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Objective: In nonalcoholic fatty liver disease (NAFLD), liver fibrosis is the strongest predictor of adverse outcomes. We sought to investigate the relationship between liver fibrosis and cardiac remodeling in participants from the general population using magnetic resonance imaging (MRI), as well as explore potential mechanistic pathways by analyzing circulating cardiovascular biomarkers. Methods: In this cross-sectional study, we prospectively included participants with type 2 diabetes and individually matched controls from the SCAPIS (Swedish CArdioPulmonary bioImage Study) cohort in Linköping, Sweden. Between November 2017 and July 2018, participants underwent MRI at 1.5 Tesla for quantification of liver proton density fat fraction (spectroscopy), liver fibrosis (stiffness from elastography), left ventricular (LV) structure and function, as well as myocardial native T1 mapping. We analyzed 278 circulating cardiovascular biomarkers using a Bayesian statistical approach. Results: In total, 92 participants were enrolled (mean age 59.5 ± 4.6 years, 32 women). The mean liver stiffness was 2.1 ± 0.4 kPa. 53 participants displayed hepatic steatosis. LV concentricity increased across quartiles of liver stiffness. Neither liver fat nor liver stiffness displayed any relationships to myocardial tissue characteristics (native T1). In a regression analysis, liver stiffness was related to increased LV concentricity. This association was independent of diabetes and liver fat (Beta = 0.26, p = 0.0053), but was attenuated (Beta = 0.17, p = 0.077) when also adjusting for circulating levels of interleukin-1 receptor type 2. Conclusion: MRI reveals that liver fibrosis is associated to structural LV remodeling, in terms of increased concentricity, in participants from the general population. This relationship could involve the interleukin-1 signaling. Clinical relevance statement: Liver fibrosis may be considered a cardiovascular risk factor in patients without cirrhosis. Further research on the mechanisms that link liver fibrosis to left ventricular concentricity may reveal potential therapeutic targets in patients with non-alcoholic fatty liver disease (NAFLD). Key Points: Previously, studies on liver fibrosis and cardiac remodeling have focused on advanced stages of liver fibrosis. Liver fibrosis is associated with left ventricular (LV) concentricity and may relate to interleukin-1 receptor type 2. Interleukin-1 signaling is a potential mechanistic interlink between early liver fibrosis and LV remodeling. [ABSTRACT FROM AUTHOR]

Multiple neural mechanisms underlying gating to working memory have been proposed with divergent results obtained in human and animal studies. Previous findings from non-human primates suggest prefrontal beta frequency bursts as a correlate of transient inhibition during selective encoding. Human studies instead suggest a similar role for sensory alpha power fluctuations. To cast light on these discrepancies we employed a sequential working memory task with distractors for human participants. In particular, we examined their whole-brain electrophysiological activity in both alpha and beta bands with the same single-trial burst analysis earlier performed on non-human primates. Our results reconcile earlier findings by demonstrating that both alpha and beta bursts in humans correlate with the filtering and control of memory items, but with region and task-specific differences between the two rhythms. Occipital beta burst patterns were selectively modulated during the transition from sensory processing to memory retention whereas prefrontal and parietal beta bursts tracked sequence order and were proactively upregulated prior to upcoming target encoding. Occipital alpha bursts instead increased during the actual presentation of unwanted sensory stimuli. Source reconstruction additionally suggested the involvement of striatal and thalamic alpha and beta. Thus, specific whole-brain burst patterns correlate with different aspects of working memory control. Oscillatory beta bursts are linked to cognitive control in primates, but their role in humans is less clear. This study demonstrates an analogous role in humans and suggests distinct function depending on their exact oscillatory frequency and cortical origin. [ABSTRACT FROM AUTHOR]

The Plasmodium falciparum life cycle includes obligate transition between a human and mosquito host. Gametocytes are responsible for transmission from the human to the mosquito vector where gamete fusion followed by meiosis occurs. To elucidate how male and female gametocytes differentiate in the absence of sex chromosomes, we perform FACS-based cell enrichment of a P. falciparum gametocyte reporter line followed by single-cell RNA-seq. In our analyses we define the transcriptional programs and predict candidate driver genes underlying male and female development, including genes from the ApiAP2 family of transcription factors. A motif-driven, gene regulatory network analysis indicates that AP2-G5 specifically modulates male development. Additionally, genes linked to the inner membrane complex, involved in morphological changes, are uniquely expressed in the female lineage. The transcriptional programs of male and female development detailed herein allow for further exploration of the evolution of sex in eukaryotes and provide targets for future development of transmission blocking therapies. P. falciparum (malaria) transmission includes the development of male and female parasite forms called gametocytes, which are taken up by the Anopheles mosquito. The authors of this study use single cell transcriptomics to define the transcriptional programs, identify key regulators and predict novel genes, involved in driving the male and female sexual cell fates. [ABSTRACT FROM AUTHOR]

Histopathological diagnosis of pulmonary tumors is essential for treatment decisions. The distinction between primary lung adenocarcinoma and pulmonary metastasis from the gastrointestinal (GI) tract may be difficult. Therefore, we compared the diagnostic value of several immunohistochemical markers in pulmonary tumors. Tissue microarrays from 629 resected primary lung cancers and 422 resected pulmonary epithelial metastases from various sites (whereof 275 colorectal cancer) were investigated for the immunohistochemical expression of CDH17, GPA33, MUC2, MUC6, SATB2, and SMAD4, for comparison with CDX2, CK20, CK7, and TTF-1. The most sensitive markers for GI origin were GPA33 (positive in 98%, 60%, and 100% of pulmonary metastases from colorectal cancer, pancreatic cancer, and other GI adenocarcinomas, respectively), CDX2 (99/40/100%), and CDH17 (99/0/100%). In comparison, SATB2 and CK20 showed higher specificity, with expression in 5% and 10% of mucinous primary lung adenocarcinomas and both in 0% of TTF-1-negative non-mucinous primary lung adenocarcinomas (25–50% and 5–16%, respectively, for GPA33/CDX2/CDH17). MUC2 was negative in all primary lung cancers, but positive only in less than half of pulmonary metastases from mucinous adenocarcinomas from other organs. Combining six GI markers did not perfectly separate primary lung cancers from pulmonary metastases including subgroups such as mucinous adenocarcinomas or CK7-positive GI tract metastases. This comprehensive comparison suggests that CDH17, GPA33, and SATB2 may be used as equivalent alternatives to CDX2 and CK20. However, no single or combination of markers can categorically distinguish primary lung cancers from metastatic GI tract cancer. [ABSTRACT FROM AUTHOR]

Vestibular evoked myogenic potentials (VEMPs) are a tool to assess otolith function and a component of sensor specific vestibular diagnostics. The aim of the present study was to measure VEMP trough bone conducted (BC) stimulation using the B250 prototype and to report amplitudes, latencies and threshold levels for patients before resection of a sporadic unilateral vestibular schwannoma (VS) in order to assess function regarding to the reported nerve of origin. Twenty-seven participants (9 male/18 female) with a mean age of 55.9 years (SD: 10.8) were included for the analysis. In the side contralateral to the tumor, in 24 (89%) of the patients cVEMP could be measured, while oVEMP were recordable in 20 patients (74%). For patients with inferior vestibular nerve of origin (n = 11), cVEMP amplitudes of the affected side were significantly lower as compared to the non-affected side, while the force threshold level was increased. No statistically significant differences were observed for neither, oVEMP amplitudes nor threshold levels in the group with superior vestibular nerve of origin (n = 7). Across groups, p13 latency was significantly increased in the affected ear while all other VEMP latencies were not different between the ears. The B250 transducer was applicable to all participants of the clinical cohort. The sample size, however, was too low for a reliable statistical analysis and only allowed for exploratory analysis. [ABSTRACT FROM AUTHOR]

