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Item does not contain fulltext BACKGROUND: Etrolizumab is a gut-targeted anti-β7 integrin monoclonal antibody. In a previous phase 2 induction study, etrolizumab significantly improved clinical remission versus placebo in patients with moderately to severely active ulcerative colitis. We aimed to compare the safety and efficacy of etrolizumab with infliximab in patients with moderately to severely active ulcerative colitis. METHODS: We conducted a randomised, double-blind, double-dummy, parallel-group, phase 3 study (GARDENIA) across 114 treatment centres worldwide. We included adults (age 18-80 years) with moderately to severely active ulcerative colitis (Mayo Clinic total score [MCS] of 6-12 with an endoscopic subscore of ≥2, a rectal bleeding subscore of ≥1, and a stool frequency subscore of ≥1) who were naive to tumour necrosis factor inhibitors. Patients were required to have had an established diagnosis of ulcerative colitis for at least 3 months, corroborated by both clinical and endoscopic evidence, and evidence of disease extending at least 20 cm from the anal verge. Participants were randomly assigned (1:1) to receive subcutaneous etrolizumab 105 mg once every 4 weeks or intravenous infliximab 5 mg/kg at 0, 2, and 6 weeks and every 8 weeks thereafter for 52 weeks. Randomisation was stratified by baseline concomitant treatment with corticosteroids, concomitant treatment with immunosuppressants, and baseline disease activity. All participants and study site personnel were masked to treatment assignment. The primary endpoint was the proportion of patients who had both clinical response at week 10 (MCS ≥3-point decrease and ≥30% reduction from baseline, plus ≥1-point decrease in rectal bleeding subscore or absolute rectal bleeding score of 0 or 1) and clinical remission at week 54 (MCS ≤2, with individual subscores ≤1); efficacy was analysed using a modified intention-to-treat population (all randomised patients who received at least one dose of study drug). GARDENIA was designed to show superiority of etrolizumab over infliximab for the primary endpoint. This trial is registered with ClinicalTrials.gov, NCT02136069, and is now closed to recruitment. FINDINGS: Between Dec 24, 2014, and June 23, 2020, 730 patients were screened for eligibility and 397 were enrolled and randomly assigned to etrolizumab (n=199) or infliximab (n=198). 95 (48%) patients in the etrolizumab group and 103 (52%) in the infliximab group completed the study through week 54. At week 54, 37 (18·6%) of 199 patients in the etrolizumab group and 39 (19·7%) of 198 in the infliximab group met the primary endpoint (adjusted treatment difference -0·9% [95% CI -8·7 to 6·8]; p=0·81). The number of patients reporting one or more adverse events was similar between treatment groups (154 [77%] of 199 in the etrolizumab group and 151 [76%] of 198 in the infliximab group); the most common adverse event in both groups was ulcerative colitis (55 [28%] patients in the etrolizumab group and 43 [22%] in the infliximab group). More patients in the etrolizumab group reported serious adverse events (including serious infections) than did those in the infliximab group (32 [16%] vs 20 [10%]); the most common serious adverse event was ulcerative colitis (12 [6%] and 11 [6%]). There was one death during follow-up, in the infliximab group due to a pulmonary embolism, which was not considered to be related to study treatment. INTERPRETATION: To our knowledge, this trial is the first phase 3 maintenance study in moderately to severely active ulcerative colitis to use infliximab as an active comparator. Although the study did not show statistical superiority for the primary endpoint, etrolizumab performed similarly to infliximab from a clinical viewpoint. FUNDING: F Hoffmann-La Roche.

Background Many patients with Coronavirus disease-2019 (Covid-19) present with radiological evidence of pneumonia. Because it is difficult to determine co-existence of bacterial pneumonia, many of these patients are initially treated with antibiotics. We compared the rates of bacterial infections and mortality in Covid-19 patients with pulmonary infiltrates versus patients diagnosed with ‘pneumonia’ the year previously. Methods We conducted a medical record review of patients admitted with Covid-19 and a pulmonary infiltrate and compared them with patients diagnosed with pneumonia admitted in the prior year before the pandemic. Data abstracted included baseline demographics, comorbidities, signs and symptoms, laboratory and microbiological results, and imaging findings. Outcomes were bacterial infections and mortality. Patients presenting with and without Covid-19 were compared using univariable and multivariable analyses. Results There were 1398 and 1001 patients admitted through the emergency department (ED) with and without Covid-19 respectively. Compared with non-Covid-19 patients, those with Covid-19 were younger (61±18 vs. 65±25 years, P

Salvage lymph node dissection is a rescue treatment for patients with nodal recurrence after radical prostatectomy. Very limited data are available on robotic salvage lymph node dissection. Our purpose was to investigate perioperative and oncological outcomes of robotic salvage lymph node dissection in a large monocentric series.Perioperative data, complications within 30 days after surgery and oncological outcomes as assessed by histology, prostate specific antigen changes, prostate specific antigen nadir after salvage lymph node dissection, and time to further therapy were analyzed. To identify predictive factors for oncological outcome, Kaplan-Meier and Cox-regression analyses were performed. For cases with a mismatch between preoperative positron emission tomography/computed tomography and the number of histologically positive lymph nodes, prostate specific membrane antigen immunohistochemistry was performed on removed lymph nodes.A total of 68 patients underwent robotic salvage lymph node dissection with a median operation time of 126 minutes, a blood loss of 50 ml, and a length of stay of 4 days. No major complications (Clavien 3) occurred. Median followup was 12.1 months. Median time to further therapy was 12.4 months, 37% of patients experienced complete biochemical response (prostate specific antigen0.2 ng/ml) and 11% reached an undetectable prostate specific antigen, which was maintained for1 year in 3 cases. Lower preoperative prostate specific antigen, longer time between radical prostatectomy and salvage lymph node dissection, preoperative prostate specific membrane antigen positron emission tomography/computed tomography and complete biochemical response after salvage lymph node dissection were significant predictors of longer therapy-free survival (all p0.005). Prostate specific membrane antigen immunohistochemistry revealed that prostate specific membrane antigen positron emission tomography/computed tomography tends to miss small lymph node metastases5 mm.Robotic salvage lymph node dissection is a feasible approach with low perioperative morbidity and delays further systemic therapy in most patients. Prostate specific membrane antigen positron emission tomography/computed tomography detection is mostly limited to tumor foci5 mm.

