Search

Measuring spontaneous swallowing frequencies (SSF), coughing frequencies (CF), and the temporal relationships between swallowing and coughing in patients could provide valuable clinical insights into swallowing function, dysphagia, and the risk of pneumonia development. Medical technology with these capabilities has potential applications in hospital settings. In the management of intensive care unit (ICU) patients, monitoring SSF and CF could contribute to predictive models for successful weaning from ventilatory support, extubation, or tracheal decannulation. Furthermore, the early prediction of pneumonia in hospitalized patients or home care residents could offer additional diagnostic value over current practices. However, existing technologies for measuring SSF and CF, such as electromyography and acoustic sensors, are often complex and challenging to implement in real-world settings. Therefore, there is a need for a simple, flexible, and robust method for these measurements. The primary objective of this study was to develop a system that is both low in complexity and sufficiently flexible to allow for wide clinical applicability. To construct this model, we recruited forty healthy volunteers. Each participant was equipped with two medical-grade sensors (Movesense MD), one attached to the cricoid cartilage and the other positioned in the epigastric region. Both sensors recorded tri-axial accelerometry and gyroscopic movements. Participants were instructed to perform various conscious actions on cue, including swallowing, talking, throat clearing, and coughing. The recorded signals were then processed to create a model capable of accurately identifying conscious swallowing and coughing, while effectively discriminating against other confounding actions. Training of the algorithm resulted in a model with a sensitivity of 70% (14/20), a specificity of 71% (20/28), and a precision of 66.7% (14/21) for the detection of swallowing and, a sensitivity of 100% (20/20), a specificity of 83.3% (25/30), and a precision of 80% (20/25) for the detection of coughing. SSF, CF and the temporal relationship between swallowing and coughing are parameters that could have value as predictive tools for diagnosis and therapeutic guidance. Based on 2 tri-axial accelerometry and gyroscopic sensors, a model was developed with an acceptable sensitivity and precision for the detection of swallowing and coughing movements. Also due to simplicity and robustness of the set-up, the model is promising for further scientific research in a wide range of clinical indications. [ABSTRACT FROM AUTHOR]

The continuing emergence of immune evasive SARS-CoV-2 variants and the previous SARS-CoV-1 outbreak collectively underscore the need for broadly protective sarbecovirus vaccines. Targeting the conserved S2 subunit of SARS-CoV-2 is a particularly promising approach to elicit broad protection. Here, we describe a nanoparticle vaccine displaying multiple copies of the SARS-CoV-1 S2 subunit. This vaccine alone, or as a cocktail with a SARS-CoV-2 S2 subunit vaccine, protects female transgenic K18-hACE2 mice from challenges with Omicron subvariant XBB as well as several sarbecoviruses identified as having pandemic potential including the bat sarbecovirus WIV1, BANAL-236, and a pangolin sarbecovirus. Challenge studies in female Fc-γ receptor knockout mice reveal that antibody-based cellular effector mechanisms play a role in protection elicited by these vaccines. These results demonstrate that our S2-based vaccines provide broad protection against clade 1 sarbecoviruses and offer insight into the mechanistic basis for protection. Understanding the induced and cross reactive immunity to sarbecoviruses is an important step in rationale and widely applicable vaccine design. Here the authors use a multivalent S2 subunit vaccine and demonstrate protection in female mice against SARS-CoV-2-like and SARS-CoV-1-like coronaviruses. [ABSTRACT FROM AUTHOR]

The fabrication of arterial flow phantoms for fluid dynamics studies suitable for particle image velocimetry (PIV) techniques has presented challenges. Current 3D-printed blood flow phantoms with suitable transparency for optical PIV (laserPIV) are restricted to rigid materials far from those of arterial properties. Conversely, while soft 3D-printed phantoms demonstrate promise for sufficient acoustical transparency for ultrasound PIV (echoPIV), their optical translucency presents challenges for laserPIV applicability. This dual-modality approach leverages the high spatial resolution of laserPIV for in-vitro applications and the ability of echoPIV to quantify flow in both in-vivo and in-vitro application (also inside stents), providing a more comprehensive understanding of flow dynamics. In this study, we present a series of coated thin-walled 3D-printed compliant phantoms suitable for dual-modality PIV flow imaging (i.e., laserPIV and echoPIV) methods, overcoming current 3D-printable material limitations. Stereolithographic (SLA) 3D printing was used to fabricate pipe flow phantoms from a set of commercial soft resins (flexible and elastic) as vascular tissue surrogates. To overcome low transparency and poor surface finish of soft resins, we coated the 3D-printed flow phantoms with a soft, optically transparent, photo-activated polymeric coating. The feasibility of performing dual-modality PIV was tested in an in-vitro flow setup. Our results show that the average normalized root mean square errors obtained from comparing laserPIV and echoPIV velocity profiles against the analytical solutions were 3.2% and 5.1%, and 3.3% and 5.3% for the flexible and elastic phantoms, respectively. These results indicate that dual-modality PIV flow imaging is feasible in the 3D-printed coated phantoms, promoting its future use in fabricating clinically-relevant flow phantoms. [ABSTRACT FROM AUTHOR]

Esophageal adenocarcinoma (EAC) is an aggressive cancer characterized by a high risk of relapse post-surgery. Current follow-up methods (serum carcinoembryonic antigen detection and PET-CT) lack sensitivity and reliability, necessitating a novel approach. Analyzing cell-free DNA (cfDNA) from blood plasma emerges as a promising avenue. This study aims to evaluate the cost-effective and genome-wide cell-free reduced representation bisulfite sequencing (cfRRBS) method combined with computational deconvolution for effective disease monitoring in EAC patients. cfDNA methylation profiling with cfRRBS was performed on 162 blood plasma samples from 33 EAC cancer patients and 28 blood plasma samples from 20 healthy donors. The estimated tumor fraction for EAC patients at the time of diagnosis was significantly different from the healthy donor plasma samples (one-sided Wilcoxon rank-sum test: p-value = 0.032). Tumor fractions above 15% and focal gains/amplifications in MYC (chr8), KRAS (chr12), EGFR (chr7) and NOTCH2 (chr1) were observed in four samples of distinct patients at the time metastatic disease was detected. This study showed feasibility to estimate tumor fractions in blood plasma of EAC patients based on cfDNA methylation using cfRRBS and computational deconvolution. Nevertheless, in this study only cancer patients with evidence of metastatic disease show high tumor fractions and copy number alterations. [ABSTRACT FROM AUTHOR]

The International Staging System for multiple myeloma recently underwent a second revision (R2-ISS) to include gain/amplification of 1q21 and account for the additive prognostic significance of multiple high-risk features. The phase 3 ICARIA-MM (isatuximab–pomalidomide–dexamethasone vs. pomalidomide–dexamethasone) and IKEMA (isatuximab–carfilzomib–dexamethasone vs. carfilzomib–dexamethasone) studies provide large datasets for retrospectively validating the prognostic value of the R2-ISS in relapsed/refractory multiple myeloma. Of 609 pooled patients, 68 (11.2%) were reclassified as R2-ISS stage I, 136 (22.3%) as R2-ISS stage II, 204 (33.5%) as R2-ISS stage III, 55 (9.0%) as stage IV, and 146 (24.0%) "Not classified". Median progression-free survival was shorter among those reclassified as R2-ISS stage II (HR 1.52, 95% CI 0.979–2.358), stage III (HR 2.59, 95% CI 1.709–3.923), and stage IV (HR 3.51, 95% CI 2.124–5.784) versus stage I. Adding isatuximab led to longer progression-free survival versus doublet therapy (adjusted HR 0.544 [95% CI 0.436–0.680]), with a consistent treatment effect observed across all R2-ISS stages. This is the first study to validate the R2-ISS with novel agents, including anti-CD38 monoclonal antibodies, and to show that R2-ISS, as a prognostic scoring system, can be applied to patients with relapsed/refractory multiple myeloma. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Orofacial Orthopedics/Fortschritte der Kieferorthopadie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Purpose: Sinonasal mucosal melanoma (SNMM) is a rare malignancy, characterised by high (local) recurrence rates and poor survival. Comprehensive understanding of tumour etiology is currently lacking, which complicates adequate tumour treatment. Besides examining trends in incidence, this study aims to assess the association between clinical characteristics, treatment practices and patient outcomes, with the objective of establishing a baseline from which SNMM management can be enhanced. Methods: All newly diagnosed SNMM cases in The Netherlands between 2001 and 2021 were included using data from The Netherlands Cancer Registry (NCR). Results: A total of 320 patients were included. The annual incidence rate for the overall population was stable over the inclusion period with an annual percentage change (APC) of only − 0.01%. The 5-year overall survival (OS) and relative survival (RS) were 24.5 and 32.4%, respectively. Relative survival did not increase over time. The addition of adjuvant radiotherapy to surgery was not associated with a higher OS and RS compared to surgery alone. Conclusion: Sinonasal mucosal melanoma is a rare disease with stable incidence rates in the Netherlands between 2001 and 2021. There has been no improvement in survival over the course of the inclusion period. The study reaffirms that adjuvant radiotherapy does not seem to improve patient outcomes. Given the generally poor outcomes for SNMM patients, novel therapeutic options ought to be considered in order to improve care. [ABSTRACT FROM AUTHOR]

