elderly patients with rheumatic AS.Trial registration numberNCT01368250.

Mitomycin C is the gold standard intravesical adjuvant therapy for intermediate-risk non-muscle-invasive bladder cancer (NMIBC). Tensions in the supply of mitomycin have emerged in France since late 2019. The ANSM in agreement with the AFU proposed to use epirubicin, already available in other European countries in this indication. The objective of our study was to report the initial French experience with the use of epirubicin in adjuvant treatment of NMIBC.We undertook a French multicenter retrospective descriptive study to collect, from the centers of the members of the CC-AFU bladder, the clinico-pathological data of the patients, the indications, the modalities of use (dose, indication, circuit in the pharmacy) and the tolerance data of epirubicin. The impact of the COVID-19 epidemic on treatment interruptions was also identified. Of the 20 centers contacted, 5 (25%) had implemented the epirubicin administration protocol developed by the CC-AFU bladder subcommittee. A total of 61 patients were treated with endovesical instillations of epirubicin between November 2019 and November 2020 for NMIBC at a single dose of 50mg.A total of 61 patients (mean age 67 years, 64-77 years) were treated with epirubicin, of which 45 (73.8%) were male. The patients had intermediate-risk NMIBC in 88.5%, the rest had high-risk disease. Induction therapy without or with maintenance was planned for 48 (78.7%) and 13 patients (21.3%), respectively. The preparation and administration of epirubicin was similar to that of mitomycin: central pharmacy preparation for same-day dispensing with immediate outpatient instillation. Unlike mitomycin, urinary alkalinization was not required. Of the 498 total instillations scheduled, 345 were performed (69.3%). The COVID-19 epidemic significantly impacted epirubicin delivery: one patient could not start treatment (1.6%), 8 patients (13.1%) had to discontinue it permanently; the rest of the patients underwent delayed instillations (18%). Other causes of discontinuation included infectious complications (9.8%). No major toxicities were reported.The implementation of an adjuvant epirubicin treatment protocol presented a good feasibility with low toxicity, without modifying the organization of the patients' care pathway. In the context of unpredictable mitomycin shortage, epirubicin represents a good therapeutic alternative in the endovesical adjuvant treatment of intermediate-risk NMIBC.3.

BackgroundCerebrovascular events (CVE) are one of the most feared complications of transcatheter aortic valve replacement (TAVR). CVE appear difficult to predict due to their multifactorial origin incompletely explained by clinical predictors. We aimed to build a deep learning-based predictive tool for TAVR-related CVE.MethodsIntegrated clinical and imaging characteristics from consecutive patients enrolled into a prospective TAVR registry were analysed. CVE comprised any strokes and transient ischemic attacks. Predictive variables were selected by recursive feature reduction to train an autoencoder predictive model. Area under the curve (AUC) represented the model’s performance to predict 30-day CVE.ResultsAmong 2,279 patients included between 2007 and 2019, both clinical and imaging data were available in 1,492 patients. Median age was 83 years and STS score was 4.6%. Acute (ConclusionsTAVR-related CVE can be estimated using a deep learning-based predictive algorithm. The model was implemented online for broad usage. (https://www.welcome.alviss.ai/#/cvecalculator).

Epidemiological studies reveal a link between osteoporosis and the risk of ischemic cardiovascular disease. We illustrate an association between coronary calcification and bone microarchitecture in older adults based on the SPAH study. This cross-sectional research comprised 256 individuals subjected to cardiac coronary computed tomography angiography (CCTA) for coronary artery calcification (CAC), high-resolution peripheral quantitative computed tomography (HR-pQCT) at the tibia and radius with standardized z score parameters, and dual-energy X-ray absorptiometry (DXA) to evaluate bone status. We used Student’s t test and the Mann–Whitney and Chi-squared tests for comparison of basal measurements. Association analysis was performed using the Poisson regression model with adjustment for CAC and sex. Multivariate analysis revealed different bone variables for predicting CAC in DXA and HR-pQCT scenarios. Although most of the bone parameters are related to vascular calcification, only cortical porosity (Ct.Po) remained uniform by HR-pQCT. Results for were as follows: the tibia—women (exp β = 1.12 (95% CI 1.10–1.13, p

