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People perform poorly in masticatory function tests despite well-functioning prostheses. However, it is unclear whether there is an agreement between subjective and objective measures of mastication.To investigate the association between subjective and objective measures of masticatory function in patients with bimaxillary implant-supported prostheses.An experimental group (n = 25, age = 70.6 ± 7.5 years, eight women) with bimaxillary implant-supported fixed prostheses and a control group (n = 25, age = 69.0 ± 5.3, 13 women) with natural dentition were recruited. The participants in the experimental group were included if they had been using the prosthesis for at least a year and had no obvious complaints with their prostheses. The control group was people with natural dentition and without any prostheses or complaints related to the masticatory system. The masticatory function was evaluated objectively with food comminution and mixing ability tests, and subjectively with jaw function limitation scale (JLFS) and oral health impact profile (OHIP).The experimental group performed poorly in both objective tests (p .001). However, there was no significant differences between the two groups in total JFLS (p = .114) and OHIP (p = .312) scores. Though, there were certain positive correlations between the food comminution test and JFLS subdomains in the control group, and a positive correlation between food comminution test and specific subdomains of OHIP in the experimental group indicating poor correlation between the subjective and objective measures.Although patients with implant prostheses show poor masticatory performance, there is no agreement in the objective and subjective measures of mastication.

Among the responders to microbial invasion, neutrophils represent the earliest and perhaps the most important immune cells that contribute to host defense with the primary role to kill invading microbes using a plethora of stored anti-microbial molecules. One such process is the production of reactive oxygen species (ROS) by the neutrophil enzyme complex NADPH-oxidase, which can be assembled and active either extracellularly or intracellularly in phagosomes (during phagocytosis) and/or granules (in the absence of phagocytosis). One soluble factor modulating the interplay between immune cells and microbes is galectin-3 (gal-3), a carbohydrate-binding protein that regulates a wide variety of neutrophil functions. Gal-3 has been shown to potentiate neutrophil interaction with bacteria, including Staphylococcus aureus, and is also a potent activator of the neutrophil respiratory burst, inducing large amounts of granule-localized ROS in primed cells. Herein, the role of gal-3 in regulating S. aureus phagocytosis and S. aureus-induced intracellular ROS was analyzed by imaging flow cytometry and luminol-based chemiluminescence, respectively. Although gal-3 did not interfere with S. aureus phagocytosis per se, it potently inhibited phagocytosis-induced intracellular ROS production. Using the gal-3 inhibitor GB0139 (TD139) and carbohydrate recognition domain of gal-3 (gal-3C), we found that the gal-3-induced inhibitory effect on ROS production was dependent on the carbohydrate recognition domain of the lectin. In summary, this is the first report of an inhibitory role of gal-3 in regulating phagocytosis-induced ROS production.

PDF file - 48K, Multi�class SAM analysis revealed 503 probes which were found to significantly differ between the four subtypes in GSE22155 at FDR=0

Supplementary Table S1. Table describing the six identified highly correlated gene expression modules in lung cancer.

Supplementary Figure S6. Expression of proliferation-associated genes in adenocarcinoma subgroups defined by clinical smoking history or gene expression phenotypes (bronchioid, magnoid, squamoid), and the association of these phenotypes with smoking history.

PDF file - 51K, Univariate analyses in the whole cohort and in melanomas with a Breslow thickness > 2mm

Purpose: For primary melanomas, tumor thickness, mitotic rate, and ulceration are well-laid cornerstones of prognostication. However, a molecular exposition of melanoma aggressiveness is critically missing. We recently uncovered a four-class structure in metastatic melanoma, which predicts outcome and informs biology. This raises the possibility that a molecular structure exists even in the early stages of melanoma and that molecular determinants could underlie histophenotype and eventual patient outcome.Experimental Design: We subjected 223 archival primary melanomas to a horizontally integrated analysis of RNA expression, oncogenic mutations at 238 lesions, histomorphometry, and survival data.Results: Our previously described four-class structure that was elucidated in metastatic lesions was evident within the expression space of primary melanomas. Because these subclasses converged into two larger prognostic and phenotypic groups, we used the metastatic lesions to develop a binary subtype-based signature capable of distinguishing between “high” and “low” grade forms of the disease. The two-grade signature was subsequently applied to the primary melanomas. Compared with low-grade tumors, high-grade primary melanomas were significantly associated with increased tumor thickness, mitotic rate, ulceration (all P < 0.01), and poorer relapse-free (HR = 4.94; 95% CI, 2.84–8.59), and overall (HR = 3.66; 95% CI, 2.40–5.58) survival. High-grade melanomas exhibited elevated levels of proliferation and BRCA1/DNA damage signaling genes, whereas low-grade lesions harbored higher expression of immune genes. Importantly, the molecular-grade signature was validated in two external gene expression data sets.Conclusions: We provide evidence for a molecular organization within melanomas, which is preserved across all stages of disease. Clin Cancer Res; 18(15); 4026–36. ©2012 AACR.

Supplementary Figure Legends. Document containing figure legends for supplementary figures.

PDF file - 79K, Significant canonical pathways (p

Supplementary Methods. Document describing in detail the different cohorts and data processing steps used.

Purpose: Cigarette smoking is the major pathogenic factor for lung cancer. The precise mechanisms of tobacco-related carcinogenesis and its effect on the genomic and transcriptional landscape in lung cancer are not fully understood.Experimental Design: A total of 1,398 (277 never-smokers and 1,121 smokers) genomic and 1,449 (370 never-smokers and 1,079 smokers) transcriptional profiles were assembled from public lung adenocarcinoma cohorts, including matched next-generation DNA-sequencing data (n = 423). Unsupervised and supervised methods were used to identify smoking-related copy-number alterations (CNAs), predictors of smoking status, and molecular subgroups.Results: Genomic meta-analyses showed that never-smokers and smokers harbored a similar frequency of total CNAs, although specific regions (5q, 8q, 16p, 19p, and 22q) displayed a 20% to 30% frequency difference between the two groups. Importantly, supervised classification analyses based on CNAs or gene expression could not accurately predict smoking status (balanced accuracies ∼60% to 80%). However, unsupervised multicohort transcriptional profiling stratified adenocarcinomas into distinct molecular subgroups with specific patterns of CNAs, oncogenic mutations, and mutation transversion frequencies that were independent of the smoking status. One subgroup included approximately 55% to 90% of never-smokers and approximately 20% to 40% of smokers (both current and former) with molecular and clinical features of a less aggressive and smoking-unrelated disease. Given the considerable intragroup heterogeneity in smoking-defined subgroups, especially among former smokers, our results emphasize the clinical importance of accurate molecular characterization of lung adenocarcinoma.Conclusions: The landscape of smoking-related CNAs and transcriptional alterations in adenocarcinomas is complex, heterogeneous, and with moderate differences. Our results support a molecularly distinct less aggressive adenocarcinoma entity, arising in never-smokers and a subset of smokers. Clin Cancer Res; 20(18); 4912–24. ©2014 AACR.

