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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.

BackgroundOptical coherence tomography (OCT) is an ultra-high resolution real-time intravascular imaging method that is gaining interest in cerebrovascular applications.ObjectiveTo compare, in a rabbit elastase aneurysm model, digital subtraction angiography (DSA) and OCT as diagnostic tools for the assessment of aneurysmal remnants and baseline characteristics of aneurysms after flow diverter (FD) implantation.MethodsWith Institutional Animal Care and Use Committee approval, saccular aneurysms were created in 28 rabbits and treated with Derivo FDs. DSA was performed before, and immediately after, stent implantation. As a follow-up, DSA and OCT were performed 28 days after device implantation.ResultsDSA and OCT were successfully performed in 23 cases. OCT could not be achieved in 5 cases owing to navigational difficulties in the stent lumen with the OCT catheter. Residual aneurysms were significantly more often visible with OCT (18/23 (78%) than with DSA 12/23 (52%), p = 0.031).ConclusionOCT was more sensitive than conventional angiography for the assessment of residual aneurysms at 28 days after FD implantation in an animal model.

Summary Background Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a global threat. We therefore analysed the bacterial characteristics of CRKP infections and the clinical outcomes of patients with CRKP infections across different countries. Methods In this prospective, multicentre, cohort study (CRACKLE-2), hospitalised patients with cultures positive for CRKP were recruited from 71 hospitals in Argentina, Australia, Chile, China, Colombia, Lebanon, Singapore, and the USA. The first culture positive for CRKP was included for each unique patient. Clinical data on post-hospitalisation death and readmission were collected from health records, and whole genome sequencing was done on all isolates. The primary outcome was a desirability of outcome ranking at 30 days after the index culture, and, along with bacterial characteristics and 30-day all-cause mortality (a key secondary outcome), was compared between patients from China, South America, and the USA. The desirability of outcome ranking was adjusted for location before admission, Charlson comorbidity index, age at culture, Pitt bacteremia score, and anatomical culture source through inverse probability weighting; mortality was adjusted for the same confounders, plus region where relevant, through multivariable logistic regression. This study is registered at ClinicalTrials.gov , NCT03646227 , and is complete. Findings Between June 13, 2017, and Nov 30, 2018, 991 patients were enrolled, of whom 502 (51%) met the criteria for CRKP infection and 489 (49%) had positive cultures that were considered colonisation. We observed little intra-country genetic variation in CRKP. Infected patients from the USA were more acutely ill than were patients from China or South America (median Pitt bacteremia score 3 [IQR 2–6] vs 2 [0–4] vs 2 [0–4]) and had more comorbidities (median Charlson comorbidity index 3 [IQR 2–5] vs 1 [0–3] vs 1 [0–2]). Adjusted desirability of outcome ranking outcomes were similar in infected patients from China (n=246), South America (n=109), and the USA (n=130); the estimates were 53% (95% CI 42–65) for China versus South America, 50% (41–61) for the USA versus China, and 53% (41–66) for the USA versus South America. In patients with CRKP infections, unadjusted 30-day mortality was lower in China (12%, 95% CI 8–16; 29 of 246) than in the USA (23%, 16–30; 30 of 130) and South America (28%, 20–37; 31 of 109). Adjusted 30-day all-cause mortality was higher in South America than in China (adjusted odds ratio [aOR] 4·82, 95% CI 2·22–10·50) and the USA (aOR 3·34, 1·50–7·47), with the mortality difference between the USA and China no longer being significant (aOR 1·44, 0·70–2·96). Interpretation Global CRKP epidemics have important regional differences in patients’ baseline characteristics and clinical outcomes, and in bacterial characteristics. Research findings from one region might not be generalisable to other regions. Funding The National Institutes of Health.

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.

SummaryBackgroundWidely varying mortality rates of critically ill Coronavirus disease 19 (COVID-19) patients in the world highlighted the need for local surveillance of baseline characteristics, treatment strategies and outcome. We compared two periods of the COVID-19 pandemic to identify important differences in characteristics and therapeutic measures and their influence on the outcome of critically ill COVID-19 patients.MethodsThis multicenter prospective register study included all patients with a SARS-CoV‑2 infection confirmed by polymerase chain reaction, who were treated in 1 of the 12 intensive care units (ICU) from 8 hospitals in Tyrol, Austria during 2 defined periods (1 February 2020 until 17 July: first wave and 18 July 2020 until 22 February 2021: second wave) of the COVID-19 pandemic.ResultsOverall, 508 patients were analyzed. The majority (n = 401) presented during the second wave, where the median age was significantly higher (64 years, IQR 54–74 years vs. 72 years, IQR 62–78 years,p p = 0.003), as was the use of vasopressors (50.3% vs. 69.2%,p = 0.001) and renal replacement therapy (12.0% vs. 19.6%,p = 0.061), which resulted in shorter ICU length of stay (10 days, IQR 5–18 days vs. 18 days, IQR 5–31 days,p p = 0.159) and hospital mortality even increased (22.4% vs. 33.4%,p = 0.039) in the second period. Age, frailty and the number of comorbidities were significant predictors of hospital mortality in a multivariate logistic regression analysis of the overall cohort.ConclusionAdvanced treatment strategies and learning effects over time resulted in reduced rates of mechanical ventilation and vasopressor use in the second wave associated with shorter ICU length of stay. Despite these improvements, age appears to be a dominant factor for hospital mortality in critically ill COVID-19 patients.

Graphical abstract, Highlights • Myxomas are rare tumors in dogs, in contrast to humans. • Myxomas may cause left ventricular outflow tract obstructions. • Primary cardiac tumors should be considered even in young dogs. • Myxomas may be cavitated and dynamic.