Objectives To test two methods for reporting of fecal incontinence (FI) in people with inflammatory bowel disease. Methods Consecutive patients from IBD clinics in six UK hospitals completed a short three-item case-finding survey about FI; they either completed the survey themselves or were asked the same questions face to face by a clinician. Results Of 1336 eligible patients with complete data (48% male; mean 43 years; 55% Crohn’s disease, 41% ulcerative colitis), 772 were asked about FI face to face, and 564 self-completed the survey: FI was reported in 63% and 56%, respectively (p = 0.012). In regression analyses, those aged 51–60, having Crohn’s disease and higher disease activity, were more likely to report FI. Of all respondents, 38.7% were interested in receiving help for their incontinence. Conclusions Fecal incontinence affects the majority of people with IBD. Although more patients reported fecal incontinence when asked face to face than self-reported, routine screening by either method in clinical practice is recommended. Over one-third of patients with IBD want help for bowel control problems.

Iron and copper chelation restricts Plasmodium growth in vitro and in mammalian hosts. The parasite alters metal homeostasis in red blood cells to its favor, for example metabolizing hemoglobin to hemozoin. Metal interactions with the mosquito have not, however, been studied. Here, we describe the metallomes of Anopheles albimanus and Aedes aegypti throughout their life cycle and following a blood meal. Consistent with previous reports, we found evidence of maternal iron deposition in embryos of Ae. aegypti, but less so in An. albimanus. Sodium, potassium, iron, and copper are present at higher concentrations during larval developmental stages. Two An. albimanus phenotypes that differ in their susceptibility to Plasmodium berghei infection were studied. The susceptible white stripe (ws) phenotype was named after a dorsal white stripe apparent during larval stages 3, 4, and pupae. During larval stage 3, ws larvae accumulate more iron and copper than the resistant brown stripe (bs) phenotype counterparts. A similar increase in copper and iron accumulation was also observed in the susceptible ws, but not in the resistant bs phenotype following P. berghei infection. Feeding ws mosquitoes with extracellular iron and copper chelators before and after receiving Plasmodium-infected blood protected from infection and simultaneously affected follicular development in the case of iron chelation. Unexpectedly, the application of the iron chelator to the bs strain reverted resistance to infection. Besides a drop in iron, iron-chelated bs mosquitoes experienced a concomitant loss of copper. Thus, the effect of metal chelation on P. berghei infectivity was strain-specific., Author summary To establish a life cycle between insect and mammalian hosts, the malaria parasite has evolved mechanisms to manage metal ions from the distinct microenvironments it encounters. Previous work has addressed how interference using metal chelation affects parasite development in human, primate, and rodent hosts. Similar studies in mosquito species that harbor Plasmodium have not been performed. Here, we address such micronutrient relationships in three steps. First, we characterized how the metallome fluctuates during development in two species of mosquito. Second, we asked whether susceptibility to Plasmodium infection correlated with a differential response in mosquito metal homeostasis. Third, we tested the effects of iron and copper chelation treatment of adult mosquitoes concerning propensity of infection and mosquito reproduction. Metal ions offer a promising target in the ongoing efforts to control the mosquito-borne disease.

Objectives This study sought to compare the frequency of prosthesis-patient mismatch (PPM) with self-expandable valves (SEV) to balloon-expandable valves (BEV). Background PPM has been associated with increased mortality after transcatheter aortic valve replacement. Data on the frequency of PPM as a function of supra-annular or intra-annular position of transcatheter heart valves are insufficient. Methods A total of 757 patients treated with SEV (CoreValve, Evolut R) and BEV (SAPIEN THV/XT/3) were enrolled in the present analysis between August 2007 and June 2017. PPM was classified based on discharge prosthetic effective orifice area indexed to body surface area (BSA) as severe ( Results Propensity score matching resulted in 224 matched pairs. At discharge, SEV were associated with a lower incidence of PPM compared with BEV (PPM, 33.5% vs. 46.9%; p = 0.004; severe PPM, 6.7% vs. 15.6%; p = 0.003). The lower frequency of severe PPM in SEV was observed even in patients with larger annulus. Although patients with BSA >1.83 m2 had a significantly lower incidence of PPM with SEV compared with BEV, there was no significant difference in patients with BSA ≤1.83 m2. We found no impact of PPM on cardiovascular mortality or New York Heart Association functional class at 1 year. Conclusions SEV were associated with a lower frequency of PPM compared with BEV irrespective of annulus area. The difference was mainly driven by larger patients with BSA >1.83 m2.