This study represents the first extensive residue analysis of prehistoric pottery from northern Belgium. It examines pottery use and culinary practices across the Mesolithic-Neolithic transition, from the late 6th to the early 4th millennium cal BC. Residue analyses were performed on more than 200 samples from nine archaeological sites, representing different cultural groups from this transitional phase. This includes the analysis of charred food residues encrusted on the vessel surfaces by elemental analysis-isotope ratio mass spectrometry (EA-IRMS), gas chromatography-mass spectrometry (GC-MS), stereomicroscopic analysis and Scanning Electron Microscopy (SEM), as well as the analysis of absorbed lipids by gas chromatography-combustion-isotope ratio mass spectrometry (GC-C-IRMS). This study provides the first evidence of ruminant dairy fats in Early Neolithic Limburg pottery, supporting the hypothesis that this pottery was produced and used by LBK farmers rather than hunter-gatherer populations. The first indigenous pottery of the Swifterbant culture was frequently used to process freshwater fish (often together with plant foods) and ruminant meat, although several of the studied vessels likely contained mixtures of resources which could also include porcine products. Ruminant dairy is nearly absent from this pottery. Similar results were obtained for pottery of the subsequent Michelsberg culture/Group of Spiere of the late 5th and early 4th millennium cal BC. The limited presence of ruminant dairy fats in this pottery contrasts with the findings for Middle Neolithic pottery from neighbouring regions, providing further evidence for the existence of regional variations in pottery use or culinary practices throughout prehistoric NW Europe. However, our current view of pottery use during the Mesolithic-Neolithic transition in northern Belgium might be biased by the difficulties in distinguishing between wild and domesticated ruminant adipose fats as well as in detecting plant foods through lipid residue analysis. [ABSTRACT FROM AUTHOR]

Purpose: Research on return to work (RTW) following transition-related gender-affirming care (GAC) is lacking. We aim to study the RTW outcomes and experiences of transgender and gender diverse (TGD) people during social and medical transition to understand their needs better and provide tailored support. Methods: In this convergent mixed-methods study, the questionnaires of 125 employed TGD people, who took steps in transition (social and GAC), were analyzed for personal- and work characteristics, medical work absences, RTW, support at work, and health literacy. In-depth interviews were held with twenty TGD people to explore perceived facilitators and barriers to RTW. Results: One hundred and nine participants reported an average of 38 sick days after GAC. The majority (90.2%) resumed their job at the same employer. Although TGD workers felt supported, their health literacy (55.1%) was lower compared to the general population. The qualitative data analysis revealed four major themes: (1) the need and access to information; (2) having multidisciplinary TGD allies; (3) the influence of the occupational position; (4) the precarious balance between work, life, and GAC. Especially participants with a low health literacy level experienced RTW barriers by struggling: (1) to find and/or apply information; (2) to navigate (occupational) health and insurance services. Conclusion: Our research has shown that RTW for TGD individuals is a multifaceted process, affected by personal factors, work-related elements, and the characteristics of the healthcare and social insurance system. Enhancing support for TGD people at work and their RTW requires a high need for centralized information and promoting health literacy while engaging relevant stakeholders, such as prevention services and employers. [ABSTRACT FROM AUTHOR]

Purpose: In arterial disease, the presence of two or more serial stenotic lesions is common. For mild lesions, it is difficult to predict whether their combined effect is hemodynamically significant. This study assessed the hemodynamic significance of idealized serial stenotic lesions by simulating their hemodynamic interaction in a computational flow model. Materials and Methods: Flow was simulated with SimVascular software in 34 serial lesions, using moderate (15 mL/s) and high (30 mL/s) flow rates. Combinations of one concentric and two eccentric lesions, all 50% area reduction, were designed with variations in interstenotic distance and in relative direction of eccentricity. Fluid and fluid–structure simulations were performed to quantify the combined pressure gradient. Results: At a moderate flow rate, the combined pressure gradient of two lesions ranged from 3.8 to 7.7 mmHg, which increased to a range of 12.5–24.3 mmHg for a high flow rate. Eccentricity caused an up to two-fold increase in pressure gradient relative to concentric lesions. At a high flow rate, the combined pressure gradient for serial eccentric lesions often exceeded the sum of the individual lesions. The relative direction of eccentricity altered the pressure gradient by 15–25%. The impact of flow pulsatility and wall deformability was minor. Conclusion: This flow simulation study revealed that lesion eccentricity is an adverse factor in the hemodynamic significance of isolated stenotic lesions and in serial stenotic lesions. Two 50% lesions that are individually non-significant can combine more often than thought to hemodynamic significance in hyperemic conditions. [ABSTRACT FROM AUTHOR]

Severe influenza A virus (IAV) infections can result in hyper-inflammation, lung injury and acute respiratory distress syndrome1–5 (ARDS), for which there are no effective pharmacological therapies. Necroptosis is an attractive entry point for therapeutic intervention in ARDS and related inflammatory conditions because it drives pathogenic lung inflammation and lethality during severe IAV infection6–8 and can potentially be targeted by receptor interacting protein kinase 3 (RIPK3) inhibitors. Here we show that a newly developed RIPK3 inhibitor, UH15-38, potently and selectively blocked IAV-triggered necroptosis in alveolar epithelial cells in vivo. UH15-38 ameliorated lung inflammation and prevented mortality following infection with laboratory-adapted and pandemic strains of IAV, without compromising antiviral adaptive immune responses or impeding viral clearance. UH15-38 displayed robust therapeutic efficacy even when administered late in the course of infection, suggesting that RIPK3 blockade may provide clinical benefit in patients with IAV-driven ARDS and other hyper-inflammatory pathologies.A newly developed RIPK3 inhibitor blocks necroptosis of lung cells, reduces lung inflammation and prevents mortality in a mouse model of influenza A virus infection. [ABSTRACT FROM AUTHOR]

In the context of recent demographic changes and related societal challenges, socially assistive robots (SARs) are considered having the potential to support independence and care of older adults. However, little is known about the preferred SAR-features of older adults with mild cognitive impairment (MCI) residing in assisted living and their caregivers. Semi-structured interviews were conducted with two stakeholder groups: older adults with MCI and their (in)formal caregivers. Inductive thematic analysis was used to analyse the data. Forty individual semi-structured interviews were conducted with older adults with MCI (N = 30) and (in)formal caregivers (N = 10). Data revealed seven common role-expectations regarding SARs for both the older adults and caregivers: (1) companion, (2) health assistant, (3) household assistant, (4) physical assistant, (5) cognitive assistant, (6) coach, (7) leisure buddy. One additional, eighth role was identified for the caregivers, i.e. job assistant. The results of this study provide a better knowledge of the features to consider during the development process of SARs in order to maximize the perceived usefulness and hence the intention to use and actual adoption. Additionally, a feasibility analysis showed which features should have the primary focus during the further software development of an existing SAR called James® within the ReMIND-project. [ABSTRACT FROM AUTHOR]