BACKGROUND AND OBJECTIVE: Older people with inflammatory bowel disease (IBD) appear to have a lower response to anti-tumour necrosis factor (TNF) therapy, with more frequent complications than younger patients. The objective of this study was to assess persistence on therapy and the safety of anti-TNF therapy in older patients (aged ≥ 60 years). METHODS: We retrospectively reviewed the database of the Sicilian Network for Inflammatory Bowel Diseases (SN-IBD), extracting data regarding IBD patients aged ≥ 60 years and controls

Summary Background Etrolizumab is a gut-targeted, anti-β7 integrin, monoclonal antibody. In an earlier phase 2 induction study, etrolizumab significantly improved clinical remission compared with placebo in patients with moderately to severely active ulcerative colitis. We aimed to evaluate the efficacy and safety of etrolizumab in patients with moderately to severely active ulcerative colitis who had been previously treated with anti-tumour necrosis factor (TNF) agents. Methods HICKORY was a multicentre, phase 3, double-blind, placebo-controlled study in adult (18–80 years) patients with moderately to severely active ulcerative colitis (Mayo Clinic total score [MCS] of 6–12 with an endoscopic subscore of ≥2, a rectal bleeding subscore of ≥1, and a stool frequency subscore of ≥1) previously treated with TNF inhibitors. Patients were recruited from 184 treatment centres across 24 countries in North America, South America, Europe, Asia, Oceania, and the Middle East. Patients needed to have an established diagnosis of ulcerative colitis for at least 3 months, corroborated by both clinical and endoscopic evidence, and evidence of disease extending at least 20 cm from the anal verge. In cohort 1, patients received open-label etrolizumab 105 mg every 4 weeks for a 14-week induction period. In cohort 2, patients were randomly assigned (4:1) to receive subcutaneous etrolizumab 105 mg or placebo every 4 weeks for the 14-week induction phase. Patients in either cohort achieving clinical response to etrolizumab induction were eligible for the maintenance phase, in which they were randomly assigned (1:1) to receive subcutaneous etrolizumab 105 mg or placebo every 4 weeks through to week 66. Randomisation was stratified by baseline concomitant treatment with corticosteroids, concomitant treatment with immunosuppressants (induction randomisation only), baseline disease activity, week 14 MCS remission status (maintenance randomisation only), and induction cohort (maintenance randomisation only). All patients and study site personnel were masked to treatment assignment. Primary endpoints were remission (Mayo Clinic total score [MCS] ≤2, with individual subscores of ≤1 and a rectal bleeding subscore of 0) at week 14, and remission at week 66 among patients with a clinical response (MCS with ≥3-point decrease and ≥30% reduction from baseline, plus ≥1 point decrease in rectal bleeding subscore or absolute rectal bleeding score of 0 or 1) at week 14. Efficacy was analysed using a modified intent-to-treat population. Safety analyses included all patients who received at least one dose of study drug during the induction phase. This study is registered at ClinicalTrials.gov , NCT02100696 . Findings HICKORY was conducted from May 21, 2014, to April 16, 2020, during which time 1081 patients were screened, and 609 deemed eligible for inclusion. 130 patients were included in cohort 1. In cohort 2,479 patients were randomly assigned to the induction phase (etrolizumab n=384, placebo n=95). 232 patients were randomly assigned to the maintenance phase (etrolizumab to etrolizumab n=117, etrolizumab to placebo n=115). At week 14, 71 (18·5%) of 384 patients in the etrolizumab group and six (6·3%) of 95 patients in the placebo group achieved the primary induction endpoint of remission (p=0·0033). No significant difference between etrolizumab and placebo was observed for the primary maintenance endpoint of remission at week 66 among patients with a clinical response at week 14 (27 [24·1%] of 112 vs 23 [20·2%] of 114; p=0·50). Four patients in the etrolizumab group reported treatment-related adverse events leading to treatment discontinuation. The proportion of patients reporting at least adverse event was similar between treatment groups for induction (etrolizumab 253 [66%] of 384; placebo 63 [66%] of 95) and maintenance (etrolizumab to etrolizumab 98 [88%] of 112; etrolizumab to placebo 97 [85%] of 114). The most common adverse event in both groups was ulcerative colitis flare. Most adverse events were mild or moderate. During induction, the most common serious adverse event was ulcerative colitis flare (etrolizumab ten [3%] of 384; placebo: two [2%] of 95). During maintenance, the most common serious adverse event in the etrolizumab to etrolizumab group was appendicitis (two [2%] of 112) and the most common serious adverse events in the etrolizumab to placebo group were ulcerative colitis flare (two [2%] of 114) and anaemia (two [2%] of 114). Interpretation HICKORY demonstrated that a significantly higher proportion of patients with moderately to severely active ulcerative colitis who had been previously treated with anti-TNF agent were able to achieve remission at week 14 when treated with etrolizumab compared with placebo; however, there was no significant difference between groups in remission at week 66 among patients with a clinical response at week 14. Funding F Hoffmann-La Roche.

Funder: RCUK | Medical Research Council (MRC); doi: https://doi.org/10.13039/501100000265, Funder: Chinese Academy of Medical Sciences (CAMS); doi: https://doi.org/10.13039/501100005150, Funder: Wellcome Trust (Wellcome); doi: https://doi.org/10.13039/100004440, NP105-113-B*07:02-specific CD8+ T cell responses are considered among the most dominant in SARS-CoV-2-infected individuals. We found strong association of this response with mild disease. Analysis of NP105-113-B*07:02-specific T cell clones and single-cell sequencing were performed concurrently, with functional avidity and antiviral efficacy assessed using an in vitro SARS-CoV-2 infection system, and were correlated with T cell receptor usage, transcriptome signature and disease severity (acute n = 77, convalescent n = 52). We demonstrated a beneficial association of NP105-113-B*07:02-specific T cells in COVID-19 disease progression, linked with expansion of T cell precursors, high functional avidity and antiviral effector function. Broad immune memory pools were narrowed postinfection but NP105-113-B*07:02-specific T cells were maintained 6 months after infection with preserved antiviral efficacy to the SARS-CoV-2 Victoria strain, as well as Alpha, Beta, Gamma and Delta variants. Our data show that NP105-113-B*07:02-specific T cell responses associate with mild disease and high antiviral efficacy, pointing to inclusion for future vaccine design.

Background Opioid use disorder (OUD) affects millions of people, causing nearly 50 000 deaths annually in the United States. While opioid exposure and OUD are known to cause widespread transcriptomic and epigenetic changes, few studies in human samples have been conducted. Understanding how OUD affects the brain at the molecular level could help decipher disease pathogenesis and shed light on OUD treatment. Methods We generated genome-wide transcriptomic and DNA methylation profiles of 22 OUD subjects and 19 non-psychiatric controls. We applied weighted gene co-expression network analysis to identify genetic markers consistently associated with OUD at both transcriptomic and methylomic levels. We then performed functional enrichment for biological interpretation. We employed cross-omics analysis to uncover OUD-specific regulatory networks. Results We found 6 OUD-associated co-expression gene modules and 6 co-methylation modules (false discovery rate Conclusions Our integrative analysis of multi-omics data in OUD postmortem brain samples suggested complex gene regulatory mechanisms involved in OUD-associated expression patterns. Candidate genes and their upstream regulators revealed in astrocyte, and glial cells could provide new insights into OUD treatment development.