Hypertension is a risk factor for both stroke and bleeding in patients with atrial fibrillation. Data are sparse regarding the interaction between blood pressure and the efficacy and safety of direct oral anticoagulants. In the ENGAGE AF-TIMI 48 trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48), 19,679 patients with atrial fibrillation and hypertension were categorized according to average systolic blood pressure (SBP) and diastolic blood pressure (DBP). The primary efficacy and safety end points were the time to the first stroke or systemic embolic event and the time to the first International Society of Thrombosis and Hemostasis major bleeding event, respectively. Risk was calculated using Cox proportional hazards models based on average SBP and DBP and adjusting for 18 clinical characteristics. The efficacy and safety of a higher dose edoxaban regimen (60/30 mg) versus warfarin were evaluated with stratification by average SBP and DBP. Stroke/systemic embolic event occurred significantly more frequently in patients with elevated average SBP (hazard ratio, 2.01; 95% CI, 1.50–2.70 for SBP ≥150 mm Hg relative to 130–139 mm Hg) or DBP (hazard ratio, 2.36; 95% CI, 1.76–3.16 for DBP ≥90 mm Hg relative to 75–P interaction =0.55) and DBP ( P interaction =0.44) compared with warfarin. The higher dose edoxaban regimen reduced the risk of major bleeding events, including intracranial hemorrhage, without modification by average SBP ( P interaction =0.29). The relative safety of edoxaban was most pronounced in patients with elevated DBP ( P interaction =0.007). The efficacy and safety of edoxaban were consistent across the full range of SBP, while the superior safety of edoxaban was most pronounced among patients with elevated DBP.

Objective: To compare healthcare resource utilization (HCRU), healthcare expenditures, and work productivity and activity impairment within a general asthma population with persistent asthma and ev...

Background Patients with liver disease have increased risk of thrombosis and bleeding but are typically excluded from trials of direct oral anticoagulant agents. Objectives This study evaluated the pharmacokinetics (PK), pharmacodynamics (PD), clinical efficacy and safety of edoxaban versus warfarin in patients with atrial fibrillation (AF) and history of liver disease. Methods ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis In Myocardial Infarction Study 48) was a randomized, double-blind trial comparing edoxaban with warfarin in patients with AF followed for 2.8 years. History of liver disease was defined as investigator-reported liver disease or >2-fold transaminase elevation at randomization. The primary efficacy and safety endpoints of stroke or systemic embolic event (SSEE) and major bleeding were assessed stratified by history of liver disease. PK/PD assessments of edoxaban included endogenous and extrinsic factor Xa activity and edoxaban concentration. Results Among 21,105 patients, 1,083 (5.1%) had a history of liver disease; they had a higher prevalence of many comorbidities. The adjusted risks of SSEE were similar (adjusted hazard ratio [HRadj]: 0.90; 95% confidence interval [CI]: 0.67 to 1.22; p = 0.50), but major bleeding was more common in patients with liver disease (HRadj: 1.38; 95% CI: 1.10 to 1.74; p = 0.005). There were no significant differences in PK/PD assessment of edoxaban in patients with versus without liver disease. The HRs for higher-dose edoxaban versus warfarin for SSEE were 0.86 (95% CI: 0.73 to 1.01) in patients without and 1.11 (95% CI: 0.54 to 2.30) with liver disease (p for interaction [pint] = 0.47), major bleeding 0.80 (95% CI: 0.70 to 0.91) in patients without and 0.91 (95% CI: 0.56 to 1.47) with liver disease (pint = 0.63). There were no significant differences in hepatic adverse events between the 2 treatment groups. Conclusions Among patients with AF receiving oral anticoagulation, bleeding, but not thromboembolic events, was increased in patients with liver disease. A history of liver disease did not alter the relative efficacy and safety of edoxaban compared with warfarin. Hepatic adverse events were similar between edoxaban and warfarin.

