Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor.

KRASG12C was recently identified to be potentially druggable by allele-specific covalent targeting of Cys-12 in vicinity to an inducible allosteric switch II pocket (S-IIP). Success of this approach requires active cycling of KRASG12C between its active-GTP and inactive-GDP conformations as accessibility of the S-IIP is restricted only to the GDP-bound state. This strategy proved feasible for inhibiting mutant KRAS in vitro; however, it is uncertain whether this approach would translate to in vivo. Here, we describe structure-based design and identification of ARS-1620, a covalent compound with high potency and selectivity for KRASG12C. ARS-1620 achieves rapid and sustained in vivo target occupancy to induce tumor regression. We use ARS-1620 to dissect oncogenic KRAS dependency and demonstrate that monolayer culture formats significantly underestimate KRAS dependency in vivo. This study provides in vivo evidence that mutant KRAS can be selectively targeted and reveals ARS-1620 as representing a new generation of KRASG12C-specific inhibitors with promising therapeutic potential.

Moving together - benefits of an online dance program on physical and mental health for older women: an exploratory mixed-method study.

BACKGROUND: Previous studies show that in-person dance training is a beneficial form of physical activity that involves mental, social, and physical dimensions. This exploratory study investigated the benefits of a 12-week online dance training intervention on mental and physical health outcomes for older women. METHODS: A convergent parallel mixed-method design was used. Forty-five older adults (74.0 ± 5.3 yrs old, 44 women) were recruited through advertisements at activity and rehabilitation centers in the North Denmark region. The intervention consisted of two weekly 60-min classes of improvisation and salsa delivered online through video call applications. Changes in physical health outcomes (body mass and composition, resting blood pressure, Senior Fitness Test battery) and self-rated health and wellbeing (health-related quality of life (HRQOL), feelings of loneliness) were assessed prior to and after 12 weeks of dancing. Focus group interviews were conducted post-intervention to further explore the benefits as well as the participant's experience of the intervention. Thematic analysis of the qualitative data was conducted. RESULTS: Thirty-two participants (all women) completed the study. Significant improvements in fitness were found for the number of arm curls performed (baseline: 12.3 ± 3.0; post-intervention: 13.7 ± 3.0, P = 0.005), 2-min step test performance (baseline: 66.5 ± 20.0 reps.; post-intervention: 73.8 ± 22.6 reps., P = 0.016), and chair sit-and-reach (baseline: 0.4 ± 11.3 cm; post-intervention: 5.5 ± 10.1 cm, P < 0.001). There was a significant increase in body mass from baseline to post-intervention (P < 0.015). The themes from the focus groups included (1) Participation, (2) Challenges, (3) Progression, (4) Motivation, (5) Perceived health and wellbeing, and (6) Online dance instruction. No significant changes were reported in HRQOL and loneliness from the quantitative data, although the qualitative data did reveal improved feelings of physical health and wellbeing. CONCLUSIONS: The intervention improved several aspects of fitness in older women and improved the participants' perceptions of their own physical abilities and wellbeing. While most participants found the online intervention enjoyable, several participants missed the feedback from the instructors that naturally occurs with in-person instruction.

Study protocol for the ACTIVE SCHOOL study investigating two different strategies of physical activity to improve academic performance in Schoolchildren.