The pleural lobes are the origin of different pathologies, including malignant tumors, e.g., pleural mesothelioma. In some cases, clinical and macroscopic presentation point strongly to the diagnosis but often enough the patient has another underlying disease; malignant neoplasms of the lung as well as other organs (skin, pancreas, prostate or kidney) can mimic pleural mesothelioma and if so, are defined as ‘pseudo-mesothelioma’. We present eight cases that are clinically and macroscopically highly suspicious for pleural mesothelioma. All patients were autopsied due to medico-legal issues and work-related diseases. Six out of eight patients underwent autopsy to exclude possibility of asbestos-related malignancy and two out of eight due to exclusion of silicosis. From the eight cases, only three were real pleural mesotheliomas. Another three were adenocarcinomas of the lung mimicking pleural mesotheliomas. One had squamous cell carcinoma of the lung. Lastly, one patient had an extraordinary case of papillary renal cell carcinoma metastasizing universally in both pleura lobes. Due to striking morphological similarities, the exact final diagnosis was only possible after extended immunohistochemical analysis of the tissues. In summary, not only is it difficult to distinguish between real or pseudo pleural mesothelioma in patients having had contact with asbestos. Even patients with no evidence of asbestos contact can have clinical and pathological events strongly suggesting asbestosis and mesothelioma, without having it.

Major depressive disorder (MDD) is one of the most prevalent and debilitating psychiatric disorders, with a large number of patients not showing an effective therapeutic response to available treatments. Several biopsychosocial factors, such as stress in childhood and throughout life, and factors related to biological aging, may increase the susceptibility to MDD development. Included in critical biological processes related to aging and underlying biological mechanisms associated with MDD is the shortening of telomeres and changes in telomerase activity. This comprehensive review discusses studies that assessed the length of telomeres or telomerase activity and function in peripheral blood cells and brain tissues of MDD individuals. Also, results from in vitro protocols and animal models of stress and depressive-like behaviors were included. We also expand our discussion to include the role of telomere biology as it relates to other relevant biological mechanisms, such as the hypothalamic-pituitary-adrenal (HPA) axis, oxidative stress, inflammation, genetics, and epigenetic changes. In the text and the discussion, conflicting results in the literature were observed, especially considering the size of telomeres in the central nervous system, on which there are different protocols with divergent results in the literature. Finally, the context of this review is considering cell signaling, transcription factors, and neurotransmission, which are involved in MDD and can be underlying to senescence, telomere shortening, and telomerase functions.

We present an endovascular approach for anatomic reconstruction of the iliac bifurcation in life-threatening arterioureteral fistula without sacrificing the pelvic arterial vascular supply. Five consecutive patients suffering from acute onset of significant gross hematuria caused by iliac-ureteral fistula resulting from previous oncologic surgery and radiation therapy were treated by transfemoral stent graft implantation in a double-barrel technique. Iliac-ureteral pseudoaneurysm coverage succeeded in an iliac neobifurcation with preservation of pelvic perfusion. Follow-up ranging from 9 to 37 months confirmed cessation of hematuria. One patient experienced stent graft thrombosis of the external iliac artery as a result of large cervical cancer invasion treated by crossover bypass. In all other patients, stent grafts were patent.

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.

Background The mechanisms underlying the association between obesity and coronavirus disease 2019 (COVID-19) severity remain unclear. After verifying that obesity was a correlate of severe COVID-19 in US Military Health System (MHS) beneficiaries, we compared immunological and virological phenotypes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in both obese and nonobese participants. Methods COVID-19–infected MHS beneficiaries were enrolled, and anthropometric, clinical, and demographic data were collected. We compared the SARS-CoV-2 peak IgG humoral response and reverse-transcription polymerase chain reaction viral load in obese and nonobese patients, stratified by hospitalization, utilizing logistic regression models. Results Data from 511 COVID-19 patients were analyzed, among whom 24% were obese and 14% severely obese. Obesity was independently associated with hospitalization (adjusted odds ratio [aOR], 1.91; 95% confidence interval [CI], 1.15–3.18) and need for oxygen therapy (aOR, 3.39; 95% CI, 1.61–7.11). In outpatients, severely obese had a log10 (1.89) higher nucleocapsid (N1) genome equivalents (GE)/reaction and log10 (2.62) higher N2 GE/reaction than nonobese (P = 0.03 and P < .001, respectively). We noted a correlation between body mass index and peak anti-spike protein IgG in inpatients and outpatients (coefficient = 5.48, P < .001). Conclusions Obesity is a strong correlate of COVID-19 severity in MHS beneficiaries. These findings offer new pathophysiological insights into the relationship between obesity and COVID-19 severity.

This is the first report of a segmental mediolysis occurring in arterioles, affecting the neck/tonsillar region and leading to a fatal hemorrhage after a tonsillectomy in a 20-year-old woman. Arteriolar mediolysis could be observed in tissue layers about 2 cm distant from the tonsillectomy region. Reparative changes were observed in the carotid and small neck arteries as well as in only one intramyocardial arteriole; however, no other vascular regions typically reported in segmental mediolysis arteriopathy were affected and aneurysm formation was not observed. No family history of vascular disease or hypertension was known. Pathophysiologically, previously reported reasons for post-tonsillectomy bleeding could be excluded. Segmental mediolysis may represent a wider spectrum of affected arteriolar vessels besides the reported small and medium sized arteries leading to aneurysms, which impedes radiographic diagnosis.

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.