Malignant central nervous system (CNS) tumors in young children have a poor prognosis and pose a therapeutic challenge. We describe 11 patients with high-risk CNS tumors (6 atypical teratoid/rhabdoid tumor, 4 nonmedulloblastoma CNS embryonal tumors, and 1 glioblastoma multiforme) who received 32 consolidation cycles of myeloablative carboplatin/thiotepa followed by autologous peripheral blood stem cell rescue. All patients underwent successful stem cell harvest without significant complications. Mean time to absolute neutrophil count ≥0.5×103/µL was 10.2±1.3 days and the mean length of hospital stay was 15.7±3.0 days. There were no regimen-related deaths. Five-year event-free survival and overall survival were 45.5±15.0% and 58.4±16.3%, respectively. Tandem carboplatin/thiotepa consolidation with autologous stem cell rescue is well-tolerated in young children with nonmedulloblastoma CNS tumors.

To analyze endothelial cell density (ECD) and central corneal thickness (CCT) following penetrating keratoplasty (PKP) inIn this retrospective, clinical, single-center, cross-sectional, observational study, patients were enrolled who underwent PKP at the Department of Ophthalmology of Saarland University Medical Center, Homburg/Saar, Germany between May 2008 and December 2016 with the diagnosis of AK. In all, 33 eyes of 33 patients (14 males, 42%) were enrolled; their mean age at the time of surgery was 39.5 ± 14.3 years. Postoperatively, AK patients received topical polyhexamethylene biguanide, propamidine isethionate, neomycin sulphate/gramicidin/polymixin B sulfate, and prednisolone acetate eye drops (5 ×/day each), and the topical treatment was tapered sequentially with 1 drop every 6 weeks over 6 months. CCT was recorded using Pentacam HR Scheimpflug tomography and ECD with the EM-3000 specular microscope before surgery and 3 and 6 months after surgery as well as after the first and second (complete) suture removal.ECD tended to decrease significantly from the time point before surgery (2232 ± 296 cells/mmIn AK, endothelial cell loss does not seem to be accelerated following PKP, despite the postoperative use of diamidine and biguanide. A subsequent prospective comparative study should confirm our retrospective longitudinal analysis.Analyse der Endothelzelldichte (ECD) und der zentralen Hornhautdicke (CCT) nach perforierender Keratoplastik bei Patienten mit Akanthamöbenkeratitis (AK).In dieser retrospektiven, klinischen, monozentrischen, observativen Querschnittsstudie wurden die Patienten, die sich zwischen Mai 2008 und Dezember 2016 an der Augenklinik des Universitätsklinikums des Saarlandes in Homburg/Saar, Deutschland, mit der Diagnose einer Akanthamöbenkeratitis einer PKP unterzogen hatten, eingeschlossen. Insgesamt wurden 33 Augen von 33 Patienten (14 Männer, 42%) eingeschlossen, das Alter zum Zeitpunkt der Operation betrug 39,5 ± 14,3 Jahre. Postoperativ erhielten die AK-Patienten topisches Polyhexamethylenbiguanid, Propamidin-Isethionat, Neomycinsulfat/Gramicidin/Polymyxin-B-Sulfat und Prednisolonacetat als Augentropfen (jeweils 5 ×/Tag), wobei die topische Behandlung sequenziell um 1 Tropfen alle 6 Wochen über 6 Monate ausgeschlichen wurde. Die CCT wurde unter Verwendung der Pentacam-HR-Scheimpflug-Tomografie, die ECD mit dem EM-3000-Spiegelmikroskop jeweils vor der Operation sowie 3 und 6 Monate nach der Operation und nach der 1. und 2. (vollständigen) Fadenentfernung erfasst.Die ECD zeigte eine abnehmende Tendenz vom Zeitpunkt vor der Operation (2232 ± 296 Zellen/mmBei der Akanthamöbenkeratitis scheint der Endothelzellverlust nach PKP trotz der postoperativen Anwendung von Diamidin und Biguanid nicht beschleunigt zu sein. Eine nachfolgende prospektive Vergleichsstudie sollte unsere retrospektive Längsschnittanalyse bestätigen.

To evaluate the clinical and radiological outcome, sum of acetabular and femoral cartilage thickness, and rate of failure in the midterm after arthroscopic treatment of femoroacetabular impingement (FAI) syndrome with femoral osteoplasty, labral repair, and rim trimming without labral detachment.This retrospective case series included patients with FAI syndrome who had undergone hip arthroscopy from January 2009 to December 2010 by a single surgeon, with a minimum follow-up of 55 months. Data from patients who had undergone arthroscopic hip procedures with labral repair, rim trimming, and femoral osteoplasty were analyzed pre- and postoperatively. Clinical outcome (nonarthritic hip score [NAHS], Short Form 36 [SF-36]), range of motion, progression of osteoarthritis (Tönnis grade), radiological parameters (α angle, lateral center-edge angle [LCEA], Tönnis angle), femoral and acetabular cartilage thickness (using magnetic resonance imaging [MRI]), and intraoperative findings were evaluated.Of 148 hip arthroscopies performed, 97 included rim trimming, labral refixation, and femoral osteoplasty. Ten cases were lost to follow-up, leaving 87 hips. Arthroscopic revision was performed on 4 hips and total hip replacement on 4 hips, and 1 hip underwent both arthroscopic revision and total hip replacement. Excluding these 9 cases of revision, for which follow-up was not possible (retrospective study), the remaining 78 hips were followed up for a minimum of 55 months (77 ± 11.4, mean ± SD; range 55 to 124). Mean NAHS (65 to 88, P.001), SF-36 physical subscale (65 to 85, P.001), and the numerical pain rating scale (NRS) (5 to 1, P.001) improved significantly. Outcome scores of minimal clinical importance (NAHS) were achieved in 67.6% of the patients. Mean range of movement improved significantly in flexion (109 to 122, P .001) and internal rotation (10 to 22.7, P.001). NAHS was positively associated with flexion of the hip postoperatively (r = 0.307, P = .011). In 16 cases, microfracture was performed (15 acetabular and 1 femoral). Preoperative α angles (anteroposterior and modified Dunn) were significantly higher in this cohort (P.001, 95% confidence interval 8.9 to 25.2, P = .001). Twenty hips (28 %) progressed to worse Tönnis grades. Initial Tönnis grades were grade 0, 38; grade 1, 48; grade 2, 8. Pre- or postoperative Tönnis grades did not show any correlation with pre- or postoperative NAHS and NRS. MRI measurements at the latest follow-up (69 patients) of the femoral and acetabular cartilage thickness did not reveal any significant reduction at the 12 o'clock position.Arthroscopic cam resection, rim trimming, and labral repair without detachment of the labrum provides good or excellent outcome in 77.1% of hips based on NAHS in the midterm. Higher range of motion in flexion is associated with higher NAHS postoperatively. Arthroscopic cam resection, rim trimming and labral repair without detachment of the labrum is a successful method for the treatment of FAI syndrome in the midterm.IV, retrospective case series.