Psychiatric disorders such as schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD) arise from complex interactions between genetic and environmental factors. Common genetic variants associated with multiple psychiatric disorders suggest that shared genetic architecture could contribute to divergent clinical syndromes. To evaluate shared transcriptional alterations across connected brain regions, Affymetrix microarrays were used to profile postmortem dorsolateral prefrontal cortex (DLPFC), hippocampus, and associative striatum from 19 well-matched tetrads of subjects with SCZ, BD, MDD, or unaffected controls. SCZ subjects showed a substantial burden of differentially expressed genes across all examined brain regions with the greatest effects in hippocampus, whereas BD and MDD showed less robust alterations. Pathway analysis of transcriptional profiles compared across diagnoses demonstrated commonly enriched pathways between all three disorders in hippocampus, significant overlap between SCZ and BD in DLPFC, but no significant overlap of enriched pathways between disorders in striatum. SCZ samples showed increased expression of transcripts associated with inflammation across all brain regions examined, which was not evident in BD or MDD, or in rat brain following chronic dosing with antipsychotic drugs. Several markers of inflammation were confirmed by RT-PCR in hippocampus, including S100A8/9, IL-6, MAFF, APOLD1, IFITM3, and BAG3. A cytokine ELISA panel showed significant increases in IL-2 and IL-12p70 protein content in hippocampal tissue collected from same SCZ subjects when compared to matched control subjects. These data suggest an overlapping subset of dysregulated pathways across psychiatric disorders; however, a widespread increase in inflammation appears to be a specific feature of the SCZ brain and is not likely to be attributable to chronic antipsychotic drug treatment.

We generated cortical interneurons (cINs) from induced pluripotent stem cells derived from 14 healthy controls and 14 subjects with schizophrenia. Both healthy control cINs and schizophrenia cINs were authentic, fired spontaneously, received functional excitatory inputs from host neurons, and induced GABA-mediated inhibition in host neurons in vivo. However, schizophrenia cINs had dysregulated expression of protocadherin genes, which lie within documented schizophrenia loci. Mice lacking protocadherin-α showed defective arborization and synaptic density of prefrontal cortex cINs and behavioral abnormalities. Schizophrenia cINs similarly showed defects in synaptic density and arborization that were reversed by inhibitors of protein kinase C, a downstream kinase in the protocadherin pathway. These findings reveal an intrinsic abnormality in schizophrenia cINs in the absence of any circuit-driven pathology. They also demonstrate the utility of homogenous and functional populations of a relevant neuronal subtype for probing pathogenesis mechanisms during development.

Aims Multivalvular disease is of increasing concern in elderly patients undergoing transcatheter aortic valve replacement (TAVR). The objective of the present analysis was to investigate the impact of concomitant mitral stenosis (MS) on clinical outcomes in patients undergoing TAVR for severe, symptomatic aortic stenosis (AS). Methods and results Among 1339 patients undergoing TAVR between August 2007 and December 2015, adequate echocardiographic data for the assessment of severity and aetiology of MS was available in 971 (72.5%) patients. Patients were stratified according to degree and aetiology of concomitant MS. Mitral stenosis was documented in 176 (18.1%) TAVR patients (mean mitral valve area 1.9 ± 0.4 cm2) and considered degenerative in 110 (62.5%) and rheumatic in 66 (37.5%) patients, respectively. Mitral stenosis was categorized as moderate/severe in 28 patients (2.9%). Baseline characteristics were comparable between patients with vs. without MS. At 1 year, patients with MS were at increased risk of cardiovascular death [36 (21.4%) vs. 66 (8.7%); adjusted hazard ratio (HRadj) 3.64, 95% confidence interval (CI) 2.38–5.56] and disabling stroke [12 (7.1%) vs. 23 (3.0%); HRadj 2.98, 95% CI 1.46–6.09] as compared to patients without MS. Differences in cardiovascular death and disabling stroke emerged within 30 days of the index procedure and were largely driven by a difference in patients with rheumatic MS [cardiovascular death: 7 (10.6%) vs. 24 (3.2%), HRadj 4.80, 95% CI 1.98–11.6; disabling stroke: 4 (6.1%) vs. 16 (2.0%), HRadj 4.18, 95% CI 1.34–13.0]. Conclusion Concomitant MS was documented in approximately one-fifth of patients undergoing TAVR for severe, symptomatic AS and associated with a three-fold increased risk of cardiovascular adverse events at 1 year. The difference emerged early and was largely driven by patients with rheumatic MS.