BackgroundRecently, liquid embolic agents have emerged for the endovascular treatment of cerebral aneurysms. Here we describe the in vivo performance of a novel liquid embolization agent (GPX Embolic Device).MethodsElastase-induced aneurysms were embolized with a GPX prototype under balloon assistance. Digital subtraction angiography was performed pre-deployment and immediately after, and at 5, 10, and 30 min post-deployment in 10 rabbits and at 1 month in 8 rabbits. The early post-deployment intra-aneurysmal flow was graded as unchanged, moderately diminished, or completely absent. At 1 month the status of aneurysm occlusion was evaluated. Adhesion to catheter material and migration of GPX was assessed.ResultsThe mean aneurysm neck diameter, width, and height were 3.6±1.0 mm, 3.0±0.8 mm, and 7.4±1.4 mm, respectively. The mean dome-to-neck ratio was 0.9±0.2. Complete stagnation of intra-aneurysmal flow was observed in 9 of 10 aneurysms (90%) within 30 min of device deployment. One aneurysm showed moderately diminished intra-aneurysmal flow at 30 min. At 1 month, 8 aneurysms were completely occluded. There was no evidence of GPX adhesion to the catheter material. Histologically, a leukocyte and foreign body reaction to GPX was detectable 28 days after embolization.ConclusionsThis is the first preclinical study reporting the performance of a protype version of the GPX Embolic Device in a wide-neck aneurysm model. GPX showed promising results by achieving and maintaining high rates of complete angiographic occlusion, but may induce an inflammatory reaction.

Background For peripheral artery disease (PAD), MR angiography (MRA) is a well-established diagnostic modality providing morphologic and dynamic information comparable to digital subtraction angiography (DSA). However, relatively large amounts of contrast agents are necessary to achieve this. Purpose To evaluate the diagnostic accuracy of time-resolved 4D MR-angiography with interleaved stochastic trajectories (TWIST-MRA) by using maximum intensity projections (MIPs) of dynamic images acquired with reduced doses of contrast agent. Study type Retrospective. Population Forty adult PAD patients yielding 1088 artery segments. Field strength/sequence A 3.0 T, time-resolved 4D MR-angiography with TWIST-MRA and MIP of dynamic images. Assessment DSA was available in 14 patients (256 artery segments) and used as reference standard. Three-segmental MIP reconstructions of TWIST-images after administration of 3 mL of gadolinium-based contrast agent (Gadoteridol/Prohance®, 0.5 M) per anatomical level (pelvis, thighs, and lower legs) yielded 256 artery segments for correlation between MRA and DSA. Three independent observers rated image quality (scale: 1 [nondiagnostic] to 4 [excellent]) and the degree of venous overlay (scale: 0 [none] to 2 [significant]) for all segments. Diagnostic accuracy for the detection of >50% stenosis and artery occlusion was calculated for all observers. Statistical tests Binary classification test (sensitivity, specificity, positive/negative predictive values, diagnostic accuracy). Intraclass correlation coefficients (ICCs), logistic regression analysis with comparison of areas under the receiver-operating-characteristics (ROC) curves (AUCs) with the DeLong method. Bland-Altman-comparison. Results High diagnostic performance was achieved for the detection of >50% stenosis (sensitivity 92.9% [84.3-99.9% (95%-CI)] and specificity 98.5% [95.7-99.8% (95%-CI)]) and artery occlusion (sensitivity 93.1% [77.2-99.2% (95%-CI)] and specificity 99.1% [96.9-99.9% (95%-CI)]). Inter-reader agreement was excellent with ICC values ranging from 0.95 to 1.0 for >50% artery stenosis and occlusion. Image quality was good to excellent for both readers (3.41 ± 0.72, 3.33 ± 0.65, and 3.38 ± 0.61 [mean ± SD]) with good correlation between observer ratings (ICC 0.71-0.81). No significant venous overlay was observed (0.06 ± 0.24, 0.23 ± 0.43 and 0.11 ± 0.45 [mean ± SD]). Data conclusion MIPs of dynamic TWIST-MRA offer a promising diagnostic alternative necessitating only reduced amounts (50%) of gadolinium-based contrast agents for the entire runoff vasculature. Evidence level 3 TECHNICAL EFFICACY: Stage 2.

Background Cardiac magnetic resonance imaging (CMR) allows for detection of fibrosis in hypertrophic cardiomyopathy (HCM) by quantification of the extracellular volume fraction (ECV). Hypothesis/Objectives To quantify native T1 mapping and ECV in cats. We hypothesize that native T1 mapping and ECV will be significantly increased in HCM cats compared with healthy cats. Animals Seventeen healthy and 12 preclinical HCM, age‐matched, client‐owned cats. Methods Prospective observational study. Tests performed included indirect blood pressure, CBC, biochemical analysis including total thyroid, urinalysis, transthoracic echocardiogram, and CMR. Cats were considered healthy if all tests were within normal limits and a diagnosis of HCM was determined by the presence of left ventricular concentric hypertrophy ≥6 mm on echocardiography. Results There were statistically significant differences in LV mass (healthy = 5.87 g, HCM = 10.3 g, P