BACKGROUND: Previous research has suggested that school-based physical activity (PA) interventions may have a positive impact on academic performance. However, existing literature on school-based interventions encompasses various forms of PA, spanning from vigorous intensity PA outside the academic classes to light intensity PA and movement integrated into academic learning tasks, and results on academic performance are inconclusive. ACTIVE SCHOOL will implement two different PA interventions for one school year and assess the effects on the pupils' academic performance, with math performance as the primary outcome. METHODS/DESIGN: The ACTIVE SCHOOL project consists of two phases: 1) Development phase and 2) Randomized Controlled Trial (RCT). In phase one, two interventions were developed in collaboration with school staff. The two interventions were tested in an 8-weeks feasibility study. In phase two, a RCT-study with three arms will be conducted in 9-10-year-old children for one school year. The RCT-study will be carried out in two intervention rounds during the school years 2023/2024 and 2024/2025. Schools will be randomized to one of two interventions or control;1) Run, Jump & Fun intervention (4 × 30 min/week of moderate-to-vigorous physical activity; 2) Move & Learn intervention (4 × 30 min/week focusing on embodied learning in math and Danish lessons); or 3) a control condition, consisting of normal teaching practices. Outcome measures include academic performance, PA level, cognitive functions, cardiorespiratory fitness, anthropometry, well-being and school motivation (collected before, during and after the intervention period). A process evaluation will be conducted to assess implementation. DISCUSSION: The ACTIVE SCHOOL study will expand knowledge regarding the impact of PA on academic performance. The study will have the potential to significantly contribute to future research, as well as the scientific and educational debate on the best way to implement PA to support education and learning. TRIAL REGISTRATION: The study was registered on the 25th of October 2022 in ClinicalTrials.gov, NCT05602948.

Ventriculostomy-associated infection (VAI) in patients with acute brain injury-a retrospective study.

BACKGROUND: Ventriculostomy-associated infection (VAI) is common after external ventricular drains (EVD) insertion but is difficult to diagnose in patients with acute brain injury. Previously, we proposed a set of criteria for ruling out VAI in traumatic brain injury. This study aimed to validate these criteria. For exploratory purposes, we sought to develop and validate a score for VAI risk assessment in patients with different types of severe acute brain injury. METHODS: This retrospective cohort study included adults with acute brain injury who received an EVD and in whom CSF samples were taken over a period of 57 months. As standard non-coated bolt-connected EVDs were used. The predictive performance of biomarkers was analyzed as defined previously. A multivariable regression model was performed with five variables. RESULTS: A total of 683 patients with acute brain injury underwent EVD placement and had 1272 CSF samples; 92 (13.5%) patients were categorized as culture-positive VAI, 130 (19%) as culture-negative VAI, and 461 (67.5%) as no VAI. A low CSF WBC/RBC ratio (< 0.037), high CSF/plasma glucose ratio (> 0.6), and low CSF protein (< 0.5g/L) showed a positive predictive value of 0.09 (95%CI, 0.05-0.13). In the multivariable logistic regression model, days to sample (OR 1.09; 95%CI, 1.03-1.16) and CSF WBC/RBC ratio (OR 34.86; 95%CI, 3.94-683.15) were found to predict VAI. CONCLUSION: In patients with acute brain injury and an EVD, our proposed combined cut-off for ruling out VAI performed satisfactorily. Days to sample and CSF WBC/RBC ratio were found independent predictors for VAI in the multivariable logistic regression model.

High-power supercontinuum lasers with a flat blue spectrum through pump modulation: a numerical study.

We numerically investigate high-power, modulational instability-based supercontinuum sources. Such sources have spectra that reach the infrared material absorption edge and as a result the spectrum has a strong narrow blue peak (dispersive wave group velocity matched to solitons at the infrared loss edge) followed by a significant dip in the neighboring longer-wavelength region. In a wide range of applications one prefers a broader and more flat blue part within a certain minimum and maximum power spectral density. From the perspective of fiber degradation it would be desirable to achieve this at reduced pump peak powers. We show that it is possible to improve the flatness by more than a factor of 3 by modulating the input peak power, although this comes at the expense of slightly higher relative intensity noise. Specifically, we consider a standard 6.6 W, 80 MHz supercontinuum source with a 455 nm blue edge, which uses 7 ps pump pulses. We then modulate its peak power to generate a pump pulse train having two and three different sub-pulses.

Prevalence of Bleeding Symptoms in Denmark Using the Patient-administered Bleeding Assessment Tool (self-BAT).