Intestinal goblet cells are secretory cells specialized in the production of mucins, and as such are challenged by the need for efficient protein folding. Goblet cells express Inositol-Requiring Enzyme-1β (IRE1β), a unique sensor in the unfolded protein response (UPR), which is part of an adaptive mechanism that regulates the demands of mucin production and secretion. However, how IRE1β activity is tuned to mucus folding load remains unknown. We identified the disulfide isomerase and mucin chaperone AGR2 as a goblet cell-specific protein that crucially regulates IRE1β-, but not IRE1α-mediated signaling. AGR2 binding to IRE1β disrupts IRE1β oligomerization, thereby blocking its downstream endonuclease activity. Depletion of endogenous AGR2 from goblet cells induces spontaneous IRE1β activation, suggesting that alterations in AGR2 availability in the endoplasmic reticulum set the threshold for IRE1β activation. We found that AGR2 mutants lacking their catalytic cysteine, or displaying the disease-associated mutation H117Y, were no longer able to dampen IRE1β activity. Collectively, these results demonstrate that AGR2 is a central chaperone regulating the goblet cell UPR by acting as a rheostat of IRE1β endonuclease activity. Synopsis: IRE1β is specifically expressed in mucin-secreting goblet cells of the mammalian gut. Here, the mucin chaperone AGR2 is identified as master regulator of IRE1β oligomerization and endonuclease activity. The protein disulfide isomerase AGR2 acts as a specific interactor of the unfolded protein response sensor IRE1β in colon epithelial cells. AGR2 inhibits IRE1β endonuclease activity by promoting IRE1β monomerization. The inflammatory bowel disease-associated AGR2H117Y mutant loses its repressive activity on IRE1β. AGR2 regulates IRE1β UPR sensor activity by holding it in a monomeric inactive state. [ABSTRACT FROM AUTHOR]

Background: Vincristine-induced peripheral neuropathy (VIPN) is a common adverse effect of vincristine, a drug often used in pediatric oncology. Previous studies demonstrated large inter- and intrapatient variability in vincristine pharmacokinetics (PK). Model-informed precision dosing (MIPD) can be applied to calculate patient exposure and individualize dosing using therapeutic drug monitoring (TDM) measurements. This study set out to investigate the PK/pharmacodynamic (PKPD) relationship of VIPN and determine the utility of MIPD to support clinical decisions regarding dose selection and individualization. Methods: Data from 35 pediatric patients were utilized to quantify the relationship between vincristine dose, exposure and the development of VIPN. Measurements of vincristine exposure and VIPN (Common Terminology Criteria for Adverse Events [CTCAE]) were available at baseline and for each subsequent dosing occasions (1–5). A PK and PKPD analysis was performed to assess the inter- and intraindividual variability in vincristine exposure and VIPN over time. In silico trials were performed to portray the utility of vincristine MIPD in pediatric subpopulations with a certain age, weight and cytochrome P450 (CYP) 3A5 genotype distribution. Results: A two-compartmental model with linear PK provided a good description of the vincristine exposure data. Clearance and distribution parameters were related to bodyweight through allometric scaling. A proportional odds model with Markovian elements described the incidence of Grades 0, 1 and ≥ 2 VIPN overdosing occasions. Vincristine area under the curve (AUC) was the most significant exposure metric related to the development of VIPN, where an AUC of 50 ng⋅h/mL was estimated to be related to an average VIPN probability of 40% over five dosing occasions. The incidence of Grade ≥ 2 VIPN reduced from 62.1 to 53.9% for MIPD-based dosing compared with body surface area (BSA)-based dosing in patients. Dose decreases occurred in 81.4% of patients with MIPD (vs. 86.4% for standard dosing) and dose increments were performed in 33.4% of patients (no dose increments allowed for standard dosing). Conclusions: The PK and PKPD analysis supports the use of MIPD to guide clinical dose decisions and reduce the incidence of VIPN. The current work can be used to support decisions with respect to dose selection and dose individualization in children receiving vincristine. [ABSTRACT FROM AUTHOR]

Background: In the era of individualized gastric cancer (GC) treatment, accurate determination of histological subtype becomes increasingly relevant. As yet, it is unclear whether preoperative chemotherapy may affect the histological subtype. The aim of this study was to assess concordance in histological subtype between pretreatment biopsies and surgical resection specimens before and after the introduction of perioperative treatment. Methods: Histological subtype was centrally determined in paired GC biopsies and surgical resection specimens of patients treated with either surgery alone (SA) in the Dutch D1/D2 study or with preoperative chemotherapy (CT) in the CRITICS trial. The histological subtype as determined in the resection specimen was considered the gold standard. Concordance rates and sensitivity and specificity of intestinal, diffuse, mixed, and "other" subtypes of GC were analyzed. Results: In total, 105 and 515 pairs of GC biopsies and resection specimens of patients treated in the SA and CT cohorts, respectively, were included. Overall concordance in the histological subtype was 72% in the SA and 74% in the CT cohort and substantially higher in the diffuse subtype (83% and 86%) compared to the intestinal (70% and 74%), mixed (21% and 33%) and "other" subtypes (54% and 54%). In the SA cohort, sensitivities and specificities were 0.88 and 0.71 in the intestinal, 0.67 and 0.93 in the diffuse, 0.20 and 0.98 in the mixed, and 0.50 and 0.93 in the "other" subtypes, respectively. Conclusion: Our results suggest that accurate determination of histological subtype on gastric cancer biopsies is suboptimal but that the impact of preoperative chemotherapy on histological subtype is negligible. [ABSTRACT FROM AUTHOR]

Teleost fishes, which are the largest and most diverse group of living vertebrates, have a rich history of ancient and recent polyploidy. Previous studies of allotetraploid common carp and goldfish (cyprinids) reported a dominant subgenome, which is more expressed and exhibits biased gene retention. However, the underlying mechanisms contributing to observed 'subgenome dominance' remains poorly understood. Here we report high-quality genomes of twenty-one cyprinids to investigate the origin and subsequent subgenome evolution patterns following three independent allopolyploidy events. We identify the closest extant relatives of the diploid progenitor species, investigate genetic and epigenetic differences among subgenomes, and conclude that observed subgenome dominance patterns are likely due to a combination of maternal dominance and transposable element densities in each polyploid. These findings provide an important foundation to understanding subgenome dominance patterns observed in teleost fishes, and ultimately the role of polyploidy in contributing to evolutionary innovations. Cyprinids fish species contain multiple subgenomes as a result of past duplications. Here, Xu et al. report new genomes of 21 cyprinid fish and conclude that observed subgenome dominance patterns are likely due to both maternal dominance and transposable element densities in each polyploid. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the efficacy of a novel, multi-active emollient in preventing and managing acute radiation dermatitis (ARD) in breast cancer patients undergoing moderate hypofractionated (HF) radiotherapy (RT) compared to standard of care. Methodsa: A monocentric, open-label, randomized clinical trial (RCT) with breast cancer patients receiving moderate HF (dose: 40.05–55.86 Gy, fractions: 15–21) was conducted between January 2022 and May 2023. The experimental group received the novel emollient, while the control group received the standard skin care. Patients applied the skin care products twice daily during the complete RT course. The primary outcome was the severity of ARD at the final RT session measured by the modified Radiation Therapy Oncology Group (RTOG) criteria. Secondary outcomes included patient symptoms, quality of life (QoL), and treatment satisfaction. Results: A total of 100 patients with 50 patients per group were enrolled. In the control group, 50% of the patients developed RTOG grade 1 ARD and 48% grade 2 or higher, while in the experimental group, the severity of ARD was significantly lower with 82% grade 1 and 16% grade 2 ARD (P =.013, χ2-test). The frequency and severity of xerosis were significantly lower in the experimental compared to the control group (Ps ≤.036, Mann Whiney U test). The impact of ARD on the QoL was low, and treatment satisfaction was high in both groups, with no significant difference. Conclusion: This RCT shows that the novel, multi-active emollient significantly reduced the ARD RTOG grade. Research in a more diverse patient population is warranted. Trial registration: ClinicalTrials.gov: NCT04929808 (11/06/2021). [ABSTRACT FROM AUTHOR]