PDF file - 91K, Flow chart describing the analysis

PDF file - 95K, The expression values for these genes were averaged across GSE22155 samples in the two classes thereby providing us with two distinct centroids

PDF file - 116K, Among the set of 36 BRAF-mutated cases, high-grade tumors showed worse survival than low-grade lesions

Purpose: Lung cancer is the worldwide leading cause of death from cancer. DNA methylation in gene promoter regions is a major mechanism of gene expression regulation that may promote tumorigenesis. However, whether clinically relevant subgroups based on DNA methylation patterns exist in lung cancer remains unclear.Experimental Design: Whole-genome DNA methylation analysis using 450K Illumina BeadArrays was performed on 12 normal lung tissues and 124 tumors, including 83 adenocarcinomas, 23 squamous cell carcinomas (SqCC), 1 adenosquamous cancer, 5 large cell carcinomas, 9 large cell neuroendocrine carcinomas (LCNEC), and 3 small-cell carcinomas (SCLC). Unsupervised bootstrap clustering was performed to identify DNA methylation subgroups, which were validated in 695 adenocarcinomas and 122 SqCCs. Subgroups were characterized by clinicopathologic factors, whole-exome sequencing data, and gene expression profiles.Results: Unsupervised analysis identified five DNA methylation subgroups (epitypes). One epitype was distinctly associated with neuroendocrine tumors (LCNEC and SCLC). For adenocarcinoma, remaining four epitypes were associated with unsupervised and supervised gene expression phenotypes, and differences in molecular features, including global hypomethylation, promoter hypermethylation, genomic instability, expression of proliferation-associated genes, and mutations in KRAS, TP53, KEAP1, SMARCA4, and STK11. Furthermore, these epitypes were associated with clinicopathologic features such as smoking history and patient outcome.Conclusions: Our findings highlight one neuroendocrine and four adenocarcinoma epitypes associated with molecular and clinicopathologic characteristics, including patient outcome. This study demonstrates the possibility to further subgroup lung cancer, and more specifically adenocarcinomas, based on epigenetic/molecular classification that could lead to more accurate tumor classification, prognostication, and tailored patient therapy. Clin Cancer Res; 20(23); 6127–40. ©2014 AACR.

Supplementary Figures 1-6. PDF containing six supplementary figures. Figure S1: Identification and validation of epitypes in the discovery cohort. Figure S2: Reproducibility of epitypes in the Sandoval et al. cohort. Figure S3: Reproducibility of epitypes in the TCGA cohort. Figure S4: Mutation transversions across epitypes for TCGA adenocarcinomas stratified by smoking status. Figure S5: Copy number alterations (CNAs) and genomic complexity in adenocarcinoma epitypes. Figure S6: Promoter and global hypermethylation with respect to smoking status and adenocarcinoma gene expression subtypes.

Supplementary Table S2. Table describing the 4136 CpG set with aberrant methylation in tumors, and the global correlation analysis of DNA methylation and gene expression in lung adenocarcinoma.

Supplementary Table S3. Table describing the functional analysis of differentially expressed genes between DNA methylation subgroups in the discovery and TCGA cohorts.

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Neutrophils store microbicidal glycoproteins in cytosolic granules to fight intruding pathogens, but their granule distribution and formation mechanism(s) during granulopoiesis remain unmapped. Herein, we perform comprehensive spatiotemporalN-glycoproteome profiling of isolated granule populations from blood-derived neutrophils and during their maturation from bone marrow-derived progenitors using glycomics-assisted glycoproteomics. Interestingly, the granules of resting neutrophils exhibited distinctive glycophenotypes including, most strikingly, peculiar highly truncatedN-glycosylation in the azurophilic granules. Excitingly, proteomics and transcriptomics data from discrete myeloid progenitor stages revealed that profound glycoproteome remodelling underpins the promyelocytic-to-metamyelocyte transition and that remodelling is driven primarily by changes in protein expression and less by the glycosylation machinery. Notable exceptions were the oligosaccharyltransferase subunits responsible for initiation ofN-glycoprotein biosynthesis that were strongly expressed in early myeloid progenitors correlating with high glycosylation efficiencies of the azurophilic granule proteins. Our study provides spatiotemporal insights into the complex neutrophilN-glycoproteome featuring an intriguing granule-specificN-glycosylation formed by dynamic remodelling during myeloid progenitor-to-neutrophil maturation.Key pointsSystems glycobiology reveals that profoundN-glycoproteome remodelling accompanies early neutrophil granulopoiesisPrecision glycoproteomics produces detailed cartography of neutrophils that exhibit site-, protein- and granule-specific N-glycosylation