Background: The aim was to compare bias and precision for 177Lu-SPECT activity-concentration estimation using a dual-headed Anger SPECT system and a ring-configured CZT SPECT system. This was investigated for imaging at 208 keV and 113 keV, respectively. Methods: Phantom experiments were performed on a GE Discovery 670 system with 5/8" NaI(Tl) crystal (dual-headed Anger system) and a GE StarGuide (ring-configured CZT system). Six spheres (1.2 mL to 113 mL) in a NEMA PET body phantom were filled with 99mTc and 177Lu, separately. Mean relative errors and coefficients of variation (CV) in estimated sphere activity concentration were studied over six timeframes of 10 min each for the two systems. For 177Lu, similar acquisitions were also performed for an anthropomorphic phantom with two spheres (10 mL and 25 mL) in a liver with non-radioactive background and a sphere-to-background ratio of 15:1. Tomographic reconstruction was performed using OS-EM with 10 subsets with compensation for attenuation, scatter, and distance-dependent spatial resolution. For the Anger system, up to 40 iterations were used and for the ring-configured CZT system up to 30 iterations were used. Results: The two systems showed similar mean relative errors and CVs for 177Lu when using an energy window around 208 keV, while the ring-configured system demonstrated a lower bias for a similar CV compared to the Anger system for 99mTc and for 177Lu when using an energy window around 113 keV. However, total activity in the phantom tended to be overestimated in both systems for these cases. Conclusions: The ring-configured CZT system is a viable alternative to the dual-headed Anger system equipped with medium-energy collimators for 177Lu-SPECT and shows a potential advantage for activity-concentration estimation when operated at 113 keV. However, further consideration of the preservation of total activity is warranted. [ABSTRACT FROM AUTHOR]

The effects of androgens on women's bone health are not fully understood. Mendelian randomization (MR) studies using sex-combined data suggest that sex hormone-binding globulin (SHBG) and bioavailable testosterone (BioT) causally affect bone traits. Given significant sex differences in hormone regulation and effects, female-specific MR studies are necessary. In the current study, we explored the causal relationships of SHBG, BioT, and total testosterone (TT) with forearm fracture (FAFx) risk in women using two-sample MR analyses. We utilized a unique female-specific FAFx outcome dataset from three European biobanks (UFO, HUNT, Estonian Biobank) comprising 111,351 women and 8823 FAFx cases, along with female-specific genetic instruments of SHBG, BioT, and TT identified in the UK Biobank. We also assessed bone mineral density (BMD) at the forearm (FA), femoral neck (FN), and lumbar spine (LS) using female-specific GWAS data from the GEFOS consortium. High SHBG (odds ratio per standard deviation increase (OR/SD): 1.53, 95% confidence intervals (CIs): 1.34–1.75), low BioT (OR/SD: 0.77, 0.71–0.84) and low TT (OR/SD 0.90, 0.83–0.98) were causally associated with increased FAFx risk. BioT was positively, and SHBG inversely, causally associated with especially FA-BMD, but also LS-BMD and FN-BMD, while TT was only significantly positively associated with FA-BMD and LS-BMD. We propose that endogenous androgens and SHBG are important for women's bone health at distal trabecular-rich bone sites such as the distal forearm and may serve as predictors for FAFx risk. [ABSTRACT FROM AUTHOR]

Purpose: To examine health-related quality of life (HRQoL) and supportive care needs among young adult (YA) cancer survivors up to 3 years post-diagnosis. Methods: A national cohort of individuals diagnosed at 18–39 years with breast, cervical, ovarian, or testicular cancer, lymphoma or brain tumor was approached with surveys at 1.5 (n = 1010, response rate 67%) and 3 (n = 722) years post-diagnosis. HRQoL was measured using the EORTC QLQ-C30. Scores were dichotomized using cut-off scores to predict supportive care needs in the Supportive Care Needs Survey-Long Form 59 (SCNS-LF59). Swedish cancer quality registers provided clinical data. Factors predicting need of support at 1.5 and 3 years post-diagnosis were identified using logistic regression. Results: HRQoL improvements over time were trivial to small. At both time points, a majority of respondents rated HRQoL levels indicating supportive care needs. At 1.5 years post-diagnosis, the risk of having support needs was lower among survivors with testicular cancer (compared to lymphoma) or university-level education, and higher among those on treatment (predominantly endocrine therapy). At 3 years post-diagnosis, when controlling for previous HRQoL scores, most correlations persisted, and poor self-rated household economy and chronic health conditions were additionally associated with supportive care needs. Conclusion: A majority of YAs diagnosed with cancer rate HRQoL at levels indicating support needs up to 3 years post-diagnosis. Testicular cancer survivors are at lower risk of having support needs. Concurrent health conditions and poor finances are linked to lower HRQoL. More efforts are needed to provide adequate, age-appropriate support to YA cancer survivors. [ABSTRACT FROM AUTHOR]

The role of immunosuppressive therapy on SARS-CoV-2 infection risk and COVID-19 severity remains unclear in unvaccinated solid organ transplant recipients. We included 1957 organ transplant recipients between July 2020 and April 2021 to analyze whether baseline immunosuppressive therapy and other risk factors are associated with SARS-CoV-2 infection and severe COVID-19. In total, 247 (12.6%) had SARS-CoV-2 (defined as positive nasopharyngeal swab and/or positive antibody titer). Of these, 57 (23.1%) had severe COVID-19, defined as oxygen supplementation, intensive care unit admission or death. Multivariable analysis identified diabetes (hazard ratio (HR) 1.39 (95% confidence interval (CI) 1.05–1.83)), chronic lung disease (HR 1.71 (95% CI 1.13–2.60)) and contact with a COVID-19 positive individual (HR 3.61 (95% CI 2.61–4.99) as independent risk factors for SARS-CoV-2 infection. There was no association between immunosuppressive therapy and infection risk. Severe COVID-19 was multivariably associated with hypertension (OR 5.45 (95% CI 1.66–17.84)), chronic kidney disease (OR 3.55 (95% CI 1.75–7.19)), corticosteroid use (OR 2.93 (95% CI 1.03–2.55)) and having a COVID-19 positive housemate (OR 6.77 (95% CI 2.65–17.28)). In conclusion, baseline corticosteroid use, but no other immunosuppressive agent, is independently associated with severe COVID-19 in unvaccinated SOT recipients after correction for hypertension, chronic kidney disease, housemates affected by COVID-19 and transplant type. [ABSTRACT FROM AUTHOR]

Surgery is the first line of treatment in gingival cancers of the mandible, and bone resection is necessary in the majority of cases. In the less extensive surgical option, marginal mandibulectomy (MM), the mandibular base is preserved. In contrast, in a segmental mandibulectomy (SM) the mandible is divided and the continuity is not preserved. If MM can be performed with comparable oncological results to SM, it is the preferred method. The aim of the present study was to identify preoperative predictors for local recurrence (LR), to support the selection of candidates for MM. Outcome measures were local recurrence free survival (LRFS) and disease specific survival (DSS). 67 patients treated with MM between 2008 and 2021 were included. Cox regression analyses of LR with hazard ratios and adjustments for postoperative radiotherapy, pathological T-stage (pT) and soft tissue margins were performed. 5-years LRFS was 63% (95% CI 46.9–75.5) and DSS 80.6% (95% CI 64.7–89.9). In conclusion we found that edentulous patients, more advanced pT-stage and positive soft tissue margins had increased risk for LR. Future studies of the correlation between cT and pT would be important to provide more robust preoperative support in the selection between MM and SM. [ABSTRACT FROM AUTHOR]

Constructed with used plastic bottles, the eco-cooler has been widely adopted in resource-poor communities in Bangladesh and other countries. We tested the eco-cooler under controlled conditions using a scientific wind tunnel in a climatic chamber. In our tests, we used seven eco-cooler designs in 27 climate conditions typical of Bangladesh (temperatures of 40 °C, 35 °C, and 30 °C; humidity levels of 70%, 60%, and 40%; and wind speeds of 4.0 m s−1, 2.0 m s−1, and 0.2 m s−1) in 92 experiments (N = 7686 measurements in 87 short experiments and N = 23,428 measurements in five long experiments). We found no significant temperature reductions with eco-cooler use, except at low wind speeds, where temperature reduced by up to 0.2 °C. In theoretical calculations extending our empirical findings, the greatest temperature drop was 0.85 °C at 4.0 m s−1 with a 40 °C static air inflow temperature. However, this temperature drop did not extend beyond the nozzles of the bottles in the eco-cooler. The eco-cooler did not work effectively as an indoor air cooler. [ABSTRACT FROM AUTHOR]