Background and Aim Ustekinumab is approved in Europe for the treatment of moderate to severe Crohn's disease (CD). Italian real‐life data are scarce, so the aim of this study was to assess the effectiveness and safety of ustekinumab in an Italian cohort of CD patients. Methods Data of patients with CD who started using ustekinumab were extracted from the cohort of the Sicilian Network for Inflammatory Bowel Disease. Primary end‐points were steroid‐free clinical remission at 8, 24, and 52 weeks of therapy and reduction of C‐reactive protein. Secondary end‐points were treatment response, treatment persistence at 12 months, and safety. Results A total of 131 patients (males 56%; mean age 46 years ±15) were included. All patients were biologics experienced except for one. At 24 and 52 weeks, 40% and 43% of patients achieved steroid‐free clinical remission, and 64% and 62% had clinical response, respectively. At the end of follow‐up, there was a significant reduction of steroid use (P = 0.012) and of the Harvey‐Bradshaw Index (P = 0.001). The probability of persistence in therapy with ustekinumab after 12 months of treatment was 89%. The only factor associated with discontinuation was older age. Conclusions Data from our real‐life cohort of treatment‐refractory CD patients suggest the satisfactory effectiveness and safety profile of ustekinumab., We assessed one‐year effectiveness and safety of ustekinumab in an real‐life cohort of treatment‐refractory CD patients. At 52 weeks 43% of patients achieved steroid‐free clinical remission and 62% had clinical response with a persistence in therapy of 98% and a significant reduction of steroid use (p = 0.012) and of HBI (p = 0.001). Data from our cohort suggest satisfactory effectiveness and safety profile of ustekinumab.

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.

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.

Background There has been growing scientific evidence in recent years that bipolar disorder (BD) is associated with alterations in the kynurenine (KYN) pathway. However, many of these studies have been limited by their focus on adults. Thus, this preliminary study investigated differences in the peripheral levels of KYN metabolites in children and adolescents with BD, unaffected offspring of parents with BD, and healthy controls (HCs). Methods Plasma samples were collected from 49 youths with BD, 19 bipolar offspring, and 31 HCs. Tryptophan (TRP), KYN, and kynurenic acid (KYNA) were separated using electrospray ionization. Results One-Way ANCOVA after controlling for age, gender, race, BMI-for-age, and smoking status showed that BD had lower levels of KYN, while unaffected high-risk offspring subjects had lower levels of TRP, KYN, and KYNA when compared to HCs. Moreover, we found that KYN, KYN/TRP, and KYNA/KYN levels predicted the severity of depressive symptoms, while the YMRS score was not associated with any metabolite. Conclusions In summary, this preliminary study has shown that KYN metabolites are decreased in both affected and unaffected subjects, strengthening the idea that the KYN pathway might underlie the familial risk of BD shown by high-risk offspring individuals. However, longitudinal studies are needed to examine whether the alterations observed in this study represent early markers of risk for later developing BD.

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.

BACKGROUND Trauma-induced coagulopathy (TIC) substantially contributes to mortality in bleeding trauma patients. OBJECTIVE The aim of the study was to administer fibrinogen concentrate in the prehospital setting to improve blood clot stability in trauma patients bleeding or presumed to bleed. DESIGN A prospective, randomised, placebo-controlled, double-blinded, international clinical trial. SETTING This emergency care trial was conducted in 12 Helicopter Emergency Medical Services (HEMS) and Emergency Doctors' vehicles (NEF or NAW) and four trauma centres in Austria, Germany and Czech Republic between 2011 and 2015. PATIENTS A total of 53 evaluable trauma patients aged at least 18 years with major bleeding and in need of volume therapy were included, of whom 28 received fibrinogen concentrate and 25 received placebo. INTERVENTIONS Patients were allocated to receive either fibrinogen concentrate or placebo prehospital at the scene or during transportation to the study centre. MAIN OUTCOME MEASURES Primary outcome was the assessment of clot stability as reflected by maximum clot firmness in the FIBTEM assay (FIBTEM MCF) before and after administration of the study drug. RESULTS Median FIBTEM MCF decreased in the placebo group between baseline (before administration of study treatment) and admission to the Emergency Department, from a median of 12.5 [IQR 10.5 to 14] mm to 11 [9.5 to 13] mm (P = 0.0226), but increased in the FC Group from 13 [11 to 15] mm to 15 [13.5 to 17] mm (P = 0.0062). The median between-group difference in the change in FIBTEM MCF was 5 [3 to 7] mm (P

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.

Associations between body mass index (BMI) and the cardiovascular (CV) and kidney efficacy of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in patients with type 2 diabetes (T2D) are uncertain; therefore, data analysed separately from the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial and the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN 6) were examined. These international, randomized, placebo-controlled trials investigated liraglutide and semaglutide (both subcutaneous) in patients with T2D and at high risk of CV events. In post hoc analyses, patients were categorized by baseline BMI (

The world’s first hand transplant was performed for a serviceman in 1964, following a blast injury. Despite a need for such effective reconstruction of military wounds, only eight further transplants have been performed for injured soldiers. This review analysed the specific factors that have informed the use of vascularized composite allotransplantation (VCA) in military patients. Nine servicemembers have received reconstructive transplants worldwide. Seven have received upper limb transplants, one a partial face transplant and one a penile transplant. These have been in Ecuador, the USA, Poland, India and Russia. Countries with clinical VCA programmes in military hospitals include Vietnam and China, whilst others have active pre-clinical VCA research programmes including the USA, the UK and Canada. Despite specific concerns in reconstructing military patients using VCA, outcomes have improved in the last decade and the field has evolved to include more complex tissue composites, across more international centres.