Epigenome-wide gene–gene (G × G) interactions associated with non-small-cell lung cancer (NSCLC) survival may provide insights into molecular mechanisms and therapeutic targets. Hence, we proposed a three-step analytic strategy to identify significant and robust G × G interactions that are relevant to NSCLC survival. In the first step, among 49 billion pairs of DNA methylation probes, we identified 175 775 G × G interactions with PBonferroni ≤ 0.05 in the discovery phase of epigenomic analysis; among them, 15 534 were confirmed with P ≤ 0.05 in the validation phase. In the second step, we further performed a functional validation for these G × G interactions at the gene expression level by way of a two-phase (discovery and validation) transcriptomic analysis, and confirmed 25 significant G × G interactions enriched in the 6p21.33 and 6p22.1 regions. In the third step, we identified two G × G interactions using the trans-omics analysis, which had significant (P ≤ 0.05) epigenetic cis-regulation of transcription and robust G × G interactions at both the epigenetic and transcriptional levels. These interactions were cg14391855 × cg23937960 (βinteraction = 0.018, P = 1.87 × 10−12), which mapped to RELA × HLA-G (βinteraction = 0.218, P = 8.82 × 10−11) and cg08872738 × cg27077312 (βinteraction = −0.010, P = 1.16 × 10−11), which mapped to TUBA1B × TOMM40 (βinteraction =−0.250, P = 3.83 × 10−10). A trans-omics mediation analysis revealed that 20.3% of epigenetic effects on NSCLC survival were significantly (P = 0.034) mediated through transcriptional expression. These statistically significant trans-omics G × G interactions can also discriminate patients with high risk of mortality. In summary, we identified two G × G interactions at both the epigenetic and transcriptional levels, and our findings may provide potential clues for precision treatment of NSCLC.

Clostridium thermocellum is a cellulolytic thermophile that is considered for the consolidated bioprocessing of lignocellulose to ethanol. Improvements in ethanol yield are required for industrial implementation, but the incompletely understood causes of amino acid secretion impede progress. In this study, amino acid secretion was investigated via gene deletions in ammonium-regulated, nicotinamide adenine dinucleotide phosphate (NADPH)-supplying and NADPH-consuming pathways as well as via physiological characterization in cellobiose-limited or ammonium-limited chemostats. First, the contribution of the NADPH-supplying malate shunt was studied with strains using either the NADPH-yielding malate shunt (Δppdk) or a redox-independent conversion of PEP to pyruvate (Δppdk ΔmalE::Peno-pyk). In the latter, branched-chain amino acids, especially valine, were significantly reduced, whereas the ethanol yield increased from 46 to 60%, suggesting that the secretion of these amino acids balances the NADPH surplus from the malate shunt. The unchanged amino acid secretion in Δppdk falsified a previous hypothesis on an ammonium-regulated PEP-to-pyruvate flux redistribution. The possible involvement of another NADPH-supplier, namely, NADH-dependent reduced ferredoxin:NADP+ oxidoreductase (nfnAB), was also excluded. Finally, the deletion of glutamate synthase (gogat) in ammonium assimilation resulted in the upregulation of NADPH-linked glutamate dehydrogenase activity and decreased amino acid yields. Since gogat in C. thermocellum is putatively annotated as ferredoxin-linked, a claim which is supported by the product redistribution observed in this study, this deletion likely replaced ferredoxin with NADPH in ammonium assimilation. Overall, these findings indicate that a need to reoxidize NADPH is driving the observed amino acid secretion, likely at the expense of the NADH needed for ethanol formation. This suggests that metabolic engineering strategies that simplify the redox metabolism and ammonium assimilation can contribute to increased ethanol yields. QC 20230419

Dosimetric uncertainty is most often not included in the process of creating and selecting plans for treatment. Treatment planning and the physician's choice of treatment plan is instead often based only on evaluation of clinical goals of the calculated absorbed dose distribution. Estimation of the dosimetric uncertainty could potentially have impact in the process of comparing and selecting volumetric modulated arc therapy (VMAT) plans. In this study, different measures for estimation of dosimetric uncertainty based on treatment plan parameters for plans with similar dose distributions were evaluated. VMAT plans with similar dose distributions but with different treatment plan designs were created using three different optimization methods for each of ten patient cases (tonsil and prostate cancer). Two plans were optimized in Eclipse, one with and one without the use of aperture shape controller, and one plan was optimized in RayStation. The studied measures related to dosimetric uncertainty of treatment plans were aperture-based complexity metric analysis, investigation of modulation level of multi leaf collimator leaves, gantry speed and dose rate, quasi-3D measurements and evaluation of simulations of realistic delivery variations. The results showed that there can be variations in dosimetric uncertainty for treatment plans with similar dose distributions. Dosimetric uncertainty assessment could therefore have impact on the choice of plan to be used for treatment and lead to a decrease in the uncertainty level of the delivered absorbed dose distribution. This study showed that aperture shape complexity had a larger impact on dosimetric uncertainty compared to modulation level of MLC, gantry speed and dose rate.

Clostridium thermocellumis a cellulolytic thermophile considered for consolidated bioprocessing of lignocellulose to ethanol. Improvements in ethanol yield are required for industrial implementation, but incompletely understood causes of amino acid secretion impede progress. In this study, amino acid secretion was investigated by gene deletions in ammonium-regulated NADPH-supplying and -consuming pathways and physiological characterization in cellobiose- or ammonium-limited chemostats. First, the contribution of the NADPH-supplying malate shunt was studied with strains using either the NADPH-yielding malate shunt (Δppdk) or redox-independent conversion of PEP to pyruvate (ΔppdkΔmalE::Peno-pyk). In the latter, branched-chain amino acids, especially valine, were significantly reduced, whereas the ethanol yield increased 46-60%, suggesting that secretion of these amino acids balances NADPH surplus from the malate shunt. Unchanged amino acid secretion in Δppdkfalsified a previous hypothesis on ammonium-regulated PEP-to-pyruvate flux redistribution. Possible involvement of another NADPH-supplier, namely NADH-dependent reduced ferredoxin:NADP+oxidoreductase (nfnAB), was also excluded. Finally, deletion of glutamate synthase (gogat) in ammonium assimilation resulted in upregulation of NADPH-linked glutamate dehydrogenase activity and decreased amino acid yields. SincegogatinC. thermocellumis putatively annotated as ferredoxin-linked, which is supported by product redistribution observed in this study, this deletion likely replaced ferredoxin with NADPH in ammonium assimilation. Overall, these findings indicate that a need to reoxidize NADPH is driving the observed amino acid secretion, likely at the expense of NADH needed for ethanol formation. This suggests that metabolic engineering strategies on simplifying redox metabolism and ammonium assimilation can contribute to increased ethanol yields.ImportanceImproving the ethanol yield ofC. thermocellumis important for industrial implementation of this microorganism in consolidated bioprocessing. A central role of NADPH in driving amino acid byproduct formation was demonstrated, by eliminating the NADPH-supplying malate shunt and separately by changing the cofactor specificity in ammonium assimilation. With amino acid secretion diverting carbon and electrons away from ethanol, these insights are important for further metabolic engineering to reach industrial requirements on ethanol yield. This study also provides chemostat data relevant for training genome-scale metabolic models and improving the validity of their predictions, especially considering the reduced degree-of-freedom in redox metabolism of the strains generated here. In addition, this study advances fundamental understanding on mechanisms underlying amino acid secretion in cellulolytic Clostridia as well as regulation and cofactor specificity in ammonium assimilation. Together, these efforts aid development ofC. thermocellumfor sustainable consolidated bioprocessing of lignocellulose to ethanol with minimal pretreatment.