Introduction: There are sex differences in the extent, severity, and outcomes of coronary artery disease. We aimed to assess the influence of sex on coronary atherosclerotic plaque activity measured using coronary 18F-sodium fluoride (18F-NaF) positron emission tomography (PET), and to determine whether 18F-NaF PET has prognostic value in both women and men. Methods: In a post-hoc analysis of observational cohort studies of patients with coronary atherosclerosis who had undergone 18F-NaF PET CT angiography, we compared the coronary microcalcification activity (CMA) in women and men. Results: Baseline 18F-NaF PET CT angiography was available in 999 participants (151 (15%) women) with 4282 patient-years of follow-up. Compared to men, women had lower coronary calcium scores (116 [interquartile range, 27–434] versus 205 [51–571] Agatston units; p = 0.002) and CMA values (0.0 [0.0-1.12] versus 0.53 [0.0-2.54], p = 0.01). Following matching for plaque burden by coronary calcium scores and clinical comorbidities, there was no sex-related difference in CMA values (0.0 [0.0-1.12] versus 0.0 [0.0-1.23], p = 0.21) and similar proportions of women and men had no 18F-NaF uptake (53.0% (n = 80) and 48.3% (n = 73); p = 0.42), or CMA values > 1.56 (21.8% (n = 33) and 21.8% (n = 33); p = 1.00). Over a median follow-up of 4.5 [4.0–6.0] years, myocardial infarction occurred in 6.6% of women (n = 10) and 7.8% of men (n = 66). Coronary microcalcification activity greater than 0 was associated with a similarly increased risk of myocardial infarction in both women (HR: 3.83; 95% CI:1.10-18.49; p = 0.04) and men (HR: 5.29; 95% CI:2.28–12.28; p < 0.001). Conclusion: Although men present with more coronary atherosclerotic plaque than women, increased plaque activity is a strong predictor of future myocardial infarction regardless of sex. [ABSTRACT FROM AUTHOR]

Objectives: To investigate tooth-specific, clinical tooth-, and patient-related factors associated with tooth loss (TL) in patients with mild to severe periodontitis treated in a periodontal practice-based research network (Perio-PBRN) over at least 5 years. Materials and methods: The Perio-PBRN consists of five German periodontal practices where clinical data were collected regarding patient age, tooth type, bleeding on probing (BOP), pocket probing depth (PPD), furcation involvement (FI), number of attended appointments, and other variables of interest. The data were evaluated regarding factors influencing TL. Results: Data from 687 patients (aged 54.5 ± 11.1 years) with mild (N = 23, 3.35%), moderate (N = 247, 35.95%) or severe (N = 417, 60.70%) periodontitis and 15,931 teeth over a mean observation period of 6.83 ± 1.40 years per patient were gathered via the Perio-PBRN. In this period, a total of 657 teeth were lost (4.12%, overall TL: 0.14 ± 0.22 teeth/patient/y). The risk of TL was significantly increased for teeth with persistent PPD ≥ 6 mm (hazard ratio: 6.81 [95% confidence interval: 5.07–9.15] in comparison to PPD < 4 mm. Additionally, BOP (3.90 [2.46–6.19]), furcation involvement, jaw, age and tooth type showed a significant influence on TL, while number of visits were not significantly associated with TL. Conclusions: Periodontal care of patients with moderate to severe disease in specialized practices was associated with a low rate of TL. Known tooth-related prognostic factors were confirmed. However, the results must be interpreted cautiously without knowledge of risk factors such as smoking and diabetes. Clinical relevance: PBRNs can help gather large amounts of periodontal practice-level data. Trial registration: The study was registered in the German Clinical Trials Register (DRKS 00011448). [ABSTRACT FROM AUTHOR]

Wood is a sustainable, benign, and high-performing green structural material readily available in nature that can be used to replace structural materials. However, insufficient mechanical performance (compared to metals and plastic), moisture sensitivity, and susceptibility to microorganism attack make it challenging to use wood as it is for advanced engineering applications. We here present an efficient approach to fabricating densified wood with minimal time and waste generation, demonstrating high mechanical strength, and decreased water penetration on the surface. Wood slabs were treated with deep eutectic solvents (DESs) to solubilize the lignin, followed by in-situ regeneration of dissolved lignin in the wood. Then, the slabs were densified with heat and pressure, turning the wood into a functionalized densified material. Lignin regeneration and morphological changes were observed via two-photon microscopy and Scanning Electron Microscopy (SEM), respectively. The final product is less susceptible to water absorption on the surface and has enhanced flexural strength (> 50% higher), surface hardness (100% increased), and minimal set recovery compared to natural wood. The improved mechanical performance is due to regenerated lignin which acts as a glue and fills spaces present within the interconnected cellulose network inside the wood, forming a highly dense composite during densification. Such enhancement in the properties of DES-densified wood composite makes it a favorable candidate for advanced structural and engineering applications. [ABSTRACT FROM AUTHOR]

Objective: Many diseases are characterised by their seasonal appearance due to circannual changes in immune defence and a lifestyle that changes over the seasons. However, there is a lack of studies regarding the influence of seasonality on periodontitis. Therefore, the aim of this non-interventional, retrospective, observational study was to investigate the influence of seasonality on periodontitis. Materials and methods: Periodontal parameters of 5,908 patients of a practice-based research network (PBRN) were analysed. Probing pocket depth (PPD), Bleeding on Probing (BOP) and tooth mobility were assessed for seasonal fluctuations. Results: Within the PBRN patient data, seasonality was significantly associated with PPD of the individual months in patients with periodontitis. Pairwise comparison between the months showed significantly higher PPD in July compared to several months. PPD appeared significantly lower in December compared to June and November. Regarding season, the proportion of deep PPDs ( 6 mm) was significantly higher in summer compared to autumn (p = 0.024). Concerning BOP, a significant difference between winter and autumn could be observed (p = 0.016). No seasonal influence was found for tooth mobility. Conclusion: This practice-network based study indicated a tendency for seasonal variations in periodontal parameters among periodontal patients. However, the differences did not achieve clinical relevance. Clinical relevance: Regarding the seasonality of several diseases there might also be an influence of seasons on the periodontium, which would have a potential influence on periodontal studies and daily periodontal examination. [ABSTRACT FROM AUTHOR]

Historians often present their interpretation of the past in written accounts. In order to gain deeper knowledge of the discipline of history, students must learn how to read and write historical accounts. In this experimental pretest–posttest study, we investigated the impact of a domain-specific reading instruction followed by domain-specific writing-strategy instruction as well as a repeated domain-specific reading instruction on the quality of written texts and on procedural knowledge regarding reading, reasoning, and writing of 142 10th grade students. Results indicated that both instructions had a positive impact on the quality of written texts and on the amount of procedural knowledge (reading, reasoning, and writing). However, students who received a domain-specific writing instruction after the reading instruction wrote better texts compared to students who only received a domain-specific reading-to-write instruction. In addition, we found positive correlations between procedural knowledge and the quality of written texts in both conditions. [ABSTRACT FROM AUTHOR]

Structural- and functional heterogeneity, as well as allosteric regulation, in homo-monomeric enzymes is a highly active area of research. One such enzyme is human nuclear-associated deoxyuridine 5'-triphosphate nucleotidohydrolase (dUTPase), which has emerged as an interesting drug target in combination therapy with traditional nucleotide analogue treatment of cancer. We report, for the first time, a full structural dynamics study of human dUTPase by NMR. dUTPase has been investigated in terms of structural dynamics in its apo form, in complex with the modified substrate resistant to hydrolysis, 2'-deoxyuridine 5'-α,β-imido-triphosphate (dUpNHpp), as well as the product, 2'-deoxy-uridine-monophosphate (dUMP). The apo form of the enzyme displayed slow dynamics in the milli- to microsecond regime in relaxation dispersion experiments, which was further slowed down to observable heterogeneity upon substrate-analogue binding. The results suggest that the non-hydrolysable substrate-analogue traps the enzyme in the conformational isomerization step that has been previously suggested to be part of the enzyme catalysis kinetics cycle. The observed heterogeneity fits well with the pattern expected to emerge from the suggested kinetic model, and no evidence for homotropic allosterism was found. The heatmaps of the slow dynamics, chemical shift perturbation upon substrate binding and conserved regions of the enzyme sequence all displayed a similar pattern, which suggests that the structural dynamics is finely tuned and important for the biological function of the enzyme for binding, conformational shift, catalysis and substrate release. [ABSTRACT FROM AUTHOR]