Stimulus repetition reduces neuronal responses in sensory areas, while leaving perceptual fidelity and behavioral performance intact. Visual gamma-band activity decreases for few stimulus repetitions in humans, yet increases for many repetitions in macaques. Using magnetoencephalography, we confirmed that gamma decreases for the first few stimulus repetitions, and, as in macaques, increases for further repetitions. Crucially, this increase did not transfer to other stimuli, suggesting that the circuit changes were specific to the inducing stimulus. The increase partially persisted when the inducing stimulus was repeated after 25 minutes of intervening stimuli. The increase was most pronounced in early visual areas, and entailed an increased feedforward influence onto higher areas. Our results suggest that early visual cortex gamma synchronization subserves adaptative neuronal processing of recurring stimuli. We propose that drive-dependent gamma phase shifting combines with spike timing-dependent synaptic plasticity to reduce overall responses, while maintaining the impact on higher areas and behavior.

Background/aim Vimentin3 (Vim3) was recently described as a tumour marker for the direct discrimination between benign and malignant kidney tumours. Here, we examined its expression in prostate cancer (PCa) cell lines and the regulation of its expression by endothelin receptors. Materials and methods Prostate cancer cell lines (PC3, DU145, LNCap) were incubated with endothelin 1 (ET-1), BQ123 [endothelin A receptor (ETAR) antagonist], BQ788 [endothelin B receptor (ETBR) antagonist], BQ123+ET-1, BQ788+ET-1 for 24 h and a scratch assay was performed. Cell extracts were analysed by western blotting and qRT-PCR. Results ET-1 induced Vim3 overexpression. Blocking the ETBR in the different prostate cancer cell lines yielded a higher migration rate, whereby Vim3 expression was significantly increased. Conclusion Vim3 concentration increases in cell lines without a functional ETBR and may be used as a marker for PCas where ETBR is frequently methylated.

Summary Introduction On February 25, 2020, the first 2 patients were tested positive for severe acute respiratory syndrome coronavirus‑2 (SARS-CoV-2) in Tyrol, Austria. Rapid measures were taken to ensure adequate intensive care unit (ICU) preparedness for a surge of critically ill coronavirus disease-2019 (COVID-19) patients. Methods This cohort study included all COVID-19 patients admitted to an ICU with confirmed or strongly suspected COVID-19 in the State of Tyrol, Austria. Patients were recorded in the Tyrolean COVID-19 intensive care registry. Date of final follow-up was July 17, 2020. Results A total of 106 critically ill patients with COVID-19 were admitted to 1 of 13 ICUs in Tyrol from March 9 to July 17, 2020. Median age was 64 years (interquartile range, IQR 54–74 years) and the majority of patients were male (76 patients, 71.7%). Median simplified acute physiology score III (SAPS III) was 56 points (IQR 49–64 points). The median duration from appearance of first symptoms to ICU admission was 8 days (IQR 5–11 days). Invasive mechanical ventilation was required in 72 patients (67.9%) and 6 patients (5.6%) required extracorporeal membrane oxygenation treatment. Renal replacement therapy was necessary in 21 patients (19.8%). Median ICU length of stay (LOS) was 18 days (IQR 5–31 days), median hospital LOS was 27 days (IQR 13–49 days). The ICU mortality was 21.7% (23 patients), hospital mortality was 22.6%. There was no significant difference in ICU mortality in patients receiving invasive mechanical ventilation and in those not receiving it (18.1% vs. 29.4%, p = 0.284). As of July 17th, 2020, two patients are still hospitalized, one in an ICU, one on a general ward. Conclusion Critically ill COVID-19 patients in Tyrol showed high severity of disease often requiring complex treatment with increased lengths of ICU and hospital stay. Nevertheless, the mortality was found to be remarkably low, which may be attributed to our adaptive surge response providing sufficient ICU resources.

Temporal dataset shift associated with changes in healthcare over time is a barrier to deploying machine learning-based clinical decision support systems. Algorithms that learn robust models by estimating invariant properties across time periods for domain generalization (DG) and unsupervised domain adaptation (UDA) might be suitable to proactively mitigate dataset shift. The objective was to characterize the impact of temporal dataset shift on clinical prediction models and benchmark DG and UDA algorithms on improving model robustness. In this cohort study, intensive care unit patients from the MIMIC-IV database were categorized by year groups (2008–2010, 2011–2013, 2014–2016 and 2017–2019). Tasks were predicting mortality, long length of stay, sepsis and invasive ventilation. Feedforward neural networks were used as prediction models. The baseline experiment trained models using empirical risk minimization (ERM) on 2008–2010 (ERM[08–10]) and evaluated them on subsequent year groups. DG experiment trained models using algorithms that estimated invariant properties using 2008–2016 and evaluated them on 2017–2019. UDA experiment leveraged unlabelled samples from 2017 to 2019 for unsupervised distribution matching. DG and UDA models were compared to ERM[08–16] models trained using 2008–2016. Main performance measures were area-under-the-receiver-operating-characteristic curve (AUROC), area-under-the-precision-recall curve and absolute calibration error. Threshold-based metrics including false-positives and false-negatives were used to assess the clinical impact of temporal dataset shift and its mitigation strategies. In the baseline experiments, dataset shift was most evident for sepsis prediction (maximum AUROC drop, 0.090; 95% confidence interval (CI), 0.080–0.101). Considering a scenario of 100 consecutively admitted patients showed that ERM[08–10] applied to 2017–2019 was associated with one additional false-negative among 11 patients with sepsis, when compared to the model applied to 2008–2010. When compared with ERM[08–16], DG and UDA experiments failed to produce more robust models (range of AUROC difference, − 0.003 to 0.050). In conclusion, DG and UDA failed to produce more robust models compared to ERM in the setting of temporal dataset shift. Alternate approaches are required to preserve model performance over time in clinical medicine.