Background and purpose When treating lung tumors with stereotactic body radiation therapy (SBRT), patient immobilization is of outmost importance. In this study, the intra‐fractional shifts of the patient (based on bony anatomy) and the tumor (based on the visible target volume) are quantified, and the associated impact on the delivered dose is estimated for a frameless immobilization approach in combination with surface guided radiation therapy (SGRT) monitoring. Methods Cone beam computed tomographies (CBCT) were collected in free breathing prior and after each treatment for 25 patients with lung tumors, in total 137 fractions. The CBCT collected after each treatment was registered to the CBCT collected before each treatment with focus on bony anatomy to determine the shift of the patient, and with focus on the visible target volume to determine the shift of the tumor. Rigid registrations with 6 degrees of freedom were used. The patients were positioned in frameless immobilizations with their position and respiration continuously monitored by a commercial SGRT system. The patients were breathing freely within a preset gating window during treatment delivery. The beam was automatically interrupted if isocenter shifts >4 mm or breathing amplitudes outside the gating window were detected by the SGRT system. The time between the acquisition of the CBCTs was registered for each fraction to examine correlations between treatment time and patient shift. The impact of the observed shifts on the dose to organs at risk (OAR) and the gross tumor volume (GTV) was assessed. Results The shift of the patient in the CBCTs was ≤2 mm for 132/137 fractions in the vertical (vrt) and lateral (lat) directions, and 134/137 fractions in the longitudinal (lng) direction and ≤4 mm in 134/137 (vrt) and 137/137 (lat, lng) of the fractions. The shift of the tumor was ≤2 mm in 116/137 (vrt), 123/137 (lat) and 115/137 (lng) fractions and ≤4 mm in 136/137 (vrt), 137/137 (lat), and 135/137 (lng) fractions. The maximal observed shift in the evaluated CBCT data was 4.6 mm for the patient and 7.2 mm for the tumor. Rotations were ≤3.3ᵒ for all fractions and the mean/standard deviation were 0.2/1.0ᵒ (roll), 0.1/0.8ᵒ (yaw), and 0.3/1.0ᵒ (pitch). The SGRT system interrupted the beam due to intra‐fractional isocenter shifts >4 mm for 21% of the fractions, but the patients always returned within tolerance without the need of repositioning. The maximal observed isocenter shift by the SGRT system during the beam holds was 8 mm. For the respiration monitoring, the beam was interrupted at least one time for 54% of the fractions. The visual tumor was within the planned internal target volume (ITV) for 136/137 fractions in the evaluated CBCT data collected at the end of each fraction. For the fraction where the tumor was outside the ITV, the D98% for the GTV decreased with 0.4 Gy. For the OARs, the difference between planned and estimated dose from the CBCT data (D2% or Dmean) was ≤2.6% of the prescribed PTV dose. No correlation was found between treatment time and the magnitude of the patient shift. Conclusions Using SGRT for motion management and respiration monitoring in combination with a frameless immobilization is a feasible approach for lung SBRT.

Background and aimsThe lockdown of sports and gambling venues during the coronavirus disease 2019 (COVID-19) pandemic caused a fear of increased gambling on other online gambling types, with a risk for transfer to more addictive gambling than otherwise. This study aimed to estimate changes in gambling activity during COVID-19-affected periods among all gamblers at a Swedish state-owned gambling operator and to analyse observable sex differences.MethodsThis study included gambling tracking data from the Swedish state-owned gambling operator Svenska Spel Sports & Casino (sports betting, online bingo, casino and poker). All individuals (n = 616,245) who gambled at least once from February 10 to July 19, 2020, were included. The study period was divided into four periods according to their expected level of COVID-19 impact on gambling opportunities: one pre-COVID period and three COVID-affected periods (sports cancellation, emerging return of sports, substantial return of sports).ResultsSports betting experienced an apparent decrease, followed by a gradual normalization and an end level substantially below prepandemic levels. For online bingo, gambling levels increased upon sports interruption and then decreased with the return to normality in sports events but remained higher than baseline levels. We observed a similar trend for online poker during the interruption of sports, but with a lower level than baseline levels when sports events normalized. We noticed a trend favouring online casinos during the sports interruption period regarding gambling intensity but not wagering levels.Discussion and conclusionsDramatic changes in the content of the gambling market may divert some gamblers to other gambling types, but maintained effects could not be demonstrated.

Deoxyguanosine kinase (DGUOK) deficiency causes mtDNA depletion and mitochondrial dysfunction. We reported long survival of DGUOK knockout (Dguok−/−) mice despite low (

Criminal recidivism is a major global concern. There is a well-known association between substance use disorders and offending. Yet, little is known about crime-specific recidivism. The aim of this study was to investigate the relationship between specific substance use and crime-specific recidivism. The study is based on 4207 Swedish prison clients with substance use assessed with Addiction Severity Index interviews between 2001 and 2006. Clients were followed for an average of 2.7 years. Risk factors for criminal recidivism were assessed with the Cox regression analysis. Sixty-eight percent of the clients returned to the criminal justice system. Apart from well-known risk factors such as male gender and young age, amphetamine, injection drug use, prior prosecution for violent and property crime, as well as homelessness and psychiatric problems, were risk factors for criminal recidivism. Sedatives and cannabis were, in this setting, negative risk factors for general recidivism. Age, heroin and injection drug use elevated the risks of recidivism to property and drug crime. Alcohol was associated with violent recidivism. When analysing different categories of crime separately, risk factors differed substantially. This further highlights the need for crime-specific research. Identifying crime-specific risk factors should be an important part of improving rehabilitation into society after imprisonment and hopefully decrease recidivism.