Spatial and genomic heterogeneity of tumors are crucial factors influencing cancer progression, treatment, and survival. However, a technology for direct mapping the clones in the tumor tissue based on somatic point mutations is lacking. Here, we propose Tumoroscope, the first probabilistic model that accurately infers cancer clones and their localization in close to single-cell resolution by integrating pathological images, whole exome sequencing, and spatial transcriptomics data. In contrast to previous methods, Tumoroscope explicitly addresses the problem of deconvoluting the proportions of clones in spatial transcriptomics spots. Applied to a reference prostate cancer dataset and a newly generated breast cancer dataset, Tumoroscope reveals spatial patterns of clone colocalization and mutual exclusion in sub-areas of the tumor tissue. We further infer clone-specific gene expression levels and the most highly expressed genes for each clone. In summary, Tumoroscope enables an integrated study of the spatial, genomic, and phenotypic organization of tumors. In this article the authors develop "Tumoroscope" to map cancer clones by integrating pathology images, exome sequencing, and spatial transcriptomics. It reveals spatial clone patterns and clone-specific gene expression in prostate and breast cancer, advancing tumor heterogeneity analysis. [ABSTRACT FROM AUTHOR]

AISI 4140 alloy steel finds extensive applications in industrial settings such as gears and blades owing to its exceptional combination of high strength and ductility. However, prolonged exposure to harsh operating conditions can result in significant mechanical failures, necessitating essential repair techniques to restore functionality and preserve the substantial value of these components. Among the various repair methods, directed energy deposition, an additive manufacturing technique, is gaining prominence for its efficacy in producing and restoring mechanically stressed components. Compared to traditional welding methods and metal spraying, laser cladding offers advantages such as reduced heat input and minimal dilution, resulting in superior metallurgical bonds. This research focuses on depositing Inconel 718 on AISI 4140 substrate using the laser cladding technique to evaluate the feasibility of this alloy for repairing AISI 4140 components. The investigation explores the influence of key laser cladding parameters, including laser power, scanning speed, and mass flow rate, on critical attributes of deposited beads such as width, height, clad angle, and dilution ratio. The results elucidate the effects of varying parameters: increasing scanning speed reduces bead dimensions and clad angle while increasing dilution. Elevating the powder-feeding rate increases bead height and wetting angle, with minimal impact on width and decreased dilution. Augmenting laser power increases bead width and reduces wetting angle, with dilution showing minimal change. Based on the findings, the optimal process parameters for future investigations are identified as a laser power of 950W, a laser scan speed of 300 mm/min, and a mass flow rate of 4.31 g/min. Furthermore, the research demonstrates good metallurgical bonding at the interface between the two dissimilar materials, affirming the feasibility of integrating them through laser cladding. [ABSTRACT FROM AUTHOR]

Computational thinking (CT) is valued as a thinking process that is required to adapt to the development of curriculum in primary education. In the context of modern information technology, English as a language subject emphasizes the necessity for changes in both learning and teaching modes. However, there is a lack of up-to-date synthesis research and a comprehensive overview surrounding CT integrated into English language curriculum learning and teaching in primary education. To address this research gap, this study conducted a systematic literature review on CT in the primary English curriculum, based on papers published from 2011 to 2021. The purpose of this review is to systematically examine and present empirical evidence on how CT can be integrated into the teaching and learning of the primary English language curriculum in educational contexts. The review was conducted based on the PRISMA 2020 statement and presents a synthesis of 32 articles. The CT-TPACK model was adopted as a lens and framework to analyze these articles. The results indicate that the relationship among CT, content knowledge of English language curriculum, pedagogy and learning knowledge, technology and resources is highlighted. Research on the integration of CT into English courses using unplugged activities is still insufficient. The research about how teachers and students use CT to support content knowledge of the English language curriculum in various educational contexts is still in its infancy. [ABSTRACT FROM AUTHOR]

Accurate grading of IDH-mutant gliomas defines patient prognosis and guides the treatment path. Histological grading is challenging, and aside from CDKN2A/B homozygous deletions in IDH-mutant astrocytomas, there are no other objective molecular markers used for grading. RNA-sequencing was conducted on primary IDH-mutant astrocytomas (n = 138) included in the prospective CATNON trial, which was performed to assess the prognostic effect of adjuvant and concurrent temozolomide. We integrated the RNA-sequencing data with matched DNA-methylation and NGS data. We also used multi-omics data from IDH-mutant astrocytomas included in the TCGA dataset and validated results on matched primary and recurrent samples from the GLASS-NL study. Since discrete classes do not adequately capture grading of these tumours, we utilised DNA-methylation profiles to generate a Continuous Grading Coefficient (CGC) based on classification scores from a CNS-tumour classifier. CGC was an independent predictor of survival outperforming current WHO-CNS5 and methylation-based classification. Our RNA-sequencing analysis revealed four distinct transcription clusters that were associated with (i) upregulation of cell cycling genes; (ii) downregulation of glial differentiation genes; (iii) upregulation of embryonic development genes (e.g. HOX, PAX, and TBX) and (iv) upregulation of extracellular matrix genes. The upregulation of embryonic development genes was associated with a specific increase of CpG island methylation near these genes. Higher grade IDH-mutant astrocytomas have DNA-methylation signatures that, on the RNA level, are associated with increased cell cycling, tumour cell de-differentiation and extracellular matrix remodelling. These combined molecular signatures can serve as an objective marker for grading of IDH-mutant astrocytomas. [ABSTRACT FROM AUTHOR]

Introduction: Evidence from Asian studies suggests that minimally-invasive gastrectomy achieves equivalent oncological but improved perioperative outcomes compared to open surgery. Oncological gastric resections are less frequent in European countries. Index procedures may play a role for the learning curve of minimally-invasive gastrectomy. The aim of our study was to evaluate if skills acquired in bariatric surgery allow a safe and oncologically adequate implementation of minimally-invasive gastrectomy in a cohort of european patients. Methods: In this single-center retrospective study, all patients who received primary bariatric surgery between January 2015 and December 2018 and minimally-invasive surgery for gastric cancer treated from June 2019 to January 2023 were evaluated. Primary endpoints were operation time, lymph node yield and lymph node fractions. Secondary endpoints included postoperative complications and oncological outcomes. Results: Learning curves for two surgeons with 350 bariatric procedures and 44 minimally-invasive gastrectomies were analyzed. For bariatric surgery, the mean operation time decreased from initially 82 ± 27 to 45 ± 21 min and 118 ± 28 to 81 ± 36 min for sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB), while the complication rate remained within the international benchmark. For laparoscopic gastrectomy (n = 30), operation times decreased but then remained stable over time. Operation times for the robotic platform were longer (302 ± 60 vs. 390 ± 48 min; p < 0.001) with the learning curve remaining incomplete after 14 procedures. R0 status was achieved in 95.5% of patients; the mean number of lymph nodes retrieved was 37 ± 14 with no differences between the groups. Complete mesogastric excision was more frequently achieved during the later laparoscopic cases whereas it occurred earlier for the robotic group (p = 0.004). Perioperative morbidity was comparable to the European benchmark. Textbook outcome was achieved in 54.4% of the cases. Conclusion: In summary, we could demonstrate a successful skill transfer from bariatric surgery to minimally-invasive laparoscopic oncological gastric surgery enabling safe and oncologically adequate minimally-invasive D2 gastrectomy in a central European patient collective. [ABSTRACT FROM AUTHOR]

