Nasal IL-13 production identifies patients with late-phase allergic responses.

BACKGROUND: There is limited knowledge on how local cytokine secretion patterns after nasal allergen challenge correlate with clinical symptoms especially with regard to the "late allergic response," which occurs in approximately 40% to 50% of patients with allergy. OBJECTIVE: We sought to characterize the immunologic and clinical nasal responses to birch pollen allergen challenge with a special focus on the late allergic response. METHODS: In this randomized, double-blind, placebo-controlled trial, birch pollen-allergic participants were challenged with birch pollen extract (n = 20) or placebo (n = 10) on 3 consecutive days. On days 1 and 3, nasal secretions were collected at selected time points over a 24-hour time course for the measurement of 33 inflammatory mediators. Clinical responses were determined through subjective symptom scores and objective nasal airflow measurements. RESULTS: Provoked participants had significantly greater clinical responses and showed significant increases in tryptase and the soluble IL-33 receptor serum stimulation 2 (sST2) in nasal secretions within minutes compared with the placebo group. Eight of 20 provoked participants displayed high IL-13 levels 2 to 8 hours after allergen provocation. This group also showed significant changes in clinical parameters, with a secondary drop in nasal airflow measured by peak nasal inspiratory flow and increased symptoms of nasal obstruction, which significantly differed from IL-13 nonresponders after 6 hours. CONCLUSIONS: IL-13 response status correlates with clinical responses and type 2 cytokine responses in the late phase after allergen provocation.

Performance of clinical risk scores and prediction models to identify pathogenic germline variants in patients with advanced prostate cancer.

PURPOSE: Determining the frequency and distribution of pathogenic germline variants (PGVs) in Austrian prostate cancer (PCa) patients and to assess the accuracy of different clinical risk scores to correctly predict PGVs. METHODS: This cross-sectional study included 313 men with advanced PCa. A comprehensive personal and family history was obtained based on predefined questionnaires. Germline DNA sequencing was performed between 2019 and 2021 irrespective of family history, metastatic or castration status or age at diagnosis. Clinical risk scores for hereditary cancer syndromes were evaluated and a PCa-specific score was developed to assess the presence of PGVs. RESULTS: PGV presence was associated with metastasis (p = 0.047) and castration resistance (p = 0.011), but not with personal cancer history or with relatives with any type of cancer. Clinical risk scores (Manchester score, PREMM5 score, Amsterdam II criteria or Johns Hopkins criteria) showed low sensitivities (3.3-20%) for assessing the probability of PGV presence. A score specifically designed for PCa patients stratifying patients into low- or high-risk regarding PGV probability, correctly classified all PGV carriers as high-risk, whereas a third of PCa patients without PGVs was classified as low risk of the presence of PGVs. CONCLUSION: Application of common clinical risk scores based on family history are not suitable to identify PCa patients with high PGV probabilities. A PCa-specific score stratified PCa patients into low- or high-risk of PGV presence with sufficient accuracy, and germline DNA sequencing may be omitted in patients with a low score. Further studies are needed to evaluate the score.

Gapless Electrocardiogram-Monitoring in stroke at high risk of atrial fibrillation.

BACKGROUND AND PURPOSE: Previous studies investigating prolonged electrocardiogram (ECG)-monitoring after ischemic stroke had significant gaps between the index event and the beginning of long-term monitoring. Atrial fibrillation (AF) detection might be higher if prolonged cardiac rhythm documentation is performed with a gapless approach without any interruption of monitoring time. METHODS: This investigator-initiated, prospective study included patients with acute ischemic stroke or transient ischemic attack at three study centers. Participants received gapless ECG-monitoring via telemetry during stroke-unit admission until implantation of an insertable cardiac monitor (ICM) within the first days after the index event. Patients acted as their own controls and also received standard 24-72-h Holter ECG. RESULTS: A total of 110 patients were included, of whom 86 (78.2%) had an embolic stroke of unknown source, 14 (12.7%) had small-vessel disease, and 10 (9.1%) had large-artery disease. AF was newly diagnosed in 17 (15.5%) patients via ICM monitoring, compared to one (0.9%) patient via Holter ECG during 6 months of follow-up (p < 0.001). The detection rate of AF within the first 30 days was 10.0%, which accounted for 64% of all new AF diagnoses. The median duration of the detected episodes was 1.7 (interquartile range = 0.2-4.7) h. All patients with new onset AF were treated with oral anticoagulation. CONCLUSIONS: Gapless ECG-monitoring is an effective strategy to significantly increase the detection rate of AF after ischemic stroke. This finding supports the use of long-term ECG-monitoring with a gapless approach without any interruption in monitoring time as the gold standard for clinical practice.