Introduction/Objectives Severe subaortic stenosis (SAS) is a congenital heart defect in dogs that often results in clinical signs and reduced survival. The objective of this study was to describe characteristics of dogs with severe, symptomatic SAS who underwent combined cutting and high-pressure balloon valvuloplasty (CB/HPBV). Animals, materials, and methods Retrospective description of the clinical characteristics, CB/HPBV procedural deviations from reported methodology and outcomes in a series of six client-owned dogs with severe, symptomatic SAS. Results Breeds included two each of Newfoundland, Golden retriever, and German shepherd. Median age was 10.1 months (range: 5–72.3 months), and median weight was 25.5 kg (range: 21.8–36.4 kg). Before CB/HPBV, clinical signs were present in all dogs; four were managed for congestive heart failure (CHF). Three dogs had concurrent congenital heart disease. Median Doppler-estimated left ventricular outflow tract pressure gradient was pre-operatively 149.7 mmHg (range: 89.9–254.7 mmHg) and post-operatively 134.1 mmHg (range: 83.9–181.2 mmHg). Median aortoseptal angle was steep at 136° (range: 109–143°). Clinical improvement was documented in all dogs, based on temporary discontinuation of diuretics and/or owner-perceived reduction in clinical signs. At the time of writing, three dogs had died suddenly, one was euthanized because of recurrence of clinical signs, and one died in CHF. Median survival time was 26.4 months after procedure (range: 6.3–45.8 months). One dog remained alive at 44 months after procedure. Conclusions Palliative CB/HPBV is a potential therapeutic option for dogs with severe, symptomatic SAS complicated by concurrent congenital heart disease, arrhythmias, or CHF.

Purpose Deferring cancer surgery can have profound adverse effects including patient mortality. During the COVID-19 pandemic, departmental reorganisation and adherence to evolving guidelines enabled provision of uninterrupted surgical care to patients with bone and soft tissue tumours (BST) in need of surgery. We reviewed the outcomes of surgeries on BST during the first two months of the pandemic at one of the tertiary BST centres in the UK. Materials and methods Between 12 March 2020 and 12 May 2020, 56 patients of a median age of 57 years (18–87) underwent surgery across two sites: index hospital (n = 27) and COVID-free facility (n = 29). Twenty-five (44.6%) patients were above the age of 60 years and 20 (35.7%) patients were in ASA III and ASA IV category. The decision to offer surgery was made in adherence with the guidelines issued by the NHS, BOOS and BSG. Results At a minimum follow-up of 30 days post-surgery, 54 (96.4%) patients were recovering well. Thirteen patients (23.2%) had post-operative complications which included four (7.1%) patients developing pulmonary embolism. The majority of complications (12/13 = 92.7%) occurred in ASA III and IV category patients. Four (7.1%) patients contracted COVID-19, of which three required escalation of care due to pulmonary complications and two (3.6%) died. Patients 60 years (p p Conclusion In spite of the favourable results in majority of our patients, our study shows that patients with sarcoma operated at the height of the pandemic are at a risk of contracting COVID-19 and also having associated with mortality. The use of a COVID-free facility, surgery in patients

ObjectiveTo determine the survival and evolution of pulmonary hypertension (PH) associated with bronchopulmonary dysplasia (BPD) in extremely premature born infants beyond 36 weeks postmenstrual age (PMA).DesignA single-centre retrospective cohort study from a university hospital.PatientsExtremely preterm (gestational age Main outcome measuresSurvival, mortality rate and PH resolution. Patient characteristics, treatment, presence and evolution of PH were collected from patient charts.ResultsTwenty-eight infants were included. All had BPD, while 23 (82%) had severe BPD and 11 infants (39%) died. Survival rates at 1, 3 and 7 months from 36 weeks PMA were 89%, 70% and 58%, respectively. In 16 of the 17 surviving infants, PH resolved over time, with a resolution rate at 1 and 2 years corrected age of 47% and 79%, respectively. At 2.5 years corrected age, the resolution rate was 94%.ConclusionsThese extremely preterm born infants with PH-BPD had a survival rate of 58% at 6 months corrected age. Suprasystemic pulmonary artery pressure was associated with poor outcome. In the current study, infants surviving beyond the corrected age of 6 months showed excellent survival and resolution of PH in almost all cases. Prospective follow-up studies should investigate whether resolution of PH in these infants can be improved by multi-modal therapies, including respiratory, nutritional and cardiovascular treatments.

BACKGROUND: Carbapenem-resistant Enterobacteriaceae (CRE) are a global threat. Here, we describe the clinical and molecular characteristics of Centers for Disease Control and Prevention (CDC)-defined CRE in the US. METHODS: The second Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae (CRACKLE-2, ClinicalTrials.gov: NCT03646227) is a prospective, multicenter, cohort study. Patients hospitalized in 49 US hospitals, with clinical cultures positive for CDC-defined CRE between 30 April 2016 and 31 August 2017 were included. Primary outcome was desirability of outcome ranking (DOOR) at 30 days. Clinical data and bacteria were collected, and whole genome sequencing (WGS) was performed. FINDINGS: 1,040 patients with unique isolates were included; 449 (43%) with infection and 591 (57%) with colonization. CDC-defined CRE admission rate was 57 CDC-defined CRE admissions/100,000 admissions (95% CI: 45–71). Three subsets of CDC-defined CRE were identified: carbapenemase-producing Enterobacteriaceae (618/1,040, 59%); non-carbapenemase-producing CRE (194/1,040, 19%); and unconfirmed CRE (228/1,040, 22%; initially reported as CRE, but susceptible to carbapenems in two central laboratories). Klebsiella pneumoniae carbapenemase (KPC)-producing clonal group 258 K. pneumoniae was the most common carbapenemase-producing Enterobacteriaceae. In 449 patients with CDC-defined CRE infections, DOOR outcomes were not significantly different in patients with carbapenemase-producing Enterobacteriaceae, non-carbapenemase-producing CRE, and unconfirmed CRE. At 30 days 107/449 (24%, 95% CI 20–28%) patients had died. INTERPRETATION: Among patients with CDC-defined CRE, similar outcomes were observed among three subgroups, including the novel unconfirmed CRE group. CDC-defined CRE represent diverse bacteria, whose spread may not respond to interventions directed to carbapenemase-producing Enterobacteriaceae. FUNDING: National Institutes of Health

Introduction Leonbergers are large-breed dogs believed to be predisposed to dilated cardiomyopathy, yet the normal echocardiographic measurements of these dogs are unknown. The aim of this study was to describe echocardiographic findings and propose breed-specific reference intervals (RIs) for Leonbergers. Animals A total of 42 clinically healthy dogs were involved in this study. Materials and methods This study was designed as a cross-sectional study of 42 Leonberger dogs undergoing complete transthoracic echocardiographic studies at a national show. Reference intervals were determined using robust method with bootstrapping. The effects of age, sex, and body weight (BW) on linear and volumetric dimensions were evaluated by regression analysis. Intra- and interobserver variability were evaluated by coefficient of variation from 10 of the studies. Results There were significant linear correlations with BW for many of the cardiac variables evaluated. However, despite the statistical significance, most regression equations had small slopes, necessitating large changes in BW for small changes in two-dimensional echocardiographic variables. As such, this study resulted in breed-specific RIs irrespective of BW. Trace mitral insufficiency (n = 18), trace aortic insufficiency (n = 15), or both (n = 1) was identified in 81% of dogs in this population. Coefficients of variation were Conclusions This study describes echocardiographic findings and provides RIs, which may be useful in echocardiographic evaluations of Leonbergers and may aid in early identification of heart disease within the breed.