Purpose: The current study aimed to investigate the use of surrogate immunohistochemical (IHC) markers of proliferation and stem cells to distinguish ameloblastoma (AB) from ameloblastic carcinoma (AC). Methods: The study assessed a total of 29 ACs, 6 ABs that transformed into ACs, and a control cohort of 20 ABs. The demographics and clinicopathologic details of the included cases of AC were recorded. The Ki-67 proliferation index was scored through automated methods with the QuPath open-source software platform. For SOX2, OCT4 and Glypican-3 IHC, each case was scored using a proportion of positivity score combined with an intensity score to produce a total score. Results: All cases of AC showed a relatively high median proliferation index of 41.7%, with statistically significant higher scores compared to ABs. ABs that transformed into ACs had similar median proliferation scores to the control cohort of ABs. Most cases of AC showed some degree of SOX2 expression, with 58.6% showing high expression. OCT4 expression was not seen in any case of AC. GPC-3 expression in ACs was limited, with high expression in 17.2% of ACs. Primary ACs showed higher median proliferation scores and degrees of SOX2 and GPC-3 expression than secondary cases. Regarding SOX2, OCT4 and GPC-3 IHC expression, no statistically significant differences existed between the cohort of ABs and ACs. Conclusion: Ki-67 IHC as a proliferation marker, particularly when assessed via automated methods, was helpful in distinguishing AC from AB cases. In contrast to other studies, surrogate IHC markers of embryonic stem cells, SOX2, OCT4 and GPC-3, were unreliable in distinguishing the two entities. [ABSTRACT FROM AUTHOR]

Background: In Sweden, surgical treatment of Hirschsprung's disease (HSCR) was centralized from four to two pediatric surgery centers 1st of July 2018. In adults, centralization of surgical care for complex or rare diseases seems to improve quality of care. There is little evidence supporting centralization of pediatric surgical care. The aim of this study was to assess surgical management and postoperative outcome in HSCR patients following centralization of care. Methods: This study retrospectively analyzed data of patients with HSCR that had undergone pull-through at a pediatric surgery center in Sweden from 1st of July 2013 to 30th of June 2023. Patients managed from 1st of July 2013 to 30th of June 2018 (before centralization) were compared with patients managed from 1st of July 2018 to 30th of June 2023 (after centralization) regarding surgical treatment, unplanned procedures under general anesthesia or readmissions up to 90 days after pull-through as well as complications classified according to Clavien–Madadi up to 30 days after pull-through. Results: In the 5-year period prior to centralization, 114 individuals from 4 treating centers were included and compared to 83 patients from 2 treating centers in the second period. There was no difference regarding age at pull-through or proportion of patients with a stoma prior to pull-through. An increase of laparoscopically assisted endorectal pull-through (8.8% to 39.8%) was observed (p < 0.001). No significant differences were seen in postoperative hospital stay, unplanned procedures under general anesthesia, or readmissions up to 90 days after pull-through. There was no difference in severe complications (Clavien–Madadi ≥ 3); however, HAEC treated with antibiotics increased following centralization (10.5–24.1%; p = 0.018). Conclusion: Centralization of care for HSCR does not seem to delay time to pull-through nor reduce severe complications, unplanned procedures under general anesthesia or readmissions up to 90 days after pull-through. The increased HAEC rate may be due to increased awareness of mild HAEC. Level of evidence: Level III. [ABSTRACT FROM AUTHOR]

One risk of continuous renal replacement therapy (CRRT) is inadvertent hypothermia (IH), which is defined as a non-therapeutic core temperature decrease below normal. In continuous renal replacement therapy, heat loss will always occur from blood pumped through the dialysis circuit to cooler environment, predisposing for hypothermia. Blood flow and effluent flows are the most important parameters causing heat loss. We investigated and compared the novel TherMax warmer to previous generation technologies during CRRT in a multicenter setting. This was a prospective observational multicenter study with historic single-center controls. The study group consisted of 100 patients in eight Swedish ICUs with clinical indication for CRRT, using the PrisMax platform and TherMax warmer. Both patient and set warmer temperatures were recorded hourly for the first 24 h. The presence of treatment hours in hypothermia (< 36.0 Celsius) and the difference between set warmer temperature and measured patient temperature in the multi-center study cohort were compared to a matched single-center historic control cohort treated with the old Prismaflex platform and adjacent Barkey warmer. In the TherMax group 77/100 (77.0%) of patients, and for controls 26/86 (30.2%) of patients were free of hypothermia (Chi square, p < 0.001). The mean number of hours spent in hypothermia was (mean ± SD) 0.66 ± 1.60 and 6.92 ± 7.79 h in the TherMax and control groups, respectively (Chi square p < 0.001). In the study group the patient temperature was higher than the set temperature on the warmer with a difference of Δ0.47 ± 0.80 °C (minor difference), whereas in the control group the set temperature on the warmer was higher than the patient temperature with a difference of Δ4.55 ± 1.00 °C (over-correction). The novel TherMax warmer technology protected against hypothermia and was significantly more accurate than the Barkey warmer. [ABSTRACT FROM AUTHOR]

According to Act Consequentialism, an act is right if and only if its outcome is not worse than the outcome of any alternative to that act. This view, however, leads to deontic paradoxes if the alternatives to an act are all other acts that can be done in the situation. A typical response is to only apply this rightness criterion to maximally specific acts and to take the alternatives to a maximally specific act to be the other maximally specific acts that can be done in the situation. (This view can then be supplanted by a separate account for the rightness of acts that are not maximally specific.) This paper defends a rival view, Binary Act Consequentialism, where, for any voluntary act, that act is right if and only if its outcome is not worse than the outcome of not doing that act. Binary Act Consequentialism, which dates back to Jeremy Bentham, has few supporters. A number of seemingly powerful objections have been considered fatal. In this paper, I rebut these objections and put forward a positive argument for the view. [ABSTRACT FROM AUTHOR]

In visual search tasks in the lab and in the real world, people routinely miss targets that are clearly visible: so-called look but fail to see (LBFTS) errors. If search displays are shown to the same observer twice, we can ask about the probability of joint errors, where the target is missed both times. If errors are "deterministic," then the probability of a second error on the same display–given that the target was missed the first time–should be high. If errors are "stochastic," the probability of joint errors should be the product of the error rate for first and second appearances. Here, we report on two versions of a T among Ls search with somewhat degraded letters to make search more difficult. In Experiment 1, Ts could either appear amidst crowded "clumps" of Ls or more in isolation. Observers made more errors when the T was in a clump, but these errors were mainly stochastic. In Experiment 2, the task was made harder by making Ts and Ls more similar. Again, errors were predominantly stochastic. If other, socially important errors are also stochastic, this would suggest that "double reading," where two observers (human or otherwise) look at each stimulus, could reduce overall error rates. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this cross-sectional survey was to assess oral health, including prevalence of periodontitis and rate of tooth loss, in a Swedish cohort of patients with inflammatory bowel disease (IBD). Methods: A questionnaire on general anamnestic and socio-economic aspects, IBD diagnosis, and various oral health aspects was distributed online. The analyses focused on the comparison between patients diagnosed with ulcerative colitis (UC) or Crohn’s disease (CD) as well as on factors associated with self-reported severe periodontitis and tooth loss. Results: Analyses were based on answers from 786 patients; 415 with UC, 371 with CD, 74% female. In both disease entities, high prevalence of severe periodontitis (i.e., 38.5%) was reported, and about 19% of the population had less than 20 remaining teeth and 6.5% a poor oral health-related quality of life. CD patients tended to be more severely affected than UC patients (p > 0.05 in the adjusted analysis). Almost 90% of CD patients were aware of being entitled to a bi-annual governmental financial support for dental care due to IBD; however, 1 out of 4 UC patients did not. Furthermore, IBD patients largely believe that the interest of their physicians in any oral lesions due to IBD diagnosis is low. Conclusions: Severe periodontitis and high rate of tooth loss are frequent in Swedish IBD patients. Clinical relevance: Even though IBD patients receive bi-annually some special financial support for dental care, it seems this is still not sufficient and more preventive measures appear necessary. [ABSTRACT FROM AUTHOR]