Massive release of TH2 cytokines induced a cytokine storm during a severe mast cell activation event in a patient with indolent systemic mastocytosis.

BACKGROUND: In subjects with systemic mastocytosis, the number of mast cells is elevated many fold. These patients frequently experience unpredictable and recurrent life-threatening mast cell activation (MCA) events. OBJECTIVE: Our aim was to analyze the derangements of chemokine and cytokine concentrations during severe MCA attacks. METHODS: Samples from a patient with indolent systemic mastocytosis were used for this study. A total of 41 chemokines and cytokines were simultaneously measured in triplicate and at multiple time points during 2 severe and 2 moderate MCA events. These were compared to 3 to 5 baseline samples, taken when clinical symptoms were not present. RESULTS: During the severe MCA event, which required 2 days of treatment in the intensive care unit, peak chemokine (C-C motif) ligand 3, IL-1ra, IL-5, IL-6, IL-10, IL-13, and granulocyte-macrophage colony-stimulating factor concentrations were statistically significantly elevated 29-, 99-, 44-, 280-, 93-, 7-, and 6-fold above baseline, respectively. A highly similar pattern was observed during the second severe MCA event. In the moderate MCA event with PCR-proven influenza A infection, the TH1-associated cytokines INF-α, INF-γ, and TNF-α were only statistically significantly elevated 5- to 7-fold above baseline. The correlation coefficients between highly elevated histamine and cytokine concentrations during the acute phase were >95%, indicating the same cellular origin, possibly activated mast cells. CONCLUSIONS: One of the severe MCA events led to life-threatening symptoms over several days. During this event, the massive release of TH2 cytokines induced a hyperinflammatory state, fulfilling published criteria for cytokine release syndrome. Administration of IL-6- and IL-5-inhibiting biologicals might significantly shorten the acute phase of severe MCA events, likely offering significant clinical benefits to mastocytosis patients.

Effect of Regular Electrotherapy on Spinal Flexibility and Pain Sensitivity in Patients with Chronic Non-Specific Neck Pain and Low Back Pain: A Randomized Controlled Double-Blinded Pilot Trial.

Background and Objectives: Chronic neck pain and low back pain are common conditions in high-income countries leading to social and medical problems such as invalidity and decreased quality of life. The aim of this study was to investigate the effect of supra-threshold electrotherapy on pain level, subjective feeling of disability, and spinal mobility in patients with chronic pain in the spinal cord. Materials and Methods: 11 men and 24 women with a mean age of 49 years were randomly divided into three groups: group 1, "therapy": supra-threshold electrotherapy was applied on the whole back after electrical calibration; group 2, "control": electrical calibration without successive electrotherapy; group 3, "control of control": no stimulation. Sessions were performed once a week and six times in total, each lasting 30 min. The numeric pain rating scale (NRS), cervical and lumbar range of motion (ROM), as well as disability in daily live were investigated before and after the sessions using questionnaires (Neck Disability Index, Roland Morris Questionnaire, Short-form Mc Gill Pain Questionnaire (SF-MPQ)). Results: Spinal mobility improved significantly in the lumbar anteflexion (baseline mean, 20.34 ± SD 1.46; post session mean, 21.43 ± SD 1.95; p = 0.003) and retroflexion (baseline mean, 13.68 ± SD 1.46; post session mean, 12.05 ± SD 1.37; p = 0.006) in the group receiving electrotherapy. Pain levels measured by the NRS and disability-questionnaire scores did not differ significantly before and after treatment in any of the groups. Conclusions: Our data indicate that regular supra-threshold electrotherapy for six times has a positive effect on lumbar flexibility in chronic neck pain and low back pain patients, whereas pain sensation or subjective feeling of disability remained unchanged.

Growth prediction model for abdominal aortic aneurysms.

BACKGROUND: The most relevant determinant in scheduling monitoring intervals for abdominal aortic aneurysms (AAAs) is maximum diameter. The aim of the study was to develop a statistical model that takes into account specific characteristics of AAA growth distributions such as between-patient variability as well as within-patient variability across time, and allows probabilistic statements to be made regarding expected AAA growth. METHODS: CT angiography (CTA) data from patients monitored at 6-month intervals with maximum AAA diameters at baseline between 30 and 66 mm were used to develop the model. By extending the model of geometric Brownian motion with a log-normal random effect, a stochastic growth model was developed. An additional set of ultrasound-based growth data was used for external validation. RESULTS: The study data included 363 CTAs from 87 patients, and the external validation set comprised 390 patients. Internal and external cross-validation showed that the stochastic growth model allowed accurate description of the distribution of aneurysm growth. Median relative growth within 1 year was 4.1 (5-95 per cent quantile 0.5-13.3) per cent. Model calculations further resulted in relative 1-year growth of 7.0 (1.0-16.4) per cent for patients with previously observed rapid 1-year growth of 10 per cent, and 2.6 (0.3-8.3) per cent for those with previously observed slow growth of 1 per cent. The probability of exceeding a threshold of 55 mm was calculated to be 1.78 per cent at most when adhering to the current RESCAN guidelines for rescreening intervals. An online calculator based on the fitted model was made available. CONCLUSION: The stochastic growth model was found to provide a reliable tool for predicting AAA growth.