INTRODUCTION: The patient-administered bleeding assessment tool (self-BAT) is a screening tool developed to identify individuals in need of work-up for bleeding disorders. Nonetheless, large studies on self-BAT scores on healthy individuals according to gender and age are lacking. AIM: Determine cut-offs for abnormal total score of self-BAT and investigate the prevalence of bleeding symptoms in blood donors and individuals representative of the general Danish population. METHODS: Blood donors, 15,600 children (<18 years) and 18,200 adults from the general Danish population, were invited to complete a Danish version of the self-BAT. To determine cut-offs for abnormal total self-BAT score, findings from healthy young children (0-11 years old), healthy adolescents (12-17 years old), healthy adult women and healthy adult men were used. RESULTS: Among healthy young children (244 girls, 260 boys), healthy adolescents (58 girls, 83 boys), healthy women (n = 437) and healthy men (n = 278) from the general population, along with healthy blood donors (116 women, 176 men), the 95th percentile for total score was two for young girls, three for young boys, four for adolescent girls, three for adolescent boys, eight for women and four for men. CONCLUSION: Our findings indicate that the abnormal total self-BAT score is ≥3 for girls aged 0-11 years old, ≥4 for boys aged 0-11 years old, ≥5 for girls aged 12-17 years old, ≥4 for boys aged 12-17 years old, ≥9 for women and ≥5 for men. To establish the accuracy of these cut-offs for diagnosing bleeding disorders, further studies are needed.

Prevalence of prostate cancer in men with haematuria: a systematic review and meta-analysis.

OBJECTIVES: To investigate the prevalence of prostate cancer in men attending evaluation for haematuria, as this could help healthcare providers to determine whether men with haematuria should have prostate examinations performed. METHODS: The study was performed according to a pre-specified protocol uploaded to the International Prospective Register of Systematic Reviews (PROSPERO; CRD42022299383). A systematic search of MEDLINE, Ovid and Google Scholar was performed in December 2021. Two independent researchers evaluated all titles, available abstracts, and full texts. We included studies on adult men (aged ≥18 years) describing haematuria and prostate cancer. RESULTS: We screened 4252 titles and abstracts when available and assessed 350 studies in full text. In total, 65 studies were included and 42 was summarised in a meta-analysis. In total, 18 752 men with haematuria were included, and the pooled prevalence (95% confidence interval [CI]) of prostate cancer was 3.0% (2.0-4.1%). In men with macroscopic haematuria, the pooled prevalence (95% CI) of prostate cancer was 5.9% (2.9-9.9%; n = 265/5373). In men with microscopic haematuria, the pooled prevalence (95% CI) of prostate cancer was 1.4% (0.8-2.2%; n = 71/6642). CONCLUSION: Our findings indicate that the prevalence of prostate cancer is considerable in men attending evaluation for haematuria. Therefore, digital rectal examination and prostate-specific antigen measurement should become a standard procedure for all men with haematuria, especially for men with macroscopic haematuria.

Geometric distortions in clinical MRI sequences for radiotherapy: insights gained from a multicenter investigation.

BACKGROUND: As magnetic resonance imaging (MRI) becomes increasingly integrated into radiotherapy (RT) for enhanced treatment planning and adaptation, the inherent geometric distortion in acquired MR images pose a potential challenge to treatment accuracy. This study aimed to evaluate the geometric distortion levels in the clinical MRI protocols used across Danish RT centers and discuss influence of specific sequence parameters. Based on the variety in geometric performance across centers, we assess if harmonization of MRI sequences is a relevant measure. MATERIALS AND METHODS: Nine centers participated with 12 MRI scanners and MRI-Linacs (MRL). Using a travelling phantom approach, a reference MRI sequence was used to assess variation in baseline distortion level between scanners. The phantom was also scanned with local clinical MRI sequences for brain, head/neck (H/N), abdomen, and pelvis. The influence of echo time, receiver bandwidth, image weighting, and 2D/3D acquisition was investigated. RESULTS: We found a large variation in geometric accuracy across 93 clinical sequences examined, exceeding the baseline variation found between MRI scanners (σ = 0.22 mm), except for abdominal sequences where the variation was lower. Brain and abdominal sequences showed lowest distortion levels ([0.22, 2.26] mm), and a large variation in performance was found for H/N and pelvic sequences ([0.19, 4.07] mm). Post hoc analyses revealed that distortion levels decreased with increasing bandwidth and a less clear increase in distortion levels with increasing echo time. 3D MRI sequences had lower distortion levels than 2D (median of 1.10 and 2.10 mm, respectively), and in DWI sequences, the echo-planar imaging read-out resulted in highest distortion levels. CONCLUSION: There is a large variation in the geometric distortion levels of clinical MRI sequences across Danish RT centers, and between anatomical sites. The large variation observed makes harmonization of MRI sequences across institutions and adoption of practices from well-performing anatomical sites, a relevant measure within RT.