Despite the overwhelming success of vaccines in preventing infectious diseases, there remain numerous globally devastating diseases without fully protective vaccines, particularly human immunodeficiency virus (HIV), malaria and tuberculosis. Nanotechnology approaches are being developed both to design new vaccines against these diseases as well as to facilitate their global implementation. The reasons why a given pathogen may present difficulties for vaccine design are unique and tied to the co-evolutionary history of the pathogen and humans, but there are common challenges that nanotechnology is beginning to help address. In each case, a successful vaccine will need to raise immune responses that differ from the immune responses raised by normal infection. Nanomaterials, with their defined compositions, commonly modular construction, and length scales allowing the engagement of key immune pathways, collectively facilitate the iterative design process necessary to identify such protective immune responses and achieve them reliably. Nanomaterials also provide strategies for engineering the trafficking and delivery of vaccine components to key immune cells and lymphoid tissues, and they can be highly multivalent, improving their engagement with the immune system. This Review will discuss these aspects along with recent nanomaterial advances towards vaccines against infectious disease, with a particular emphasis on HIV/AIDS, malaria and tuberculosis. Several globally significant infectious diseases are not yet treatable with vaccination; nanomaterials are being investigated to provide new strategies for vaccine development.

IntroductionA wealth of evidence supports short-term efficacy of lifestyle interventions in type 2 diabetes (T2D). However, little is known about long-term effects of lifestyle interventions in real-life settings.MethodsThis observational, single-arm study evaluated long-term impact of ‘Voeding Leeft: Reverse-Diabetes2-Now’, a 6-month multicomponent lifestyle programme, on glycaemic control and glucose-lowering medication (GLmed) use, other T2D parameters and quality of life in 438 T2D participants at 6, 12, 18 and 24 months using paired sample t-tests, χ2 and generalised linear models.ResultsAt 24 months, 234 participants provided information on GLmed and HbA1c (‘responders’). 67% of the responders used less GLmed, and 28% ceased all GLmed. Notably, 71% of insulin users at baseline (n=47 of 66 insulin users) were off insulin at 24 months. Mean HbA1c levels were similar at 24 months compared with baseline (55.6±12.8 vs. 56.3±10.5 mmol/mol, p=0.43), but more responders had HbA1c levels ≤53 mmol/mol at 24 months (53% vs 45% at baseline). Furthermore, triglyceride levels (−0.34±1.02 mmol/L, p=0.004), body weight (−7.0±6.8 kg, p2, pConclusionThis study indicates robust, durable real-life benefits of this lifestyle group programme after up to 24 months of follow-up, particularly in terms of medication use, body weight and quality of life in T2D patients.

PURPOSE: To measure the stiffness of the placenta in healthy and preeclamptic patients in the second and third trimesters of pregnancy using ultrasound shear-wave elastography (SWE). We also aimed to evaluate the effect of age, gestational age, gravidity, parity and body mass index (BMI) on placental stiffness and a possible correlation of stiffness with perinatal outcomes. METHODS: In a case–control study, we recruited a total of 47 singleton pregnancies in the second and third trimesters of which 24 were healthy and 23 were diagnosed with preeclampsia. In vivo placental stiffness was measured once at the time of recruitment for each patient. Pregnancies with posterior placentas, multiple gestation, gestational hypertension, chronic hypertension, diabetes, autoimmune disease, fetal growth restriction and congenital anomalies were excluded. RESULTS: The mean placental stiffness was significantly higher in preeclamptic pregnancies compared to controls in the third trimester (difference of means = 16.8; 95% CI (9.0, 24.5); P < 0.001). There were no significant differences in placental stiffness between the two groups in the second trimester or between the severe preeclampsia and preeclampsia without severe features groups (difference of means = 9.86; 95% CI (−5.95, 25.7); P ≥ 0.05). Peripheral regions of the placenta were significantly stiffer than central regions in the preeclamptic group (difference of means = 10.67; 95% CI (0.07, 21.27); P < 0.05), which was not observed in the control group (difference of means = 0.55; 95% CI (−5.25, 6.35); P > 0.05). We did not identify a correlation of placental stiffness with gestational age, maternal age, gravidity or parity. However, there was a statistically significant correlation with BMI (P < 0.05). In addition, pregnancies with higher placental stiffness during the 2nd and 3rd trimesters had significantly reduced birth weight (2890 ± 176 vs. 2420 ± 219 g) and earlier GA (37.8 ± 0.84 vs. 34.3 ± 0.98 weeks) at delivery (P < 0.05). CONCLUSION: Compared to healthy pregnancies, placentas of preeclamptic pregnancies are stiffer and more heterogeneous. Placental stiffness is not affected by gestational age or the severity of preeclampsia but there is a correlation with higher BMI and poor perinatal outcomes.

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.

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.

ZusammenfassungDie Akanthamöbenkeratitis ist ein „Chamäleon“. Sie präsentiert sich klassischerweise mit gräulichen Epithelveränderungen, Perineuritis, oberflächlichen multifokalen stromalen Infiltraten und Ringinfiltrat. Bei klinischem Verdacht auf Akanthamöbenkeratitis ist eine Polymerase-Ketten-Reaktion, eine Kultivierung oder die histopathologische Untersuchung zur Diagnosestellung notwendig. Die konfokale Mikroskopie hat sich als noninvasive Ad-hoc-Diagnostik bei Initialverdacht instituiert.

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.

