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Background: The EU LifeCycle Project was launched in 2017 to combine, harmonize, and analyze data from more than 250,000 participants across Europe and Australia, involving cohorts participating in the EU-funded LifeCycle Project. The purpose of this cohort description is to provide a detailed overview of the major measures within mental health domains that are available in 17 European and Australian cohorts participating in the LifeCycle Project. Methods: Data on cognitive, behavioral, and psychological development has been collected on participants from birth until adulthood through questionnaire and medical data. We developed an inventory of the available data by mapping individual instruments, domain types, and age groups, providing the basis for statistical harmonization across mental health measures. Results: The mental health data in LifeCycle contain longitudinal and cross-sectional data from birth throughout the life course, covering domains across a wide range of behavioral and psychopathology indicators and outcomes, including executive function, depression, ADHD, and cognition. These data span a unique combination of qualitative data collected through behavioral/cognitive/mental health questionnaires and examination, as well as data from biological samples and indices in the form of imaging (MRI, fetal ultrasound) and DNA methylation data. Harmonized variables on a subset of mental health domains have been developed, providing statistical equivalence of measures required for longitudinal meta-analyses across instruments and cohorts. Conclusion: Mental health data harmonized through the LifeCycle project can be used to study life-course trajectories and exposure-outcome models that examine early life risk factors for mental illness and develop predictive markers for later-life disease.

PURPOSE Cisplatin plus gemcitabine is a standard regimen for first-line treatment of advanced non–small-cell lung cancer (NSCLC). Phase II studies of pemetrexed plus platinum compounds have also shown activity in this setting. PATIENTS AND METHODS This noninferiority, phase III, randomized study compared the overall survival between treatment arms using a fixed margin method (hazard ratio [HR] < 1.176) in 1,725 chemotherapy-naive patients with stage IIIB or IV NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 1. Patients received cisplatin 75 mg/m2 on day 1 and gemcitabine 1,250 mg/m2 on days 1 and 8 (n = 863) or cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 on day 1 (n = 862) every 3 weeks for up to six cycles. RESULTS Overall survival for cisplatin/pemetrexed was noninferior to cisplatin/gemcitabine (median survival, 10.3 v 10.3 months, respectively; HR = 0.94; 95% CI, 0.84 to 1.05). Overall survival was statistically superior for cisplatin/pemetrexed versus cisplatin/gemcitabine in patients with adenocarcinoma (n = 847; 12.6 v 10.9 months, respectively) and large-cell carcinoma histology (n = 153; 10.4 v 6.7 months, respectively). In contrast, in patients with squamous cell histology, there was a significant improvement in survival with cisplatin/gemcitabine versus cisplatin/pemetrexed (n = 473; 10.8 v 9.4 months, respectively). For cisplatin/pemetrexed, rates of grade 3 or 4 neutropenia, anemia, and thrombocytopenia ( P ≤ .001); febrile neutropenia ( P = .002); and alopecia ( P < .001) were significantly lower, whereas grade 3 or 4 nausea ( P = .004) was more common. CONCLUSION In advanced NSCLC, cisplatin/pemetrexed provides similar efficacy with better tolerability and more convenient administration than cisplatin/gemcitabine. This is the first prospective phase III study in NSCLC to show survival differences based on histologic type.

Background: We aimed to develop census-linked longitudinal mortality data for Japan and assess their validity as a new resource for estimating socioeconomic inequalities in health. Methods: Using deterministic linkage, we identified, from national censuses for 2000 and 2010 and national death records, persons and deceased persons who had unique personal identifiers (generated using sex, birth year/month, address, and marital status). For the period 2010–2015, 1,537,337 Japanese men and women aged 30–79 years (1.9% in national census) were extracted to represent the sample population. This population was weighted to adjust for confounding factors. We estimated age-standardized mortality rates (ASMRs) by education level and occupational class. The slope index of inequality (SII) and relative index inequality (RII) by educational level were calculated as inequality measures. Results: The reweighted sample population’s mortality rates were somewhat higher than those of the complete registry, especially in younger age-groups and for external causes. All-cause ASMRs (per 100,000 person-years) for individuals aged 40–79 years with high, middle, and low education levels were 1,078 (95% confidence interval [CI], 1,051–1,105), 1,299 (95% CI, 1,279–1,320), and 1,670 (95% CI, 1,634–1,707) for men, and 561 (95% CI, 536–587), 601 (95% CI, 589–613), and 777 (95% CI, 745–808) for women, respectively, during 2010–2015. SII and RII by educational level increased among both sexes between 2000–2005 and 2010–2015, which indicates that mortality inequalities increased. Conclusion: The developed census-linked longitudinal mortality data provide new estimates of socioeconomic inequalities in Japan that can be triangulated with estimates obtained with other methods.

Background and purpose A wide range of neuroradiological findings has been reported in patients with coronavirus disease 2019 (COVID-19), ranging from subcortical white matter changes to infarcts, haemorrhages and focal contrast media enhancement. These have been descriptively but inconsistently reported and correlations with clinical findings and biomarkers have been difficult to extract from the literature. The purpose of this study was to quantify the extents of neuroradiological findings in a cohort of patients with COVID-19 and neurological symptoms, and to investigate correlations with clinical findings, duration of intensive care and biomarkers in blood. Material and methods Patients with positive SARS-CoV-2 and at least one new-onset neurological symptom were included from April until July 2020. Nineteen patients were examined regarding clinical symptoms, biomarkers in blood and MRI of the brain. In order to quantify the MRI findings, a semi-quantitative neuroradiological severity scale was constructed a priori, and applied to the MR images by two specialists in neuroradiology. Results and conclusions The score from the severity scale correlated significantly with blood biomarkers of CNS injury (glial fibrillary acidic protein, total-tau, ubiquitin carboxyl-terminal hydrolase L1) and inflammation (C-reactive protein), Glasgow Coma Scale score, and the number of days spent in intensive care. The underlying radiological assessments had inter-rater agreements of 90.5%/86% (for assessments with 2/3 alternatives). Total intraclass correlation was 0.80. Previously reported neuroradiological findings in COVID-19 have been diverse and heterogenous. In this study, the extent of findings in MRI examination of the brain, quantified using a structured report, shows correlation with relevant biomarkers.

PURPOSE To evaluate the efficacy and tolerability of two doses of gefitinib (Iressa [ZD1839]; AstraZeneca, Wilmington, DE), a novel epidermal growth factor receptor tyrosine kinase inhibitor, in patients with pretreated advanced non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS This was a randomized, double-blind, parallel-group, multicenter phase II trial. Two hundred ten patients with advanced NSCLC who were previously treated with one or two chemotherapy regimens (at least one containing platinum) were randomized to receive either 250-mg or 500-mg oral doses of gefitinib once daily. RESULTS Efficacy was similar for the 250- and 500-mg/d groups. Objective tumor response rates were 18.4% (95% confidence interval [CI], 11.5 to 27.3) and 19.0% (95% CI, 12.1 to 27.9); among evaluable patients, symptom improvement rates were 40.3% (95% CI, 28.5 to 53.0) and 37.0% (95% CI, 26.0 to 49.1); median progression-free survival times were 2.7 and 2.8 months; and median overall survival times were 7.6 and 8.0 months, respectively. Symptom improvements were recorded for 69.2% (250 mg/d) and 85.7% (500 mg/d) of patients with a tumor response. Adverse events (AEs) at both dose levels were generally mild (grade 1 or 2) and consisted mainly of skin reactions and diarrhea. Drug-related toxicities were more frequent in the higher-dose group. Withdrawal due to drug-related AEs was 1.9% and 9.4% for patients receiving gefitinib 250 and 500 mg/d, respectively. CONCLUSION Gefitinib showed clinically meaningful antitumor activity and provided symptom relief as second- and third-line treatment in these patients. At 250 mg/d, gefitinib had a favorable AE profile. Gefitinib 250 mg/d is an important, novel treatment option for patients with pretreated advanced NSCLC.

To investigate mortality and reoperation rates following limited distal repair after acute type A aortic dissection (ATAAD) at a single medium volume institution. We analyzed all patients that underwent limited distal repair (ascending aortic or hemiarch replacement) following ATAAD between January 1998 and April 2020 at our institution. During the study period, 489 patients underwent ATAAD surgery, of which 457 (94%) underwent limited distal repair with a 30-day mortality of 12.9%. Among 30-day survivors, late follow-up was 97.7% complete with a mean follow-up of 6.0 ± 5.5 years. years. In all, 50 patients (11%) required a reoperation during the study period at a mean of 3.4 ± 3.4 years after initial repair, with a 30-day mortality of 12%. An aortic reoperation was required in 4.1 (2.0-6.1)%, 10.3 (7.1-13.6)%, 15.1 (10.9-19.4)% and 18.0 (13.0-22.9)% of patients at 1, 5, 10 and 15 years. A distal reoperation was required in 3.0 (1.2-4.7)%, 8.0 (5.1-10.9)%, 10.3 (6.8-13.8)% and 12.4 (8.2-16.5)% of patients and 4.4 (2.3-6.4)%, 10.4 (7.1-13.7)%, 13.9 (9.8-18.0)% and 16.9 (12.0-21.9)% of patents had a distal event at 1, 5, 10 and 15 years, respectively. Limited distal repair with an ascending aortic or hemiarch replacement was associated with acceptable survival and rates of reoperations and distal events. Limited distal repair is a safe and feasible standard approach to ATAAD surgery at a medium-volume center.