On the mechanism of painful burn sensation in tattoos on magnetic resonance imaging (MRI). Magnetic substances in tattoo inks used for permanent makeup (PMU) identified: Magnetite, goethite, and hematite.

BACKGROUND: Persons with cosmetic tattoos occasionally experience severe pain and burning sensation on magnetic resonance imaging (MRI). OBJECTIVE: To explore the culprit magnetic substances in commonly used permanent makeup inks. MATERIAL AND METHODS: 20 inks used for cosmetic tattooing of eyebrows, eyeliners, and lips were selected. Ink bottles were tested for magnetic behavior with a neodymium magnet. Eight iron oxide inks qualified for the final study. Metals were analyzed by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). The magnetic fraction of inks was isolated and analyzed by X-ray fluorescence (XRF). Magnetic iron compounds were characterized by Mössbauer spectroscopy and powder X-ray diffraction (XRD). RESULTS: ICP-MS showed iron in all magnetic samples, and some nickel and chromium. Mössbauer spectroscopy and XRD detected ferromagnetic minerals, particularly magnetite, followed by goethite and hematite. CONCLUSION: This original study of cosmetic ink stock products made with iron oxide pigments reports magnetic impurities in inks for cosmetic tattooing, e.g., magnetite, goethite, and hematite. These may be the main cause of MRI burn sensation in cosmetic tattoos. The mechanism behind sensations is hypothesized to be induction of electrical stimuli of axons from periaxonal pigment/impurity activated by magnetic force. Magnetite is considered the lead culprit.

Rowing exercise increases cardiorespiratory fitness and brachial artery diameter but not traditional cardiometabolic risk factors in spinal cord-injured humans.

PURPOSE: This study assessed the effects of upper-body rowing exercise on cardiorespiratory fitness, traditional cardiometabolic risk factors, and vascular health in individuals with spinal cord injury (SCI). METHODS: Seventeen male and female adults with chronic (> 1 yr) motor-complete and incomplete SCI (level of injury: C4-L3) were randomized to control (CON, n = 9) or exercise (UBROW, n = 8). Participants in UBROW performed 12-week, 3 weekly sessions of 30-min upper-body ergometer rowing exercise, complying with current exercise guidelines for SCI. Cardiorespiratory fitness ([Formula: see text]O2peak), traditional risk factors (lipid profile, glycemic control) as well as inflammatory and vascular endothelium-derived biomarkers (derived from fasting blood samples) were measured before and after 6 (6W) and 12 weeks (12W). Brachial artery resting diameter and flow-mediated dilation (FMD) were determined by ultrasound as exploratory outcomes. RESULTS: UBROW increased [Formula: see text]O2peak from baseline (15.1 ± 5.1 mL/kg/min; mean ± SD) to 6W (16.5 ± 5.3; P < 0.01) and 12W (17.5 ± 6.1; P < 0.01). UBROW increased resting brachial artery diameter from baseline (4.80 ± 0.72 mm) to 12W (5.08 ± 0.91; P < 0.01), with no changes at 6W (4.96 ± 0.91), and no changes in CON. There were no significant time-by-group interactions in traditional cardiometabolic blood biomarkers, or in unadjusted or baseline diameter corrected FMD. Explorative analyses revealed inverse correlations between changes (∆12W-baseline) in endothelin-1 and changes in resting diameter (r = - 0.56) and FMD% (r = - 0.60), both P < 0.05. CONCLUSION: These results demonstrate that 12 weeks of upper-body rowing complying with current exercise guidelines for SCI improves cardiorespiratory fitness and increases resting brachial artery diameter. In contrast, the exercise intervention had no or only modest effects on traditional cardiometabolic risk factors. The study was registered at Clinicaltrials.gov (N-20190053, May 15, 2020).