BACKGROUND Genetic, epidemiologic, and clinical evidence suggests that, in horses, there are manifestations of hypersensitivity that can occur together. OBJECTIVES To investigate whether concurrent insect bite hypersensitivity (IBH) and severe equine asthma (EA) is associated with higher allergen-specific and total serum immunoglobulin E (IgE) concentrations than only EA or IBH. ANIMALS Healthy control horses (C, n = 40), horses with IBH (IBH, n = 24), severe EA (EA, n = 18), and both conditions (IBH/EA, n = 23) were included. METHODS In our retrospective comparative study, sera from horses with signs of severe EA, IBH, and control animals were used. IgE specific for 15 recombinant (r) allergens as well as total serum IgE concentrations were measured by enzyme-linked immunosorbent assay. RESULTS Group IBH (median sum r-Culicoides IgE: optical density at 405 nm [OD ] = 3.54 [0.48-15.07]) and group IBH/EA (OD = 4.55 [0.46-17.15]) had significantly (P .05) differences between group IBH and group IBH/EA. No significant differences among the groups were found for the other r-allergens or total serum IgE concentration. Compared to controls, horses with severe IBH had significantly increased IgE concentration to 5 Culicoides r-allergens (P

Background Atrioventricular conduction delays (AVCD) are common after transcatheter aortic valve implantation (TAVI) and frequently require implantation of a permanent pacemaker (PPM). Autopsy studies demonstrated the role of ischemia, inflammation, and oedema in the pathogenesis of AVCD. Corticosteroids (CS) reduce inflammation and oedema and hence might lead to a lower rate of AVCD. Methods Based on a prospective single-center registry, we performed a propensity score (PS) matched analysis of subjects treated with or without systemic CS (>2.5 mg prednisolone-equivalent per day) at the time of TAVI. The primary endpoint was a composite of PPM-implantation and new-onset left bundle branch block (LBBB) within 30 days after TAVI. Results Among 2213 consecutive patients undergoing TAVI (51.5% female, mean age 82.1 ± 6.1 years) 89 patients were treated with systemic CS, of which 87 were included in the PS matched analysis. At 30 days, rates of the composite of PPM and LBBB were comparable between patients with versus without CS both in the overall cohort (33.7% versus 33.0%, p = 0.89) and the PS matched cohort (34.5% versus 40.2%, p = 0.443). There were no differences in a composite of major or minor vascular complications and major or life-threatening bleeding events between patients with versus without CS in the overall cohort (34.8% versus 26.6%, p = 0.088) or the PS matched cohort (33.3% versus 33.3%, p ≥ 0.999). Conclusion In this exploratory study, intake of systemic CS among patients undergoing TAVI was not associated with differences in rates of AVCD, vascular complications, or bleeding events after TAVI.

Objective To assess the efficacy of golimumab (GLM) as a treatment option for juvenile idiopathic arthritis (JIA)-associated uveitis refractory to adalimumab (ADA). Methods Retrospective single-centre study including patients with JIA receiving GLM for active uveitis after failing ADA. JIA- and uveitis-related data, including intraocular inflammation, best-corrected visual acuity, corticosteroid-sparing potential, and ocular complications were evaluated at start of GLM treatment, at 1 month and 3 months, and every 3 months thereafter during GLM administration. We further investigated the association of response to GLM with primary and secondary failure of ADA treatment. Results Ten patients were studied, all female (17 affected eyes, mean age 14.3 + 6.7 yrs., mean follow-up 25.2 + 21.7 mos). Two patients were switched to GLM because of primary non-response to ADA. Eight were switched because of loss of response (LOR). In 5 of the latter LOR was associated with neutralizing anti-ADA-antibodies. Response to GLM was observed in all 8 patients with LOR, while the 2 patients with primary non-response to ADA also did not respond to GLM. Three of the 8 responders experienced LOR. At the end of follow-up 4 of the 5 remaining responders had achieved complete response. One had achieved partial response. Conclusion GLM is an efficacious therapeutic option in patients who experience LOR to ADA. Our data indicate that patients without primary response to ADA should be rather switched to a biologic agent with a different mode of action instead of further blocking the TNF-alpha pathway.