Background: Magnetic resonance (MR) imaging is the modality used for baseline assessment of locally advanced rectal cancer (LARC) and restaging after neoadjuvant treatment. The overall audited quality of MR imaging in large multicentre trials on rectal cancer is so far not routinely reported. Materials and methods: We collected MR images obtained within the Rectal Cancer And Pre-operative Induction Therapy Followed by Dedicated Operation (RAPIDO) trial and performed an audit of the technical features of image acquisition. The required MR sequences and slice thickness stated in the RAPIDO protocol were used as a reference. Results: Out of 920 participants of the RAPIDO study, MR investigations of 668 and 623 patients in the baseline and restaging setting, respectively, were collected. Of these, 304/668 (45.5%) and 328/623 (52.6%) MR images, respectively, fulfilled the technical quality criteria. The main reason for non-compliance was exceeding slice thickness 238/668, 35.6% in the baseline setting and 162/623, 26.0% in the restaging setting. In 166/668, 24.9% and 168/623, 27.0% MR images in the baseline and restaging setting, respectively, one or more of the required pulse sequences were missing. Conclusion: Altogether, 49.0% of the MR images obtained within the RAPIDO trial fulfilled the image acquisition criteria required in the study protocol. High-quality MR imaging should be expected for the appropriate initial treatment and response evaluation of patients with LARC, and efforts should be made to maximise the quality of imaging in clinical trials and in clinical practice. Critical relevance statement: This audit highlights the importance of adherence to MR image acquisition criteria for rectal cancer, both in multicentre trials and in daily clinical practice. High-resolution images allow correct staging, treatment stratification and evaluation of response to neoadjuvant treatment. Key points: - Complying to MR acquisition guidelines in multicentre trials is challenging. - Neglection on MR acquisition criteria leads to poor staging and treatment. - MR acquisition guidelines should be followed in trials and clinical practice. - Researchers should consider mandatory audits prior to study initiation. [ABSTRACT FROM AUTHOR]

Background: The increasing number of physicians that are trained in point-of-care ultrasound (POCUS) warrants critical evaluation and improvement of current training methods. Performing POCUS is a complex task and it is unknown which (neuro)cognitive mechanisms are most important in competence development of this skill. This systematic review was conducted to identify determinants of POCUS competence development that can be used to optimize POCUS training. Methods: PubMed, Web of Science, Cochrane Library, Emcare, PsycINFO and ERIC databases were searched for studies measuring ultrasound (US) skills and aptitude. The papers were divided into three categories: "Relevant knowledge", "Psychomotor ability" and 'Visuospatial ability'. The 'Relevant knowledge' category was further subdivided in 'image interpretation', 'technical aspects' and 'general cognitive abilities'. Visuospatial ability was subdivided in visuospatial subcategories based on the Cattell-Horn-Carroll (CHC) Model of Intelligence v2.2, which includes visuospatial manipulation and visuospatial perception. Post-hoc, a meta-analysis was performed to calculate pooled correlations. Results: 26 papers were selected for inclusion in the review. 15 reported on relevant knowledge with a pooled coefficient of determination of 0.26. Four papers reported on psychomotor abilities, one reported a significant relationship with POCUS competence. 13 papers reported on visuospatial abilities, the pooled coefficient of determination was 0.16. Conclusion: There was a lot of heterogeneity in methods to assess possible determinants of POCUS competence and POCUS competence acquisition. This makes it difficult to draw strong conclusions on which determinants should be part of a framework to improve POCUS education. However, we identified two determinants of POCUS competence development: relevant knowledge and visuospatial ability. The content of relevant knowledge could not be retrieved in more depth. For visuospatial ability we used the CHC model as theoretical framework to analyze this skill. We could not point out psychomotor ability as a determinant of POCUS competence. [ABSTRACT FROM AUTHOR]

The world population is aging and more and more people suffer from dementia, which makes remembering and orientation in time and space difficult. Moreover dementia has a strong negative effect on the quality of living of the people suffering from it, but also of their relatives. In this paper, we investigate if and how the playback of carefully chosen and recognizable sounds, such as music, a clock tower, or nature sounds, can help these people and have a positive effect on the behavioral and psychological symptoms of dementia (BPSD). The selection and playback of these sounds, augmenting the existing soundscape, is performed in a personalized manner, since sounds can elicit a different response in different people. Caregivers can provide feedback on the soundscape based on the resident's behavior and response to hearing the sounds. This allows a continuous adaptation of the soundscape. The soundscape system was tested with 19 people suffering from dementia and resident of 6 different nursing homes. Comparison of the nursing home environment before and after installation of the soundscape system showed that most residents (13/19) experienced this as an improvement of the sound environment. [ABSTRACT FROM AUTHOR]

Isocapnic hyperventilation (ICHV) is occasionally used to maintain the end-expired CO2 partial pressure (PETCO2) when the inspired CO2 (PICO2) rises. Whether maintaining PETCO2 with ICHV during an increase of the PICO2 also maintains arterial PCO2 (PaCO2) remains poorly documented. 12 ASA PS I–II subjects undergoing a robot-assisted radical prostatectomy (RARP) (n = 11) or cystectomy (n = 1) under general endotracheal anesthesia with sevoflurane in O2/air (40% inspired O2) were enrolled. PICO2 was sequentially increased from 0 to 0.5, 1.0, 1.5 and 2% by adding CO2 to the inspiratory limb of the circle system, while increasing ventilation to a target PETCO2 of 4.7–4.9% by adjusting respiratory rate during controlled mechanical ventilation. Pa-ETCO2 gradients were determined after a 15 min equilibration period at each PICO2 level and compared using ANOVA. Mean (standard deviation) age, height, and weight were 66 (6) years, 171 (6) cm, and 75 (8) kg, respectively. Capnograms were normal and hemodynamic parameters remained stable. PETCO2 could be maintained within 4.7–4.9% in all subjects at all times except in 1 subject with 1.5% PICO2 and 5 subjects with 2.0% PICO2; data from the one subject in whom both 1.5 and 2.0% PICO2 resulted in PETCO2 > 5.1% were excluded from analysis. Pa-ETCO2 gradients did not change when PICO2 increased. The effect of a modest rise of PICO2 up to 1.5% on PETCO2 during RARP can be readily overcome by increasing ventilation without altering the Pa-ETCO2 gradients. At higher PICO2, airway pressures may become a limiting factor, which requires further study. [ABSTRACT FROM AUTHOR]

Purpose: People living with HIV (PLHIV) have reported challenges associated with daily oral antiretroviral therapy (ART), including missed doses, negative psychological impact, and difficulty remaining discreet while at home or traveling. Recently approved long-acting injectable (LAI) ART may help eliminate these concerns. The purpose of this study was to examine patient preferences and estimate health state utilities associated with oral and LAI treatment for ART. Methods: Four health state vignettes were developed based on published literature, clinician interviews, and a pilot study. All vignettes included the same description of HIV, but differed in treatment regimens: (A) single daily oral tablet, (B) two daily oral tablets, (C) injections once monthly, and (D) injections every two months. PLHIV in the UK reported their preferences and valued the health states in time trade-off utility interviews. Results: The sample included 201 PLHIV (83.1% male; mean age = 44.9y). The health states frequently selected as most preferable were D (n = 119; 59.2%) and A (n = 75; 37.3%). Utility differences among health states were relatively small, which is typical for treatment process utilities (mean utilities: A, 0.908; B, 0.905; C, 0.900; D, 0.910). Statistically significant differences in utility were found for one vs. two tablets and injections every month vs. every two months (p < 0.001). Participants' quotations highlight the wide range of reasons for treatment process preferences. Conclusions: Current results indicate that many PLHIV would prefer LAI ART. The reported utilities may be useful in economic modeling comparing oral vs. LAI ART. [ABSTRACT FROM AUTHOR]