Change in treatment preferences in pediatric diaphyseal forearm fractures: a Danish nationwide register study of 36,244 fractures between 1997 and 2016.

BACKGROUND AND PURPOSE: The choice between invasive and non-invasive treatment of diaphyseal forearm fractures in children can be difficult. We investigated the trends in choice of treatment of pediatric diaphyseal forearm fractures over a 20-year period.  Patients and methods: This is a population-based register study with data from 1997 to 2016 retrieved from the Danish National Patient Registry. The primary outcome was choice of primary treatment within 1 week divided into non-invasive treatment (casting only or closed reduction including casting) and invasive (Kirshner wires, intramedullary nailing [IMN], and open reduction internal fixation [ORIF]). The secondary outcomes were further sub-analyses on invasive treatment and age groups. RESULTS: 36,244 diaphyseal forearm fractures were investigated, yielding a mean incidence of 172 per 105/year. The proportion of fractures treated invasively increased from 1997 to 2016, from 4% to 23%. The use of Kirschner wires increased from 1% to 9%, IMN increased from 1% to 14%, and ORIF decreased from 2% to 1%. The changes were evident in all age groups but smaller in the 0-3-year age group. CONCLUSION: We found an increase in invasive treatment of pediatric diaphyseal forearm fractures over the investigated period. A change in invasive methods was also found, as the rate of IMN increased over the investigated period and became the predominant surgical treatment choice.

αα-Hub domains and intrinsically disordered proteins: A decisive combo.

Hub proteins are central nodes in protein-protein interaction networks with critical importance to all living organisms. Recently, a new group of folded hub domains, the αα-hubs, was defined based on a shared αα-hairpin supersecondary structural foundation. The members PAH, RST, TAFH, NCBD, and HHD are found in large proteins such as Sin3, RCD1, TAF4, CBP, and harmonin, which organize disordered transcriptional regulators and membrane scaffolds in interactomes of importance to human diseases and plant quality. In this review, studies of structures, functions, and complexes across the αα-hubs are described and compared to provide a unified description of the group. This analysis expands the associated molecular concepts of "one domain-one binding site", motif-based ligand binding, and coupled folding and binding of intrinsically disordered ligands to additional concepts of importance to signal fidelity. These include context, motif reversibility, multivalency, complex heterogeneity, synergistic αα-hub:ligand folding, accessory binding sites, and supramodules. We propose that these multifaceted protein-protein interaction properties are made possible by the characteristics of the αα-hub fold, including supersite properties, dynamics, variable topologies, accessory helices, and malleability and abetted by adaptability of the disordered ligands. Critically, these features provide additional filters for specificity. With the presentations of new concepts, this review opens for new research questions addressing properties across the group, which are driven from concepts discovered in studies of the individual members. Combined, the members of the αα-hubs are ideal models for deconvoluting signal fidelity maintained by folded hubs and their interactions with intrinsically disordered ligands.

Sex differences in microvascular function across lower leg muscles in humans.