Background No data on the recently introduced infliximab (IFX) biosimilar SB2 in inflammatory bowel disease (IBD) are available. Methods The Sicilian Prospective Observational Study of Patients With IBD Treated With Infliximab Biosimilar SB2 is a multicenter, observational, prospective study performed among the cohort of the Sicilian Network for Inflammatory Bowel Disease. All consecutive IBD patients starting the IFX biosimilar SB2 from its introduction in Sicily (March 2018) to September 2019 (18 months) were enrolled. Results Two hundred seventy-six patients (Crohn disease: 49.3%, ulcerative colitis: 50.7%) were included: 127 (46.0%) were naïve to IFX and naïve to anti-tumor necrosis factor medications (anti-TNFs), 65 (23.5%) were naïve to IFX and previously exposed to anti-TNFs, 17 (6.2%) were switched from an IFX originator to SB2, 43 (15.6%) were switched from the biosimilar CT-P13 to SB2, and 24 (8.7%) were multiply switched (from IFX originator to CT-P13 to SB2). The cumulative number of infusions of SB2 was 1798, and the total follow-up time was 182.7 patient-years. Sixty-seven serious adverse events occurred in 57 patients (20.7%; incidence rate: 36.7 per 100 patient-year), and 31 of these events caused the withdrawal of the drug. The effectiveness after 8 weeks of treatment was evaluated in patients naïve to IFX (n = 192): 110 patients (57.3%) had steroid-free remission, while 56 patients had no response (29.2%). At the end of follow-up, 72 patients (26.1%) interrupted the treatment, without significant differences in treatment persistency estimations between the five groups (log-rank P = 0.15). Conclusions The safety and effectiveness of SB2 seem to be overall similar to those reported for the IFX originator and CT-P13.

Background Vedolizumab (VDZ) is the first biological therapy for Inflammatory Bowel Disease (IBD) tested, in pivotal trials, on patients up to 80 years old and has usually been presented as a safer choice in frail patients. However, real-world data on the effectiveness and safety of VDZ in elderly (≥ 65 years) are scarce. The aim of this study is to explore the effectiveness and safety of VDZ in a large real-life cohort of elderly IBD patients, with a 2 years follow-up. Methods The Long-term Italian Vedolizumab Effectiveness (LIVE) study included CD and UC patients started on VDZ from April 2016 to June 2017 at 40 centres of the Italian Group for the study of inflammatory bowel disease (IG-IBD). Patients were prospectively followed-up to June 2019. Co-primary endpoints were to evaluate cumulative VDZ treatment persistence and safety. Results Of 966 patients, 174 (18%; 81 CD, 93 UC) were ≥ 65 years old at enrolment. Mean disease duration at baseline was 10.9 years ± SD10 (CD 12.5 ± 11, UC 9.6 ± 9). VDZ was used as a first biologic therapy in 78 patients (44.8%). 25 patients (14.4%) had a history of previous cancer. The majority of CD patients had a stricturing behaviour (45, 55.6%) and had already undergone surgery (41, 49.4%). 48 UC patients (51.6%) had extensive colitis. Moderate-to-severe endoscopic activity was present in 80% of CD and in 92% of UC, according to SES-CD and endoscopic Mayo score, respectively. Cumulative VDZ treatment persistence at 12 and 24 months was 71.8% (71.6% CD and 72.0% UC) and 54% (54.2% CD and 53.8%% UC), respectively. 52.9% (40 CD; 52 UC), 4.0%, 3.5%% and 2.9% of patients were on concomitant steroids at baseline, 6, 12, and 24 months, respectively. Clinical remission at 12 and 24 months was achieved in 28.7% (31 CD and 29 UC) and in 31.6% (25 CD and 30 UC) of patients. Mean C-reactive protein was 15.6 mg/l ± SD 20 (CD 15.9 ± 21; UC 15.2 ± 19) at baseline and dropped to 8.4 mg/l ± 10 (CD 8.0 ± 8, UC 8.9 ± 11) at 12 months and to 5.9 mg/l ± 6 (CD 5.8 ± 5, UC 6 ± 7) at 24 months. Dose escalation was necessary for 20.3% and 24.7% of patients within the first 12 and 24 months. 44 adverse events were reported: 16 infections.,6 new diagnosis of cancer/dysplasia (2 colon, 1 kidney, 1 prostate, 1 lung, 1 melanoma), 4 arthritis, 3 skin rash, 2 drug-induced cholestasis,11 miscellaneous. 11 patients (6.3%) underwent VDZ withdrawal because of adverse events (6 new diagnosis of cancer/dysplasia; 4 infections; 1 cholestasis). One patient died for pneumonia complications. Conclusion In this preliminary analysis of the largest reported real-world cohorts of elderly IBD patients treated with VDZ, up to 55% of patients persisted on therapy after two years; an acceptable safety profile was observed throughout the entire follow-up period.

Objectives Evidence suggests accelerated aging mechanisms in bipolar disorder (BD), including DNA methylation (DNAm) aging in blood. However, it is unknown whether such mechanisms are also evident in the brain, in particular in association with other biological clocks. To investigate this, we interrogated genome-wide DNAm in postmortem hippocampus from 32 BD-I patients and 32 non-psychiatric controls group-matched for age and sex from the NIMH Human Brain Collection Core. Methods DNAm age and epigenetic aging acceleration were estimated using the Horvath method. Telomere length (TL) and mitochondrial DNA (mtDNA) copy number were quantified by real-time PCR. Between-group differences were assessed by linear regression and univariate general linear models with age, sex, race, postmortem interval, tissue pH, smoking, and body mass index included as co-variates. Results Groups did not differ for epigenetic aging acceleration when considering the entire sample. However, after splitting the sample by the median age, an epigenetic aging acceleration was detected in patients compared to controls among older subjects (P = .042). While TL did not differ between groups, a reduction in mtDNA copy number was observed in patients compared to controls (P = .047). In addition, significant correlations were observed between epigenetic aging acceleration and TL (r = -.337, P = .006), as well as between TL and mtDNA copy number (r = .274, P = .028). Conclusions Hippocampal aging may underlie neurocognitive dysfunctions observed in BD patients. Moreover, our results suggest a complex cross-talk between biological clocks in hippocampus that may underlie clinical manifestations of premature aging in BD.