Memsorb™ (DMF Medical, Halifax, Canada) is a novel device based upon membrane oxygenator technology designed to eliminate CO2 from exhaled gas when using a circle anesthesia circuit. Exhaled gases pass through semipermeable hollow fibers and sweep gas flowing through these fibers creates a diffusion gradient for CO2 removal. In vivo Memsorb™ performance was tested during target-controlled closed-circuit anesthesia (TCCCA) with desflurane in O2/air using a Zeus IE® anesthesia workstation (Dräger, Lübeck, Germany). Clinical care protocols for using this novel device were guided by in vitro performance results from a prior study (submitted simultaneously). After IRB approval, written informed consent was obtained from 10 ASA PS I–III patients undergoing robot-assisted radical prostatectomy. TCCCA targets were 39% inspired O2 concentration (FIO2) and 5.0% end-expired desflurane concentration (FETdes). Minute ventilation (MV) was adjusted to maintain 4.5–6.0% FETCO2. The O2/air (40% O2) sweep flow into the Memsorb™ was manually adjusted in an attempt to keep inspired CO2 concentration (FICO2) ≤ 0.8%. The following data were collected: FIO2, FETdes, FICO2, FETCO2, MV, fresh gas flow (FGF, O2 and air), sweep flow, and cumulative desflurane usage (Vdes). Vdes of the Zeus IE®—Memsorb™ combination was compared with historical Vdes observed in a previous study when soda lime (DrägerSorb 800 +) was used. Results are reported as median and inter-quartiles. A combination of manually adjusting sweep flow (26 [21,27] L/min) and MV sufficed to maintain FICO2 ≤ 0.8% and FETCO2 ≤ 6.0%, except in one patient in whom the target Zeus IE® FGF had to be increased to 0.7 L/min for 6 min. FIO2 and FETdes were maintained close to their targets. Zeus IE® FGF after 5 min was 0 [0,0] mL/min. Average Vdes after 50 min was higher with Memsorb™ (20.3 mL) compared to historical soda lime canister data (12.3 mL). During target-controlled closed-circuit anesthesia in patients undergoing robot-assisted radical prostatectomy, the Memsorb™ maintained FICO2 ≤ 0.8% and FETCO2 ≤ 6.0%, and FIO2 remained close to target. Modest amounts of desflurane were lost with the use of the Memsorb™. The need for adjustments of sweep flow, minute ventilation, and occasionally Zeus IE® FGF indicates that the Memsorb™ system should preferentially be integrated into an automated closed-loop system. [ABSTRACT FROM AUTHOR]

Soda lime-based CO2 absorbents are safe, but not ideal for reasons of ecology, economy, and dust formation. The Memsorb™ is a novel CO2 removal device that uses cardiopulmonary bypass oxygenator technology instead: a sweep gas passes through semipermeable hollow fibers, adding or removing gas from the circle breathing system. We studied the in vitro performance of a prototype Memsorb™ used with a Zeus IE® anesthesia machine when administering sevoflurane and desflurane in O2/air mixtures. The Zeus IE® equipped with Memsorb™ ventilated a 2L breathing bag with a CO2 inflow port in its tip. CO2 kinetics were studied by using different combinations of CO2 inflow (VCO2), Memsorb™ sweep gas flow, and Zeus IE® fresh gas flow (FGF) and ventilator settings. More specifically, it was determined under what circumstances the inspired CO2 concentration (FICO2) could be kept < 0.5%. O2 kinetics were studied by measuring the inspired O2 concentration (FIO2) resulting from different combinations of Memsorb™ sweep gas flow and O2 concentrations, and Zeus IE® FGFs and O2 concentrations. Memsorb™'s sevoflurane and desflurane waste was determined by measuring their injection rates during target-controlled closed-circuit anesthesia (TCCCA), and were compared to historical controls when using a soda lime absorbent (Draegersorb 800+) under identical conditions. With 160 mL/min VCO2 and 5 L/min minute ventilation (MV), lowering the sweep gas flow at any fixed Zeus IE® FGF increased FICO2 in a non-linear manner. Sweep gas flow adjustments kept FICO2 < 0.5% over the entire Zeus IE® FGF range tested with VCO2 up to 280 mL/min; tidal volume and respiratory rate affected the required sweep gas flow. At 10 L/min MV and low FGF (< 1.5 L/min), even a maximum sweep flow of 43 L/min was unable to keep FICO2 ≤ 0.5%. When the O2 concentration in the Zeus IE® FGF and the Memsorb™ sweep gas flow differed, FIO2 drifted towards the sweep gas O2 concentration, and more so as FGF was lowered; this effect was absent once FGF > minute ventilation. During sevoflurane and desflurane TCCCA, the Zeus IE® FGF remained zero while agent usage per % end-expired agent increased with increasing end-expired target agent concentrations and with a higher target FIO2. Agent waste during target-controlled delivery was higher with Memsorb™ than with the soda lime product, with the difference remaining almost constant over the FGF range studied. With a 5 L/min MV, Memsorb™ successfully removes CO2 with inflow rates up to 240 mL/min if an FICO2 of 0.5% is accepted, but at 10 L/min MV and low FGF (< 1.5 L/min), even a maximum sweep flow of 43 L/min was unable to keep FICO2 ≤ 0.5%. To avoid FIO2 deviating substantially from the O2 concentration in the fresh gas, the O2 concentration in the fresh gas and sweep gas should match. Compared to the use of Ca(OH)2 based CO2 absorbent, inhaled agent waste is increased. The device is most likely to find its use integrated in closed loop systems. [ABSTRACT FROM AUTHOR]

Both ecological and economic considerations dictate minimising wastage of volatile anaesthetics. To reconcile apparent opposing stakes between ecological/economical concerns and stability of anaesthetic delivery, new workstations feature automated software that continually optimizes the FGF to reliably obtain the requested gas mixture with minimal volatile anaesthetic waste. The aim of this study is to analyse the kinetics and consumption pattern of different approaches of sevoflurane delivery with the same 2% end-tidal goal in all patients. The consumption patterns of sevoflurane of a Flow-i were retrospectively studied in cases with a target end-tidal sevoflurane concentration (Etsevo) of 2%. For each setting, 25 cases were included in the analysis. In Automatic Gas Control (AGC) regulation with software version V4.04, a speed setting 6 was observed; in AGC software version V4.07, speed settings 2, 4, 6 and 8 were observed, as well as a group where a minimal FGF was manually pursued and a group with a fixed 2 L/min FGF. In 45 min, an average of 14.5 mL was consumed in the 2L-FGF group, 5.0 mL in the minimal-manual group, 7.1 mL in the AGC4.04 group and 6.3 mL in the AGC4.07 group. Faster speed AGC-settings resulted in higher consumption, from 6.0 mL in speed 2 to 7.3 mL in speed 8. The Etsevo target was acquired fastest in the 2L-FGF group and the Etsevo was more stable in the AGC groups and the 2L-FGF groups. In all AGC groups, the consumption in the first 8 min was significantly higher than in the minimal flow group, but then decreased to a comparable rate. The more recent AGC4.07 algorithm was more efficient than the older AGC4.04 algorithm. This study indicates that the AGC technology permits very significant economic and ecological benefits, combined with excellent stability and convenience, over conventional FGF settings and should be favoured. While manually regulated minimal flow is still slightly more economical compared to the automated algorithm, this comes with a cost of lower precision of the Etsevo. Further optimization of the AGC algorithms, particularly in the early wash-in period seems feasible. In AGC mode, lower speed settings result in significantly lower consumption of sevoflurane. Routine clinical practice using what historically is called "low flow anaesthesia" (e.g. 2 L/min FGF) should be abandoned, and all anaesthesia machines should be upgraded as soon as possible with automatic delivery technology to minimize atmospheric pollution with volatile anaesthetics. [ABSTRACT FROM AUTHOR]