Studies have reported sex-based differences in conduit artery function, however little is known about possible sex-based differences in microvascular function, and possible influence of muscle group. Blood-oxygen-level-dependent (BOLD) MR images acquired during ischemia-reperfusion assess the reactive hyperemic response in the microvasculature of skeletal muscle. We tested the hypothesis that women have greater microvascular reactivity, reflected by faster time-to-peak (TTP) and time-to-half-peak (TTHP) of the BOLD response, across all lower leg muscles. In healthy, young men (n = 18) and women (n = 12), BOLD images of both lower legs were acquired continuously during 30 s of rest, 5 min of cuff occlusion and 2 min of reperfusion, in a 3 T MR scanner. Segmentation of tibialis anterior (TA), soleus (SO), gastrocnemius medial (GM), and the peroneal group (PG) were performed using image registration, and TTP and TTHP of the BOLD response were determined for each muscle. Overall, women had faster TTP (p = 0.001) and TTHP (p = 0.01) than men. Specifically, women had shorter TTP and TTHP in TA (27.5-28.4%), PG (33.9-41.6%), SO (14.7-19.7%) and GM (15.4-18.8%). Overall, TTP and TTHP were shorter in TA compared with PG (25.1-31.1%; p ≤ 0.007), SO (14.3-16%; p ≤ 0.03) and GM (15.6-26%; p ≤ 0.01). Intra class correlations analyses showed large variation in absolute agreement (range: 0.10-0.81) of BOLD parameters between legs (within distinct muscles). Faster TTP and TTHP across all lower leg muscles, in women, provide novel evidence of sex-based differences in microvascular function of young adults matched for age, body mass index, and physical activity level.

Diagnostic criteria of CNS infection in patients with external ventricular drainage after traumatic brain injury: a pilot study.

BACKGROUND: Ventriculostomy-related infection (VRI) is a common complication in patients with traumatic brain injury (TBI) treated with an external ventricular drain (EVD). The aim of this study was to investigate incidence and characteristics of patients with VRI, and to explore diagnostic criteria to confidently rule out VRI in patients with TBI. METHODS: This retrospective cohort pilot study included adults with severe TBI who were admitted to the ICU and received an EVD, during a 26-month period. Patients were categorized as having Culture-positive VRI, Culture-negative VRI, or No VRI. Variables that were potentially associated with Culture-positive VRI was analyzed, and predictive values were calculated. RESULTS: 75 of 215 patients with severe TBI (35%) underwent EVD placement; nine of these (12%) were classified as Culture-negative VRI and eight (11%) as Culture-positive VRI. The CSF cell counts that led to VRI treatment were compared with 46 CSF cell counts from No VRI patients. A CSF/plasma glucose ratio below 0.6 had a negative predictive value (NPV) for culture-verified VRI of 0.97 (95% CI: 0.85-1), whereas a combination of three CSF-derived biomarkers within the reference limits (white/red blood cell ratio, CSF/plasma glucose ratio, and protein content) ruled out Culture-positive VRI in this cohort (PPV 0, 95% CI: 0-0.14). C-reactive protein did not reliably predict VRI. CONCLUSIONS: In this pilot study of patients after severe, a combination of biomarkers within reference limits ruled out VRI (PPV 0, CI: 0-0.14). Hypoglycorrhachia was a sensitive marker of VRI (NPV 0.97, CI: 0.85-1). Systemic signs and markers of infection did not predict VRI.

Fluorescein-guided resection of cerebral metastases is associated with greater tumor resection.

BACKGROUND: Sodium fluorescein (fluorescein) crosses a disrupted blood-brain barrier similarly to gadolinium contrast in contrast-enhancing cerebral tumors. When exposed to light with 560 nm wavelength during surgery, fluorescein emits a yellow-green fluorescent light that can be visualized through an operating microscope equipped with an appropriate emission filter. The distribution of the fluorescence correlates with the contrast on a gadolinium contrast-enhanced MRI. OBJECTIVE: The objective of this single-center retrospective study was to investigate if the use of fluorescein would increase the extent of resection and to examine if fluorescein guided resection influences postoperative neurological status. METHODS: During the study period from August 2014 to August 2018, 117 patients were operated for cerebral metastases. Of these, 56 operations were guided by fluorescein and 61 by traditional white light. All patients had an early postoperative MRI within 72 h after surgery. RESULTS: The use of fluorescein increased the extent of resection in patients with cerebral metastases. The use of fluorescein was not associated with increased postoperative sequelae or neurological damage regardless of underlying primary cancer. CONCLUSION: Fluorescein is a helpful supplement in the neurosurgical treatment of cerebral metastases.