Criminal recidivism is a major global concern. There is a well-known association between substance use disorders and offending. Yet, little is known about crime-specific recidivism. The aim of this study was to investigate the relationship between specific substance use and crime-specific recidivism. The study is based on 4207 Swedish prison clients with substance use assessed with Addiction Severity Index interviews between 2001 and 2006. Clients were followed for an average of 2.7 years. Risk factors for criminal recidivism were assessed with the Cox regression analysis. Sixty-eight percent of the clients returned to the criminal justice system. Apart from well-known risk factors such as male gender and young age, amphetamine, injection drug use, prior prosecution for violent and property crime, as well as homelessness and psychiatric problems, were risk factors for criminal recidivism. Sedatives and cannabis were, in this setting, negative risk factors for general recidivism. Age, heroin and injection drug use elevated the risks of recidivism to property and drug crime. Alcohol was associated with violent recidivism. When analysing different categories of crime separately, risk factors differed substantially. This further highlights the need for crime-specific research. Identifying crime-specific risk factors should be an important part of improving rehabilitation into society after imprisonment and hopefully decrease recidivism.

Among early‐stage non‐small‐cell lung cancer (NSCLC) patients, cg05293407TRIM27 was significantly and exclusively associated with survival of lung squamous cell carcinoma patients, who had higher smoking intensity compared to lung adenocarcinoma patients. Generally, the significant association between cg05293407TRIM27 and survival only remained in NSCLC patients having medium‐to‐high pack‐year of smoking. The cg05293407TRIM27‐smoking synergistic interaction might account for histologically heterogeneous effects of TRIM27 DNA methylation on NSCLC survival., Tripartite motif containing 27 (TRIM27) is highly expressed in lung cancer, including non‐small‐cell lung cancer (NSCLC). Here, we profiled DNA methylation of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) tumours from 613 early‐stage NSCLC patients and evaluated associations between CpG methylation of TRIM27 and overall survival. Significant CpG probes were confirmed in 617 samples from The Cancer Genome Atlas. The methylation of the CpG probe cg05293407TRIM27 was significantly associated with overall survival in patients with LUSC (HR = 1.65, 95% CI: 1.30–2.09, P = 4.52 × 10−5), but not in patients with LUAD (HR = 1.08, 95% CI: 0.87–1.33, P = 0.493). As incidence of LUSC is associated with higher smoking intensity compared to LUAD, we investigated whether smoking intensity impacted on the prognostic effect of cg05293407TRIM27 methylation in NSCLC. LUSC patients had a higher average pack‐year of smoking (37.49LUAD vs 54.79LUSC, P = 1.03 × 10−19) and included a higher proportion of current smokers than LUAD patients (28.24%LUAD vs 34.09%LUSC, P = 0.037). cg05293407TRIM27 was significantly associated with overall survival only in NSCLC patients with medium–high pack‐year of smoking (HR = 1.58, 95% CI: 1.26–1.96, P = 5.25 × 10−5). We conclude that cg05293407TRIM27 methylation is a potential predictor of LUSC prognosis, and smoking intensity may impact on its prognostic value across the various types of NSCLC.

Transcriptional factor p53 is a master regulator of energy metabolism. Energy metabolism strongly depends on thiamine (vitamin B1) and/or its natural derivatives. Thiamine diphosphate (ThDP), which is a major thiamine derivative, affects p53 binding to DNA. In order to elucidate the mechanism of regulation of thiamine-dependent metabolism by p53, we assessed putative p53-binding sites near transcription starting points in genes coding for transporters and enzymes, whose function is associated with thiamine and/or its derivatives. The predictions were validated by studying cell metabolic response to the p53 inducer cisplatin. Expression of p53 and its known target, p21, has been evaluated in cisplatin-treated and control human lung adenocarcinoma A549 cells that possess functional p53 pathway. We also investigated the activity of enzymes involved in the thiamine-dependent energy metabolism. Along with upregulating the expression of p53 and p21, cisplatin affected the activities of metabolic enzymes, whose genes were predicted as carrying the p53-binding sites. The activity of glutamate dehydrogenase GDH2 isoenzyme strongly decreased, while the activities of NADP+-dependent isocitrate dehydrogenase (IDH) and malic enzymes, as well as the activity of 2-oxoglutarate dehydrogenase complex at its endogenous ThDP level, were elevated. Simultaneously, the activities of NAD+-dependent IDH, mitochondrial aspartate aminotransferase, and two malate dehydrogenase isoenzymes, whose genes were not predicted to have the p53-binding sequences near the transcription starting points, were upregulated by cisplatin. The p53-dependent regulation of the assayed metabolic enzymes correlated with induction of p21 by p53 rather than induction of p53 itself.

PurposeThe purpose of the present study is to assist academics and practitioners in supporting and managing digital production innovation projects using managerial controls. The focus is on projects that deliver innovations containing new combinations of physical, digital and/or cyber-physical components, developed to be used within a production system. More specifically, this paper aims to explore the applicability of different managerial controls for managing and supporting digital production innovation projects, i.e. projects that are characterized by high levels of complexity and uncertainty.Design/methodology/approachThis is a multiple-case study in which interview data was collected from five digital production innovation projects in two manufacturing firms. The empirical data was used to analyze success factors, challenges and obstacles in different phases of the studied projects, and to connect these to the application of different types of managerial controls.FindingsThe findings provide an increased understanding of who to control, what to control and how to control in digital production innovation projects.Research limitations/implicationsThis paper is focused specifically on the perception of managerial controls in digital production innovation projects and has not explicitly focused on manufacturing companies' intended usage of managerial controls. This paper's focus on manufacturing companies with producing customers and on projects developing solutions for their respective customers' production systems also encourages further studies at other companies undergoing a comparable transition. Given the necessary system perspective on managerial controls that is being highlighted, this paper emphasizes further research needs on how firms can also apply managerial controls to support external collaborations.Practical implicationsThe results have a number of managerial implications regarding digital production innovation projects. The most prominent findings revealed the importance of giving attention to the managerial controls related to the decision-making process and the involvement from stakeholders outside the organization itself. In particular, it was shown that managerial controls securing a more holistic involvement in the decision-making process should be applied, and that managerial controls suitable for customers and partners need to be developed.Originality/valueThe study is among the first studies to focus on the application and perceived effectiveness of managerial controls in digital production innovation projects. The ways in which managerial controls are applied to collaborations with customers and partners and the ways in which action, cultural and personnel controls are combined and aligned to support the corporate decision-making process particularly stand out as essential for manufacturing companies' Industry 4.0 transition.