Background: Clinical practice recommendations for the management of acute appendicitis in pregnancy are lacking. Objective: To develop an evidence-informed, trustworthy guideline on the management of appendicitis in pregnancy. We aimed to address the questions of conservative or surgical management, and laparoscopic or open surgery for acute appendicitis. Methods: We performed a systematic review, meta-analysis, and evidence appraisal using the GRADE methodology. A European, multidisciplinary panel of surgeons, obstetricians/gynecologists, a midwife, and 3 patient representatives reached consensus through an evidence-to-decision framework and a Delphi process to formulate the recommendations. The project was developed in an online authoring and publication platform (MAGICapp). Results: Research evidence was of very low certainty. We recommend operative treatment over conservative management in pregnant patients with complicated appendicitis or appendicolith on imaging studies (strong recommendation). We suggest operative treatment over conservative management in pregnant patients with uncomplicated appendicitis and no appendicolith on imaging studies (weak recommendation). We suggest laparoscopic appendectomy in patients with acute appendicitis until the 20th week of gestation, or when the fundus of the uterus is below the level of the umbilicus; and laparoscopic or open appendectomy in patients with acute appendicitis beyond the 20th week of gestation, or when the fundus of the uterus is above the level of the umbilicus, depending on the preference and expertise of the surgeon. Conclusion: Through a structured, evidence-informed approach, an interdisciplinary panel provides a strong recommendation to perform appendectomy for complicated appendicitis or appendicolith, and laparoscopic or open appendectomy beyond the 20th week, based on the surgeon's preference and expertise. Guideline registration number: IPGRP-2022CN210. [ABSTRACT FROM AUTHOR]

Purpose: Evaluation of the impact of catheter ablation for ventricular extrasystoles (VES) in structurally normal hearts on quality of life (QOL) and symptomatology. Methods: Symptom analysis assessed with a disease-specific questionnaire, EHRA score for AF, and QOL analysis at baseline and 1 year after ablation. Results: The study enrolled 39 patients between April 2016 and November 2019. Two patients were excluded from further analysis. At baseline, palpitations were reported in 31/37 (84%); syncope in 12/37 (32%); other cardiac symptoms in 33/37 (89%) of patients. The EHRA score was 3 or 4 in 13 patients (35%). With the modified arrhythmia-specific questionnaire (MASQ) psychological and physical scores were 46 and 39%. The overall perception of health in the SF-36 was 56 ± 16%. Ablation was performed in 35/37 (95%). At regular follow-up, symptoms were reported in 14/37 (38%) patients. ECG suggested a good procedural outcome in 65% with VES burden on Holter < 1% in 68%. At follow-up, palpitations were reported in 61% (P < 0.07); syncope in only 1 patient (P < 0.05). The EHRA score was 3 or 4 in only one patient (P < 0.05). MASQ scores improved to 62 and 60% (both p < 0.001). The overall perception of health in the SF-36 became 64 ± 17% (P < 0.02). Conclusions: Patients with VES suffer from a wide variety of symptoms and have a low quality of life, as demonstrated by the EHRA score and conventional questionnaires. After catheter ablation, palpitations are still reported, but become less frequently present. Syncope becomes rare. Quality of life improves significantly from all perspectives. [ABSTRACT FROM AUTHOR]

Participation has become an important measure of outcome in child rehabilitation as young children with developmental disabilities are increasingly at risk of decreased participation. Therefore, this study garnered information on clinicians' perspectives regarding perceived facilitators and barriers when rendering participation-based interventions using a qualitative research design. Semi-structured interviews of clinicians (Ns = 12, 25–57 years) were conducted and evaluated via an inductive thematic analysis. Results denote that current mechanisms of providing participation-based interventions resembled traditionally focused interventions; thus, resulting in a knowledge-to-practice gap. Clinicians desired more opportunities to communicate with caregivers and to be able to influence the children' s natural environments. They also identified shortness of time, resources, and rigid health care regulations as barriers hampering the efficacy of participation-based services. [ABSTRACT FROM AUTHOR]

Background: Vincristine, a chemotherapeutic agent that extensively binds to β-tubulin, is commonly dosed at 1.4–2.0 mg/m2 capped at 2 mg. For infants, doses vary from 0.025–0.05 mg/kg or 50–80% of the mg/m2 dose. However, evidence for lower doses in infants compared to older children is lacking. This study was conducted to unravel the complex pharmacokinetics of vincristine, including the effects of age, to assist optimal dosing in this population. Methods: 206 patients (0.04–33.9 years; 25 patients < 1 years), receiving vincristine, with 1297 plasma concentrations were included. Semi-mechanistic population pharmacokinetic analyses were performed using non-linear mixed effects modelling. Results: A three-compartment model, with one saturable compartment resembling saturable binding to β-tubulin and thus, saturable distribution, best described vincristine pharmacokinetics. Body weight and age were covariates significantly influencing the maximal binding capacity to β-tubulin, which increased with increasing body weight and decreased with increasing age. Vincristine clearance (CL) was estimated as 30.6 L/h (95% confidence interval (CI) 27.6–33.0), intercompartmental CL (Q) as 63.2 L/h (95%CI 57.2–70.1), volume of distribution of the central compartment as 5.39 L (95%CI 4.23–6.46) and of the peripheral compartment as 400 L (95%CI 357–463) (all parameters correspond to a patient of 70 kg). The maximal binding capacity was 0.525 mg (95%CI 0.479–0.602) (for an 18 year old patient of 70 kg), with a high association rate constant, fixed at 1300 /h and a dissociation constant of 11.5 /h. Interpretation: A decrease of vincristine β-tubulin binding capacity with increasing age suggests that young children tolerate higher doses of vincristine. [ABSTRACT FROM AUTHOR]

In relapsed and refractory multiple myeloma (RRMM), there are few treatment options once patients progress from the established standard of care. Several bispecific T-cell engagers (TCE) are in clinical development for multiple myeloma (MM), designed to promote T-cell activation and tumor killing by binding a T-cell receptor and a myeloma target. In this study we employ both computational and experimental tools to investigate how a novel trispecific TCE improves activation, proliferation, and cytolytic activity of T-cells against MM cells. In addition to binding CD3 on T-cells and CD38 on tumor cells, the trispecific binds CD28, which serves as both co-stimulation for T-cell activation and an additional tumor target. We have established a robust rule-based quantitative systems pharmacology (QSP) model trained against T-cell activation, cytotoxicity, and cytokine data, and used it to gain insight into the complex dose response of this drug. We predict that CD3-CD28-CD38 killing capacity increases rapidly in low dose levels, and with higher doses, killing plateaus rather than following the bell-shaped curve typical of bispecific TCEs. We further predict that dose–response curves are driven by the ability of tumor cells to form synapses with activated T-cells. When competition between cells limits tumor engagement with active T-cells, response to therapy may be diminished. We finally suggest a metric related to drug efficacy in our analysis—"effective" receptor occupancy, or the proportion of receptors engaged in synapses. Overall, this study predicts that the CD28 arm on the trispecific antibody improves efficacy, and identifies metrics to inform potency of novel TCEs. [ABSTRACT FROM AUTHOR]

Recent research on normal human tissues identified omnipresent clones of cells, driven by somatic mutations known to be responsible for carcinogenesis (e.g., in TP53 or NOTCH1). These new insights are fundamentally changing current tumor evolution models, with broad oncological implications. Most studies are based on surgical remnant tissues, which are not available for many organs and rarely in a pan-organ setting (multiple organs from the same individual). Here, we describe an approach based on clinically annotated post-mortem tissues, derived from whole-body donors that are routinely used for educational purposes at human anatomy units. We validated this post-mortem approach using UV-exposed and unexposed epidermal skin tissues and confirm the presence of positively selected NOTCH1/2-, TP53- and FAT1-driven clones. No selection signals were detected in a set of immune genes or housekeeping genes. Additionally, we provide the first evidence for smoking-induced clonal changes in oral epithelia, likely underlying the origin of head and neck carcinogenesis. In conclusion, the whole-body donor-based approach provides a nearly unlimited healthy tissue resource to study mutational clonality and gain fundamental mutagenic insights in the presumed earliest stages of tumor evolution. [ABSTRACT FROM AUTHOR]