Perioperative levetiracetam for seizure prophylaxis in seizure-naive brain tumor patients with focus on neurocognitive functioning.

INTRODUCTION: In seizure-naive brain tumor patients, the efficacy of perioperative prophylactic antiepileptic drug treatment remains controversial. In case of administration, the common preferred drug is levetiracetam (LEV) because of its favorable pharmacological profile. Research to date has not sufficiently determined how LEV affects cognition in the short term, as is the case in the perioperative period. The objective of this prospective study was to examine the neurocognitive functioning of seizure-naive brain tumor patients after receiving LEV perioperatively. METHODS: Fortythree patients with supratentorial brain tumor scheduled for surgery received LEV three days before until six days after surgery as seizure prophylaxis. Cognitive functioning (NeuroCogFX), LEV plasma-levels, hematotoxicity, side-effects, as well as health-related quality of life (HRQoL, Qolie31), were recorded preoperatively before (Baseline) and after onset of LEV (Pre-Op), 4-6 days postoperatively (Post-Op) and 21 days postoperatively (Follow-Up). RESULTS: No significant changes in cognitive functioning and HRQoL were seen after onset of preoperative LEV. There was a significant improvement of NeuroCogFX total-score at Follow-Up (p = 0.004) compared to Baseline. The overall-score Qolie31 showed simultaneous improvement patterns as cognitive functioning (p < 0.001). The most frequent side effect related to study drug was somnolence (in 28.6% of patients). CONCLUSIONS: A significant improvement of cognitive functioning, as well as an improvement in HRQoL, were detected postoperatively. This is presumably due to the debulking effect of the surgery. Nevertheless, LEV has no detrimental effect on cognitive functioning in the perioperative phase in seizure-naive brain tumor patients. TRIAL REGISTRATION: This study was registered prospectively (Date: 25/11/2015; EudraCT: 2015-003,916-19).

A Randomized Clinical Trial of Anti-IL-6 Antibody Clazakizumab in Late Antibody-Mediated Kidney Transplant Rejection.

BACKGROUND: Late antibody-mediated rejection (ABMR) is a leading cause of transplant failure. Blocking IL-6 has been proposed as a promising therapeutic strategy. METHODS: We performed a phase 2 randomized pilot trial to evaluate the safety (primary endpoint) and efficacy (secondary endpoint analysis) of the anti-IL-6 antibody clazakizumab in late ABMR. The trial included 20 kidney transplant recipients with donor-specific, antibody-positive ABMR ≥365 days post-transplantation. Patients were randomized 1:1 to receive 25 mg clazakizumab or placebo (4-weekly subcutaneous injections) for 12 weeks (part A), followed by a 40-week open-label extension (part B), during which time all participants received clazakizumab. RESULTS: Five (25%) patients under active treatment developed serious infectious events, and two (10%) developed diverticular disease complications, leading to trial withdrawal. Those receiving clazakizumab displayed significantly decreased donor-specific antibodies and, on prolonged treatment, modulated rejection-related gene-expression patterns. In 18 patients, allograft biopsies after 51 weeks revealed a negative molecular ABMR score in seven (38.9%), disappearance of capillary C4d deposits in five (27.8%), and resolution of morphologic ABMR activity in four (22.2%). Although proteinuria remained stable, the mean eGFR decline during part A was slower with clazakizumab compared with placebo (-0.96; 95% confidence interval [95% CI], -1.96 to 0.03 versus -2.43; 95% CI, -3.40 to -1.46 ml/min per 1.73 m2 per month, respectively, P=0.04). During part B, the slope of eGFR decline for patients who were switched from placebo to clazakizumab improved and no longer differed significantly from patients initially allocated to clazakizumab. CONCLUSIONS: Although safety data indicate the need for careful patient selection and monitoring, our preliminary efficacy results suggest a potentially beneficial effect of clazakizumab on ABMR activity and progression.

Early Postoperative Basal Insulin Therapy versus Standard of Care for the Prevention of Diabetes Mellitus after Kidney Transplantation: A Multicenter Randomized Trial.