Background Alzheimer’s disease (AD) is the most common form of age-related neurodegenerative diseases. Cerebral deposition of Aβ peptides, especially Aβ42, is considered the major neuropathological hallmark of AD and the putative cause of AD-related neurotoxicity. Aβ peptides are produced by sequential proteolytic processing of APP, with β-secretase (BACE) being the initiating enzyme. Therefore, BACE has been considered an attractive therapeutic target in AD research and several BACE inhibitors have been tested in clinical trials, but so far, all have had negative outcomes or even led to worsening of cognitive function. AD can be triggered by Aβ years before the first symptoms appear and one reason for the failures could be that the clinical trials were initiated too late in the disease process. Another possible explanation could be that BACE inhibition alters physiological APP processing in a manner that impairs synaptic function, causing cognitive deterioration. Methods The aim of this study was to investigate if partial BACE inhibition, mimicking the putative protective effect of the Icelandic mutation in the APP gene, could reduce Aβ generation without affecting synaptic transmission. To investigate this, we used an optical electrophysiology platform, in which effects of compounds on synaptic transmission in cultured neurons can be monitored. We employed this method on primary cortical rat neuronal cultures treated with three different BACE inhibitors (BACE inhibitor IV, LY2886721, and lanabecestat) and monitored Aβ secretion into the cell media. Results We found that all three BACE inhibitors tested decreased synaptic transmission at concentrations leading to significantly reduced Aβ secretion. However, low-dose BACE inhibition, resulting in less than a 50% decrease in Aβ secretion, did not affect synaptic transmission for any of the inhibitors tested. Conclusion Our results indicate that Aβ production can be reduced by up to 50%, a level of reduction of relevance to the protective effect of the Icelandic mutation, without causing synaptic dysfunction. We therefore suggest that future clinical trials aimed at prevention of Aβ build-up in the brain should aim for a moderate CNS exposure of BACE inhibitors to avoid side effects on synaptic function.

Microplastics (MP) are transported from land-based sources from rivers to marine waters. However, there is currently little knowledge about MP fate from land sources to marine waters. Traffic is estimated to be one of the largest sources of MP; hence, stormwater is expected to be an important transportation route of MP to marine waters. The aim of this study was to investigate the effect of the size and density of tyre wear particles in road run-off on their fate in the Göta River in Sweden using hydrodynamic modelling. The model of the stretch of Göta River, Sweden’s largest river, passing through Gothenburg (Sweden’s second largest city) and out to the sea, was set up using MIKE 3 FM software. Literature data were used to define the MP characteristics: concentrations in stormwater, prevalent particle sizes, density of MP commonly occurring in road run-off and settling velocities. Results show that higher concentrations of MP are found on the south side of the river, compared with the north side, due to higher annual average daily traffic loads along the south side of the river. The mixing processes in the river and the MP concentrations were generally influenced by the vertical water density gradient caused by saline water from the Kattegat strait. While most MP with higher density and larger size settle in the river, smaller MP with density close to 1.0 g/cm3 do not settle in the river and therefore reach the Kattegat strait and the marine environments. Further research is needed to describe the fate and transport of microplastics in the stormwater system, including treatment facilities, i.e. biofouling, aggregation, degradation and/or further fragmentation and settling. Electronic supplementary material The online version of this article (10.1007/s11356-020-08637-z) contains supplementary material, which is available to authorized users.

Background: Criminal recidivism is a major global concern. There is a well-known relation between substance use disorders and offending. Yet, little is known about crime-specific recidivism. The aim of this study was to investigate the relation between specific substance use and crime-specific recidivism. Methods: The study is based on 4,207 Swedish prison clients with substance use assessed with Addiction Severity Index interviews between 2001 and 2006. Clients were followed for an average of 2.7 years. Risk factors for criminal recidivism were assessed with Cox regression analysis. Results: Sixty-eight percent of the clients returned to the criminal justice system. Apart from well-known risk factors such as male gender and young age, amphetamine, injection drug use, prior prosecution for violent and property crime as well as homelessness and psychiatric problems were risk factors for criminal recidivism. Sedatives and cannabis were in this setting negative risk factors for general recidivism. Age, heroin and injection drug use elevated risks of recidivism to property and drug crime. Alcohol was associated with violent recidivism. Conclusions: Looking at different categories of crime separately, risk factors differed substantially. This further highlight the need for crime-specific research. Identifying crime-specific risk factors should be an important part of improving rehabilitation into society after imprisonment and hopefully decrease recidivism.