Manufacturing companies are currently undergoing a digitalization transformation in which digitally enabled, new, and innovative advanced service offerings are being launched. These so-called “digital services” represent a shift in the business logic of manufacturing firms, from up-front product sales to advanced service contracts. This business model shift has profound implications for cost structures, risk management, and revenue streams, providing manufacturing companies with the key challenge of rethinking how to capture value. Using a multiple case study of 11 companies, the purpose of this article is to enhance knowledge on how to design new revenue models for digital services. Results reveal a revenue model design framework of key phases and activities that carries implications for the emerging literature on digital servitization, as well as the business model innovation literature. The findings reveal a highly customer-centric, iterative, and agile process where close collaboration with key customers during the early stages guides the framing of revenue models for digital services. For practitioners, it provides hands-on advice on how to implement the design, development, and scaling processes for revenue models in the context of new digital services. Validerad;2023;Nivå 2;2023-04-18 (joosat)

INTRODUCTION: Radiofrequency (RF) treatment of the genicular nerves is a promising treatment for chronic osteoarthritic and persistent postsurgical knee pain (PPSP), refractory to conventional medical management. METHODS: The RECORGEN study is a retrospective single-center cohort study of patients treated with ultrasound-guided conventional RF of the genicular nerves for chronic knee pain in Hospital Oost-Limburg, Genk from September 2017 to June 2020. Subgroup analysis based on etiology of pain (PPSP and degenerative knee pain) was performed in addition to the total study population analysis. Outcome parameters were global perceived effect (GPE), Numeric Rating Scale for pain, consumption of strong opioids, and safety of the treatment at 6 weeks and cross-sectionally at a variable time point. Treatment success was defined as GPE≥50%. RESULTS: Sixty-eight cases were screened of which 59 (46 diagnosed with PPSP and 13 with degenerative knee pain) were included in the study. Treatment success at 6 weeks was achieved in 19 of 59 interventions (32.2%) and was similar in both groups. Seventeen responders were evaluated at follow-up. 45.1% (8/17) continued to have a positive effect at the second time point. The mean duration of effect of the RF treatment was 8.3 months. Safety analysis at 6 weeks and at the second time point showed a good safety profile of the treatment. CONCLUSION: Conventional RF of the genicular nerves was clinically successful in more than 30% of the study population refractory to conventional medical management. Overall, the treatment was well tolerated. The mean duration of effect was 8.3 months. ispartof: PAIN PRACTICE vol:22 issue:3 pages:340-348 ispartof: location:United States status: published

Resumen El sindrome de Sjogren es una entidad de origen reumatico, con caracteristicas autoinmune complejas, en la que se ven comprometidas principalmente las glandulas salivales y las lagrimales. Tiene 2 formas de presentacion, una primaria y otra secundaria, y en ambas se observa una afeccion de las glandulas exocrinas. El espectro clinico del sindrome de Sjogren es muy heterogeneo y se clasifica en manifestaciones glandulares y extraglandulares, no excluyentes entre si. Se recomienda que se haga un control medico mas estricto a todo paciente que curse con una inflamacion parotidea, purpura, hipergammaglobulinemia y anticuerpos anti-SSa, anti-SSb, puesto que presenta mayor riesgo de cursar con una presentacion sistemica grave. Los estudios poblacionales que han intentado describir la incidencia y la prevalencia del sindrome de Sjogren en diferentes paises son hasta cierto punto discordantes entre un registro y otro. El sindrome de Sjogren es mas frecuente en mujeres, pero en hombres predomina mas la afectacion ocular; puede presentarse en todas las edades, principalmente entre la tercera y la quinta decadas de la vida; en ninos es raro. Se considera ademas como una conectivopatia frecuente, en la cual los datos de la tasa de incidencia global y de prevalencia se encuentran subestimados.

Disability is a disruption or limitation of a person’s body functions in carrying out daily activities. A person with physical disabilities needs an assistive device such as a wheelchair. The latest wheelchair development is the smart wheelchair. Smart wheelchairs require a control system to detect obstacles quickly. This aims to provide safety, especially for users. One of the obstacles that are quite dangerous is descending stairs. Therefore the researchers propose a descending stairs detection system for smart wheelchairs. The proposed method in this study is the gray level co-occurrence matrix (GLCM) as the feature extraction algorithm, learning vector quantization (LVQ) as the classification algorithm, and sequential forward selection (SFS) for feature selection. Based on the simulation result, the SFS feature selection gets two selected GLCM features. The best accuracy is 94.5% with the selected features, namely contrast and dissimilarity. This result has an increase in accuracy when compared to using the GLCM 6 feature method with the LVQ classification that does not use feature selection, where the method gets 92.5% accuracy in off-time testing. Accuracy decreased to 78.21% when detecting floors and 89.06% when detecting descending stairs in real-time system testing.

Over the last decades, rapid technological and scientific advances have led to a merge of molecular sciences and clinical medicine, resulting in a better understanding of disease mechanisms and the development of novel therapies that exploit specific molecular lesions or profiles driving disease. Precision oncology is here used as an example, illustrating the potential of precision/personalized medicine that also holds great promise in other medical fields. Real-world implementation can only be achieved by dedicated healthcare connected centers which amass and build up interdisciplinary expertise reflecting the complexity of precision medicine. Networks of such centers are ideally suited for a nation-wide outreach offering access to precision medicine to patients independent of their place of residence. Two of these multicentric initiatives, Genomic Medicine Sweden (GMS) and the Centers for Personalized Medicine (ZPM) initiative in Germany have teamed up to present and share their views on core concepts, potentials, challenges, and future developments in precision medicine. Together with other initiatives worldwide, GMS and ZPM aim at providing a robust and sustainable framework, covering all components from technology development to clinical trials, ethical and legal aspects as well as involvement of all relevant stakeholders, including patients and policymakers in the field.

BackgroundLopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-β-1a and hydroxychloroquine efficacy for COVID-19 have been evaluated, but detailed evaluation is lacking.ObjectiveTo determine the efficacy of lopinavir/ritonavir, lopinavir/ritonavir-IFN-β-1a, hydroxychloroquine or remdesivir for improving the clinical, virological outcomes in COVID-19 inpatients.DesignOpen-label, randomized, adaptive, controlled trial.SettingMulti-center trial with patients from France.Participants583 COVID-19 inpatients requiring oxygen and/or ventilatory supportInterventionStandard of care (SoC, control), SoC plus lopinavir/ritonavir (400 mg lopinavir and 100 mg ritonavir every 12h for 14 days), SoC plus lopinavir/ritonavir plus IFN-ß-1a (44 μg of subcutaneous IFN-ß-1a on days 1, 3, and 6), SoC plus hydroxychloroquine (400 mg twice on day 1 then 400 mg once daily for 9 days) or SoC plus remdesivir (200 mg intravenously on day 1 then 100 mg once-daily for hospitalization duration or 10 days).MeasurementsThe primary outcome was the clinical status at day 15, measured by the WHO 7-point ordinal scale. Secondary outcomes included SARS-CoV-2 quantification in respiratory specimens and safety analyses.ResultsAdjusted Odds Ratio (aOR) for the WHO 7-point ordinal scale were not in favor of investigational treatments: lopinavir/ritonavirversuscontrol, aOR 0.83, 95%CI, 0.55 to 1.26, P=0.39; lopinavir/ritonavir-IFN-β-1aversuscontrol, aOR 0.69, 95%CI, 0.45 to 1.04, P=0.08; hydroxychloroquineversuscontrol, aOR 0.93, 95%CI, 0.62 to 1.41, P=0.75. No significant effect on SARS-CoV-2 RNA clearance in respiratory tract was evidenced. Lopinavir/ritonavir-containing treatments were significantly associated with more SAE.LimitationsNot a placebo-controlled, no anti-inflammatory agents tested.ConclusionNo improvement of the clinical status at day 15 nor SARS-CoV-2 RNA clearance in respiratory tract specimens by studied drugs. This comforts the recent Solidarity findings.RegistrationNCT04315948.FundingPHRC 2020, Dim OneHealth, REACTing

