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Human papillomavirus (HPV)-driven head and neck squamous cell carcinomas (HNSCC) generally have a more favourable prognosis. We hypothesized that HPV-associated HNSCC may be identified by an miRNA-signature according to their specific molecular pathogenesis, and be characterized by a unique transcriptome compared to HPV-negative HNSCC. We performed miRNA expression profiling of two p16/HPV DNA characterized HNSCC cohorts of patients treated by adjuvant radio(chemo)therapy (multicentre DKTK-ROG n = 128, single-centre LMU-KKG n = 101). A linear model predicting HPV status built in DKTK-ROG using lasso-regression was tested in LMU-KKG. LMU-KKG tumours ( n = 30) were transcriptome profiled for differential gene expression and miRNA-integration. A 24-miRNA signature predicted HPV-status with 94.53% accuracy (AUC: 0.99) in DKTK-ROG, and 86.14% (AUC: 0.86) in LMU-KKG. The prognostic values of 24-miRNA- and p16/HPV DNA status were comparable. Combining p16/HPV DNA and 24-miRNA status allowed patient sub-stratification and identification of an HPV-associated patient subgroup with impaired overall survival. HPV-positive tumours showed downregulated MAPK , Estrogen , EGFR , TGFbeta , WNT signaling activity. miRNA-mRNA integration revealed HPV-specific signaling pathway regulation, including PD-L1 expression/PD-1 checkpoint pathway in cancer in HPV-associated HNSCC. Integration of clinically established p16/HPV DNA with 24-miRNA signature status improved clinically relevant risk stratification, which might be considered for future clinical decision-making with respect to treatment de-escalation in HPV-associated HNSCC.

We describe a sequential multistaining protocol for immunohistochemistry, immunofluorescence and CyTOF imaging for formalin-fixed, paraffin-embedded specimens (FFPE) in the formalin gas-phase (FOLGAS), enabling sequential multistaining, independent from the primary and secondary antibodies and retrieval. Histomorphologic details are preserved, and crossreactivity and loss of signal intensity are not detectable. Combined with a DAB-based hydrophobic masking of metal-labeled primary antibodies, FOLGAS allows the extended use of CyTOF imaging in FFPE sections.

Background: Gastric bypass (GBP) is a surgical method with good evidence of sustainable weight loss, reduced obesity-related comorbidities, and improved health-related quality of life (HRQoL). However, long-term data post-GBP is scarce on HRQoL related to other factors than weight loss, such as impact of socio-economic, age, and gender., Aim: To investigate long-term HRQoL in GBP patients., Methods: The study was conducted as a cross-sectional study covering 3 to 9 years post-GBP measuring HRQoL using RAND-36. Association to weight loss, time since surgery, gender, educational level, occupation, and age was analyzed. The participants were included on the basis that they had received a GBP that was performed by Region Skåne, the southernmost administrative healthcare region in Sweden. Recruitment to the study was by mail invitation for an online survey., Results: Of the total population of 5310 persons receiving the questionnaire, 1339 of the 1372 responders fulfilled the inclusion criteria. Those with low educational level, unemployed, persons on sick leave or disability support, and those with less weight loss reported the lowest HRQoL. The longer time since surgery, the lower the HRQoL., Conclusion: Less weight loss, longer time since GBP, lower educational level, and lower degree of employment all affect HRQoL negatively after GBP surgery.

Pathological biopsy protocols require tissue marking dye (TMD) for orientation. In some cases (e.g., close margin), additional immunohistochemical analyses can be necessary. Therefore, the correlation between the applied TMD during macroscopy and the examined TMD during microscopy is crucial for the correct orientation, the residual tumour status and the subsequent therapeutic regime. In this context, our group observed colour changes during routine immunohistochemistry. Tissue specimens were marked with various TMD and processed by two different methods. TMD (blue, red, black, yellow and green) obtained from three different providers (A, B and C, and Whiteout/Tipp-Ex ® ) were used. Immunohistochemistry was performed manually via stepwise omission of reagents to identify the colour changing mechanism. Blue colour from provider A changed during immunohistochemistry into black, when 3,3'-Diaminobenzidine-tetrahydrochloride-dihydrate (DAB) and H 2 O 2 was applied as an immunoperoxidase-based terminal colour signal. No other applied reagents, nor tissue texture or processing showed any influence on the colour. The remaining colours from provider A and the other colours did not show any changes during immunohistochemistry. Our results demonstrate an interesting and important pitfall in routine immunohistochemistry-based diagnostics that pathologists should be aware of. Furthermore, the chemical rationale behind the observed misleading colour change is discussed.