BACKGROUND: Post-transplantation diabetes mellitus (PTDM) might be preventable. METHODS: This open-label, multicenter randomized trial compared 133 kidney transplant recipients given intermediate-acting insulin isophane for postoperative afternoon glucose ≥140 mg/dl with 130 patients given short-acting insulin for fasting glucose ≥200 mg/dl (control). The primary end point was PTDM (antidiabetic treatment or oral glucose tolerance test-derived 2 hour glucose ≥200 mg/dl) at month 12 post-transplant. RESULTS: In the intention-to-treat population, PTDM rates at 12 months were 12.2% and 14.7% in treatment versus control groups, respectively (odds ratio [OR], 0.82; 95% confidence interval [95% CI], 0.39 to 1.76) and 13.4% versus 17.4%, respectively, at 24 months (OR, 0.71; 95% CI, 0.34 to 1.49). In the per-protocol population, treatment resulted in reduced odds for PTDM at 12 months (OR, 0.40; 95% CI, 0.16 to 1.01) and 24 months (OR, 0.54; 95% CI, 0.24 to 1.20). After adjustment for polycystic kidney disease, per-protocol ORs for PTDM (treatment versus controls) were 0.21 (95% CI, 0.07 to 0.62) at 12 months and 0.35 (95% CI, 0.14 to 0.87) at 24 months. Significantly more hypoglycemic events (mostly asymptomatic or mildly symptomatic) occurred in the treatment group versus the control group. Within the treatment group, nonadherence to the insulin initiation protocol was associated with significantly higher odds for PTDM at months 12 and 24. CONCLUSIONS: At low overt PTDM incidence, the primary end point in the intention-to-treat population did not differ significantly between treatment and control groups. In the per-protocol analysis, early basal insulin therapy resulted in significantly higher hypoglycemia rates but reduced odds for overt PTDM-a significant reduction after adjustment for baseline differences-suggesting the intervention merits further study.Clinical Trial registration number: NCT03507829.

Nineteen percent of meniscus repairs are being revised and failures frequently occur after the second postoperative year: a systematic review and meta-analysis with a minimum follow-up of 5 years.

PURPOSE: Meniscus repair has gained increasing interest over the last two decades as loss of meniscus tissue predisposes to early onset knee arthritis. Although there are many reports of meniscus repair outcome in short-term studies, data on the long-term outcome of meniscus repair are still scarce. The purpose of this meta-analysis was to evaluate the overall failure rate of meniscus repair with a minimum follow-up of 5 years. Additionally, possible factors influencing meniscus repair outcome were assessed. METHODS: PubMed and Scopus were searched for studies of the last 20 years reporting on meniscus repair outcome with a minimum follow-up of 5 years. The study was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The search terms used for this study were ([meniscus OR meniscal] AND repair). Titles and abstracts were evaluated by two authors independently. Using meta package of R (version 3.6.2), random-effect models were performed to pool failure rates. Subgroup analyses were performed and effect estimates in form of an odds ratio with 95% CIs were established. RESULTS: In total, 12 studies with 864 patients were included. Degenerative tears were excluded in two studies and one study only included traumatic meniscus tears. Other studies did not state whether the cause of meniscus tear was degenerative or traumatic. Studies reporting meniscus repair outcome on root repairs, revision anterior cruciate ligament reconstruction, discoid menisci or ramp lesions were excluded. Revision surgery was used as failure definition in all included studies. The overall failure rate of meniscal repair at a mean follow-up of 86 months was 19.1%. There was no significant difference in meniscus repair outcome when performed in combination with anterior cruciate ligament reconstruction compared to isolated meniscus repair (18.7% vs. 28%; n.s.) or when performed on the lateral meniscus compared to the medial meniscus (19.5% vs. 24.4%; n.s.). There was no significant difference of meniscus repair outcome between vertical/longitudinal tears and bucket-handle tears (n.s.). Thirty-six percent of meniscus repair failures occur after the second postoperative year. The only significant finding was that inside-out repair results in a lower failure rate compared to all-inside repair (5.6% vs. 22.3%; p = 0.009) at 5 years. CONCLUSION: The overall meniscus repair failure rate remains nineteen percent in long-term studies. The cause of failure is poorly documented, and it remains unclear whether failure of the meniscus repair itself or additional adjacent tears lead to revision surgery. Despite the given technical advantages of all-inside repair devices, this meta-analysis cannot demonstrate superior outcomes compared to inside-out or outside-in repair at 5 years. LEVEL OF EVIDENCE: IV.

Metabolome and lipidome derangements during a severe mast cell activation event in a patient with indolent systemic mastocytosis.