Background Infections with SARS-CoV-2 continue to cause significant morbidity and mortality. Interleukin (IL)-1 and IL-6 blockade have been proposed as therapeutic strategies in COVID-19, but study outcomes have been conflicting. We sought to study whether blockade of the IL-6 or IL-1 pathway shortened the time to clinical improvement in patients with COVID-19, hypoxic respiratory failure, and signs of systemic cytokine release syndrome. Methods We did a prospective, multicentre, open-label, randomised, controlled trial, in hospitalised patients with COVID-19, hypoxia, and signs of a cytokine release syndrome across 16 hospitals in Belgium. Eligible patients had a proven diagnosis of COVID-19 with symptoms between 6 and 16 days, a ratio of the partial pressure of oxygen to the fraction of inspired oxygen (PaO2:FiO(2)) of less than 350 mm Hg on room air or less than 280 mm Hg on supplemental oxygen, and signs of a cytokine release syndrome in their serum (either a single ferritin measurement of more than 2000 mu g/L and immediately requiring high flow oxygen or mechanical ventilation, or a ferritin concentration of more than 1000 mu g/L, which had been increasing over the previous 24 h, or lyrnphopenia below 800/mL with two of the following criteria: an increasing ferritin concentration of more than 700 mu g/L, an increasing lactate dehydrogenase concentration of more than 300 international units per L, an increasing C-reactive protein concentration of more than 70 mg/L, or an increasing D-dimers concentration of more than 1000 ng/mL). The COV-AID trial has a 2 x 2 factorial design to evaluate IL-1 blockade versus no IL-1 blockade and IL-6 blockade versus no IL-6 blockade. Patients were randomly assigned by means of permuted block randomisation with varying block size and stratification by centre. In a first randomisation, patients were assigned to receive subcutaneous anakinra once daily (100 mg) for 28 days or until discharge, or to receive no IL-1 blockade (1:2). In a second randomisation step, patients were allocated to receive a single dose of siltuximab (11 mg/kg) intravenously, or a single dose of tocilizumab (8 mg/kg) intravenously, or to receive no IL-6 blockade (1:1:1). The primary outcome was the time to clinical improvement, defined as time from randomisation to an increase of at least two points on a 6-category ordinal scale or to discharge from hospital alive. The primary and supportive efficacy endpoints were assessed in the intention-to-treat population. Safety was assessed in the safety population. This study is registered online with ClinicalTrials.gov (NCT04330638) and EudraCT (2020-001500-41) and is complete. Findings Between April 4, and Dec 6,2020,342 patients were randomly assigned to IL-1 blockade n=112) or no IL-1 blockade (n=230) and simultaneously randomly assigned to IL-6 blockade (n=227; 114 for tocilizumab and 113 for siltuximab) or no IL-6 blockade (n=115). Most patients were male (265 [77%] of 342), median age was 65 years (IQR 54-73), and median Systematic Organ Failure Assessment (SOFA) score at randomisation was 3 (2-4). All 342 patients were included in the primary intention-to-treat analysis. The estimated median time to clinical improvement was 12 days (95% CI 10-16) in the IL-1 blockade group versus 12 days (10-15) in the no IL-1 blockade group (hazard ratio [HR] 0.94 [95% CI 0.73-1.21]). For the IL-6 blockade group, the estimated median time to clinical improvement was 11 days (95% CI 10-16) versus 12 days (11-16) in the no IL-6 blockade group (HR 1.00[0-78-1-29]). 55 patients died during the study, but no evidence for differences in mortality between treatment groups was found. The incidence of serious adverse events and serious infections was similar across study groups. Interpretation Drugs targeting IL-1 or IL-6 did not shorten the time to clinical improvement in this sample of patients with COVID-19, hypoxic respiratory failure, low SOFA score, and low baseline mortality risk. Copyright (C) 2021 Elsevier Ltd. All rights reserved. Belgian Health Care Knowledge Center; VIB Grand Challenges program The authors acknowledge professional support and committed efforts from various organisations and individuals involved in this trial and thank all trial participants and clinicians involved in patient recruitment at the different participating sites. This study was funded by KCE, and KCE was involved in various aspects of the study design, management, and execution (Nelle Stocquart, Jillian Harrison). The VIB Grand Challenges Program (Sofie Bekaert) funded measurements of cytokines and the Ghent University Special Research Fund (BOF) supported the clinical follow-up of patients at Ghent University Hospital (UZ Ghent). The clinical trial team of the Department of Respiratory Medicine at UZ Ghent (Stefanie Vermeersch, Benedicte Demeyere, Anja Delporte) were involved in protocol development, amendment filing, and eCRF construction. The Health Innovation and Research Institute of UZ Ghent was involved in eCRF design, protocol design, ethical committee reporting, drug dispensing, trial monitoring, data cleaning, and sponsor site management (Charlotte Clauwaert, Dries Loncke, Hanife Kokur, Lieselot Van Landuyt, Joke Tommelein, Hélène De Naeyer). The hospital pharmacy of UZ Ghent dispensed drugs to all study sites (Els Kestens). Team members of the Primary Immune Deficiency laboratory (Karlien Claes, Veronique Debacker, Lisa Roels, Zara Declercq) handled samples from all study sites. The authors acknowledge the insights of the data safety monitoring board (Drs Renaat Peleman, Geert Leroux-Roels, Steven Callens, Frank Vermassen, Piet Hoebeke, Karim Vermaelen, A Dupont, Tomasz Burzykowski, and Marnik Vuylsteke under the chairmanship of SR).

The Horizon2020 LifeCycle Project is a cross-cohort collaboration which brings together data from multiple birth cohorts from across Europe and Australia to facilitate studies on the influence of early-life exposures on later health outcomes. A major product of this collaboration has been the establishment of a FAIR (findable, accessible, interoperable and reusable) data resource known as the EU Child Cohort Network. Here we focus on the EU Child Cohort Network's core variables. These are a set of basic variables, derivable by the majority of participating cohorts and frequently used as covariates or exposures in lifecourse research. First, we describe the process by which the list of core variables was established. Second, we explain the protocol according to which these variables were harmonised in order to make them interoperable. Third, we describe the catalogue developed to ensure that the network's data are findable and reusable. Finally, we describe the core data, including the proportion of variables harmonised by each cohort and the number of children for whom harmonised core data are available. EU Child Cohort Network data will be analysed using a federated analysis platform, removing the need to physically transfer data and thus making the data more accessible to researchers. The network will add value to participating cohorts by increasing statistical power and exposure heterogeneity, as well as facilitating cross-cohort comparisons, cross-validation and replication. Our aim is to motivate other cohorts to join the network and encourage the use of the EU Child Cohort Network by the wider research community. The LifeCycle project received funding from the European Union’s Horizon 2020 research and innovation programme (Grant Agreement No. 733206 LifeCycle). All study specific acknowledgements and funding are presented in the supplementary material. This manuscript reflects only the author’s view and the Commission is not responsible for any use that may be made of the information it contains.

This paper shows how one of the most popular savings products in Europe -- life insurance financial products -- shares market risk across investor cohorts. Insurers smooth returns by varying reserves that offset fluctuations in asset returns. Reserves are passed on between successive investor cohorts, causing redistribution across cohorts. Using regulatory and survey data on the 1.4 trillion euro French market, we estimate this redistribution to be quantitatively large: 1.4% of savings value per year on average, or 0.8% of GDP. These findings challenge a large theoretical literature that assumes inter-cohort risk sharing is impossible. We develop and provide evidence for a model in which the elasticity of investor demand to predictable returns determines the amount of risk sharing that is possible. The evidence is consistent with low elasticity, sustaining inter-cohort risk sharing despite predictable returns. Demand elasticity is higher for investors with a larger investment amount, suggesting that low investor sophistication enables inter-cohort risk sharing.

The prognosis in systemic lupus erythematosus (SLE) has improved due to better treatment and care, but cardiovascular disease (CVD) still remains an important clinical problem, since the risk of CVD in SLE is much higher than among controls. Atherosclerosis is the main cause of CVD in the general population, and in SLE, increased atherosclerosis, especially the prevalence of atherosclerotic plaques, has been demonstrated. Atherosclerosis is an inflammatory condition, where immunity plays an important role. Interestingly, oxidized low-density lipoprotein, defective clearance of dead cells, and inflammation, with a pro-inflammatory T-cell profile are characteristics of both atherosclerosis and SLE. In addition to atherosclerosis as an underlying cause of CVD in SLE, there are also other non-mutually exclusive mechanisms, and the most important of these are antiphospholipid antibodies (aPL) leading to the antiphospholipid antibody syndrome with both arterial and venous thrombosis. aPL can cause direct pro-inflammatory and prothrombotic effects on endothelial and other cells and also interfere with the coagulation, for example, by inhibiting annexin A5 from its antithrombotic and protective effects. Antibodies against phosphorylcholine (anti-PC) and other small lipid-related epitopes, sometimes called natural antibodies, are negatively associated with CVD and atherosclerosis in SLE. Taken together, a combination of traditional risk factors such as hypertension and dyslipidemia, and nontraditional ones, especially aPL, inflammation, and low anti-PC are implicated in the increased risk of CVD in SLE. Close monitoring of both traditional risk factors and nontraditional ones, including treatment of disease manifestations, not lest renal disease in SLE, is warranted.