Meta-analysis, a systematic statistical examination that combines the results of several independent studies, has the potential of obtaining problem- and implementation-independent knowledge and understanding of metaheuristic algorithms, but has not yet been applied in the domain of operations research. To illustrate the procedure, we carried out a meta-analysis of the adaptive layer in adaptive large neighborhood search (ALNS). Although ALNS has been widely used to solve a broad range of problems, it has not yet been established whether or not adaptiveness actually contributes to the performance of an ALNS algorithm. A total of 134 studies were identified through Google Scholar or personal e-mail correspondence with researchers in the domain, 63 of which fit a set of predefined eligibility criteria. The results for 25 different implementations of ALNS solving a variety of problems were collected and analyzed using a random effects model. This dataset contains a detailed comparison of ALNS with the non-adaptive variant per study and per instance, together with the meta-analysis summary results. The data enable to replicate the analysis, to evaluate the algorithms using other metrics, to revisit the importance of ALNS adaptive layer if results from more studies become available, or to simply consult the ready-to-use formulas in the summary file to carry out a meta-analysis of any research question. The individual studies, the meta-analysis and its results are described and interpreted in detail in Renata Turkeš, Kenneth Sörensen, Lars Magnus Hvattum, Meta-analysis of Metaheuristics: Quantifying the Effect of Adaptiveness in Adaptive Large Neighborhood Search, in the European Journal of Operational Research., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships which have, or could be perceived to have, influenced the work reported in this article., (© 2020 The Author(s).)

Rationale and Objectives: Emphysema is a hallmark of chronic obstructive pulmonary disease. The primary aim of this study was to investigate inter- and intraobserver agreement of visual assessment of mild emphysema in low-dose multidetector computed tomography of subjects in the pilot SCAPIS in order to certify consistent detection of mild emphysema. The secondary aim was to investigate the performance of quantitative densitometric measurements in the cohort., Materials and Methods: Participants with emphysema (n = 100, 56 males and 44 females) reported in the electronic case report form of pilot SCAPIS and 100 matched controls (gender, age, height, and weight) without emphysema were included. To assess interobserver variability the randomized examinations were evaluated by two thoracic radiologists. For intraobserver variability three radiologists re-evaluated randomized examinations which they originally evaluated. The results were evaluated statistically by Krippendorff's α. The dataset was also assessed quantitively for % lung attenuation value -950 HU (LAV950), mean lung density and total lung volume by commercially available software., Results: Emphysema was visually scored as mild and Krippendorff's α was ≥0.8 for both the inter- and intraobserver agreement regarding presence of emphysema and approaching 0.8 regarding presence and extent of emphysema by location in the upper lobes. Mean LAV950 was not different between the emphysematous and the nonemphysematous participants; 8.3% and 8.4%, respectively., Conclusion: The inter- and intraobserver agreement for visual detection of mild emphysema in low-dose multidetector computed tomography was good. Surprisingly, quantitative analysis could not reliably identify participants with mild emphysema, which hampers the use of automatic evaluation., (Copyright © 2019 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Background: Mutations in MYLK cause non-syndromic familial thoracic aortic aneurysms and dissections (FTAAD). Very little is known about the phenotype of affected families. We sought to characterize the aortic disease and the presence of other vascular abnormalities in FTAAD caused by a deletion in MYLK and to compare thoracic aortic diameter and stiffness in mutation carriers and non-carriers., Methods: We studied FTAAD in a 5-generation family that included 19 living members. Exome sequencing was performed to identify the underlying gene defect. Aortic elastic properties measured by TTE, MRI and pulse wave velocity were then compared between mutation carriers and non-carriers., Results: Exome sequencing led to the identification of a 2-bp deletion in MYLK (c3272_3273del, p.Ser1091*) that led to a premature stop codon and nonsense-mediated decay. Eleven people were mutation carriers and eight people were non-carriers. Five aortic ruptures or dissections occurred in this family, with two survivors. There were no differences in aortic diameter or stiffness between carriers and non-carriers of the mutation., Conclusions: Individuals carrying this deletion in MYLK have a high risk of presenting with an acute aortic dissection or rupture. Aortic events occur over a wide range of ages and are not always preceded by obvious aortic dilatation. Aortic elastic properties do not differ between carriers and non-carriers of this mutation, rendering it uncertain whether and when carriers should undergo elective prophylactic surgery.

Background: The underlying pathology in aortic stenosis (AS) and coronary artery stenosis (CAS) is similar including atherosclerosis and calcification. We hypothesize that coronary artery calcification (CAC) is likely to correlate with aortic root calcification (ARC) rather than with aortic valve calcification (AVC), due to tissue similarity between the two types of vessel rather than with the valve leaflet tissue., Material and Methods: We studied 212 consecutive patients (age 72.5 ± 7.9 years, 91 females) with AS requiring aortic valve replacement (AVR) in two Heart Centers, who underwent multidetector cardiac CT preoperatively. CAC, AVC and ARC were quantified using Agatston scoring. Correlations were tested by Spearman's test and Mann-Whitney U-test was used for comparing different subgroups; bicuspid (BAV) vs tricuspid (TAV) aortic valve., Results: CAC was present in 92%, AVC in 100% and ARC in 82% of patients. CAC correlated with ARC (rho = 0.51, p < 0.001) but not with AVC. The number of calcified coronary arteries correlated with ARC (rho = 0.45, p < 0.001) but not with AVC. 29/152 patients had echocardiographic evidence of BAV and 123 TAV, who were older (p < 0.001) but CAC was associated with TAV even after adjusting for age (p = 0.01). AVC score was associated with BAV after adjusting for age (p = 0.03) but ARC was not. Of the total cohort, 82 patients (39%) had significant coronary stenosis (>50%), but these were not different in the pattern of calcification from those without CAS. CAC was consistently higher in patients with risk factors for atherosclerosis compared to those without., Conclusion: The observed relationship between coronary and aortic root calcification suggests a diffuse arterial disease. The lack of relationship between coronary and aortic valve calcification suggests a different pathology., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