A new gene defect in Fleckvieh calves leads to a syndrome with partial phenotype overlap with bovine hereditary zinc deficiency. A mutation in a gene encoding phospholipase D4 ( PLD4), an endosomal exonuclease, causes the disorder. In mice, PLD4 activity indirectly regulates the Toll-like receptor 9 (TLR9) pathway via degradation of microbial DNA. PLD4 absence thus results in visceral macrophage activation comparable to human macrophage activation syndrome. In this study, disease progression and the role of macrophages in affected calves were monitored clinically, clinicopathologically, and histologically over time. Breeding data identified 73 risk matings of heterozygous carriers resulting in 54 potentially PLD4-deficient calves born on farms. PLD4 status was examined via 5′-exonuclease assay, detecting 6 calves carrying the defect. These were purchased and monitored daily until final necropsy. The calves developed progressive skin lesions starting with small scaling areas terminating in severe crusting dermatitis, especially in areas with mechanical exposure. Histological and immunohistochemical analyses indicated that macrophages with cytoplasmic vacuolation increased considerably in skin sections obtained weekly during the disease course. Macrophage increase correlated with increased dermal lesion severity. Macrophage activation was confirmed by prominent phagocytic activity in the superficial dermis using electron microscopy. Dermal mRNA abundance of CCL2 and CCL3 measured by quantitative polymerase chain reaction verified macrophage activation. Further increase in mRNA of downstream molecule MyD88 and cytokine IL12b connected bovine PLD4 deficiency to increased TLR9 pathway activation. In contrast to human macrophage activation syndrome, the main feature of bovine PLD4 deficiency was local disease in organs with contact to microbial DNA (skin, intestine, lungs).

The question of what to feed becomes a new challenge as an infant reaches the transition to complementary foods. Limited information is available that provides a texture progression map for complementary food introduction. Thus, the objective of this study was to determine the relationship between age and food texture experiences (FTE) in young children aged 4-36 months in the United States. A parent-reported survey was fielded with 328 children categorized into five age groups (AGs): 4-8 mo (AG1), 9-12 mo (AG2), 13-18 mo (AG3), 19-24 mo (AG4), 25-36 mo (AG5). The present study analyzed four questions focused on food texture experiences, with statistical analyses including probit and logit models, and analysis of variance. Results showed that all 16 food textures were tried at least once (>50%) by AG3. The question answered by participants, "How well does your child manage a specific texture" showed that significant differences existed among AGs for the management of ten food textures (including chewy, hard, soft), whereas teething alone had no effect. The most refused textures by the children were: AG1 - crispy (27%), AG2 - leafy (23%), AG3 - leafy (40%), AG4- tough meat (52%), and AG5 - leafy (51%). With increasing AG, the refusal probability of nine food textures, including chewy, leafy, and rubbery, also increased (p

BackgroundCurrently available treatments for Parkinson’s disease (PD) do not slow clinical progression nor target alpha-synuclein, the main pathology associated with the disease.ObjectiveThe study objective was to evaluate the efficacy and safety of prasinezumab, a humanized monoclonal antibody that binds aggregated alpha-synuclein, in individuals with early PD. The study rationale, design, and baseline characteristics of enrolled subjects are presented here.MethodsThe PASADENA study is a multicenter, randomized, double-blind, placebo-controlled treatment study. Individuals with early PD, recruited across the US and Europe, received monthly intravenous doses of prasinezumab (1500 mg or 4500 mg) or placebo for a 52-week period (Part 1), followed by a 52-week extension (Part 2) in which all participants received active treatment. Key inclusion criteria were: aged 40–80 years; Hoehn & Yahr (H&Y) Stage I or II; time from diagnosis ≤2 years; having bradykinesia plus one other cardinal sign of PD (e.g. resting tremor, rigidity); DAT-SPECT imaging consistent with PD; and either treatment naïve or on a stable monoamine oxidase B (MAO-B) inhibitor dose. Study design assumptions for sample size and study duration were built using a patient cohort from the Parkinson’s Progression Marker Initiative (PPMI). In this report, baseline characteristics are compared between the treatment-naïve and MAO-B inhibitor-treated PASADENA cohorts and between the PASADENA and PPMI populations.ResultsOf the 443 patients screened, 316 were enrolled into the PASADENA study between June 2017 and November 2018, with an average age of 59.9 years and 67.4% being male. The mean time from diagnosis at baseline was 10.11 months, with 75.3% in H&Y Stage II. Baseline motor and non-motor symptoms (assessed using Movement Disorder Society – Unified Parkinson’s Disease Rating Scale [MDS-UPDRS]) were similar in severity between the MAO-B inhibitor-treated and treatment-naïve PASADENA cohorts (MDS-UPDRS Total score [standard deviation (SD)]; 30.21 [11.96], 32.10 [13.20], respectively). The overall PASADENA population (63.6% treatment naïve and 36.4% on MAO-B inhibitor) also showed a similar severity in MDS-UPDRS scores (e.g. MDS-UPDRS Total score [SD]; 31.41 [12.78], 32.63 [13.04], respectively) to the PPMI cohort (all treatment naïve).ConclusionsThe PASADENA study population is suitable to investigate the potential of prasinezumab to slow disease progression in individuals with early PD.Trial RegistrationNCT03100149