CTLA4-haploinsufficiency is a complex disease of immune dysregulation presenting with a broad spectrum of clinical manifestations. CTLA4-Fc fusion proteins such as abatacept have been described to alleviate immune dysregulation in several adult cases of CTLA4-haploinsufficiency. However, until now only few cases of pediatric CTLA4-haploinsufficiency treated with abatacept have been described. Here we present two pediatric cases of severe CTLA4-haploinsufficiency refractory to conventional immunosuppressive therapies that responded rapidly to treatment with abatacept. No side effects were observed during a follow-up period of 7–15 months. While one patient has successfully undergone HSCT the second patient continues to receive abatacept. Our cases demonstrate safe medium-term use of abatacept in the pediatric population.

Introduction The efficacy and safety of the oral factor Xa inhibitor edoxaban compared to warfarin stratified by CHA2DS2VASc scores have not been described. Methods The ENGAGE AF-TIMI 48 trial randomized patients with atrial fibrillation to once-daily edoxaban or warfarin. We classified patients based on CHA2DS2VASc score and compared pharmacokinetics (edoxaban concentration), pharmacodynamics (anti-factor Xa [FXa] with edoxaban, time-in-therapeutic range for warfarin), efficacy (stroke or systemic embolism [SSE]), safety (major bleeding [MB], intracranial hemorrhage), and cardiovascular mortality, for the approved edoxaban regimen vs warfarin. Results The distribution CHA2DS2VASc score were:≤3, N = 4159 (29.6%); 4, N = 4066 (28.9%); 5, N = 3165 (22.5%); and ≥6, N = 2681 (19.1%). Increasing rates of SSE (1.05 to 2.99%/year) and MB (2.27 to 4.66%/year) were observed in the warfarin arm as the CHA2DS2VASc score increased. The hazard ratios per unit increase of CHA2DS2VASc score were 1.29 (1.21-1.38) and 1.26 (1.17-1.36) for SSE, and 1.20 (1.13-1.27) and 1.19 (1.12-1.27) for MB, with warfarin and edoxaban, respectively. Time-in-therapeutic range in warfarin-treated patients was similar and high (median 68%-69%) across CHA2DS2VASc scores, whereas edoxaban trough concentration, exogenous anti-FXa activity and %inhibition of endogenous FXa were higher at increasing CHA2DS2VASc scores. Edoxaban reduced SSE, MB, intracranial hemorrhage, and cardiovascular mortality vs warfarin to a similar degree across the range of CHA2DS2VASc scores (P-int = 0.90, 0.96, 0.21, and 0.37, respectively). Because of higher event rates the number of events prevented with edoxaban tended to be greater in patients with higher CHA2DS2VASc scores. Conclusion The benefit and safety of edoxaban versus warfarin is maintained across CHA2DS2VASc scores. While the relative risk reductions remain similar, edoxaban provides incrementally larger absolute reductions in outcomes over warfarin in patients with higher CHA2DS2VASc scores.

The strong restrictive measures adopted in 2020 against the spread of the COVID-19 pandemic in Italy have deeply affected the general population's mental health. In the current longitudinal study, we specifically focus on sense of coherence (SOC), both in terms of comprehensibility/manageability and meaningfulness, among a large sample of Italian adults; SOC is a potential resource likely to foster the ability to cope with stressors. A total of 2,191 Italian participants (65.8% female) aged 18-82 completed an anonymous online self-report questionnaire at Time 1 (during the lockdown, March 2020) and at Time 2 (at the resumption of most activities, July 2020). The Repeated Measures Latent Profile Analysis (RMLPA) allowed us to identify seven different SOC profiles based on the change in both SOC dimensions, ranging from a strong "crisis" in terms of this resource in the face of the pandemic to a solid possibility to count on it. Interestingly, female and younger respondents were more likely to belong to those profiles characterized by lower levels of SOC, and these profiles have specific relations with fear and wellbeing. The implications of these results and the further expansion of the study are discussed.Supplemental data for this article is available online at https://doi.org/10.1080/00223980.2021.1952151 .