The accuracy and precision of patient positioning is crucial in radiotherapy; however, there are no publications available using synthetic computed tomography (sCT) that evaluate rotations in head and neck (HN) patients positioning or the effect of translation and rotation combined. The aim of this work was to evaluate the differences between using sCT with the CT for 2D- and 3D-patient positioning in a magnetic resonance imaging (MRI)-only workflow.This study included 14 HN cancer patients, with generated sCT data (MRI Planner v2.2) and the CT deformably registered to the MRI. Patient positioning was evaluated by comparing sCT against CT data: 3D cone beam CT (CBCT) was registered to the deformed CT (dCT) and sCT in six degrees of freedom (DoF) with a rigid auto-registration algorithm and bone threshold, and 2D deformed digital reconstructed radiographs (dDRR) and synthetic DRRs (sDRR) were manually registered to orthogonal projections in five DoF by six blinded observers. The difference in displacement in all DoF were calculated for dCT and sCT, as well as for dDRR and sDRR. The interobserver variation was evaluated by separate application of the paired dDRR and sDRR registration matrices to the original coordinates of the planning target volume (PTV) structures and calculation of the Euclidean distance between the corresponding points. The Dice similarity coefficient (DSC) was calculated between dDRR/sDRR-registered PTVs.The mean difference in patient positioning using CBCT was 0.7 mm and 0.3° and using orthogonal projections 0.4 mm and 0.2° in all directions. The maximum Euclidean distance was 5.1 mm, the corresponding mean (1SD) Euclidean distance and mean DSC were 3.5 ± 0.7 mm and 0.93, respectively.This study shows that the sCT-based patient positioning gives a comparable result with that based on CT images, allowing sCT to replace CT as reference for patient treatment positioning.

Background This study examines the destiny of macromolecules in different full-scale biogas processes. From previous studies it is clear that the residual organic matter in outgoing digestates can have significant biogas potential, but the factors dictating the size and composition of this residual fraction and how they correlate with the residual methane potential (RMP) are not fully understood. The aim of this study was to generate additional knowledge of the composition of residual digestate fractions and to understand how they correlate with various operational and chemical parameters. The organic composition of both the substrates and digestates from nine biogas plants operating on food waste, sewage sludge, or agricultural waste was characterized and the residual organic fractions were linked to substrate type, trace metal content, ammonia concentration, operational parameters, RMP, and enzyme activity. Results Carbohydrates represented the largest fraction of the total VS (32–68%) in most substrates. However, in the digestates protein was instead the most abundant residual macromolecule in almost all plants (3–21 g/kg). The degradation efficiency of proteins generally lower (28–79%) compared to carbohydrates (67–94%) and fats (86–91%). High residual protein content was coupled to recalcitrant protein fractions and microbial biomass, either from the substrate or formed in the degradation process. Co-digesting sewage sludge with fat increased the protein degradation efficiency with 18%, possibly through a priming mechanism where addition of easily degradable substrates also triggers the degradation of more complex fractions. In this study, high residual methane production (> 140 L CH4/kg VS) was firstly coupled to operation at unstable process conditions caused mainly by ammonia inhibition (0.74 mg NH3-N/kg) and/or trace element deficiency and, secondly, to short hydraulic retention time (HRT) (55 days) relative to the slow digestion of agricultural waste and manure. Conclusions Operation at unstable conditions was one reason for the high residual macromolecule content and high RMP. The outgoing protein content was relatively high in all digesters and improving the degradation of proteins represents one important way to increase the VS reduction and methane production in biogas plants. Post-treatment or post-digestion of digestates, targeting microbial biomass or recalcitrant protein fractions, is a potential way to achieve increased protein degradation.

We describe how a model of effective interactions between quantum fluctuations under certain assumptions can be constructed in a way so that the large-scale limit gives an effective theory that matches general relativity in vacuum regions. This is an investigation of a possible scenario of spacetime emergence from quantum interactions directly in the spacetime, and of how effective quantum behaviour might provide a useful link between detailed properties of quantum interactions and general relativity. The quantum fluctuations are assumed to entangle sufficiently for a cohesive spacetime to form, so that their effective properties can be described relative to a D-dimensional reference frame. To obtain the desired features of a smooth metric with a vanishing Ricci tensor, the quantum fluctuations are modelled as Gaussian probability distributions, with a shape set relative to the interactions coming from the surroundings. At small scales, the propagation through the spacetime is modelled by a Gaussian random walk., 27 pages, journal reference added

The associated publication reports proteogenomic analysis of non-small cell lung cancer, where we identified molecular subtypes with distinct immune evasion mechanisms and therapeutic targets, and validated our classification method in separate clinical cohorts. This protocol describes histological, tertiary lymphoid structure (TLS), and immunohistochemical evaluation of clinical samples. Specifically, immunohistochemistry was performed for PD-L1, CD3, and CD8 on tumor microarrays (TMAs) derived from formalin-fixed paraffin embedded (FFPE) samples.

The associated publication reports proteogenomic analysis of non-small cell lung cancer (NSCLC), where we identified molecular subtypes with distinct immune evasion mechanisms and therapeutic targets, and validated our classification method in separate clinical cohorts. This protocol describes sections of the bioinformatics analysis of the multi-omics data, namely, data analysis and processing for panel sequencing, identification of cancer- and driver-related proteins in proteomics data, proteogenomics search, and machine learning-based classifiers for NSCLC subtyping. Specifically, a cohort classifier was built using support-vector machine-recursive feature elimination (SVM-RFE) algorithm applied to in-depth proteomics data from a cohort of 141 samples. The classifier was then validated in three external datasets. Another classifier, suitable for single-sample subtyping, was built using k-top scoring pairs (k-TSP) algorithm applied to label-free data from a cohort of 136 samples. The k-TSP-based classifier was validated in two independent cohorts and an additional external dataset.

The associated publication reports proteogenomic analysis of non-small cell lung cancer (NSCLC), where we identified molecular subtypes with distinct immune evasion mechanisms and therapeutic targets, and validated our classification method in separate clinical cohorts. The in-depth proteomic analysis pointed to a potential role of STK11 inactivation in liver-specific signaling and subsequent cancer growth and immune evasion mechanisms. This protocol describes in vitro validation of the downstream effects of STK11-AMPK signaling on HNF1A and FGL1 in a liver and two lung cancer cell lines.

The associated publication reports proteogenomic analysis of non-small cell lung cancer, where we identified molecular subtypes with distinct immune evasion mechanisms and therapeutic targets, and validated our classification method in separate clinical cohorts. This protocol describes the sample preparation and mass spectrometry (MS)-based in-depth and rapid proteomic analyses of tumor and biopsy samples. We deployed single-pot solid-phase-enhanced sample preparation (SP3). For the in-depth analysis, we used TMT labeling, followed by high-resolution isoelectric focusing (HiRIEF) prefractionation and LC-MS with data-dependent acquisition (DDA). The reported protocol achieved analytical depth of close to 14,000 quantified proteins and almost 10,000 across the entire cohort of 141 samples. The rapid analysis was label-free, based on LC-MS with data-independent acquisition (DIA). The median number of identified proteins was 3,967 and 3,552 in two independent cohorts of tumor samples (n = 141 and 208, respectively), and 2,494 in another cohort of biopsy material (n = 84).