BackgroundIn order to optimize interventions and services in the community, it is important to identify the profile of persons who are able to stay at home and of those who are being admitted into residential care. Understanding their needs and their use of resources is essential. The main objective of the study is to identify persons who are likely to enter residential care based upon their needs and resource utilization, so that care providers can plan interventions effectively and optimize services and resources to meet the persons’ needs.MethodsThis is a longitudinal quasi-experimental study. The data consists of primary data from the community setting collected every six months during the period of 2010–2016. Interventions had the goal of keeping older people longer at home. Participants were at least 65 years old and were living in the community. The interRAI Resource Utilization Group system (RUG-III) was used to calculate the case-mix indexes (CMI) of all participants. Comparisons were made between the case-mix of those who were still living at home and those who were admitted into residential care at follow-up.ResultsA total of 10,289 older persons participated in the study (81.2 ± 7.1 yrs., 69.1% female). From this population, 853 participants (8.3%) were admitted into residential care. The CMI of the persons receiving night care at home were the highest (1.6 at baseline and 1.7 at the entry point of residential care), followed by persons receiving occupational therapy (1.5 at baseline and 1.6 at the entry point of residential care) and persons enrolled in case management interventions with rehabilitation (1.4 at baseline and 1.6 at the entry point of residential care). The CMIs at follow-up were significantly higher than at baseline and the linear regression model showed that admission to residential care was a significant factor in the model.ConclusionsThe study showed that the RUG-III system offers possibilities for identifying persons at risk of institutionalization. Interventions designed to avoid early nursing home admission can make use of the RUG-III system to optimize care planning and the allocation of services and resources. Based on the RUG-III case-mix, resources can be allocated to keep older persons at home longer, bearing in mind the complexity of care and the availability of services in the community.

OBJECTIVE The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial (ClinicalTrials.gov reg. no. NCT01179048) demonstrated a reduced risk of cardiovascular (CV) events for patients with type 2 diabetes who received the glucagon-like peptide 1 receptor agonist liraglutide versus placebo. The mechanisms behind this CV benefit remain unclear. We aimed to identify potential mediators for the CV benefit observed with liraglutide in the LEADER trial. RESEARCH DESIGN AND METHODS We performed exploratory analyses to identify potential mediators of the effect of liraglutide on major adverse CV events (MACE; composite of CV death, nonfatal myocardial infarction, or nonfatal stroke) from the following candidates: glycated hemoglobin (HbA1c), body weight, urinary albumin-to-creatinine ratio (UACR), confirmed hypoglycemia, sulfonylurea use, insulin use, systolic blood pressure, and LDL cholesterol. These candidates were selected as CV risk factors on which liraglutide had an effect in LEADER such that a reduction in CV risk might result. We used two methods based on a Cox proportional hazards model and the new Vansteelandt method designed to use all available information from the mediator and to control for confounding factors. RESULTS Analyses using the Cox methods and Vansteelandt method indicated potential mediation by HbA1c (up to 41% and 83% mediation, respectively) and UACR (up to 29% and 33% mediation, respectively) on the effect of liraglutide on MACE. Mediation effects were small for other candidates. CONCLUSIONS These analyses identify HbA1c and, to a lesser extent, UACR as potential mediators of the CV effects of liraglutide. Whether either is a marker of an unmeasured factor or a true mediator remains a key question that invites further investigation.

Aims The aim of this pilot study was to investigate the safety, feasibility, tolerability, and acceptability of an assisted mobilization of advanced heart failure patients, using a lightweight, exoskeleton-type robot (Myosuit, MyoSwiss AG, Zurich, Switzerland). Methods and results Twenty patients in functional NYHA class III performed activities of daily life (ADL, n = 10) or participated in a single, standardized, 60 min rehabilitation exercise unit (REU, n = 10) with and without the Myosuit. The outcome assessment included the evaluation of vital signs, adverse events, rates of perceived exertion and dyspnoea (RPE, RPD), the ability to perform ADL or REU, and the individual acceptability. The mean age of the subjects was 49.4 (±11.0) years; 80% were male. The mean left ventricular ejection fraction was 22.1% (±7.4%) and the median NT-proBNP 2054 pg/mL (IQR 677, 3270 pg/mL). In all patients, mobilization with the Myosuit was feasible independently or with minor support. The mean individual difference in the total walking distance of the patients without and with robotic assistance was −26.5 m (95% confidence interval (CI) −142 to 78 m, P = 0.241). No adverse events occurred. RPE and RPD showed no significant difference with or without the device (ADL: RPE −0.1 m, 95% CI −1.42 to 1.62, P = 0.932 and RPD −0.95 m, 95% CI −0.38 to 2.28, P = 0.141; REU: RPE 1.1 m, 95% CI −2.90 to 0.70, P = 0.201 and RPD 0.5 m, 95% CI −2.02 to 1.02, P = 0.435). All median responses in the acceptability questionnaire were positive. The patients felt safe and enjoyed the experience; 85% would be interested in participating in robot-assisted training on a regular basis. Conclusion This feasibility pilot trial provides first indications that a robotic exoskeleton-assisted mobilization of patients with advanced heart failure is safe, feasible, well-tolerated, and well-accepted. The results are highly encouraging to further pursue this innovative approach in rehabilitation programmes. This trial was registered at ClinicalTrials.gov: NCT04839133., ESC Heart Failure, 9 (3), ISSN:2055-5822

Alternatives to conventional chicken meat and egg production are increasingly under discussion, especially because of the common practice of killing male day-old chicks from laying lines which has been banned from the beginning of 2022 in Germany and is planned to be banned during 2022 in other countries. Production of dual-purpose chicken lines is one possible solution, as such lines combine moderate laying and growth performance. The microbiological status of products from such breeds must be comparable to existing products on the market for food safety purposes. Additionally, the production of such products will take longer because of the feeding regimes required, and again, comparability should be safeguarded for the best consumer protection. The dual-purpose chicken line, Lohmann Dual (males), was compared to males from the laying line Lohmann Brown Plus, conventional laying hens (all slaughtered and processed in the same conventional laying hen abattoir), and conventional broilers (slaughtered in a conventional broiler abattoir). Neck skin samples were taken before chilling at the end of each slaughter line to determine the microbial status of the carcasses. Additionally, fresh and cooked meat sensory analysis was performed on meat from broilers and male and female Lohmann Dual and Lohmann Brown Plus chickens (for three carcasses of each group) at the German Agricultural Society Test Center in Kassel. The focus was on the performance of male Lohmann Dual compared to the other lines. There was no difference in theEnterobacteriaceaecount of the dual-purpose chicken line compared to conventional broilers, whereas laying hens had a significantly higher microbial load before chilling, as based on neck skin examinations (p