Purpose: Benefits of prophylactic platelet (PLT) transfusion before dentoalveolar surgery are unclear. This study investigated the effect of prophylactic PLT transfusions on the incidence of postoperative bleeding (POB) in patients with thrombocytopenia and a PLT count ≤ 75*109/L. Methods: The cohort in this retrospective study comprised 83 patients with thrombocytopenia ≤ 75*109/L who had undergone dentoalveolar surgery. Exclusion criteria were other coagulation deficiencies or medications that would affect hemostasis. In all, 144 teeth had been removed. POB events were extracted and compared between the group that had received prophylactic PLT transfusion before dentoalveolar surgery and the group that had not. Results: POB events were observed in 5 of 83 patients (6.0%) who had a median PLT count of 35*109/L before any transfusion. The group with no postoperative bleeding (NPOB) had a median PLT count of 34*109/L. Two (4.2%) of the 48 patients who had received prophylactic PLT transfusions before dentoalveolar surgery developed POB. Three (8.6%) of the 35 patients who had not received a transfusion experienced POB. The difference between these two groups was not significant (p = 0.646). When two or more teeth were removed in the same session, a significantly higher incidence of POB was observed (p = 0.042). Conclusions: Our data indicate that prophylactic PLT transfusions in thrombocytopenic patients with PLT counts ≤ 75*109/L do not reduce the incidence of POB after dentoalveolar surgery. However, caution is warranted when extracting multiple teeth in the same surgical session since we found this to be significantly associated with an increased risk of POB. [ABSTRACT FROM AUTHOR]

Purpose: To study the association between the use of drugs for hypertension or heart failure, particularly diuretics, and risk of death in COVID-19. Methods: We conducted a cohort study, based on record linked individual-based data from national registers, of all Swedish inhabitants 50 years and older (n = 3,909,321) at the start of the first SARS-CoV-2 wave in Sweden. The association between use of angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB), thiazides, loop diuretics, aldosterone antagonists, beta blocking agents and calcium channel blockers at the index date 6 March 2020, and death in COVID-19 during 7 March to 31 July 2020, was analysed using Cox-proportional hazards regression, adjusted for a wide range of possible confounders. Results: Use of loop diuretics was associated with higher risk [adjusted hazard ratio (HR) 1.26; 95% confidence interval (95% CI) 1.17–1.35] and thiazides with reduced risk (0.78; 0.69–0.88) of death in COVID-19. In addition, lower risk was observed for ACEI and higher risk for beta-blocking agents, although both associations were weak. For ARB, aldosterone antagonists and calcium channel blockers no significant associations were found. Conclusion: In this nationwide cohort of nearly 4 million persons 50 years and older, the use of loop diuretics was associated with increased risk of death in COVID-19 during the first SARS-CoV-2 wave in Sweden. This contrasted to the decreased risk observed for thiazides. As treatment with loop diuretics is common, particularly in the elderly, the group most affected by severe COVID-19, this finding merit further investigation. [ABSTRACT FROM AUTHOR]

Background and Objective: Tacrolimus is an immunosuppressant commonly administered after solid organ transplantation. It is characterized by a narrow therapeutic window and high variability in exposure, demanding personalized dosing. In recent years, population pharmacokinetic models have been suggested to guide model-informed precision dosing of tacrolimus. We aimed to provide a comprehensive overview of population pharmacokinetic models and model-informed precision dosing software modules of tacrolimus in all solid organ transplant settings, including a simulation-based investigation of the impact of covariates on exposure and target attainment. Methods: We performed a systematic literature search to identify population pharmacokinetic models of tacrolimus in solid organ transplant recipients. We integrated selected population pharmacokinetic models into an interactive software tool that allows dosing simulations, Bayesian forecasting, and investigation of the impact of covariates on exposure and target attainment. We conducted a web survey amongst model-informed precision dosing software tool providers and benchmarked publicly available tools in terms of models, target populations, and clinical integration. Results: We identified 80 population pharmacokinetic models, including 44 one-compartment and 36 two-compartment models. The most frequently retained covariates on clearance and distribution parameters were cytochrome P450 3A5 polymorphisms and body weight, respectively. Our simulation tool, hosted at https://lpmx.shinyapps.io/tacrolimus/, allows thorough investigation of the impact of covariates on exposure and target attainment. We identified 15 model-informed precision dosing software tool providers, of which ten offer a tacrolimus solution and nine completed the survey. Conclusions: Our work provides a comprehensive overview of the landscape of available tacrolimus population pharmacokinetic models and model-informed precision dosing software modules. Our simulation tool allows an interactive thorough exploration of covariates on exposure and target attainment. [ABSTRACT FROM AUTHOR]

Purpose: This study examines the willingness of Spanish and Lithuanian grain farmers to adopt a combined approach of preventive site-specific spraying (PSSS) and selective harvesting (SH), two precision agricultural technologies (below referred to as PSSS-SH) aimed at mitigating the risk of mycotoxin contamination in barley and wheat. Methods: Data were collected from 190 commercial grain farmers using a choice experimental survey. The empirical analysis relied on the estimation of mixed logit and integrated latent class models. Results: The surveyed farmers were heterogeneous in their preference for the PSSS-SH technology, with a majority (81%) reporting that they were willing to adopt and pay for the PSSS-SH technology. Furthermore, the farmers' willingness to adopt PSSS-SH technology was influenced by the trade-offs between the potential production, economic and environmental changes. Conclusion: Profit maximization is not the only motivation for a farmer's decision to adopt PSSS-SH, there are also important non-financial benefits that align with the observed choices. Furthermore, the perceived usefulness of the technology, the willingness and readiness to use the technology, and the farmer characteristics (e.g. cooperative membership, employment status, share of household income from grain production and past experience with precision farming technology) were positively associated with uptake of the PSSS-SH technology. Therefore, extension programmes should have a special focus on the perceived usefulness of the technology, the willingness and readiness of farmers to use it, and its unique characteristics. [ABSTRACT FROM AUTHOR]

The ability to orient attention to one's environment is a prerequisite for developing executive functions (EF) from preschool age. Very preterm children are vulnerable for delays in visual orienting function (VOF) and EF deficits. This study aimed to investigate associations between objective VOF and subjective parent-reported EF in very preterm–born children at 3 years corrected age (CA). In a prospective cohort study (BOND) involving 90 children born < 30 weeks, VOF and EF were assessed using an eye tracking–based method and BRIEF-P questionnaire. Associations between abnormal VOF (viewing reaction times) and EF scores (BRIEF-P scores) were studied using multivariable regression. Using a modified Delphi method, a subset of eight items related to VOF and EF was explored. Abnormal VOF was observed in 31% of the children and abnormal global EF composite scores in 41%. Abnormal VOF was not associated with global or domain-level EF scores. However, children with abnormal VOF more frequently had EF problems related to attentional behavior: "easily sidetracked" (OR 4.18 (CI: 1.21–14.41), p = 0.02) and "short attention span" (OR 4.52 (CI: 1.34–15.22), p = 0.02). Conclusion: Although abnormal VOF was not associated with global, parent-reported, EF at 3 years CA, secondary analyses did show a relation to specific attention and concentration span items. Further research is needed to study the role of VOF in objectifying preschool EF assessments in very preterm born children. What is known: • Very preterm children are vulnerable for executive function (EF) deficits and for delays in visual orienting function, as compared to term-born children • The ability to orient attention to one's visual environment is an important prerequisite for EF early in life and is easy to measure objectively with visual orienting function (VOF) assessment What is new: • VOF measurement at 3 years of age relates to parent-reported attention and concentration span items, important aspects of executive functions • Future work should explore the clinical additional value of early VOF measurement in children at risk for EF deficits [ABSTRACT FROM AUTHOR]