ZusammenfassungDie moderne Chirurgie ermöglicht immer komplexere operative Eingriffe bei immer älteren und komorbiden Patienten. Dies geht mit einem potenziell erhöhten Risiko für perioperative Infektionen (SSI) einher. Für deren Vermeidung sind Sauberkeit, Händedesinfektion und steriles Arbeiten essenziell, während einige traditionelle Hygienemaßnahmen zur Prävention untauglich sind. In diesem Beitrag werden Unterschiede der relevantesten Leitlinien zu SSI ggf. besonders herausgestellt.

PURPOSE: Upper blepharoplasty may be related to dry eye symptoms since the function of the orbicularis oculi muscle may affect the tear film. We aimed to assess the effect of blepharoplasty with or without the removal of a strip of orbicularis oculi muscle on tear film dynamics and dry eye symptoms.METHODS: A double-blind, randomized, controlled trial comparing upper blepharoplasty without (group A) or with (group B) orbicularis oculi muscle excision was performed on 54 healthy Caucasian patients. Tear film dynamics and dry eye symptoms were evaluated using multiple dry eye parameters, i.e. tear osmolarity, Schirmer test I, corneal/conjunctival staining, tear break-up time (TBUT), Oxford Scheme, Sicca Ocular Staining Score and Ocular Surface Disease Index questionnaire. All the parameters were assessed preoperatively and 6 and 12 months after upper blepharoplasty. All the groups' outcomes were compared.RESULTS: The differences were not significant between the two upper blepharoplasty techniques regarding most of the above-mentioned outcomes. Subjective symptoms of ocular irritation, consistent with dry eye disease and vision-related impairment, were reduced after upper blepharoplasty independent of the type of the technique applied, while the pre and postoperative outcomes of the objective tear dynamics did not differ 12 months after surgery. However, group B demonstrated a significant increase in tear osmolarity and TBUT at the 6-month follow-up visit.CONCLUSION: An upper blepharoplasty alleviates subjective dry eye complaints in the long term, while not changing the tear dynamics. The improvement was independent of the blepharoplasty technique used.

Objectives GCA is a large vessel vasculitis in which metabolically active immune cells play an important role. GCA diagnosis is based on CRP/ESR and temporal artery biopsies (TABs), in combination with 18F-fluorodeoxyglucose ([18F]FDG)-PET/CT relying on enhanced glucose uptake by glycolytic macrophages. Here, we studied circulating Pyruvate Kinase M2 (PKM2), a glycolytic enzyme, as a possible systemic marker of vessel wall inflammation in GCA. Methods Immunohistochemical detection of PKM2 was performed on inflamed (n = 12) and non-inflamed (n = 4) TABs from GCA patients and non-GCA (n = 9) patients. Dimeric PKM2 levels were assessed in plasma of GCA patients (n = 44), age-matched healthy controls (n = 41), metastatic melanoma patients (n = 7) and infection controls (n = 11). CRP, ESR and macrophage markers calprotectin and YKL-40 were correlated with plasma PKM2 levels. To detect the cellular source of plasma PKM2 in tissue, double IF staining was performed on inflamed GCA TABs. [18F]FDG-PET scans of 23 GCA patients were analysed and maximum standard uptake values and target to background ratios were calculated. Results PKM2 is abundantly expressed in TABs of GCA patients. Dimeric PKM2 plasma levels were elevated in GCA and correlated with CRP, ESR, calprotectin and YKL-40 levels. Elevated plasma PKM2 levels were downmodulated by glucocorticoid treatment. PKM2 was detected in both macrophages and T cells at the site of vascular inflammation. Circulating PKM2 levels correlated with average target to background ratios PET scores. Conclusion Elevated plasma PKM2 levels reflect active vessel inflammation in GCA and may assist in disease diagnosis and in disease monitoring.

This work investigates behavior of flying capacitor multi-level (FCML) converters in single phase buck-type power factor correction (PFC) applications. Recent developments in FCML converters using GaN transistors are leveraged to improve power density of a single-phase 240 V RMS ac to direct 48 V dc conversion stage in data center power delivery applications. Here, we experimentally demonstrate this concept in a digitally controlled six-level FCML converter hardware prototype. The experimental prototype can deliver 4.5 A average output current at 48 V, resulting in 216 W output power. A key contribution of this work is experimental demonstration of an FCML buck converter in a single-phase PFC application where the flying capacitor voltages follow fractions of the rectified input voltage by swinging at twice-line frequency.

This research investigated accessibility and connectivity of a public transport network calculated under two equally popular analytical approaches, namely the topological network analysis and the temporal network analysis, using the bus network in Ho Chi Minh City (HCMC), Vietnam as a case study. Specifically, we presented an apple-to-apple comparison of the two approaches to answer the question “What is the degree of discrepancy and/or loss of information, if any, in analyses using the topological network approach compared to those from the supposedly more computationally demanding temporal network approach?”. Stop-based accessibility metrics as well as measures of most-used infrastructure (bus stops and bus routes) were calculated, compared, and discussed for both approaches. In calculating shortest path between stop pairs, we adapted the multi-criteria profile connection scan algorithm for paths with earliest departure earliest arrival and minimal transfers. In representing the HCMC bus network, which had 253 directed routes servicing 4350 stops, the number of nodes and the number of edges in the temporal network over a 24-hour period were a few orders of magnitude larger than those in the topological network. Computing the shortest path between all stop pairs in the temporal network over a 3-hour period took at least an order of magnitude longer than that in the topological network. While results of network accessibility and most-used infrastructure from both representations of the bus network shared some qualitative similarities, they clearly demonstrated disadvantages of the topological network approach in capturing the temporal heterogeneity of a public transport network operation.

Purpose Intramedullary nailing (IMN) of fractures is associated with increased rates of inflammatory complications. The pathological mechanism underlying this phenomenon is unclear. However, polymorphonuclear granulocytes (PMNs) seem to play an important role. We hypothesized that a femur fracture and standardized IMN in pigs is associated with altered appearance of PMNs in circulation and enhanced activation status of these cells. Methods A porcine model including a femur fracture and IMN was utilized. Animals were randomized for control [anesthesia + mechanical ventilation only (A/MV)] and intervention [A/MV and unilateral femur fracture (FF) + IMN] conditions. PMN numbers and responsiveness, integrin (CD11b), L-selectin (CD62L) and Fcγ-receptor (CD16 and CD32)-expression levels were measured by flowcytometry of blood samples. Animals were observed for 72 h. Results Circulatory PMN numbers did not differ between groups. Early PMN-responsiveness was retained after insult. PMN-CD11b expression increased significantly upon insult and peaked after 24 h, whereas CD11b in control animals remained unaltered (P = 0.016). PMN-CD16 expression levels in the FF + IMN-group rose gradually over time and were significantly higher compared with control animals, after 48 h (P = 0.016) and 72 h (P = 0.032). PMN-CD62L and CD32 expression did not differ significantly between conditions. Conclusion This study reveals that a femur fracture and subsequent IMN in a controlled setting in pigs is associated with enhanced activation status of circulatory PMNs, preserved PMN-responsiveness and unaltered circulatory PMN-presence. Indicating that monotrauma plus IMN is a specific and substantial stimulus for the cellular immune system. Early alterations of circulatory PMN receptor expression dynamics may be predictive for the intensity of the post traumatic response.

The stress hormone cortisol modulates fuel metabolism, cardiovascular homoeostasis, mood, inflammation and cognition. The CORtisol NETwork (CORNET) consortium previously identified a single locus associated with morning plasma cortisol. Identifying additional genetic variants that explain more of the variance in cortisol could provide new insights into cortisol biology and provide statistical power to test the causative role of cortisol in common diseases. The CORNET consortium extended its genome-wide association meta-analysis for morning plasma cortisol from 12,597 to 25,314 subjects and from ~2.2 M to ~7 M SNPs, in 17 population-based cohorts of European ancestries. We confirmed the genetic association with SERPINA6/SERPINA1. This locus contains genes encoding corticosteroid binding globulin (CBG) and α1-antitrypsin. Expression quantitative trait loci (eQTL) analyses undertaken in the STARNET cohort of 600 individuals showed that specific genetic variants within the SERPINA6/SERPINA1 locus influence expression of SERPINA6 rather than SERPINA1 in the liver. Moreover, trans-eQTL analysis demonstrated effects on adipose tissue gene expression, suggesting that variations in CBG levels have an effect on delivery of cortisol to peripheral tissues. Two-sample Mendelian randomisation analyses provided evidence that each genetically-determined standard deviation (SD) increase in morning plasma cortisol was associated with increased odds of chronic ischaemic heart disease (0.32, 95% CI 0.06–0.59) and myocardial infarction (0.21, 95% CI 0.00–0.43) in UK Biobank and similarly in CARDIoGRAMplusC4D. These findings reveal a causative pathway for CBG in determining cortisol action in peripheral tissues and thereby contributing to the aetiology of cardiovascular disease.