Purpose Amongst others, [68Ga]Ga-PSMA-11 and [18F]PSMA-1007 are available for the detection of recurrent prostate cancer (rPC). There are currently limited data comparing the performance of these two radioligands with respect to clinical outcomes or their cost efficacy, which this study aims to address. Methods Two hundred and forty-four patients undergoing PSMA PET/CT for rPC were retrospectively analysed for this study (one hundred and twenty two with each radiopharmaceutical) to generate rates of PET positivity, negativity and unclear findings. Patients underwent follow-up to determine the rate of additional examinations and to confirm PET findings. A Markov chain decision analysis was implemented to model clinical decision-making processes and to analyse clinical performance of the two tracers. We determine their clinical cost efficacies using cost data from several countries where both radiotracers are in routine use. Results The PET positivity rate was non-significantly higher for [18F]PSMA-1007 compared to [68Ga]Ga-PSMA-11 (91.8% vs. 86.9%, p = 0.68), whereas the rate of uncertain findings was significantly greater (17.2% vs. 8.25%, p = 0.02). The probability of a true positive finding was higher for [68Ga]Ga-PSMA-11 (0.90, 95% CI 0.70-0.98) vs. [18F]PSMA-1007 (0.81, 95% CI 0.66–0.91). A significantly (p < 0.0001) higher PPV for [68Ga]Ga-PSMA-11 (0.99, 95% CI 0.99–1.0 vs. 0.86) was found compared to [18F]PSMA-1007 (0.86, 95% CI 0.82–1.00). Intervention efficacy analysis favoured [68Ga]Ga-PSMA-11, where the number needed to image (to achieve a true positive finding) was 10.58 and the number needed to image to harm (to achieve a false positive finding) was − 8.08. A cost efficacy analysis favours [68Ga]Ga-PSMA-11 in three of the four jurisdictions analysed where health economic data was available (Switzerland, Israel, Australia) and [18F]PSMA-1007 in one jurisdiction (Denmark). Conclusion The analysis reveals a non-significantly higher PET positivity rate for [18F]PSMA-1007, but finds significantly greater rates of uncertain findings and false positive findings when compared to [68Ga]Ga-PSMA-11. We find differences in the two tracers in terms of clinical performance and cost efficacy. The method presented herein is generalisable and can be used with clinical or cost data for other countries or tracers.

[Objectives]: During the last decade, some changes in the epidemiology of invasive infections have been reported; however, specific studies with patient-level data are scarce. The aim of this study was to describe and evaluate the epidemiologic changes in bloodstream infections (BSI) during the last decade in Andalucía, Spain., [Methods]: Data from two prospective cohorts of BSI in adults with the same methodology performed 10 years apart in 11 hospitals (eight tertiary and three community) in Andalucía, Spain, were compared; the 2006–7 cohort study was performed between October 2006 and March 2007, and the 2016–17 cohort study was performed between October 2016 and March 2017. Population-based incidence rates were calculated and extrapolated for 1 year. Relative risk ratios were calculated between the 2 periods. Multivariate analyses were performed by logistic regression., [Results]: Overall, 1262 episodes of BSI were included, 563 (44.6%) in 2006–7 and 699 (55.3%) in 2016–17. Multivariate models selected the following changes in patients' features in 2016–17, after controlling for type of acquisition: higher age (odds ratio (OR) = 1.02; 95% confidence interval [CI] 1.01–1.03), lower urinary catheter (OR = 0.37; 95% CI, 0.26–0.48) and lower Pitt score (OR = 0.76; 95% CI, 0.71–0.82). Adjusted estimations considering patients' features and exposure to procedures showed a reduction in coagulase-negative staphylococci (OR = 0.47; 95% CI, 0.32–0.69), and an increase in Proteus spp. (OR = 3.12; 95% CI, 1.18–8.23) and Candida spp. (OR = 3.01; 95% CI, 1.03–8.86)., [Conclusions]: We found relevant epidemiologic changes in BSI in our area, including rates, frequency of acquisition types, changes in patient's profiles and aetiologic agents.

Background The effects of anticoagulants at extremes of body weight (BW) are not well described. The aim of this study was to analyze the pharmacokinetics/pharmacodynamics and clinical outcomes in patients randomized to warfarin, higher dose edoxaban (HDER), and lower dose edoxaban (LDER) regimens at extremes of BW in ENGAGE AF-TIMI 48.Methods and Results We analyzed three BW groups: low BW (LBW: 95th percentile, ≥120 kg, N = 1,093). In the warfarin arm, LBW patients had higher rates of stroke/systemic embolism (SSE: 6.5 vs. 4.7 in MBW vs. 1.6% in HBW, P trend Conclusion Patients with LBW in ENGAGE AF-TIMI 48 had in general a more fragile clinical status and poorer international normalized ratio control. The pharmacokinetic/pharmacodynamic profile of edoxaban was consistent across extremes of BW, resulting in similar efficacy compared with warfarin, while major or clinically relevant non-MB and net outcomes were most favorable with edoxaban as compared to warfarin in LBW patients.