BACKGROUND: The number of mast cells in various organs is elevated manifold in individuals with systemic mastocytosis. Degranulation can lead to life-threatening symptomatology. No data about the alterations of the metabolome and lipidome during an attack have been published. OBJECTIVE: Our aim was to analyze changes in metabolomics and lipidomics during the acute phase of a severe mast cell activation event. METHODS: A total of 43 metabolites and 11 lipid classes comprising 200 subvariants from multiple plasma samples in duplicate, covering 72 hours of a severe mast cell activation attack with nausea and vomiting, were compared with 2 baseline samples by using quantitative liquid chromatography-mass spectrometry. RESULTS: A strong enterocyte dysfunction reflected in an almost 20-fold reduction in the functional small bowel length was extrapolated from strongly reduced ornithine and citrulline concentrations and was very likely secondary to severe endothelial cell dysfunction with hypoperfusion and extensive vascular leakage. Highly increased histamine and lactate concentrations accompanied the peak in clinical symptoms. Elevated asymmetric and symmetric dimethylarginine levels combined with reduced arginine levels compromised endothelial nitric oxide synthase activity and nitric oxide signaling. Specific and extensive depletion of many lysophosphatidylcholine variants indicates localized autotaxin activation and lysophosphatidic acid release. A strong correlation of clinical parameters with histamine concentrations and symptom reduction after 100-fold elevated plasma diamine oxidase concentrations implies that histamine is the key driver of the acute phase. CONCLUSIONS: Rapid elimination of elevated histamine concentrations through use of recombinant human diamine oxidase, supplementation of lysophosphatidylcholine for immunomodulation, inhibition of autotaxin activity, and/or blockade of lysophosphatidic acid receptors might represent new treatment options for life-threatening mast cell activation events.

Robust group sequential designs for trials with survival endpoints and delayed response.

Randomized clinical trials in oncology typically utilize time-to-event endpoints such as progression-free survival or overall survival as their primary efficacy endpoints, and the most commonly used statistical test to analyze these endpoints is the log-rank test. The power of the log-rank test depends on the behavior of the hazard ratio of the treatment arm to the control arm. Under the assumption of proportional hazards, the log-rank test is asymptotically fully efficient. However, this proportionality assumption does not hold true if there is a delayed treatment effect. Cancer immunology has evolved over time and several cancer vaccines are available in the market for treating existing cancers. This includes sipuleucel-T for metastatic hormone-refractory prostate cancer, nivolumab for metastatic melanoma, and pembrolizumab for advanced nonsmall-cell lung cancer. As cancer vaccines require some time to elicit an immune response, a delayed treatment effect is observed, resulting in a violation of the proportional hazards assumption. Thus, the traditional log-rank test may not be optimal for testing immuno-oncology drugs in randomized clinical trials. Moreover, the new immuno-oncology compounds have been shown to be very effective in prolonging overall survival. Therefore, it is desirable to implement a group sequential design with the possibility of early stopping for overwhelming efficacy. In this paper, we investigate the max-combo test, which utilizes the maximum of two weighted log-rank statistics, as a robust alternative to the log-rank test. The new test is implemented for two-stage designs with possible early stopping at the interim analysis time point. Two classes of weights are investigated for the max-combo test: the Fleming and Harrington (1981) Gρ,γ$G^{\rho , \gamma }$ weights and the Magirr and Burman (2019) modest (τ∗)$ (\tau ^{*})$  weights.

MRI-guided adaptive brachytherapy in locally advanced cervical cancer (EMBRACE-I): a multicentre prospective cohort study.