Morphing can be used to alter human body models (HBMs) to represent a diverse population of occupants in car crashes. The mid-sized male SAFER HBM v9 was parametrically morphed to match 22 Post Mortem Human Subjects, loaded in different configurations. Kinetics and kinematics were compared for the morphed and baseline HBMs. In frontal impacts, the morphed HBMs correlated closer with the kinematics of obese subjects, but lower to small females. In lateral impacts HBM responses were too stiff. This study outlines a necessary evaluation of all HBMs that should be morphed to represent the diverse population in vehicle safety evaluations.

Context Antenatal hyperglycemia is associated with increased risk of future adverse health outcomes in both mother and child. Variations in offspring’s epigenome can reflect the impact and response to in utero glycemic exposure, and may have different consequences for the child. Objective We examined possible differences in associations of basal glucose status and glucose handling during pregnancy with both clinical covariates and offspring cord tissue DNA methylation. Research Design and Methods This study included 830 mother-offspring dyads from the Growing Up in Singapore Towards Healthy Outcomes cohort. The fetal epigenome of umbilical cord tissue was profiled using Illumina HumanMethylation450 arrays. Associations of maternal mid-pregnancy fasting (fasting plasma glucose [FPG]) and 2-hour plasma glucose (2hPG) after a 75-g oral glucose challenge with both maternal clinical phenotypes and offspring epigenome at delivery were investigated separately. Results Maternal age, prepregnancy body mass index, and blood pressure measures were associated with both FPG and 2hPG, whereas Chinese ethnicity (P = 1.9 × 10-4), maternal height (P = 1.1 × 10-4), pregnancy weight gain (P = 2.2 × 10-3), prepregnancy alcohol consumption (P = 4.6 × 10-4), and tobacco exposure (P = 1.9 × 10-3) showed significantly opposite associations between the 2 glucose measures. Most importantly, we observed a dichotomy in the effects of these glycemic indices on the offspring epigenome. Offspring born to mothers with elevated 2hPG showed global hypomethylation. CpGs most associated with the 2 measures also reflected differences in gene ontologies and had different associations with offspring birthweight. Conclusions Our findings suggest that 2 traditionally used glycemic indices for diagnosing gestational diabetes may reflect distinctive pathophysiologies in pregnancy, and have differential impacts on the offspring’s DNA methylome.

Obesity associates with reduced life expectancy, type 2 diabetes, hypertension and cardiovascular disease, and is characterized by chronic inflammation. Phosphorylcholine (PC) is an epitope on oxidized low-density lipoprotein, dead cells and some microorganisms. Antibodies against PC (anti-PC) have anti-inflammatory properties. Here, we explored the role of anti-PC in hospitalized versus non-hospitalized obese. One-hundred-and-twenty-eight obese (BMI ≥ 30 kg/m2) individuals (59.8 (± 5.5) years, 53.9% women) from the Malmö Diet and Cancer Cardiovascular Cohort were examined and IgM, IgG1 and IgG2 anti-PC were analyzed by ELISA. Individuals with at least one recorded history of hospitalization prior to study baseline were considered hospitalized obese (HO). Associations between IgM, IgG1 and IgG2 anti-PC and HO (n = 32)/non-hospitalized obese (NHO) (n = 96), but also with metabolic syndrome and diabetes were analysed using logistic regressions. Both IgM and IgG1 anti-PC were inversely associated with HO, also after controlling for age and sex. When further adjusted for waist circumference, systolic blood pressure, glucose levels and smoking status, only IgG1 anti-PC remained significantly associated with HO. In multivariate models, each 1 standard deviation of increment in anti-PC IgG1 levels was inversely associated with prevalence of HO (odds ratio 0.57; CI 95% 0.33–0.98; p = 0.044). IgG2 anti-PC did not show any associations with HO. Low levels of IgM and IgG1 anti-PC are associated with higher risk of being a HO individual independent of sex and age, IgG1 anti-PC also independently of diabetes and metabolic syndrome. The anti-inflammatory properties of these antibodies may be related to inflammation in obesity and its complications.

The coronavirus disease 2019 (COVID‐19) pandemic resulted in an enormous influx of seriously ill patients in the hospitals worldwide. After its initial impact in Asia, Europe also suffered greatly. Caring for COVID‐19 patients whist maintaining treatment for patients with other conditions was a complex planning and management challenge. A series of interventions has been implemented to increase hospital capacity in response to the pandemic. Hospital provision interventions included the purchase of equipment, the establishment of additional hospital facilities and the redeployment of staff and other resources. Ensuring safe and high quality care to both COVID‐19 patients and those with other conditions was a crucial aspect of the Belgian response in this current health crisis.

Aims Previous research on racial/ethnic disparities in relation to cardiac arrest has mainly focused on black vs. white disparities in the USA. The great majority of these studies concerns out-of-hospital cardiac arrest (OHCA). The current nationwide registry study aims to explore whether there are ethnic differences in treatment and survival following in-hospital cardiac arrest (IHCA), examining possible disparities towards Middle Eastern and African minorities in a European context. Methods and results In this retrospective registry study, 24 217 patients from the IHCA part of the Swedish Registry of Cardiopulmonary Resuscitation were included. Data on patient ethnicity were obtained from Statistics Sweden. Regression analysis was performed to assess the impact of ethnicity on cardiopulmonary resuscitation (CPR) delay, CPR duration, survival immediately after CPR, and the medical team’s reported satisfaction with the treatment. Middle Eastern and African patients were not treated significantly different compared to Nordic patients when controlling for hospital, year, age, sex, socioeconomic status, comorbidity, aetiology, and initial heart rhythm. Interestingly, we find that Middle Eastern patients were more likely to survive than Nordic patients (odds ratio = 1.52). Conclusion Overall, hospital staff do not appear to treat IHCA patients differently based on their ethnicity. Nevertheless, Middle Eastern patients are more likely to survive IHCA.

The trends in incidence of lung cancer in never smokers are unclear as well as the significance of risk factors. We studied time trends in the incidence and risk factors of lung cancer in never smokers in Finland in a large, pooled cohort. We pooled data from seven Finnish health cohorts from the period between 1972 and 2015 with 106 193 never smokers. The harmonized risk factors included education, alcohol consumption, physical activity, height, and BMI. We retrieved incident lung cancers from the nation-wide Finnish Cancer Registry. We estimated average annual percent change (AAPC) and the effects of risk factors on cause-specific hazard ratios (HRs) of lung cancer using Poisson regression. We detected 47 lung cancers in never smoking men (n = 31 859) and 155 in never smoking women (n = 74 334). The AAPC of lung cancer incidence was -3.30% (95% confidence interval [CI]: -5.68% - -0.88%, P = 0.009) in never smoking men and 0.00% (95% CI: -1.57%-1.60%, P = 0.996) in never smoking women. Of the five studied risk factors only greater height in women had a statistically significant increased risk of lung cancer (multivariate HR = 1.84, 95%CI: 1.08-3.12). It is plausible that tobacco control measures focused on working places have reduced passive smoking among men more than among women, which could explain the declining trend in lung cancer incidence in never smoker men but not in never smoker women. As tobacco control measures have not been targeted to domestic environments, it is likely that women's exposure to passive smoking has continued longer. This article is protected by copyright. All rights reserved.

In this paper we demonstrate a high wall-plug efficiency and low threshold current for heterogeneously integrated III-V-on-Silicon distributed feedback (DFB) lasers. Above 12% wall plug efficiency is achieved for a 200 µm long DFB laser diode at 25 °C. Up to two times 6 mW of optical power is coupled into the silicon waveguide and more than 40 dB side-mode suppression ratio is obtained. We also discuss the non-return-to-zero on-off keying modulation at 20 Gb/s and the transmission over a 2 km long optical fiber.

Background For muscle-invasive bladder cancer (MIBC), no tissue biomarkers are available for clinical use to predict response to neoadjuvant chemotherapy. Objective To investigate how molecular subtypes impact pathological response and survival in patients receiving preoperative cisplatin-based chemotherapy. Design, setting, and participants Classification of a retrospective cohort of 149 patients was performed by tumor transcriptomic profiling and immunostaining. A cohort treated with radical cystectomy alone and public data sets were used for comparison and external validation. Outcome measurements and statistical analysis Complete pathological response in the cystectomy specimen (ypT0N0) and survival were compared in predefined molecular subtypes. Differential gene expression and chemotherapy response were explored beyond molecular subtypes. Results and limitations Patients with genomically unstable (GU) and urothelial-like (Uro) tumors had higher proportions of complete pathological response (16/31 [52%] and 17/54 [31%]), versus five out of 24 (21%) with the basal/squamous (Ba/Sq) subtype following neoadjuvant chemotherapy and radical cystectomy. Molecular subtype was independently associated with improved survival for patients with GU tumors (hazard ratio [HR] 0.29, 95% confidence interval [CI]: 0.11–0.79) and UroC tumors (HR 0.37, 95% CI: 0.14–0.94) compared with Ba/Sq tumors, adjusting for clinical stage. In addition, expression of the gene coding for osteopontin (SPP1) showed a subtype-dependent effect on chemotherapy response. Conclusions Urothelial cancer of the luminal-like (GU and Uro) subtypes is more responsive to cisplatin-based neoadjuvant chemotherapy. A second-generation of subtype-specific biomarkers, for example, SPP1, may be a way forward to develop a more precision-based treatment approach for neoadjuvant chemotherapy in MIBC. Patient summary This study shows that tumor classification by gene expression profiling and molecular subtyping can identify patients who are more likely to benefit from chemotherapy before radical cystectomy for muscle-invasive bladder cancer. Together with other markers for response, molecular subtypes could have a role in selective administration of such chemotherapy.