The stable boundary layer (SBL) subjected to large-scale subsidence is studied through large-eddy simulations (LESs) with fixed surface temperature and a linear subsidence velocity profile. These boundary layers reach a steady state, where thermal equilibrium is established by a balance between surface cooling and subsidence-induced heating. We identify three governing dimensionless groups by scaling the governing equations with the geostrophic wind and Coriolis frequency, and systematically investigate the impact of these external parameters on global flow properties and mean profiles in the steady state. The SBL depth, low-level jet, and the magnitude of the turbulent momentum flux are reduced when the dimensionless subsidence rate or Buoyancy number increases, while surface heat flux is enhanced. The normalized mean profiles of potential temperature and heat flux are predominantly controlled by the subsidence number, whereas they converge for simulations with different buoyancy and surface Rossby numbers. Within the surface layer, dimensionless velocity and potential temperature gradients in the steady SBL with subsidence show acceptable agreement to Monin–Obukhov similarity theory, whereas the data suggests improved similarity when a recently proposed mixed scaling parameter is used. We furthermore develop empirical correlations for the stability parameter h θ / L O and a thermal shape factor, and propose a new unidirectional geostrophic drag law, to form a closed set of equations that estimates relevant flow properties from external parameters. The estimation errors compared to the LES data are less than 5% for friction velocity and surface heat flux, and at most 10% for the SBL depth h θ . [ABSTRACT FROM AUTHOR]

Introduction: Combined radiotherapy and immune checkpoint inhibition is a potential treatment option for head and neck squamous cell carcinoma (HNSCC). Immunocompetent mouse models can help to successfully develop radio- immunotherapy combinations and to increase our understanding of the effects of radiotherapy on the tumor microenvironment for future clinical translation. Therefore, the aim of this study was to develop a homogeneous, reproducible HNSCC model originating from the Mouse Oral Cancer 1 (MOC1) HNSCC cell line, and to explore the radiotherapy-induced changes in its tumor microenvironment, using flow cytometry and PD-L1 microSPECT/CT imaging. Materials and Methods: In vivo growing tumors originating from the parental MOC1 line were used to generate single cell derived clones. These clones were screened in vitro for their ability to induce programmed cell death ligand 1 (PD-L1) and major histocompatibility complex class I (MHC-I) following IFNγ exposure. Clones with different IFNγ sensitivity were inoculated in C57BL/6 mice and assessed for tumor outgrowth. The composition of the tumor microenvironment of a stably growing (non)irradiated MOC1-derived clone was assessed by immunohistochemistry, flow cytometry and PD-L1 microSPECT/CT. Results: Low in vitro inducibility of MHC-I and PD-L1 by IFNγ was associated with increased tumor outgrowth of MOC1 clones in vivo. Flow cytometry analysis of cells derived from a stable in vivo growing MOC1 clone MOC1.3D5low showed expression of MHC-I and PD-L1 on several cell populations within the tumor. Upon irradiation, MHC-I and PD-L1 increased on leukocytes (CD45.2+) and cancer associated fibroblasts (CD45.2−/EpCAM−/CD90.1+). Furthermore, PD-L1 microSPECT/CT showed increased tumor uptake of radiolabeled PD-L1 antibodies with a heterogeneous spatial distribution of the radio signal, which co-localized with PD-L1+ and CD45.2+ areas. Discussion: PD-L1 and MHC-I inducibility by IFNγ in vitro is associated with tumor outgrowth of MOC1 clones in vivo. In tumors originating from a stably growing MOC1-derived clone, expression of these immune-related markers was induced by irradiation shown by flow cytometry on several cell populations within the tumor microenvironment such as immune cells and cancer associated fibroblasts. PD-L1 microSPECT/CT showed increased tumor uptake following radiotherapy, and autoradiography showed correlation of uptake with areas that are heavily infiltrated by immune cells. Knowledge of radiotherapy-induced effects on the tumor microenvironment in this model can help optimize timing and dosage for radio- immunotherapy combination strategies in future research. [ABSTRACT FROM AUTHOR]

The well-known Rule07 is a simple thus efficient way to compare available technologies for IR imaging detectors in terms of dark current. The noise is then often estimated using a shot noise approximation on the dark current. Both II–VI and III–V communities use this rule of thumb as a reference for well-performing IR photodiodes. For HOT applications, a dark current close to this rule07 is considered a necessary condition but not a sufficient one to obtain a high-performance IR imager. Indeed, when limited by shot noise, rule07 describes well the noise behavior of the considered device. However, when considering low-frequency noise, it fails to describe the expected performances. In this paper, we focus on another figure-of-merit, dedicated to detector low-frequency noise rather than dark current. Systemic 1/f noise investigation in an IR detector was first reported by Tobin et al. in 1980. There is today a relative consensus on the fact that measured 1/f noise is proportional to the dark current. The ratio between the amplitude of the 1/f noise and the dark current of the same devices may therefore be used as a figure-of-merit for a given technology. This ratio (called the Tobin factor α T ) therefore appears adequate to compare different technologies as a figure-of-merit qualifying 1/f noise properties. This dimensionless ratio can also be very useful for optimizing a particular technology or process. However, in order to be relevant, this figure-of-merit must be estimated carefully as it appears, for instance, pixel pitch-dependent. Different examples of Tobin coefficient extraction are presented in this paper. We show that, depending on the technologies, the values of the Tobin coefficient can spread over several orders of magnitude. However, only low values result in high-quality IR imagers. Today, the best results we obtained show that α T = 10 - 5 is a state-of-art value to be compared with. [ABSTRACT FROM AUTHOR]

The gain in short-wave infrared and mid-wave infrared HgCdTe avalanche photodiodes (APDs) with large diameters has been analyzed using an already established model based on an empirical expression proposed by Okuto–Crowell (OC) and a new model derived for the impact ionization in HgCdTe. This model is based on a simplified but physical description of the carrier dynamics during the multiplication. It is shown that OC model has limitations in giving a precise description of the measured avalanche gains, and that is difficult, in view of present available data, to derive a universal expression for the model parameters to predict the avalanche gain in HgCdTe APDs as a function of the Cd composition, operating temperature, and multiplication layer geometry. The new model is shown to give a better fit of the gain data, associated with a scaling of the model parameters with the band gap. [ABSTRACT FROM AUTHOR]

Children with chronic kidney disease (CKD) are at risk for vitamin deficiency or excess. Vitamin status can be affected by diet, supplements, kidney function, medications, and dialysis. Little is known about vitamin requirements in CKD, leading to practice variation. The Pediatric Renal Nutrition Taskforce (PRNT), an international team of pediatric kidney dietitians and pediatric nephrologists, was established to develop evidence-based clinical practice points (CPPs) to address challenges and to serve as a resource for nutritional care. Questions were formulated using PICO (Patient, Intervention, Comparator, Outcomes), and literature searches undertaken to explore clinical practice from assessment to management of vitamin status in children with CKD stages 2–5, on dialysis and post-transplantation (CKD2-5D&T). The CPPs were developed and finalized using a Delphi consensus approach. We present six CPPs for vitamin management for children with CKD2-5D&T. We address assessment, intervention, and monitoring. We recommend avoiding supplementation of vitamin A and suggest water-soluble vitamin supplementation for those on dialysis. In the absence of evidence, a consistent structured approach to vitamin management that considers assessment and monitoring from dietary, physical, and biochemical viewpoints is needed. Careful consideration of the impact of accumulation, losses, comorbidities, and medications needs to be explored for the individual child and vitamin before supplementation can be considered. When supplementing, care needs to be taken not to over-prescribe. Research recommendations are suggested. [ABSTRACT FROM AUTHOR]