BACKGROUND: The concept of the use of MRI for image-guided adaptive brachytherapy (IGABT) in locally advanced cervical cancer was introduced 20 years ago. Here, we report on EMBRACE-I, which aimed to evaluate local tumour control and morbidity after chemoradiotherapy and MRI-based IGABT. METHODS: EMBRACE-I was a prospective, observational, multicentre cohort study. Data from patients from 24 centres in Europe, Asia, and North America were prospectively collected. The inclusion criteria were patients older than 18 years, with biopsy-proven squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix, The International Federation of Gynecology and Obstetrics (FIGO) stage IB-IVA disease or FIGO stage IVB disease restricted to paraaortic lymph metastasis below the L1-L2 interspace, suitable for curative treatment. Treatment consisted of chemoradiotherapy (weekly intravenous cisplatin 40 mg/m2, 5-6 cycles, 1 day per cycle, plus 45-50 Gy external-beam radiotherapy delivered in 1·8-2 Gy fractions) followed by MRI-based IGABT. The MRI-based IGABT target volume definition and dose reporting was according to Groupe Européen de Curiethérapie European Society for Radiation Oncology recommendations. IGABT dose prescription was open according to institutional practice. Local control and late morbidity were selected as primary endpoints in all patients available for analysis. The study was registered with ClinicalTrials.gov, NCT00920920. FINDINGS: Patient accrual began on July 30, 2008, and closed on Dec 29, 2015. A total of 1416 patients were registered in the database. After exclusion for not meeting patient selection criteria before treatment, being registered but not entered in the database, meeting the exclusion criteria, and being falsely excluded, data from 1341 patients were available for analysis of disease and data from 1251 patients were available for assessment of morbidity outcome. MRI-based IGABT including dose optimisation was done in 1317 (98·2%) of 1341 patients. Median high-risk clinical target volume was 28 cm3 (IQR 20-40) and median minimal dose to 90% of the clinical target volume (D90%) was 90 Gy (IQR 85-94) equi-effective dose in 2 Gy per fraction. At a median follow-up of 51 months (IQR 20-64), actuarial overall 5-year local control was 92% (95% CI 90-93). Actuarial cumulative 5-year incidence of grade 3-5 morbidity was 6·8% (95% CI 5·4-8·6) for genitourinary events, 8·5% (6·9-10·6) for gastrointestinal events, 5·7% (4·3-7·6) for vaginal events, and 3·2% (2·2-4·5) for fistulae. INTERPRETATION: Chemoradiotherapy and MRI-based IGABT result in effective and stable long-term local control across all stages of locally advanced cervical cancer, with a limited severe morbidity per organ. These results represent a positive breakthrough in the treatment of locally advanced cervical cancer, which might be used as a benchmark for clinical practice and all future studies. FUNDING: Medical University of Vienna, Aarhus University Hospital, Elekta AB, and Varian Medical Systems.

Silent Brain Infarction After Endovascular Arch Procedures: Preliminary Results from the STEP Registry.

OBJECTIVE: Few data exist concerning the rate of silent cerebral ischaemic events following endovascular treatment of the aortic arch. The objective of this work was to quantify these lesions using the STEP registry (NCT04489277). METHODS: This multicentre retrospective cohort study included consecutive patients treated with an aortic endoprosthesis deployed in Ishimaru zone 0-3 and brain diffusion weighted magnetic resonance imaging (DW-MRI) within seven days following the procedure. DW-MRI was performed to identify the location and number of new silent brain infarctions (SBI). All endografts were carbon dioxide flushed prior to implantation. RESULTS: The study population included 91 patients (mean age, 69 years; men, 64%) from two academic centres treated between September 2018 and January 2020. The procedure was elective in 71 patients (78%). The treatment was performed for a dissection, degenerative aneurysm, or other aortic disease in 44 (49%), 34 (37%), and 13 (14%) patients, respectively. Endografts were deployed in zone 0, 1, 2 or 3 in 23 (25%), 10 (11%), 47 (52%), and 11 (12%) patients, respectively. Endografts were branched (25%), fenestrated (17%), or tubular (58%). At 30 days, there were no deaths or clinical strokes. On cerebral DW-MRI, a total of 245 SBI were identified in 45 patients (50%). Lesions were in the left hemisphere in 63% of the patients (153/245), predominantly in the middle territory (94/245). Deployment in zone 0-1 (p = .026), placement of a branched or fenestrated endograft (p = .038), a proximal endoprosthesis diameter ≥ 40 mm (p = .038), and an urgent procedure (p = .005) were significantly associated with the presence of SBI on univariable analysis, while urgent procedure was found to be an independent predictor on multivariable analysis (binary logistic regression) (p = .002). CONCLUSION: SBI following endovascular repair of the aortic arch is frequent, although there were no clinical strokes. Innovative strategies to reduce the risk of embolisation need to be developed.

Delayed treatment effects, treatment switching and heterogeneous patient populations: How to design and analyze RCTs in oncology.

In the analysis of survival times, the logrank test and the Cox model have been established as key tools, which do not require specific distributional assumptions. Under the assumption of proportional hazards, they are efficient and their results can be interpreted unambiguously. However, delayed treatment effects, disease progression, treatment switchers or the presence of subgroups with differential treatment effects may challenge the assumption of proportional hazards. In practice, weighted logrank tests emphasizing either early, intermediate or late event times via an appropriate weighting function may be used to accommodate for an expected pattern of non-proportionality. We model these sources of non-proportional hazards via a mixture of survival functions with piecewise constant hazard. The model is then applied to study the power of unweighted and weighted log-rank tests, as well as maximum tests allowing different time dependent weights. Simulation results suggest a robust performance of maximum tests across different scenarios, with little loss in power compared to the most powerful among the considered weighting schemes and huge power gain compared to unfavorable weights. The actual sources of non-proportional hazards are not obvious from resulting populationwise survival functions, highlighting the importance of detailed simulations in the planning phase of a trial when assuming non-proportional hazards.We provide the required tools in a software package, allowing to model data generating processes under complex non-proportional hazard scenarios, to simulate data from these models and to perform the weighted logrank tests.