Background Fecal metabolomic profiles differ between pediatric inflammatory bowel disease (IBD) patients and controls and may provide new insights in the pathophysiology of IBD. The role of amino acids, however, is not fully elucidated. We aimed to assess fecal amino acid profiles in pediatric IBD. Methods In this case-control study, treatment-naïve, newly diagnosed pediatric IBD patients and a non-IBD control group, matched based on sex and age, were included in 2 tertiary centres. Fecal amino acid profiles were assessed using a targeted high-performance liquid chromatography technique. A random forest classifier method was used to develop a prediction model differentiating IBD from controls and predicting IBD phenotype. The association between IBD localization and amino acid concentrations was tested with ordinal regression models. Results We included 78 newly diagnosed IBD patients (40 Crohn’s disease [CD], 38 ulcerative colitis [UC]) and 105 controls. Patients with IBD could be differentiated from controls with an accuracy of 82% (sensitivity 63%, specificity 97%). Twenty-nine out of the 42 measured unique amino acids were included in the prediction model. Increased levels of tryptophan, taurine, alanine, ornithine, valine, histidine, and leucine were the most differentiating features. Children with CD and UC could be differentiated from the controls with an accuracy of 80% and 90%, respectively. Inflammatory bowel disease phenotype could not be predicted. Tryptophan, valine, and histidine levels were positively associated with more extended disease in UC patients (P < .05). Conclusions Fecal amino acids may enhance understanding of the role of host-microbial interactions in the pathophysiology of IBD and may evolve into biomarkers for pediatric IBD diagnostic and personalized medicine.

Cooperative Intelligent Transport Systems (C-ITS) enable information to be shared wirelessly between vehicles and infrastructure in order to improve transport safety and efficiency. Delivering C-ITS services using existing cellular networks offers both financial and technological advantages, not least since these networks already offer many of the features needed by C-ITS, and since many vehicles on our roads are already connected to cellular networks. Still, C-ITS pose stringent requirements in terms of availability and latency on the underlying communication system; requirements that will be hard to meet for currently deployed 3G, LTE, and early-generation 5G systems. Through a series of experiments in the MONROE testbed (a cross-national, mobile broadband testbed), the present study demonstrates how cellular multi-access selection algorithms can provide close to 100% availability, and significantly reduce C-ITS transaction times. The study also proposes and evaluates a number of low-complexity, low-overhead single-access selection algorithms, and shows that it is possible to design such solutions so that they offer transaction times and availability levels that rival those of multi-access solutions.

Patients receiving chimeric antigen receptor T cells (CAR-T cells) therapy may be particularly susceptible to coronavirus disease 2019 (COVID-19) because of several factors including the immunosuppression associated to the underlying disease and delayed cytopenias. Regrettably, data on outcomes of CAR-T recipients with COVID-19 are extremely scarce. The aim of this study was to investigate the characteristics and outcomes of COVID-19 in patients treated with CAR-T therapy. The European Hematology Association - Scientific Working Group Infection in Hematology endorsed a survey to collect and analyze data from patients developing COVID-19 after CAR-T therapy. Overall, 459 patients treated with CAR-T cells were reported from 18 European centers. The prevalence of COVID-19 cases was 4.8%. Median time from CAR-T therapy and COVID-19 diagnosis was 169 days. Severe infection occurred in 66.7% of patients and 43.3% of the subjects required admission to ICU. The COVID-19 mortality was 33%. In multivariable analysis, the disease status at the time of COVID-19 trended marginally towards adverse outcome (P=0.075). In conclusion, we documented a high fatality rate for CAR-T patients with COVID-19, supporting the need to design successful interventions to mitigate the risk of infection in this vulnerable group of patients.

Prior expectations can bias how we perceive pain. Using a drift diffusion model, we recently showed that this influence is primarily based on changes in perceptual decision-making (indexed as shift in starting point). Only during unexpected application of high-intensity noxious stimuli, altered information processing (indexed as increase in drift rate) explained the expectancy effect on pain processing. Here, we employed functional magnetic resonance imaging to investigate the neural basis of both these processes in healthy volunteers. On each trial, visual cues induced the expectation of high- or low-intensity noxious stimulation or signaled equal probability for both intensities. Participants categorized a subsequently applied electrical stimulus as either low- or high-intensity pain. A shift in starting point towards high pain correlated negatively with right dorsolateral prefrontal cortex activity during cue presentation underscoring its proposed role of "keeping pain out of mind". This anticipatory right dorsolateral prefrontal cortex signal increase was positively correlated with periaqueductal gray (PAG) activity when the expected high-intensity stimulation was applied. A drift rate increase during unexpected high-intensity pain was reflected in amygdala engagement and increased functional connectivity between amygdala and PAG. Our findings suggest involvement of the PAG in both decision-making bias and altered information processing to implement expectancy effects on pain. PERSPECTIVE: Modulation of pain through expectations has been linked to changes in perceptual decision-making and altered processing of afferent information. Our results suggest involvement of the dorsolateral prefrontal cortex, amygdala, and periaqueductal gray in these processes.

Background Despite the fact that primary adhesive capsulitis of the glenohumeral joint is often considered to be a self-limiting condition, not all patients make a full recovery. Manipulation under anesthesia (MUA) is performed to forcibly rupture the contracted capsule in a controlled manner. However, the technique, timing, and use of additional injections are often debated. In this study we report the outcomes following the addition of capsular distension and counter-traction to MUA as a treatment for adhesive capsulitis. Methods A retrospective case-cohort study comparing three groups: group 1; MUA alone (n=54), group 2; MUA with capsular distension (n=114), group 3; MUA with capsular distension and counter-traction (n=167). Re-MUA rate, Constant-Murley Shoulder (CMS) and visual analog scale (for pain) (VAS) scores were measured after six weeks and six months. Results Re-MUA rate fell with the addition of both capsular distension and counter-traction: 63% in group 1, 39% in group 2, and 18% in group 3. Those in group 3 recorded the biggest improvement of CMS score after six weeks (+90% versus +68% for group 2 and +58% for group 1), with all groups showing improvements compared to pre-treatment. The only independent risk factor identified for re-MUA was smoking. If a second MUA was performed, CMS (+67%) and VAS (+61%) scores improved, but at six months CMS scores (74.57±7.6 versus 83.30±5.5) and the VAS score (10.57±1.8 versus 12.96±1.5) remained inferior to those who only needed a single MUA. Discussion and/or Conclusion MUA combined with capsular distension and counter-traction reduces the need for a second MUA and results in a faster improvement of functional outcome (CMS score) and reduction of pain (VAS score) compared to MUA or MUA with capsular distension. The results of this case-cohort study are of clinical relevance since they show that the efficacy of an MUA can be improved through relatively simple adaptations of the treatment protocol.