The beginning of the Phanerozoic was marked by abundant phytoplankton, the occurrence of animals and a newly established ecosystem structure, which in turn, resulted in different modes of organic matter (OM) cycling and preservation. In this study, we present an integrated paleontological and geochemical study of the Lower Cambrian Yanjiahe and Shuijingtuo formations in the Three Gorges area, South China. Rock samples were analyzed for major and trace elements, in order to evaluate the marine productivity. Fossil samples were recovered using palynological methods, destructive analytical techniques, SEM analysis and thin section microscopy. The organic-walled microfossils in the investigated sections include marine microphytoplankton, linings of sponge spicules, small shelly fossils and some unnamed sheet-like and net-like microfossils (animal parts). Additionally, fecal structures and coprolites fossils were found. Three intervals in the Luojiacun Section were proposed to discuss the links among microfossil assemblages and their influence on OM cycling and preservation. We found that the marine microphytoplankton was the main source of OM in the investigated sections. The appearance of fecal structures groups and massive appearance of animals in the pelagic zone indicate a higher transfer efficiency of OM aggregates through the water column. Oxygenated conditions in the water-column would have led to a moderate to low preservation of OM, an effect which would have been further enhanced by the potential presence of bioturbators. Overall, our study reveals the contribution of various organisms to the sedimentary OM and highlights the links and feedbacks among microfossil assemblages, OM recycling efficiency and OM preservation in the tipping point of the Phanerozoic "new world". [ABSTRACT FROM AUTHOR]

Purpose: The feasibility of using a compressed interwoven Supera stent as a flow diverting device for popliteal aneurysms was recently demonstrated in patients. It is unclear, however, what the optimal flow diverting strategy is, because of the fusiform shape of popliteal aneurysms and their exposure to triphasic flow. To assess this flow diverting strategy for popliteal aneurysms, flow profiles and thrombus formation likelihood were investigated in popliteal aneurysm models. Materials and Methods: Six popliteal aneurysm models were created and integrated into a pulsatile flow set-up. These models covered a bent and a straight anatomy in three configurations: control, single-lined and dual-lined Supera stents. Two-dimensional flow velocities were visualized by laser particle image velocimetry. In addition, the efficacy of the stent configurations for promoting aneurysm thrombosis was assessed by simulations of residence time and platelet activation. Results: On average for the two anatomies, the Supera stent led to a twofold reduction of velocities in the aneurysm for single-lined stents, and a fourfold reduction for dual-lined stents. Forward flow was optimally diverted, whereas backward flow was generally deflected into the aneurysm. The dual-lined configuration led to residence times of 15–20 s, compared to 5–15 s for the single stent configurations. Platelet activation potential was not increased by the flow diverting stents. Conclusion: A compressed Supera stent was successfully able to divert flow in a popliteal aneurysm phantom. A dual-lined configuration demonstrated superior hemodynamic characteristics compared to its single-lined counterpart. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to investigate if non-invasive central pressure estimations are accurate in patients with an abdominal aortic aneurysm, before and after endovascular repair. Secondary evaluation was if measurement-accuracy was dependent on anatomical characteristics. Methods: Procedural invasive and non-invasive pressure-measurements were performed simultaneously both before and after endovascular repair in 20 patients with an infrarenal abdominal aortic aneurysm. Invasive catheter measurements were performed in the abdominal aorta. A tonometric device was used to perform non-invasive pressure–wave-analysis at the radial artery. A generalized transfer-function was used to generate an ascending aortic waveform for both measurements, allowing for direct comparison. Results: Pre-treatment the mean differences between methods were − 5.5 mmHg (p =.904), − 11.8 (p <.001), and − 7.2 mmHg (p =.124) for central systolic, diastolic, and mean pressure, respectively. The accuracy was dependent of aneurysm sac volume and intraluminal thrombus volume. Post-treatment limits of agreement were smaller for all pressure parameters compared to pre-treatment. The mean differences were 6.5 mmHg (p =.007), − 6.4 (p <.020), and 1.6 mmHg (p =.370) for central systolic, diastolic, and mean pressure, respectively. Conclusion: In untreated AAA's the accuracy of non-invasive central pressure estimation was acceptable (mean difference between 5 and 10 mmHg) when compared to invasive pressures, but dependent of AAA characteristics. After EVAR the accuracy of central pressure estimation improved (reduction of 75% of the mean difference between pre and post measurements) Trial Registration Number: NCT03469388; 3-5-2018. [ABSTRACT FROM AUTHOR]

Introduction: Nipple-sparing mastectomy (NSM) with immediate breast reconstruction (IBR) is increasingly used for both breast cancer (TNSM) and risk reduction (RRNSM). The aim of the study is to report the results of the INSPIRE registry assessing health-related quality of life (HRQoL) comparing baseline and 1-year follow-up, regarding surgical indications and chemotherapy (CT) received. Methods: INSPIRE is a prospective database including women undergoing NSM and IBR from 18 countries. HRQoL was measured using EORTC QLQC30 and QLQ-BR23 before surgery and after 1 year. Results: A total of 677 women were included, of whom 537 (79.3%) underwent TNSM and 140 (21.6%) RRNSM: in total, 806 NSM (556 TNSM and 250 RRNSM). Nipple involvement was present in 7.73% of TNSM and incidental carcinoma in 1.2% of the RRNSM group. Out of the overall 537 patients with systemic treatment, 177 (32.96%) received neoadjuvant chemotherapy (NCT) and 118 (21.92%) adjuvant chemotherapy (CT). A total of 227 patients (28.16%) developed at least one complication postoperatively, 164 (29.5%) in the TNSM group and 63 (25.2%) in the RRNSM group. The TNSM group improved in global health status and emotional functioning after 1 year. No differences were found when comparing HRQoL at 1 year between patients who received NCT and those who received adjuvant CT. The RRNSM group showed improvement in HRQoL, with better emotional functioning and fatigue after 1 year. Conclusions: This registry reports HRQoL findings after NSM. The impact of CT on worse HRQoL is independent from its timing. Patients with RRNSM showed an improved HRQoL at 1-year follow-up. Discussion of HRQoL outcomes with patients will facilitate the informed decision-making when considering NSM. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the prognostic value of tumor markers in a European cohort of patients with resectable gastric cancer. Methods: We performed a post hoc analysis of the CRITICS trial, in which 788 patients received perioperative therapy. Association between survival and pretreatment CEA, CA 19-9, alkaline phosphatase, neutrophils, hemoglobin and lactate dehydrogenase were explored in uni- and multivariable Cox regression analyses. Likelihoods to receive potentially curative surgery were investigated for patients without elevated tumor markers versus one of the tumor markers elevated versus both tumor markers elevated. The association between tumor markers and the presence of circulating tumor DNA (ctDNA) was explored in 50 patients with available ctDNA data. Results: In multivariable analysis, in which we corrected for allocated treatment and other baseline characteristics, elevated pretreatment CEA (HR 1.43; 95% CI 1.11–1.85, p < 0.001) and CA 19-9 (HR 1.79; 95% CI 1.42–2.25, p < 0.001) were associated with worse OS. Likelihoods to receive potentially curative surgery were 86%, 77% and 60% for patients without elevated tumor marker versus either elevated CEA or CA 19-9 versus both elevated, respectively (p < 0.001). Although both preoperative presence of ctDNA and tumor markers were prognostic for survival, no association was found between these two parameters. Conclusion: CEA and CA 19-9 were independent prognostic factors for survival in a large cohort of European patients with resectable gastric cancer. No relationship was found between tumor markers and ctDNA. These factors could potentially guide treatment choices and should be included in future trials to determine their definitive position. Trial registration: ClinicalTrial.gov identifier: NCT00407186. EudraCT number: 2006-00413032. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to analyze the stoma-related reinterventions, complications and readmissions after an anterior resection for rectal cancer, based on a cross-sectional nationwide cohort study with 3-year follow-up. Methods: Rectal cancer patients who underwent a resection with either a functional anastomosis, a defunctioned anastomosis, or Hartmann's procedure (HP) with an end colostomy in 2011 in 71 Dutch hospitals were included. The primary outcome was number of stoma-related reinterventions. Results: Of the 2095 patients with rectal cancer, 1400 patients received an anterior resection and were included in this study; 257 received an initially functional anastomosis, 741 a defunctioned anastomosis, and 402 patients a HP. Of the 1400 included patients, 62% were males, 38% were females and the mean age was 67 years (SD 11.1). Following a primary functional anastomosis, 48 (19%) patients received a secondary stoma. Stoma-related complications occurred in six (2%) patients, requiring reintervention in one (0.4%) case. In the defunctioned anastomosis group, stoma-related complications were present in 92 (12%) patients, and required reintervention in 23 (3%) patients, in 10 (1%) of these more than 1 year after initial resection. Stoma-related complications occurred in 92 (23%) patients after a HP, and required reintervention in 39 (10%) patients in 17 (4%) of cases more than 1 year after initial resection. The permanent stoma rate was 11% and 20%, in the functional anastomosis and the defuctioned anastomosis group, respectively. The end colostomy in the HP group was reversed in 4% of cases. Conclusions: Construction of a stoma after resection for rectal cancer with preservation of the sphincter is accompanied with long-term stoma-related morbidity. Stoma complications are more frequent after a HP. Even after 1 year, a significant number of reinterventions are required. [ABSTRACT FROM AUTHOR]