Tigecycline is a novel glycylcycline broad-spectrum antibiotic offering good coverage for critically ill patients experiencing complicated infections. A known side effect is a coagulation disorder with distinct hypofibrinogenemia. To date, the information on possible risk factors and outcomes is sparse. Therefore, the aim of this study is to examine the time course of fibrinogen level changes during tigecycline therapy in critically ill patients. Moreover, we sought to identify risk factors for coagulopathy and to report on clinically important outcomes. We retrospectively reviewed all intensive care patients admitted to our General and Surgical Intensive Care Unit receiving tigecycline between 2010 and 2018. A total of 130 patients were stratified into two groups based on the extent of fibrinogen decrease. Patients with a greater fibrinogen decrease received a higher dose, a longer treatment and more dose changes of tigecycline, respectively. In regard to the underlying pathology, these patients showed higher inflammation markers as well as a slightly reduced liver synthesis capacity. We, therefore, conclude that such a fibrinogen decrease may be based upon further impairment of liver synthesis during severe inflammatory states. To decrease the risk of bleeding, cautious monitoring of coagulation in critically ill patients treated with high-dose tigecycline is warranted.

Intratumoral T cells that might otherwise control tumors are often identified in an ‘exhausted’ state, defined by specific epigenetic modifications as well as upregulation of genes such as CD38, CTLA-4 and PD-1. While the term might imply inactivity, there has been little study of this state at the phenotypic level in tumors to understand the extent of their incapacitation. Starting with the observation that T cells move more quickly through mouse tumors as residence time increases and they progress towards exhaustion, we elaborated a non-stimulatory live-biopsy method for real-time study of T cell behaviors within individual patient tumors. Using two-photon microscopy, we studied native CD8 T cells interacting with APCs and with cancer cells in different micro-niches of human tumors, finding that T cell speed was variable by region and by patient, was independent of T cell density and was inversely correlated with local tumor density. Across a range of tumor types, we found a strong relationship between CD8 T cell motility and exhausted T cell state that corresponds to observations made in mouse models where exhausted T cells move faster. While this is a small study, it demonstrates at least two types of T cell dynamic states in individual human tumors and supports the existence of an active program in ‘exhausted’ T cells that extends beyond incapacitating them.

Background: Multiple drug resistance-associated protein 2 (MRP2) is regarded as transport protein for xenobiotics such as cyclosporine A (CyA). We have shown that MRP2 is downregulated though miRNA133a binding to its 3`UTR region, induced by endothelin-1 (ET-1) via the ETB-receptor in minimal change nephrosis (MCN) and membranous nephropathy (MN). The status in focal-segmental sclerosis, (FSGS) where CyA is a treatment option, is still unknown. The mechanism of CyA nephrotoxicity in renal transplantation is also still elusive. In particular, co-morbidities/clinical parameters, the morphological extent of MR2 damage and the involvement of miRNA133a leading to nephrotoxicity have not been investigated. Aims: To analyze co-morbidities, the role of ET- 1 and miRNA133a for development of CyA renal toxicity and in FSGS. Methods: Analysis of co-morbidities/clinical factors in 230 biopsies from 124 patients. In 35 CyA patients (tubular damage, arteriolar damage, no damage; plus 5 cases of so- called null biopsies as controls), and in FSGS (n=8) immune histology and subsequent morphometry of MRP2 expression was performed and a qRT-PCR for the detection of miRNA133a was analysed. Human proximal tubular cell culture was used for studying the effect of ET-1 alone or in combination with CyA on MRP2 and miRNA133a levels. MiRNA levels were further determined in the ETB-receptor knock-out rat (ETBR sl/sl; wt vs. ko -/- ETBR) after 5/6 nephrectomy as a model for FSGS. Results: No single clinical parameter was clearly responsible for CyA nephrotoxicity. Morphometric analysis revealed an increasing degree of damage: from no CyA toxicity, to arteriolar CyA toxicicity, to combined arteriolar and tubular toxicity; the maximum degree was seen in tubular toxicity. The effect could be studied in human proximal tubular cell culture, where the combination of ET-1 and CyA showed a higher effect of tubular damage than ET- alone. CyA induced mostly tubular but also arteriolar damage by downregulating the mrp2 gene via the upregulation of miRNA133a. In FSGS, with only a small difference to normal conditions observed by immune histology, by qRT-PCR Mrp2 was downregulated, while miRNA133a was clearly upregulated. Under proteinuric conditions of renal ablation, ET-BR knock-out animals were protected from miRNA133a upregulation. Conclusion: Downregulation of MRP2 by miRNA133a is an important mechanism of CyA nephrotoxicity and in FSGS. The intensity of cytotoxicity may increase if FSGS is treated with CyA. Potential urinary analysis as detection assay and treatment options by an ETB-receptor antagonist are discussed. The therapeutic potential in steroid resistant syndrome such as in African pediatric FSGS cases is outlined.

Tuberculosis has been described as a global health crisis since the 1990s, with an estimated 1.4 million deaths in the last year. Herein, a series of 20 1H-indoles were synthesized and evaluated as in vitro inhibitors of Mycobacterium tuberculosis (Mtb) growth. Furthermore, the top hit compounds were active against multidrug-resistant strains, without cross-resistance with first-line drugs. Exposing HepG2 and Vero cells to the molecules for 72 h showed that one of the evaluated structures was devoid of apparent toxicity. In addition, this 3-phenyl-1H-indole showed no genotoxicity signals. Finally, time-kill and pharmacodynamic model analyses demonstrated that this compound has bactericidal activity at concentrations close to the Minimum Inhibitory Concentration, coupled with a strong time-dependent behavior. To the best of our knowledge, this study describes the activity of 3-phenyl-1H-indole against Mtb for the first time.