Objective: We studied a cohort of patients with nonsyndromic complete atrioventricular septal defect with and without concomitant complex cardiac anatomy and compared the outcomes after surgical repair. Methods: Between 1993 and 2018, 62 nonsyndromic patients underwent complete atrioventricular septal defect repair. Sixteen patients (26%) had complex complete atrioventricular septal defect with variables representing concomitant cardiac anatomic complexity: tetralogy of Fallot, double outlet right ventricle, total anomalous pulmonary venous return, concomitant aortic arch reconstruction, multiple ventricular septal defects, staged repair of coarctation of the aorta, and a persisting left superior vena cava. The mean follow-up was 12.7 ± 7.9 years. Baseline variables were retrospectively evaluated and analyzed using univariable logistic regression. Survival was studied using Kaplan–Meier estimates, and group comparisons were performed using the log-rank test. A competing-risk analysis estimated the risk of reoperation with death as the competing event. A Gray's test was used to test equality of the cumulative incidence curves between groups. Results: The perioperative mortality was 3.2% (2/62). Actuarial survival was 100% versus 66.7% ± 14.9% at 10 years in the noncomplex and complex groups, respectively (P < .01). There was no significant difference in the overall reoperation rate between the noncomplex group (7/46; 15%) and the complex group (4/16; 25%) (odds ratio, 1.86; 95% confidence interval, 0.46-7.45; P = .30). The competing-risk analysis demonstrated no significant difference in reoperation between the groups (P = .28). Conclusions: Our data show that nonsyndromic patients without complex cardiac anatomy have a good long-term survival and an acceptable risk of reoperation similar to contemporary outcomes for patients with complete atrioventricular septal defect with trisomy 21. However, the corresponding group of nonsyndromic patients with concomitant complex cardiac lesions are still a high-risk population, especially regarding mortality. (Less)

STUDY OBJECTIVES: Mandibular advancement devices (MADs) are a noninvasive treatment option for patients with obstructive sleep apnea (OSA) and act by increasing the upper airway volume. However, the exact therapeutic mechanism of action remains unclear. The aim of this study was to assess MAD mechanisms using functional imaging that combines imaging techniques and computational fluid dynamics and assess associations with treatment outcome. METHODS: One hundred patients with OSA were prospectively included and treated with a custom-made MAD at a fixed 75% protrusion. A low-dose computed tomography scan was made with and without MADs for computational fluid dynamics analysis. Patients underwent a baseline and 3-month follow-up polysomnography to evaluate treatment efficacy. A reduction in apnea-hypopnea index ≥ 50% defined treatment response. RESULTS: Overall, 71 patients completed both 3-month follow-up polysomnography and low-dose computed tomography scan with computational fluid dynamics analysis. MAD treatment significantly reduced the apnea-hypopnea index (16.5 [10.4–23.6] events/h to 9.1 [3.9–16.4] events/h; P < .001, median [quartile 1–quartile 3]) and significantly increased the total upper airway volume (8.6 [5.4–12.8] cm(3) vs 10.7 [6.4–15.4] cm(3); P = .003), especially the velopharyngeal volume (2.1 [0.5–4.1] cm(3) vs 3.3 [1.8–6.0] cm(3); P < .001). However, subanalyses in responders and nonresponders only showed a significant increase in the total upper airway volume in responders, not in nonresponders. CONCLUSIONS: MAD acts by increasing the total upper airway volume, predominantly due to an increase in the velopharyngeal volume. Responders showed a significant increase in the total upper airway volume with MAD treatment, while there was no significant increase in nonresponders. Findings add evidence to implement functional imaging using computational fluid dynamics in routine MAD outcome prediction. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: Predicting Therapeutic Outcome of Mandibular Advancement Device Treatment in Obstructive Sleep Apnea; URL: https://clinicaltrials.gov/ct2/show/NCT01532050; Identifier: NCT01532050. CITATION: Van Gaver H, Op de Beeck S, Dieltjens M, et al. Functional imaging improves patient selection for mandibular advancement device treatment outcome in sleep-disordered breathing: a prospective study. J Clin Sleep Med. 2022;18(3):739–750.

Summary Background Use of third-generation cephalosporins, such as cefotaxime, is associated with an increased risk of selection for antimicrobial resistance, so alternative antibiotics need to be considered. The aim of the present study was to evaluate intestinal colonisation with third-generation cephalosporin-resistant pathogens following use of temocillin—an alternative antibiotic to cefotaxime that is potentially less prone to disturbing the intestinal microbiota—in empirical treatment of febrile urinary tract infection (UTI). Methods We did a randomised, multicentre, superiority, open-label phase 4 trial in patients who had been admitted to inpatient care in 12 Swedish hospitals with suspected or diagnosed febrile UTI (complicated or uncomplicated). To meet inclusion criteria, a patient was required to have at least one sign or symptom of pyelonephritis (ie, flank pain; costovertebral angle tenderness; and changes to urinary frequency or urgency or dysuria), a fever of 38·0°C or higher, and a positive urine dipstick (for nitrites, white blood cells, or both). Participants were also required to have an indication for intravenous antibiotic treatment. Participants were randomly assigned (1:1) to receive either 2 g temocillin or 1–2 g cefotaxime, by local investigators opening consecutive sealed randomisation envelopes that were generated centrally in advance. Both drugs were administered intravenously every 8 h. The trial was open label for investigators and patients, but those doing the microbiological analyses were masked to the groups. Participants were treated with antibiotics for 7–10 days (or up to 14 days if they had bacteraemia), at least 3 days of which were on the study drug; at day 4 and later, participants who were showing improvement could be given an oral antibiotic (ciprofloxacin, ceftibuten, cefixime, or co-trimoxazole). Patients not showing improvement were regarded as having treatment failures. Rectal swabs were collected at three timepoints: at baseline (before the first dose), after the last dose of study drug, and 7–10 days after treatment stopped. The composite primary outcome was colonisation with Enterobacterales with reduced susceptibility to third-generation cephalosporins, or colonisation with toxin-producing Clostridioides difficile, or both, to evaluate disturbance of the intestinal microbiota. The study is registered in the EU Clinical Trials Register (EudraCT 2015-003898-15). Findings Between May 20, 2016, and July 31, 2019, 207 patients were screened for eligibility, of whom 55 patients were excluded. 152 participants were randomly assigned to groups: 77 (51%) patients received temocillin, 75 (49%) patients received cefotaxime. The composite primary endpoint was met by 18 (26%) of 68 participants receiving temocillin versus 30 (48%) of 62 patients receiving cefotaxime (risk difference −22% [95% CI −42% to −3%]), showing superiority of temocillin versus cefotaxime (ie, less disturbance of the intestinal microbiota). 43 adverse events were reported in 40 (52%) of 77 patients in the temocillin group, versus 46 adverse events in 34 (45%) of 75 patients in the cefotaxime group. Most events were of mild to moderate severity. 21 (27%) patients in the temocillin and 17 (23%) patients in the cefotaxime group had an adverse event that was considered to be associated with the study drug. Interpretation Temocillin was found to be less selective than cefotaxime of Enterobacterales with reduced susceptibility to third-generation cephalosporins, and it could therefore be a favourable alternative in the empirical treatment of febrile UTI. Use of this antibiotic could reduce hospital transmission and health-care-associated infections by these pathogens. Funding Public Health Agency of Sweden.

Background: Over the last decades, many brain imaging studies have contributed to new insights in the pathogenesis of psychiatric disease. However, in spite of these developments, progress in the development of novel therapeutic drugs for prevalent psychiatric health conditions has been limited. Objective: In this review, we discuss translational, diagnostic and methodological issues that have hampered drug development in CNS disorders with a particular focus on psychiatry. The role of preclinical models is critically reviewed and opportunities for brain imaging in early stages of drug development using PET and fMRI are discussed. The role of PET and fMRI in drug development is reviewed emphasizing the need to engage in collaborations between industry, academia and phase I units. Conclusion: Brain imaging technology has revolutionized the study of psychiatric illnesses, and during the last decade, neuroimaging has provided valuable insights at different levels of analysis and brain organization, such as effective connectivity (anatomical), functional connectivity patterns and neurochemical information that may support both preclinical and clinical drug development. Since there is no unifying pathophysiological theory of individual psychiatric syndromes and since many symptoms cut across diagnostic boundaries, a new theoretical framework has been proposed that may help in defining new targets for treatment and thus enhance drug development in CNS diseases. In addition, it is argued that new proposals for data-mining and mathematical modelling as well as freely available databanks for neural network and neurochemical models of rodents combined with revised psychiatric classification will lead to new validated targets for drug development.

ObjectiveTo assess the value of the Emergency Department–Pediatric Early Warning Score (ED-PEWS) for triage of children with comorbidity.DesignSecondary analysis of a prospective cohort.Setting and patients53 829 consecutive ED visits of children InterventionED-PEWS, a score consisting of age and six physiological parameters.Main outcome measureA three-category reference standard as proxy for true patient urgency. We assessed discrimination and calibration of the ED-PEWS for children with comorbidity (complex and non-complex) and without comorbidity. In addition, we evaluated the value of adding the ED-PEWS to the routinely used Manchester Triage System (MTS).Results5053 (9%) children had underlying non-complex morbidity and 5537 (10%) had complex comorbidity. The c-statistic for identification of high-urgency patients was 0.86 (95% prediction interval 0.84–0.88) for children without comorbidity, 0.87 (0.82–0.92) for non-complex and 0.86 (0.84–0.88) for complex comorbidity. For high and intermediate urgency, the c-statistic was 0.63 (0.62–0.63), 0.63 (0.61–0.65) and 0.63 (0.55–0.73) respectively. Sensitivity was slightly higher for children with comorbidity (0.73–0.75 vs 0.70) at the cost of a lower specificity (0.86–0.87 vs 0.92). Calibration was largely similar. Adding the ED-PEWS to the MTS for children with comorbidity improved performance, except in the setting with few high-urgency patients.ConclusionsThe ED-PEWS has a similar performance in children with and without comorbidity. Adding the ED-PEWS to the MTS for children with comorbidity improves triage, except in the setting with few high-urgency patients.