ELBW infants receive inadvertent sodium load above the recommended intake.

BACKGROUND: To determine total sodium load, including inadvertent load, during the first 2 postnatal weeks, and its influence on serum sodium, morbidity, and mortality in extremely low birth weight (ELBW, birth weight <1000 g) infants and to calculate sodium replacement models. METHODS: Retrospective data analysis on ELBW infants with a gestational age <28 + 0/7 weeks. RESULTS: Ninety patients with a median birth weight of 718 g and a median gestational age of 24 + 6/7 weeks were included. Median sodium intake during the first 2 postnatal weeks was 10.2 mmol/kg/day, which was significantly higher than recommended (2-5 mmol/kg/day). Sodium intake did not affect the risk for hypernatremia. Each mmol of sodium intake during the first postnatal week was associated with an increased risk of bronchopulmonary dysplasia (45%) and higher-grade intraventricular hemorrhage (31%), during the second postnatal week for necrotizing enterocolitis (19%), and during both postnatal weeks of mortality (13%). Calculations of two sodium replacement models resulted in a decrease in sodium intake during the first postnatal week of 3.2 and 4.0 mmol/kg/day, respectively. CONCLUSIONS: Sodium load during the first 2 postnatal weeks of ELBW infants was significantly higher than recommended owing to inadvertent sodium intake and was associated with a higher risk of subsequent morbidity and mortality, although the study design does not allow conclusions on causality. Replacement of 0.9% saline with alternative carrier solutions might reduce sodium intake. IMPACT: Sodium intake in ELBW infants during the first 2 postnatal weeks was twofold to threefold higher than recommended; this was mainly caused by inadvertent sodium components. High sodium intake is not related to severe hypernatremia but might be associated with a higher morbidity in terms of BPD, IVH, and NEC. Inadvertent sodium load can be reduced by replacing high sodium-containing carrier solutions with high levels of sodium with alternative hypotonic and/or balanced fluids, model based.

Pull-out forces of headless compression screws in variations of synthetic bone models imitating different types of scaphoid fractures in good bone quality.

Screw osteosynthesis using headless compression screws has become the accepted gold standard for the surgical treatment of scaphoid fractures. Optimal screw specifications remain controversially discussed. We aimed to investigate the influence of bone model composition on screw stability tests using headless compression screws in different scaphoid fracture models. We conducted pull-out tests using Acutrak2®mini, HCS®, HKS®, HBS®, Herbert/Whipple® and Twinfix® screws. To imitate cortical and cancellous bone, two-layer polyurethane (PU) models with two distinct densities were produced. The cylinders were cut at different positions to replicate fracture localisations at increasing distances. The maximum pull-out force required to achieve up to 1 mm of pull-out distance (Nto 1 mm) was measured. Acutrak2®mini and HCS® followed by Twinfix® showed the greatest average pull-out forces. Nto 1 mm was, on average, greater in the cortico-cancellous model than in the cancellous cylinder with the Acutrak2®mini and the Herbert/Whipple® screws, while it was the least with the HBS® and the Twinfix® screws; there were also differences between the HCS® and HKS®. There were no differences between the different fracture simulations in the synthesis strength using either the HKS® or HBS®. The pull-out forces of the HCS® and Twinfix® remained high also in simulations with the smaller screw base fragments. Varying imitations of cancellous and cortico-cancellous bone and fracture localisation reveal important information about the ex vivo strength of screw syntheses. The grip of the cortical structure should be used with the screws that fit more firmly in cortico-cancellous bone.

Very early changes in serum creatinine are associated with 30-day mortality after cardiac surgery: A cohort study.