Multisystem inflammatory syndrome in children (MIS-C) is a newly recognized disease process that can complicate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We present what we believe to be the earliest case of MIS-C, occurring in February 2020. Our patient’s SARS-CoV-2 infection was caused by an emerging lineage with the D614G variant in the spike protein. This lineage would subsequently become the predominant cause of SARS-CoV-2 outbreaks in Europe and the United States where MIS-C was first described.

BACKGROUND Disease phenotype and outcome of late-onset Crohn's disease are still poorly defined. METHODS In this Italian nationwide multicentre retrospective study, patients diagnosed ≥65 years (late-onset) were compared with young adult-onset with 16-39 years and adult-onset Crohn's disease 40-64 years. Data were collected for 3 years following diagnosis. RESULTS A total of 631 patients (late-onset 153, adult-onset 161, young adult-onset 317) were included. Colonic disease was more frequent in late-onset (P < 0005), stenosing behaviour was more frequent than in adult-onset (P < 0003), but fistulising disease was uncommon. Surgery rates were not different between the three age groups. Systemic steroids were prescribed more frequently in young adult-onset in the first year, but low bioavailability steroids were used more frequently in late-onset in the first 2 years after diagnosis (P < 0.036, P < 0.041, respectively). The use of immunomodulators and anti-TNF's even in patients with more complicated disease, that is, B2 or B3 behaviour (Montreal classification), remained significantly inferior (P < 0.0001) in late-onset compared to young adult-onset. Age at diagnosis, Charlson comorbidity index, and steroid used in the first year were negatively associated with the use of immunomodulators and biologics. Comorbidities, related medications and hospitalizations were more frequent in late-onset. Polypharmacy was present in 56% of elderly Crohn's disease patients. CONCLUSION Thirty-two percent of late-onset Crohn's disease presented with complicated disease behaviour. Despite a comparable use of steroids and surgery, immunomodulators and biologics were used in a small number of patients.

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BACKGROUND AND AIM There are few clinical data on Adalimumab (ADA) biosimilars in inflammatory bowel disease. We aimed to perform a multicenter, observational, prospective study on safety and effectiveness of ADA biosimilar ABP 501 in patients with inflammatory bowel disease. METHODS All consecutive patients from the cohort of the Sicilian Network for Inflammatory Bowel Disease treated with ADA biosimilar ABP 501 from February 2019 to February 2020 were enrolled. Patients were divided into three groups: group A, naive to ADA and naive to anti-tumor necrosis factors; group B, naive to ADA and previously exposed to anti-tumor necrosis factors; and group C: switched from ADA originator to ABP 501. RESULTS A total of 559 patients (median age 39 years; Crohn's disease 88.0%, ulcerative colitis 12.0%) were included, with a follow-up time of 403.4 patient-years. Thirty-six serious adverse events occurred in 36 patients (6.4%; incidence rate [IR]: 8.9 per 100 person-years [PY]). The IR of serious adverse events was higher among patients in group A compared with group C (17.4 vs 4.8 per 100 PY; IR ratio = 3.61; P

Treatment of severe COVID-19 is currently limited by clinical heterogeneity and incomplete description of specific immune biomarkers. We present here a comprehensive multi-omic blood atlas for patients with varying COVID-19 severity in an integrated comparison with influenza and sepsis patients versus healthy volunteers. We identify immune signatures and correlates of host response. Hallmarks of disease severity involved cells, their inflammatory mediators and networks, including progenitor cells and specific myeloid and lymphocyte subsets, features of the immune repertoire, acute phase response, metabolism and coagulation. Persisting immune activation involving AP-1/p38MAPK was a specific feature of COVID-19. The plasma proteome enabled sub-phenotyping into patient clusters, predictive of severity and outcome. Systems-based integrative analyses including tensor and matrix decomposition of all modalities revealed feature groupings linked with severity and specificity compared to influenza and sepsis. Our approach and blood atlas will support future drug development, clinical trial design and personalized medicine approaches for COVID-19., Graphical Abstract, A multi-omic analysis of patient blood samples reveals both similarities and specific features of COVID-19 when compared with samples obtained from sepsis or influenza patients which could yield better targetted therapies for severe COVID-19.

Background Recently, our group showed that Vim3 is overexpressed in tissue samples of renal oncocytomas and Mxi‐2 in clear cell renal carcinoma (ccRCC). The mechanism leading to the truncation of both proteins is known and involves with two miRs, both detectable in urine. Since the analysis of miRs is time‐consuming, our aim was to identify the truncated proteins in urine instead. Furthermore, urine samples from small renal masses (SRMs) (n = 45, In urine sample from clear cell renal carcinoma (RCC) and oncocytoma patients, two miRs (miR‐15a and miR‐498) were significantly overexpressed. This overexpression of the miRs leads to the production of two truncated proteins (Mxi‐2 and Vim3), both detectable in urine samples. We analyzed n = 350 urine samples from healthy patients and those with different urological tumors. The noticed overexpression of Mxi‐2 and Vim3 in urine samples significantly correlates with the tumor entity. Overexpression of Mxi‐2 in RCC samples and Vim3 in oncocytomas, also in small renal cancers (

Stalled progress in controlling Plasmodium falciparum malaria highlights the need for an effective and deployable vaccine. RTS,S/AS01, the most effective malaria vaccine candidate to date, demonstrated 56% efficacy over 12 months in African children. We therefore assessed a new candidate vaccine for safety and efficacy., info:eu-repo/semantics/published

Background Ebola virus (EBOV) epidemics pose a major public health risk. There currently is no licensed human vaccine against EBOV. The safety and immunogenicity of a recombinant EBOV glycoprotein (GP) nanoparticle vaccine formulated with or without Matrix-M adjuvant were evaluated to support vaccine development. Methods A phase 1, placebo-controlled, dose-escalation trial was conducted in 230 healthy adults to evaluate 4 EBOV GP antigen doses as single- or 2-dose regimens with or without adjuvant. Safety and immunogenicity were assessed through 1-year postdosing. Results All EBOV GP vaccine formulations were well tolerated. Receipt of 2 doses of EBOV GP with adjuvant showed a rapid increase in anti-EBOV GP immunoglobulin G titers with peak titers observed on Day 35 representing 498- to 754-fold increases from baseline; no evidence of an antigen dose response was observed. Serum EBOV-neutralizing and binding antibodies using wild-type Zaire EBOV (ZEBOV) or pseudovirion assays were 3- to 9-fold higher among recipients of 2-dose EBOV GP with adjuvant, compared with placebo on Day 35, which persisted through 1 year. Conclusions Ebola virus GP vaccine with Matrix-M adjuvant is well tolerated and elicits a robust and persistent immune response. These data suggest that further development of this candidate vaccine for prevention of EBOV disease is warranted.