Introduction Many diseases can imitate inflammatory bowel disease [IBD] clinically and pathologically. This review outlines the differential diagnosis of IBD and discusses morphological pointers and ancillary techniques that assist with the distinction between IBD and its mimics. Methods European Crohn’s and Colitis Organisation [ECCO] Topical Reviews are the result of an expert consensus. For this review, ECCO announced an open call to its members and formed three working groups [WGs] to study clinical aspects, pathological considerations, and the value of ancillary techniques. All WGs performed a systematic literature search. Results Each WG produced a draft text and drew up provisional Current Practice Position [CPP] statements that highlighted the most important conclusions. Discussions and a preliminary voting round took place, with subsequent revision of CPP statements and text and a further meeting to agree on final statements. Conclusions Clinicians and pathologists encounter a wide variety of mimics of IBD, including infection, drug-induced disease, vascular disorders, diverticular disease, diversion proctocolitis, radiation damage, and immune disorders. Reliable distinction requires a multidisciplinary approach.

Objective:Effective infection prevention and control (IPC) measures are key for protecting patients from nosocomial infections and require knowledge of transmission mechanisms in different settings. We performed a detailed outbreak analysis of the transmission and outcome of coronavirus disease 2019 (COVID-19) in a geriatric ward by combining whole-genome sequencing (WGS) with epidemiological data.Design:Retrospective cohort study.Setting:Tertiary-care hospital.Participants:Patients and healthcare workers (HCWs) from the ward with a nasopharyngeal sample (NPS) positive for severe acute respiratory coronavirus virus 2 (SARS-CoV-2) RNA during the outbreak period.Methods:Patient data regarding clinical characteristics, exposure and outcome were collected retrospectively from medical records. Stored NPSs from 32 patients and 15 HCWs were selected for WGS and phylogenetic analysis.Results:The median patient age was 84 years and 17 (53%) of 32 were male. Also, 14 patients (44%) died within 30 days of sampling. Viral loads were significantly higher among the deceased. WGS was successful in 28 (88%) of 32 patient samples and 14 (93%) of 15 HCW samples. Moreover, 3 separate viral clades were identified: 1 clade and 2 subclades among both patient and HCW samples. Integrated epidemiological and genetic analyses revealed 6 probable transmission events between patients and supported hospital-acquired COVID-19 among 25 of 32 patients.Conclusions:WGS provided an insight into the outbreak dynamics and true extent of nosocomial COVID-19. The extensive transmission between patients and HCWs indicated that current IPC measures were insufficient. We recommend increased use of WGS in outbreak investigations to identify otherwise unknown transmission links and to evaluate IPC measures.

We aimed to identify serum metabolites related to abnormal glucose metabolism (AGM) among women with gestational diabetes mellitus (GDM). The study recruited 50 women diagnosed with GDM during mid-late pregnancy and 50 non-GDM matchees in a Singapore birth cohort. At the 5-year post-partum follow-up, we applied an untargeted approach to investigate the profiles of serum metabolites among all participants. We first employed OPLS-DA and logistic regression to discriminate women with and without follow-up AGM, and then applied area under the curve (AUC) to assess the incremental indicative value of metabolic signatures on AGM. We identified 23 candidate metabolites that were associated with postpartum AGM among all participants. We then narrowed down to five metabolites [p-cresol sulfate, linoleic acid, glycocholic acid, lysoPC(16:1) and lysoPC(20:3)] specifically associating with both GDM and postpartum AGM. The combined metabolites in addition to traditional risks showed a higher indicative value in AUC (0.92–0.94 vs. 0.74 of traditional risks and 0.77 of baseline diagnostic biomarkers) and R2 (0.67–0.70 vs. 0.25 of traditional risks and 0.32 of baseline diagnostic biomarkers) in terms of AGM indication, compared with the traditional risks model and traditional risks and diagnostic biomarkers combined model. These metabolic signatures significantly increased the AUC value of AGM indication in addition to traditional risks, and might shed light on the pathophysiology underlying the transition from GDM to AGM.

This paper proposes an optimization framework based on the OpenMDAO software library intended for engineer-to-order products and applies it to the conceptual design of a Mobile Miner. A Mobile Miner is a complex machine and a flexible alternative to Tunnel Boring Machines for small-scale tunneling and mining applications. The proposed framework is intended for use in early design and quotation stages with the objective to get fast estimates of important product characteristics, such as excavation rate and cutter lifetime. The ability to respond fast to customer requests is vital when offering customized products for specific applications and thereby to stay competitive on the global market. This is true for most engineer-to-order products and especially for mining equipment where each construction project is unique with different tunnel geometries and rock properties. The presented framework is applied to a specific use-case where the design of the miner's cutter wheel is in focus and a set of Pareto optimal designs are obtained. Furthermore, the framework extends the capabilities of OpenMDAO by including support for mixed-variable formulations and it supports an exploratory approach to design optimization.

Background Ketamine can act as antidepressant in patients with major depressive disorder (MDD) who are treatment-resistant. P11 has been implicated in ketamine's mechanism of action and proposed as biomarker for treatment response to other antidepressants. This study explores the effect of ketamine on peripheral p11 and the potential role for p11 as response marker for ketamine treatment. Methods Thirty Selective Serotonin Reuptake Inhibitor resistant MDD patients were randomized to either 0.5 mg/kg ketamine or placebo intravenous treatment. Using multicolor Flow Cytometry, peripheral p11 levels were measured before and 1-2 days after treatment. Results P11 levels were decreased within the ketamine group in both cytotoxic T cell and T helper cells populations, although this did not significantly differ from changes seen in the placebo group. Baseline p11 levels in cytotoxic T cells were significantly correlated with antidepressant response to ketamine treatment. Limitations This study was part of a larger study examining the effect of ketamine on the serotonin system in MDD patients, therefore the number of study subjects was limited to that of the primary study. Conclusions High baseline p11 levels in cytotoxic T cells were associated with a stronger reduction of depressive symptoms in MDD patients after ketamine treatment. Future studies should confirm if peripheral p11 levels could be used as a predictor of ketamine treatment response.

International audience; Rationale: Elexacaftor-tezacaftor-ivacaftor is a CFTR (cystic fibrosis [CF] transmembrane conductance regulator) modulator combination, developed for patients with CF with at least one Phe508del mutation. Objectives: To evaluate the effects of elexacaftor-tezacaftor- ivacaftor in patients with CF and advanced respiratory disease. Methods: A prospective observational study, including all patients aged ⩾12 years and with a percent-predicted FEV1 (ppFEV1)

Context Comprehensive assessment of metabolism in maternal obesity and pregnancy disorders can provide information about the shared maternal-fetal milieu and give insight into both maternal long-term health and intergenerational transmission of disease burden. Objective To assess levels, profiles, and change in the levels of metabolic measures during pregnancies complicated by obesity, gestational diabetes (GDM), or hypertensive disorders. Design, Setting and Participants A secondary analysis of 2 study cohorts, PREDO and RADIEL, including 741 pregnant women. Main Outcome Measures We assessed 225 metabolic measures by nuclear magnetic resonance in blood samples collected at median 13 [interquartile range (IQR) 12.4-13.7], 20 (IQR 19.3-23.0), and 28 (27.0-35.0) weeks of gestation. Results Across all 3 time points women with obesity [body mass index (BMI) ≥ 30kg/m2] in comparison to normal weight (BMI 18.5-24.99 kg/m2) had significantly higher levels of most very-low-density lipoprotein-related measures, many fatty and most amino acids, and more adverse metabolic profiles. The change in the levels of most metabolic measures during pregnancy was smaller in obese than in normal weight women. GDM, preeclampsia, and chronic hypertension were associated with metabolic alterations similar to obesity. The associations of obesity held after adjustment for GDM and hypertensive disorders, but many of the associations with GDM and hypertensive disorders were rendered nonsignificant after adjustment for BMI and the other pregnancy disorders. Conclusions This study shows that the pregnancy-related metabolic change is smaller in women with obesity, who display metabolic perturbations already in early pregnancy. Metabolic alterations of obesity and pregnancy disorders resembled each other suggesting a shared metabolic origin.

Trophoblast-specific expression of human leukocyte antigen G (HLA-G) induces immune tolerance for the developing fetus. Pathological HLA-G expression later in life might contribute to immune escape of various cancers. We studied the still controversial role of HLA-G in colorectal carcinoma (CRC) using the MEM-G/1 antibody and a tissue microarray series of CRC tumors (n=317). HLA-G expression appeared in 20% of the tumors and showed high intratumoral heterogeneity. HLA-G positivity was associated with better differentiation (p=0.002) and non-mucinous histology (p=0.008). However, HLA-G expression alone showed no prognostic value: 5-years disease-specific survival among patients with HLA-G expression was 68.9% (95% CI: 62.7-75.0%) compared to 74.8% (95% CI: 63.2-86.3%) among those without expression. These results support a modulatory role of HLA-G in CRC. This article is protected by copyright. All rights reserved.