Reliability of Running Economy Measurements: Influence of Shoe Familiarisation.

The purpose was to investigate differences in reliability of running economy measurements between familiar and unfamiliar shoes. Thirty-seven runners were included who all ran in familiar and unfamiliar running shoes while running economy was measured at steady state using a treadmill. Each participant was tested on two different visits (three sessions in total), with two trials in each of the three shoe conditions completed at each visit. Coefficient of variation, standard deviation of differences, and limits of agreement of running economy were used to quantify the repeatability (within-visit variation) and reproducibility (between-visit variation). The coefficient of variation showed a marginal difference in reproducibility across shoe conditions, whereas no differences were seen in coefficient of variation, standard deviation of the differences, or limits of agreement for repeatability across shoes. All three shoe conditions showed greater repeatability than reproducibility for running economy, and enhanced repeatability at visit 3 compared to visit 2. Our results indicate that familiarisation to shoes might not be needed for reliable measurements of running economy. Based on our results, when evaluating benefits in running shoes we suggest that running economy be assessed within the same day. Further, our data suggest a beneficial effect of using multiple familiarisation sessions if small differences between shoe conditions are expected.

Non-Contact Paper Thickness and Quality Monitoring Based on Mid-Infrared Optical Coherence Tomography and THz Time Domain Spectroscopy.

In industrial paper production, online monitoring of a range of quality parameters is essential for ensuring that the performance and appearance of the final product is suitable for a given application. In this article, two optical sensing techniques are investigated for non-destructive, non-contact characterization of paper thickness, surface roughness, and production defects. The first technique is optical coherence tomography based on a mid-infrared supercontinuum laser, which can cover thicknesses from ~20-90 µm and provide information about the surface finish. Detection of subsurface voids, cuts, and oil contamination was also demonstrated. The second technique is terahertz time domain spectroscopy, which is used to measure paper thicknesses of up to 443 µm. A proof-of-concept thickness measurement in freely suspended paper was also demonstrated. These demonstrations highlight the added functionality and potential of tomographic optical sensing methods towards industrial non-contact quality monitoring.

A dispensable paralog of succinate dehydrogenase subunit C mediates standing resistance towards a subclass of SDHI fungicides in Zymoseptoria tritici.

Succinate dehydrogenase inhibitor (SDHI) fungicides are widely used for the control of a broad range of fungal diseases. This has been the most rapidly expanding fungicide group in terms of new molecules discovered and introduced for agricultural use over the past fifteen years. A particular pattern of differential sensitivity (resistance) to the stretched heterocycle amide SDHIs (SHA-SDHIs), a subclass of chemically-related SDHIs, was observed in naïve Zymoseptoria tritici populations not previously exposed to these chemicals. Subclass-specific resistance was confirmed at the enzyme level but did not correlate with the genotypes of the succinate dehydrogenase (SDH) encoding genes. Mapping and characterization of the molecular mechanisms responsible for standing SHA-SDHI resistance in natural field isolates identified a gene paralog of SDHC, termed ZtSDHC3, which encodes for an alternative C subunit of succinate dehydrogenase, named alt-SDHC. Using reverse genetics, we showed that alt-SDHC associates with the three other SDH subunits, leading to a fully functional enzyme and that a unique Qp-site residue within the alt-SDHC protein confers SHA-SDHI resistance. Enzymatic assays, computational modelling and docking simulations for the two SQR enzymes (altC-SQR, WT_SQR) enabled us to describe enzyme-inhibitor interactions at an atomistic level and to propose rational explanations for differential potency and resistance across SHA-SDHIs. European Z. tritici populations displayed a presence (20-30%) / absence polymorphism of ZtSDHC3, as well as differences in ZtSDHC3 expression levels and splicing efficiency. These polymorphisms have a strong impact on SHA-SDHI resistance phenotypes. Characterization of the ZtSDHC3 promoter in European Z. tritici populations suggests that transposon insertions are associated with the strongest resistance phenotypes. These results establish that a dispensable paralogous gene determines SHA-SDHIs fungicide resistance in natural populations of Z. tritici. This study paves the way to an increased awareness of the role of fungicidal target paralogs in resistance to fungicides and demonstrates the paramount importance of population genomics in fungicide discovery.