Many studies have reported visual cortical gamma-band activity related to stimulus processing and cognition. Most respective studies used artificial stimuli, and the few studies that used natural stimuli disagree. Electrocorticographic (ECoG) recordings from awake macaque areas V1 and V4 found gamma to be abundant during free viewing of natural images. In contrast, a study using ECoG recordings from V1 of human patients reported that many natural images induce no gamma and concluded that it is not necessary for seeing. To reconcile these apparently disparate findings, we reanalyzed those same human ECoG data recorded during presentation of natural images. We find that the strength of gamma is positively correlated with different image-computable metrics of image structure. This holds independently of the precise metric used to quantify gamma. In fact, an average of previously used gamma metrics reflects image structure most robustly. Gamma was sufficiently diagnostic of image structure to differentiate between any possible pair of images with >70% accuracy. Thus, while gamma might be weak for some natural images, the graded strength of gamma reflects the graded degree of image structure, and thereby conveys functionally relevant stimulus properties.

Background The search for biomarkers of bipolar disorder (BD), including epigenetic alterations, has heavily relied on peripheral investigations that do not necessarily reflect brain-specific mechanisms. In this study we aimed to assess peripheral extracellular vesicles (EVs)’ microRNAs and determine their use as a novel source of biomarkers in BD. Methods We assessed peripheral blood EVs’ microRNAs from 20 patients with BD type I and 21 age- and sex-matched healthy controls by microarray, and further explored the predicted biological functions of significantly differentially expressed microRNAs. Results Our results identified 33 nominally significant microRNAs (p 1.5) altered in BD patients, including miRNAs previously reported to be altered in post-mortem tissues of patients. Pathway analyses identified some brain-relevant mechanisms enriched in these miRNAs, including axon guidance by netrin and the serotonin receptor pathway. Limitations Relatively small sample size, potential confounding effects of mood states, medication use, and comorbidities, analysis of total rather than brain-specific EVs, and lack of validation of significant miRNAs by other methods. Conclusions This study provides important preliminary evidence of the potential use of EVs as a novel source of biomarkers in BD. Overall, our findings of brain-relevant mechanisms in these vesicles suggest their potential use in living patients as a peripheral window to the brain.

Critical care 23(1), 1-4 (2019). doi:10.1186/s13054-019-2524-4, Published by Springer, Berlin ; Heidelberg

Epidemiological and clinical studies have shown a relevant association between heart rate and cardiovascular mortality. Experimental studies identified vascular effects of heart rate reduction with the If channel inhibitor ivabradine. Therefore, the effects of heart rate reduction on endothelial function and indices of arterial stiffness were examined in patients with stable coronary artery disease in a prospective, placebo-controlled clinical crossover study.Twenty-three patients (18 men and 5 women) with a resting heart rate (HR) of at least 70 beats per minute (bpm) and stable coronary artery disease were enrolled in this study. In a cross-over design, all patients were treated with ivabradine (Iva, 7.5 mg b.i.d.) and placebo for 6 months each. Iva reduced heart rate by 11.4 bpm (Iva 58.8 ± 8.2 bpm vs. placebo 70.2 ± 8.3 bpm, P 0.0001). Augmentation index (AIx75), carotid-femoral pulse wave velocity (cfPWV) and central aortic blood pressure were measured using applanation tonometry (SphygmoCor). HRR by Iva increased AIx75 by 12.4% (Iva 24.3 ± 10.5% vs. placebo 21.3 ± 10.1%, P 0.05) and reduced cfPWV by 14.1% (Iva 6.3 ± 1.7 m/s vs. placebo 7.3 ± 1.4 m/s, P 0.01). Iva increased mean central blood pressure by 7.8% (Iva 107.5 ± 15.4 mmHg vs. placebo 99.1 ± 12.2 mmHg, P 0.001). Endothelial function was determined measuring the flow-mediated vasodilation (FMD) of the brachial artery. HRR by Iva increased FMD by 18.5% (Iva 7.3 ± 2.2% vs. placebo 6.0 ± 2.0%, P 0.001). Aortic distensibility was characterized by MRI. HRR by Iva increased aortic distensibility by 33.3% (Iva 0.003 ± 0.001/mmHg vs. placebo 0.002 ± 0.010/mmHg, P 0.01) and circumferential cyclic strain by 37.1% (Iva 0.062 ± 0.027 vs. placebo 0.039 ± 0.018, P 0.0001).Heart rate reduction with Iva increased endothelium-dependent vasodilation and reduced arterial stiffness in patients with stable CAD. These findings corroborate and expand the results collected in experimental studies and indicate the importance of heart rate as a determinant of vascular function.

FXII deficiency results in spontaneous prolongation of activated partial thromboplastin time (aPTT), which is widely used to monitor thromboprophylaxis. Misinterpretation of spontaneously prolonged aPTT may result in omission of thromboembolic treatment or even unnecessary transfusion of blood products. This retrospective analysis was performed to calculate a threshold level of FXII resulting in aPTT prolongation. 79 critically ill patients with spontaneous prolongation of aPTT were included. A correlation analysis and a ROC curve for aPTT prolongation predicted by FXII level were created to find the FXII threshold level. Prolongation of aPTT was associated with disease severity. A significant inverse proportionality between FXII and aPTT was seen. A ROC curve for aPTT prolongation, predicted by FXII level (AUC 0.85; CI 0.76–0.93), revealed a FXII threshold level of 42.5%. Of our patients 50.6% experienced a FXII deficiency, in 80.0% of whom we found aPTT to be prolonged without a significantly higher bleeding rate. The FXII deficiency was more common in patients with higher SAPS3 scores, septic shock, transfusion of red blood cells and platelet concentrates as well as in patients receiving renal replacement therapy. Patients with a FXII deficiency and prolonged aPTT less often received anticoagulatory therapy although they were more severely ill. The rate of thromboembolic events was higher in these patients although the difference was not statistically significant. Of all patients with spontaneous aPTT prolongation 50.6% had a FXII level of 42.5% or less. Those patients received insufficient thromboembolic prophylaxis.