Background: There is an increased risk of suicidality in gambling disorder (GD) and economic hardship is common in the population. Economic hardship itself is a risk factor for suicidality. This study aims to explore the risk of intentional self-harm in GD utilizing social welfare payment (SWP) as a proxy for economic hardship and exploring how economic hardship, gender, criminality, socioeconomic-, and psychiatric risk factors might contribute to intentional self-harm in GD.Methods: This is a nationwide register-based study of 848 individuals diagnosed with GD in the Swedish healthcare system during the years of 2011–2014 with an average follow up of 4.9 years. Pearson's Chi-square analyses were carried out for comparisons regarding psychiatric comorbidity and intentional self-harm with regards to gender and SWPs. Univariable and multivariable Cox regression were utilized to analyse risk factors for intentional self-harm.Results: A large part of the study population received SWPs (45.5% with an insignificant overrepresentation of women) and psychiatric disorders were more common in these individuals (p < 0.001). Conviction for crime in general (p < 0.001) as well as intentional self-harm (p = 0.025) were also more common amongst recipients of SWPs. Criminal conviction in general was abundant (26.5%). In the stepwise multivariable regression, substance-related diagnoses as well as anxiety, depressive, and personality disorders remained risk factors for intentional self-harm and no significant results were found with regards to gender, criminal history, or SWPs.Conclusions: Social welfare payment was common among GD patients and intentional self-harm was more common amongst recipients than GD patients as a whole. Social welfare payments were however not a significant risk factor for intentional self-harm. However, attention to suicidality and self-injurious behavior should be paid from social services controlling SWPs due to the large prevalence of intentional self-harm in this group. In accordance with previous studies, comorbid psychiatric disorders such as anxiety, depression, substance use, and personality disorders increased the risk of intentional self-harm.

Background: Thymidine kinase 2 (TK2) catalyses the phosphorylation of deoxythymidine (dThd) and deoxycytidine (dCtd) within mitochondria. TK2 deficiency leads to mtDNA depletion or accumulation of multiple deletions. In patients, TK2 mutations typically manifest as a rapidly progressive myopathy with infantile onset, leading to respiratory insufficiency and encephalopathy in the most severe clinical presentations. TK2-deficient mice develop the most severe form of the disease and die at average postnatal day 16. dThd+dCtd administration delayed disease progression and expanded lifespan of a knockin murine model of the disease. Methods: We daily administered TK2 knockout mice (Tk2KO) from postnatal day 4 with equimolar doses of dThd+dCtd, dTMP+dCMP, dThd alone or dCtd alone. We monitored body weight and survival and studied different variables at 12 or 29 days of age. We determined metabolite levels in plasma and target tissues, mtDNA copy number in tissues, and the expression and activities of enzymes with a relevant role in mitochondrial dNTP anabolism or catabolism. Findings: dThd+dCtd treatment extended average lifespan of Tk2KO mice from 16 to 34 days, attenuated growth retardation, and rescued mtDNA depletion in skeletal muscle and other target tissues of 12-day-old mice, except in brain. However, the treatment was ineffective in 29-day-old mice that still died prematurely. Bioavailability of dThd and dCtd markedly decreased during mouse development. Activity of enzymes catabolizing dThd and dCtd increased with age in small intestine. Conversely, the activity of the anabolic enzymes decreased in target tissues during mouse development. We also found that administration of dThd alone had the same impact on survival to that of dThd+dCtd, whereas dCtd alone had no influence on lifespan. Interpretation: dThd+dCtd treatment recruits alternative cytosolic salvage pathways for dNTP synthesis, suggesting that this therapy would be of benefit for any Tk2 mutation. dThd accounts for the therapeutic effect of the combined treatment in mice. During the first weeks after birth, mice experience marked tissue-specific metabolic regulations and ontogenetic changes in dNTP metabolism-related enzymes that limit therapeutic efficacy to early developmental stages. Fund: This study was funded by grants from the Spanish Ministry of Industry, Economy and Competitiveness, the Spanish Instituto de Salud Carlos III, the Fundación Inocente, Inocente, AFM Téléthon and the Generalitat de Catalunya. The disclosed funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Keywords: TK2, Deoxynucleoside therapy, mtDNA depletion, Encephalomyopathy, Thymidine, Deoxycytidine

Purpose Evaluate the performance of three commercial deformable image registration (DIR) solutions on computed tomography (CT) image-series of the thorax. Methods DIRs were performed on CT image-series of a thorax phantom with tumor inserts and on six 4-dimensional patient CT image-series of the thorax. The center of mass shift (CMS), dice similarity coefficient (DSC) and dose-volume-histogram (DVH) parameters were used to evaluate the accuracy. Dose calculations on deformed patient images were compared to calculations on un-deformed images for the gross tumor volume (GTV) (Dmean, D98%), lung (V20Gy, V12Gy), heart and spinal cord (D2%). Results Phantom structures with constant volume and shifts ≤30 mm were reproduced with visually acceptable accuracy (DSC ≥ 0.91, CMS ≤ 0.9 mm) for all software solutions. Deformations including volume changes were less accurate with 9/12 DIRs considered visually unacceptable. In patients, organs were reproduced with DSC ≥ 0.83. GTV shifts ≤1.6 cm were reproduced with visually acceptable accuracy by all software while larger shifts resulted in failures for at least one of the software. In total, the best software succeeded in 18/25 DIRs while the worst succeeded in 12/25 DIRs. Visually acceptable DIRs resulted in deviations ≤3.0% of the prescribed dose and ≤3.6% of the total structure volume in the evaluated DVH-parameters. Conclusions The take home message from the results of this study is the importance to have a visually acceptable registration. DSC and CMS are not predictive of the associated dose deviation. Visually acceptable DIRs implied dose deviations ≤3.0%.