The EMmY trial is sponsored by Queen Mary University of London and funded by Barts Charity, grant number MGU0373. EP and AH are also supported by the NIHR Collaboration for Leadership in Applied Health Research at Barts Health NHS Foundation Trust (NIHR ARC North Thames). KSK is distinguished investigator funded by the Beatriz Galindo (senior modality) grant to the University of Granada by the Spanish Ministry of Education., Objectives To determine the feasibility and acceptability of conducting a randomised trial on the effects of myo-inositol in preventing gestational diabetes in high-risk pregnant women. Design A multicentre, double-blind, placebo-controlled, pilot randomised trial with nested qualitative evaluation. Setting Five inner city UK National Health Service hospitals Participants Multiethnic pregnant women at 12+0 and 15+6 weeks’ gestation with risk factors for gestational diabetes. Interventions 2 g of myo-inositol or placebo, both included 200 μg folic acid, twice daily until delivery. Primary outcome measures Rates of recruitment, randomisation, adherence and follow-up. Secondary outcome measures Glycaemic indices (including homoeostatic model assessment-insulin resistance HOMA-IR), gestational diabetes (diagnosed using oral glucose tolerance test at 28 weeks and by delivery), maternal, perinatal outcomes, acceptability of intervention and costs. Results Of the 1326 women screened, 58% (773/1326) were potentially eligible, and 27% (205/773) were recruited. We randomised 97% (198/205) of all recruited women (99 each in intervention and placebo arms) and ascertained outcomes in 90% of women (178/198) by delivery. The mean adherence was 52% (SD 44) at 28 weeks’ and 34% (SD 41) at 36 weeks’ gestation. HOMA-IR and serum insulin levels were lower in the myo-inositol vs placebo arm (mean difference −0.6, 95% CI −1.2 to 0.0 and −2.69, 95% CI −5.26 to −0.18, respectively). The study procedures were acceptable to women and healthcare professionals. Women who perceived themselves at high risk of gestational diabetes were more likely to participate and adhere to the intervention. The powder form of myo-inositol and placebo, along with nausea in pregnancy were key barriers to adherence. Conclusions A future trial on myo-inositol versus placebo to prevent gestational diabetes is feasible. The intervention will need to be delivered in a non-powder form to improve adherence. There is a signal for efficacy in reducing insulin resistance in pregnancy with myo-inositol., Queen Mary University of London, Barts Charity MGU0373, NIHR Collaboration for Leadership in Applied Health Research at Barts Health NHS Foundation Trust (NIHR ARC North Thames), University of Granada by the Spanish Ministry of Education

IMPORTANCE Squamous cell carcinoma (SCC) is the most frequent malignant neoplasm found in solid organ transplant recipients and is associated with a more aggressive disease course and higher risk of metastasis and death than in the general population. OBJECTIVES To report the clinicopathologic features of and identify factors associated with aggressive SCC in solid organ transplant recipients. METHODS This retrospective multicentric case series included 51 patients who underwent solid organ transplantation and were found to have aggressive SCC, defined by nodal or distant metastasis or death by local progression of primary SCC. Standard questionnaires were completed by the researchers between July 18, 2005, and January 1, 2015. Data were analyzed between February 22, 2016, and July 12, 2016. RESULTS Of the 51 participants, 43 were men and 8 were women, with a median age of 51 years (range, 19-71 years) at time of transplantation and 62 years (range, 36-77 years) at time of diagnosis of aggressive SCC. The distribution of aggressive SCC was preferentially on the face (34 [67%]) and scalp (6 [12%]), followed by the upper extremities (6 [12%]). A total of 21 tumors (41%) were poorly differentiated, with a median tumor diameter of 18.0 mm (range, 4.0-64.0 mm) and median tumor depth of 6.2 mm (range, 1.0-20.0 mm). Perineural invasion was present in 20 patients (39%), while 23 (45%) showed a local recurrence. The 5-year overall survival rate was 23%, while 5-year disease-specific survival was 30.5%. CONCLUSIONS AND RELEVANCE Results of this case series suggest that anatomical site, differentiation, tumor diameter, tumor depth, and perineural invasion are important risk factors in aggressive SCC in solid organ transplant recipients.