Cerebral dopamine neurotrophic factor (CDNF) is an unconventional neurotrophic factor that is a disease-modifying drug candidate for Parkinson’s disease. CDNF has pleiotropic protective effects on stressed cells, but its mechanism of action remains incompletely understood. Here, we use state-of-the-art advanced structural techniques to resolve the structural basis of CDNF interaction with GRP78, the master regulator of the unfolded protein response (UPR) pathway. Subsequent binding studies confirm the obtained structural model of the complex, eventually revealing the interaction site of CDNF and GRP78. Finally, mutating the key residues of CDNF mediating its interaction with GRP78 not only results in impaired binding of CDNF but also abolishes the neuroprotective activity of CDNF-derived peptides in mesencephalic neuron cultures. These results suggest that the molecular interaction with GRP78 mediates the neuroprotective actions of CDNF and provide a structural basis for development of next generation CDNF-based therapeutic compounds against neurodegenerative diseases.CDNF is a clinical trial candidate in Parkinson’s disease but the mechanism of action is not fully understood. Here, the authors use SAXS and NMR techniques to resolve the structure of CDNF in complex with GRP78 and show that this interaction is required for the neuroprotective action of CDNF. [ABSTRACT FROM AUTHOR]

Purpose: Previous studies have demonstrated an association between video-gaming experience (VGE) and improved robotics skills. We aimed to evaluate the initial learning curve for the Ily® robotics system (Sterlab, Sophia Antipolis, France) when applied to flexible ureteroscopy (FU) among both medical students and urology surgeons. Methods: There were two groups, surgeons and students. An initial questionnaire was completed detailing basic demographics and experience. In part one, both groups performed two simple timed tasks using an Ily® mounted single-use RAU. In part two, group 1 repeated both tasks using a hand-held FU. A subjective assessment of comfort, intuitiveness and a NASA Task Load Index were then completed. Results: There was a total of 28 participants. Among medical students with VGE (n = 9, 64%)., average calyceal inspection time was 185 ± 80 s; 133 ± 42 s; 121 ± 71 s. For non-gamers (n = 5, 36%), average times were longer at 221 ± 97 s; 134 ± 35 s; 143 ± 68 s respectively. Average calyceal inspection time for videogaming surgeons (n = 8, 57%) was 126 ± 95 s; 98 ± 40 s; 107 ± 71 s, respectively. For non-gamers average inspection times were longer at 150 ± 73 s; 114 ± 82 s; 111 ± 47 s, respectively. None of these differences achieved statistical significance. Surgeons trial speeds were, however, significantly faster by hand-held compared to RAU: by 103, 81 and 82 s respectively (p < 0.05). Conclusion: These results show that ex- or current- video gamers do not have a significant advantage in time to perform FU. Any early advantage conferred to ex- or current- gamers may be rapidly overcome. [ABSTRACT FROM AUTHOR]

Background: Patellar instability is a well-known pathology in which kinematics can be investigated using metrics such as tibial tuberosity tracheal groove (TTTG), the bisect offset (BO), and the lateral patellar tilt (LPT). We used dynamic computed tomography (CT) to investigate the patellar motion of healthy subjects in weight-bearing conditions to provide normative values for TTTG, BO, and LPT, as well as to define whether BO and LPT are affected by the morphology of the trochlear groove. Methods: Dynamic scanning was used to acquire images during weight-bearing in 21 adult healthy volunteers. TTTG, BO, and LPT metrics were computed between 0° and 30° of knee flexion. Sulcus angle, sulcus depth, and lateral trochlear inclination were calculated and used with the TTTG for simple linear regression models. Results: All metrics gradually decreased during eccentric movement (TTTG, -6.9 mm; BO, -12.6%; LPT, -4.3°). No significant differences were observed between eccentric and concentric phases at any flexion angle for all metrics. Linear regression between kinematic metrics towards full extension showed a moderate fit between BO and TTTG (R2 0.60, β 1.75) and BO and LPT (R2 0.59, β 1.49), and a low fit between TTTG and LPT (R2 0.38, β 0.53). A high impact of the TTTG distance over BO was shown in male participants (R2 0.71, β 1.89) and patella alta individuals (R2 0.55, β 1.91). Conclusion: We provided preliminary normative values of three common metrics during weight-bearing dynamic CT and showed the substantial impact of lateralisation of the patella tendon over patella displacement. Relevance statement: These normative values can be used by clinicians when evaluating knee patients using TTTG, BO, and LPT metrics. The lateralisation of the patellar tendon in subjects with patella alta or in males significantly impacts the lateral displacement of the patella. Key Points: Trochlear groove morphology had no substantial impact on motion prediction. The lateralisation of the patellar tendon seems a strong predictor of lateral displacement of the patella in male participants. Participants with patella alta displayed a strong fit between the patellar lateral displacement and tilt. TTTG, BO, and LPT decreased during concentric movement. Concentric and eccentric phases did not show differences for all metrics. [ABSTRACT FROM AUTHOR]

Hematopoietic stem cells (HSCs) react to various stress conditions. However, it is unclear whether and how HSCs respond to severe anemia. Here, we demonstrate that upon induction of acute anemia, HSCs rapidly proliferate and enhance their erythroid differentiation potential. In severe anemia, lipoprotein profiles largely change and the concentration of ApoE increases. In HSCs, transcription levels of lipid metabolism-related genes, such as very low-density lipoprotein receptor (Vldlr), are upregulated. Stimulation of HSCs with ApoE enhances their erythroid potential, whereas HSCs in Apoe knockout mice do not respond to anemia induction. VldlrhighHSCs show higher erythroid potential, which is enhanced after acute anemia induction. VldlrhighHSCs are epigenetically distinct because of their low chromatin accessibility, and more chromatin regions are closed upon acute anemia induction. Chromatin regions closed upon acute anemia induction are mainly binding sites of Erg. Inhibition of Erg enhanced the erythroid differentiation potential of HSCs. Our findings indicate that lipoprotein metabolism plays an important role in HSC regulation under severe anemic conditions. How hematopoietic stem cells respond, if at all, to acute anemia has remained unclear. Here, the authors show that acute anemia triggers hematopoietic stem cell proliferation and guides differentiation towards erythroid cells in a process mediated by apolipoprotein E. [ABSTRACT FROM AUTHOR]

Physical reservoir computing leverages the dynamical properties of complex physical systems to process information efficiently, significantly reducing training efforts and energy consumption. Magnetic skyrmions, topological spin textures, are promising candidates for reservoir computing systems due to their enhanced stability, non-linear interactions and low-power manipulation. Traditional spin-based reservoir computing has been limited to quasi-static detection or real-world data must be rescaled to the intrinsic timescale of the reservoir. We address this challenge by time-multiplexed skyrmion reservoir computing, that allows for aligning the reservoir's intrinsic timescales to real-world temporal patterns. Using millisecond-scale hand gestures recorded with Range-Doppler radar, we feed voltage excitations directly into our device and detect the skyrmion trajectory evolution. This method scales down to the nanometer level and demonstrates competitive or superior performance compared to energy-intensive software-based neural networks. Our hardware approach's key advantage is its ability to integrate sensor data in real-time without temporal rescaling, enabling numerous applications. Physical reservoir computing allows real-time low power information processing. Here, the authors report reservoir computing with magnetic skyrmions able to detect millisecond time-scale hand gestures, matching software neural networks' performance. [ABSTRACT FROM AUTHOR]

The tumour immune microenvironment (TIME) in breast cancer is acknowledged with an increasing role in treatment response and prognosis. With a growing number of immune markers analysed, digital image analysis may facilitate broader TIME understanding, even in single-plex IHC data. To facilitate analyses of the latter an open-source image analysis pipeline, Tissue microarray MArker Quantification (TMArQ), was developed and applied to single-plex stainings for p53, CD3, CD4, CD8, CD20, CD68, FOXP3, and PD-L1 (SP142 antibody) in a 218-patient triple negative breast cancer (TNBC) cohort with complementary pathology scorings, clinicopathological, whole genome sequencing, and RNA-sequencing data. TMArQ’s cell counts for analysed immune markers were on par with results from alternative methods and consistent with both estimates from human pathology review, different quantifications and classifications derived from RNA-sequencing as well as known prognostic patterns of immune response in TNBC. The digital cell counts demonstrated how immune markers are coexpressed in the TIME when considering TNBC molecular subtypes and DNA repair deficiency, and how combination of immune status with DNA repair deficiency status can improve the prognostic stratification in chemotherapy treated patients. These results underscore the value and potential of integrating TIME and specific tumour intrinsic alterations/phenotypes for the molecular understanding of TNBC. [ABSTRACT FROM AUTHOR]