Venous Thromboembolism in Pediatric Cancer Patients with Central Venous Catheter-A Systematic Review and Meta-analysis.

Pediatric cancer patients hold an increased risk of venous thromboembolism (VTE) due to their cancer. Central venous catheters (CVCs) further increase the VTE risk. This systematic literature review elucidates the VTE incidence in pediatric cancer patients with CVC. MEDLINE and EMBASE were searched in August 2020 without time limits. We included studies reporting original data on patients ≤18 years with any CVC type and any cancer type, who were examined for VTE with ≥7 days follow-up. In total, 682 unique records were identified, whereof 189 studies were assessed in full text. Altogether, 25 studies were included, containing 2,318 pediatric cancer patients with CVC, of which 17% suffered VTE. Fifteen studies (n = 1,551) described CVC-related VTE and reported 11% CVC-related VTE. Concerning cancer type, 991 children suffered from acute lymphoblastic leukemia (ALL) and 616 from solid tumors. Meta-analysis revealed VTE incidence (95% confidence interval) of 21% (8-37) for ALL and 7% (0.1-17) for solid tumors. Additionally, 20% of children with tunneled or nontunneled CVC and 12% of children with implantable ports suffered VTE. In conclusion, pediatric cancer patients with CVC have substantial VTE risk. Children with ALL and CVC have higher VTE incidence than children with solid tumors and CVC. Implantable port catheter should be preferred over tunneled or nontunneled CVC to reduce VTE risk. Thrombophilia investigation does not seem relevant in pediatric cancer patients with CVC and VTE. To prevent VTE, intensified catheter care is recommended, especially in children with ALL.

Basement membrane proteins in various arterial beds from individuals with and without type 2 diabetes mellitus: a proteome study.

BACKGROUND: Basement membrane (BM) accumulation is a hallmark of micro-vessel disease in diabetes mellitus (DM). We previously reported marked upregulation of BM components in internal thoracic arteries (ITAs) from type 2 DM (T2DM) patients by mass spectrometry. Here, we first sought to determine if BM accumulation is a common feature of different arteries in T2DM, and second, to identify other effects of T2DM on the arterial proteome. METHODS: Human arterial samples collected during heart and vascular surgery from well-characterized patients and stored in the Odense Artery Biobank were analysed by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). We included ascending thoracic aortas (ATA) (n = 10 (type 2 DM, T2DM) and n = 10 (non-DM)); laser capture micro-dissected plaque- and media compartments from carotid plaques (n = 10 (T2DM) and n = 9 (non-DM)); and media- and adventitia compartments from ITAs (n = 9 (T2DM) and n = 7 (non-DM)). RESULTS: We first extended our previous finding of BM accumulation in arteries from T2DM patients, as 7 of 12 pre-defined BM proteins were significantly upregulated in bulk ATAs consisting of > 90% media. Although less pronounced, BM components tended to be upregulated in the media of ITAs from T2DM patients, but not in the neighbouring adventitia. Overall, we did not detect effects on BM proteins in carotid plaques or in the plaque-associated media. Instead, complement factors, an RNA-binding protein and fibrinogens appeared to be regulated in these tissues from T2DM patients. CONCLUSION: Our results suggest that accumulation of BM proteins is a general phenomenon in the medial layer of non-atherosclerotic arteries in patients with T2DM. Moreover, we identify additional T2DM-associated effects on the arterial proteome, which requires validation in future studies.