BACKGROUND: Acute kidney injury predicts adverse outcomes after cardiac surgery. OBJECTIVES: To determine whether ultra-short-term changes (within 120 min) in serum creatinine (SCrea) levels after cardiac surgery predict clinical outcomes (30-day mortality). DESIGN: Observational cohort study. SETTING: Austrian tertiary referral centre. PATIENTS: A total of 7651 patients scheduled to undergo elective cardiac surgery. MAIN OUTCOME MEASURES: We analysed SCrea levels measured pre-operatively (baseline) and within 120 min after surgery. We also adjusted the postoperative SCrea levels for fluid balance. Patients were grouped according to the difference between the pre and postoperative SCrea levels (ΔSCreaAdmICU). We performed univariable and multivariable analyses to determine the association between changes in SCrea levels and 30-day mortality. RESULTS: After cardiac surgery, the SCrea level decreased in 5923 patients and increased in 1728 patients. Increased SCrea levels were associated with a 21% increase in 30-day mortality. Even minimal increases in SCrea (0 to <26.5 µmol l) were significantly associated with 30-day mortality [hazard ratio (HR), 1.98; 95% confidence interval (CI), 1.54 to 2.55; P < 0.001]. Adjustments for fluid balance strengthened the above association (increases of 0 to <26.5 µmol l: HR, 1.78; 95% CI, 1.40 to 2.26; P < 0.001; increases of at least 26.5 µmol l: HR, 2.40; 95% CI, 1.68 to 3.42; P < 0.001). CONCLUSION: Even minimal, ultra-short-term increases in SCrea levels after cardiac surgery are associated with increased 30-day mortality. Adjustment for fluid balance strengthens this association. The change in SCrea between baseline and after admission to the Intensive Care Unit (ΔSCreaAdmICU) can serve as a simple, cheap and widely available marker for very early risk stratification after cardiac surgery.

Oligomannosidic glycans at Asn-110 are essential for secretion of human diamine oxidase.

N-Glycosylation plays a fundamental role in many biological processes. Human diamine oxidase (hDAO), required for histamine catabolism, has multiple N-glycosylation sites, but their roles, for example in DAO secretion, are unclear. We recently reported that the N-glycosylation sites Asn-168, Asn-538, and Asn-745 in recombinant hDAO (rhDAO) carry complex-type glycans, whereas Asn-110 carries only mammalian-atypical oligomannosidic glycans. Here, we show that Asn-110 in native hDAO from amniotic fluid and Caco-2 cells, DAO from porcine kidneys, and rhDAO produced in two different HEK293 cell lines is also consistently occupied by oligomannosidic glycans. Glycans at Asn-168 were predominantly sialylated with bi- to tetra-antennary branches, and Asn-538 and Asn-745 had similar complex-type glycans with some tissue- and cell line-specific variations. The related copper-containing amine oxidase human vascular adhesion protein-1 also exclusively displayed high-mannose glycosylation at Asn-137. X-ray structures revealed that the residues adjacent to Asn-110 and Asn-137 form a highly conserved hydrophobic cleft interacting with the core trisaccharide. Asn-110 replacement with Gln completely abrogated rhDAO secretion and caused retention in the endoplasmic reticulum. Mutations of Asn-168, Asn-538, and Asn-745 reduced rhDAO secretion by 13, 71, and 32%, respectively. Asn-538/745 double and Asn-168/538/745 triple substitutions reduced rhDAO secretion by 85 and 94%. Because of their locations in the DAO structure, Asn-538 and Asn-745 glycosylations might be important for efficient DAO dimer formation. These functional results are reflected in the high evolutionary conservation of all four glycosylation sites. Human DAO is abundant only in the gastrointestinal tract, kidney, and placenta, and glycosylation seems essential for reaching high enzyme expression levels in these tissues.

Empagliflozin in posttransplantation diabetes mellitus: A prospective, interventional pilot study on glucose metabolism, fluid volume, and patient safety.

The safety and efficacy of sodium-glucose cotransporter 2 inhibitors in posttransplantation diabetes mellitus is unknown. We converted stable kidney transplant patients to 10 mg empagliflozin, aiming at replacing their insulin therapy (<40 IU/d). N = 14 participants (the required sample size) completed the study visits through 4 weeks and N = 8 through 12 months. Oral glucose tolerance test (OGTT)-derived 2-hour glucose (primary end point) increased from 232 ± 82 mg/dL (baseline) to 273 ± 116 mg/dL (4 weeks, P = .06) and to 251 ± 71 mg/dL (12 months, P = .41). Self-monitored blood glucose and hemoglobin A1c were also clinically inferior with empagliflozin monotherapy, such that insulin was reinstituted in 3 of 8 remaining participants. Five participants (2 of them dropouts) vs nine of 24 matched reference patients developed bacterial urinary tract infections (P = .81). In empagliflozin-treated participants, oral glucose insulin sensitivity decreased and beta-cell glucose sensitivity increased at the 4-week and 12-month OGTTs. Estimated glomerular filtration rate and bioimpedance spectroscopy-derived extracellular and total body fluid volumes decreased by 4 weeks, but recovered. All participants lost body weight. No participant developed ketoacidosis; 1 patient developed balanitis. In conclusion, although limited by sample size and therefore preliminary, these results suggest that empagliflozin can safely be used as add-on therapy, if posttransplant diabetes patients are monitored closely (NCT03113110).