On the basis of the combination of the well-known knapsack problem and a widely used risk management technique in organizations (that is, the risk matrix), an approach was developed to carry out a cost-benefits analysis to efficiently take prevention investment decisions. Using the knapsack problem as a model and combining it with a well-known technique to solve this problem, bundles of prevention measures are prioritized based on their costs and benefits within a predefined prevention budget. Those bundles showing the highest efficiencies, and within a given budget, are identified from a wide variety of possible alternatives. Hence, the approach allows for an optimal allocation of safety resources, does not require any highly specialized information, and can therefore easily be applied by any organization using the risk matrix as a risk ranking tool., (© 2013 Society for Risk Analysis.)

Background: Hantavirus infections cause potentially life-threatening disease in humans world-wide. Infections with American hantaviruses may lead to hantavirus pulmonary syndrome characterised by severe cardiopulmonary distress with high mortality. Pulmonary involvement in European Puumala hantavirus (PUUV) infection has been reported, whereas knowledge of potential cardiac manifestations is limited. We aimed to comprehensively investigate cardiopulmonary involvement in patients with PUUV-infection., Methods: Twenty-seven hospitalised patients with PUUV-infection were examined with lung function tests, chest high-resolution CT (HRCT), echocardiography including speckle tracking strain rate analysis, ECG and measurements of cardiac biomarkers N-terminal pro-B-type natriuretic peptide (NT-ProBNP) and troponin T. Patients were re-evaluated after 3 months. Twenty-five age and sex-matched volunteers acted as controls for echocardiography data., Results: Two-thirds of the patients experienced respiratory symptoms as dry cough or dyspnoea. Gas diffusing capacity was impaired in most patients, significantly improving at follow-up but still subnormal in 38%. HRCT showed thoracic effusions or pulmonary oedema in 46% of the patients. Compared to controls, the main echocardiographic findings in patients during the acute phase were significantly higher pulmonary vascular resistance, higher systolic pulmonary artery pressure, lower left ventricular ejection fraction and impaired left atrial myocardial motion. Pathological ECG, atrial fibrillation or T-wave changes, was demonstrated in 26% of patients. NT-ProBNP concentrations were markedly increased and were inversely associated with gas diffusing capacity but positively correlated to pulmonary vascular resistance. Furthermore, patients experiencing impaired general condition at follow-up had significantly lower gas diffusing capacity and higher pulmonary vascular resistance, compared to those feeling fully recovered., Conclusions: In a majority of patients with PUUV-infection, both cardiac and pulmonary involvement was demonstrated with implications on patients' recovery. The results demonstrate vascular leakage in the lungs that most likely is responsible for impaired gas diffusing capacity and increased pulmonary vascular resistance with secondary pulmonary hypertension and right heart distress. Interestingly, NT-ProBNP was markedly elevated even in the absence of overt ventricular heart failure. The method of simultaneous investigations of important cardiac and respiratory measurements improves the interpretation of the underlying pathophysiologic mechanisms.

Six-membered cyclic carbonates are potential monomers for phosgene and/or isocyanate free polycarbonates and polyurethanes via ring-opening polymerization. A two-step process for their synthesis comprising lipase-catalyzed transesterification of a polyol, trimethylolpropane (TMP) with dimethylcarbonate (DMC) in a solvent-free system followed by thermal cyclization was optimized to improve process efficiency and selectivity. Using full factorial designed experiments and partial least squares (PLS) modeling for the reaction catalyzed by Novozym®435 (N435; immobilized Candida antarctica lipase B), the optimum conditions for obtaining either high proportion of monocarbonated TMP and TMP-cyclic-carbonate (3 and 4), or dicarbonated TMP and monocarbonated TMP-cyclic-carbonate (5 and 6) were found. The PLS model predicted that the reactions using 15%-20% (w/w) N435 at DMC:TMP molar ratio of 10-30 can reach about 65% total yield of 3 and 4 within 10 h, and 65%-70% total yield of 5 and 6 within 32-37 h, respectively. High consistency between the predicted results and empirical data was shown with 66.1% yield of 3 and 4 at 7 h and 67.4% yield of 5 and 6 at 35 h, using 18% (w/w) biocatalyst and DMC:TMP molar ratio of 20. Thermal cyclization of the product from 7 h reaction, at 110°C in the presence of acetonitrile increased the overall yield of cyclic carbonate 4 from about 2% to more than 75% within 24 h. N435 was reused for five consecutive batches, 10 h each, to give 3+4 with a yield of about 65% in each run., (Copyright © 2012 American Institute of Chemical Engineers (AIChE).)