Introduction: Pretreatment enlarged lateral lymph nodes (LLN) in patients with locally advanced low rectal cancer are predictive for local recurrences after neoadjuvant (chemo)radiotherapy (n(C)RT) followed by total mesorectal excision (TME). Not much is known of the impact on oncological outcomes when in addition malignant features are present in enlarged LLN. Patients and Methods: A multicenter retrospective cohort study was conducted at five tertiary referral centers in the Netherlands and Australia. All patients were diagnosed with locally advanced low rectal cancer with LLN on pretreatment magnetic resonance imaging (MRI) and underwent n(C)RT followed by TME. LLN were considered enlarged with a short axis of ≥ 5 mm. Malignant features were defined as nodes with internal heterogeneity and/or border irregularity. Outcomes of interest were local recurrence-free survival (LRFS), distant metastatic-free survival (DMFS), and overall survival (OS). Results: Out of 115 patients, the majority was male (75%) and the median age was 64 years (range 26–85 years). Median pretreatment LLN short axis was 7 mm (range 5–28 mm), and 60 patients (52%) had malignant features. After a median follow-up of 47 months, patients with larger LLN (7 + mm) had a worse LRFS (p = 0.01) but no difference in DMFS (p = 0.37) and OS (p = 0.54) compared with patients with smaller LLN (5–6 mm). LLN patients with malignant features had no difference in LRFS (p = 0.20) but worse DMFS (p = 0.004) and OS (p = 0.006) compared with patients without malignant features in the LLN. Cox regression analysis identified LLN short axis as an independent factor for LR. Malignant features in LLN were an independent factor for DMFS. Conclusion: The current study suggests that pretreatment enlarged LLN that also harbor malignant features are predictive of a worse DMFS. More studies will be required to further explore the role of malignant features in LLN. [ABSTRACT FROM AUTHOR]

Obesity is a major risk factor for the development of type II diabetes. Increases in adipose tissue mass trigger insulin resistance via the release of pro-inflammatory cytokines from adipocytes and macrophages. CREB and the CRTC coactivators have been found to promote insulin resistance in obesity, although the mechanism is unclear. Here we show that high fat diet feeding activates the CREB/CRTC pathway in adipocytes by decreasing the expression of SIK2, a Ser/Thr kinase that phosphorylates and inhibits CRTCs. SIK2 levels are regulated by the adipogenic factor C/EBPα, whose expression is reduced in obesity. Exposure to PPARγ agonist rescues C/EBPα expression and restores SIK2 levels. CRTC2/3 promote insulin resistance via induction of the chemokines CXCL1/2. Knockout of CRTC2/3 in adipocytes reduces CXCL1/2 expression and improves insulin sensitivity. As administration of CXCL1/2 reverses salutary effects of CRTC2/3 depletion, our results demonstrate the importance of the CREB/CRTC pathway in modulating adipose tissue function. Yoon et al show that a high fat diet in mice activates the CREB/CRTC pathway in adipocytes by decreasing the expression of Salt Inducible Kinase 2 (SIK2), a Ser/Thr kinase that otherwise phosphorylates and sequesters CREB coactivators in the cytoplasm. Their data demonstrates the importance of the CREB/CRTC pathway in mediating effects of obesity on adipocyte function. [ABSTRACT FROM AUTHOR]

Purpose The Work Rehabilitation Questionnaire (WORQ) was developed to evaluate work functioning in vocational rehabilitation, but was not yet available in Dutch. The goal of this study is twofold: a description of the cross-cultural adaptation process (part 1) of the WORQ to be used in Flanders (The Dutch speaking part of Belgium, WORQ-VL) and a presentation of the first psychometric testing of the WORQ-VL (part 2). Methods For part 1, the guidelines for cross-cultural adaptation of self-report measures by Beaton et al. were used to structure the cross-cultural adaptation. For part 2, a cross-sectional study was conducted in patients with musculoskeletal disorders [sample A: hand and wrist rehabilitation (n = 21) and sample B: fibromyalgia patients (n = 93)] who completed the WORQ-VL. Internal consistency and factor structure were examined in the total sample, whereas convergent and discriminant validity of the WORQ-VL were researched in sample A. Results First results on the convergent validity and discriminant validity (small sample size) and internal consistency of the WORQ-VL are promising. The exploratory factor analysis revealed seven factors which were labeled as 'cognition', 'physical', 'mood', 'activities of daily living', 'sensory', 'emotional' and 'social'. The best evidence was found for the 'physical' subscale of the WORQ-VL: strong correlations were found with the 'physical functioning' and 'role limitations—physical' subscales of the Short-Form Health Survey, respectively r = −.84 and r = −.59, p <.01. As expected, predominantly weak correlations were found with hand grip strength, kinesiophobia, hand-related aesthetics and satisfaction (ranging between r = −.38 and r =.34, p >.05). Conclusions The WORQ-VL is a user-friendly and valuable ICF-based self-report questionnaire to evaluate work functioning. Future studies are highly needed to examine the value of the WORQ within different patient populations and settings in order to examine further the added value of this self-report measure. [ABSTRACT FROM AUTHOR]

The present paper derives best practices to accurately simulate the installation process of a Blind Rivet Nut (BRN) using FEA. A BRN is a mechanical fastener used to equip plate material with a threaded part. The installation of a BRN inherently induces a high contact force which can have detrimental consequences when applied to non-metals such as polymer composite materials. The effects of the localized stress in the plate on the mechanical performance of the BRN can be studied with the aid of finite element simulations. To this end, the joining by forming process itself is accurately simulated using a computational efficient axisymmetric 2D model. The 2D model enables to predict the metal flow and internal state of stress after setting with sufficient accuracy. The latter is validated using a full 3D model and a multitude of experimental observations. It is shown that the large strain flow curve of the BRN material needs to be adequately identified. An industrially relevant calibration procedure is presented mitigating the experimental effort. In addition, material test selection in case of highly anisotropic BRN materials is discussed based on a thorough stress state analysis. Finally, the sensitivity of the BRN geometry to a change in the most relevant geometrical parameters is demonstrated. The presented experimental methods and numerical models provide fundamental insights in the forming mechanism including process-induced ductile damage while installing the BRN. The latter will foster the development of new BRN applications in multi-material mechanical design. [ABSTRACT FROM AUTHOR]

Background: There is no consensus on the use of neoadjuvant radiotherapy for tumors of the upper third of the rectum. Due to conflicting findings in high-quality trials and significant long-term side effects associated with neoadjuvant radiotherapy, the benefit of neoadjuvant radiotherapy for upper third rectal tumors is less certain than for lower two third rectal tumors. This metaanalysis compares oncological outcomes with neoadjuvant radiotherapy and surgery versus surgery alone for upper third rectal tumors. Patients and Methods: PubMed, Embase, and the Cochrane library databases were searched. Randomized controlled trials (RCT) comparing neoadjuvant radiotherapy and surgery versus surgery alone for resectable rectal cancer were included. Individual patient data were sought from the principal investigator of each eligible trial for comparative data on patients with upper third rectal tumors. The main outcomes measured were survival outcomes, oncological outcomes, postoperative morbidity, and late toxicity. Results: Individual patient data from two RCTs examining outcomes in 758 patients were obtained. Published data from one further RCT containing comparable data on upper third rectal tumors were included in analysis of local recurrence. In patients with curative surgery, there was no significant reduction in local recurrence or significant improvement in overall survival or disease-free survival with neoadjuvant radiotherapy (LR RR: 0.38, 95% CI 0.14–1.04, p = 0.06) (OS RR: 1.10, 95% CI 0.98–1.24, p = 0.11) (DFS RR: 1.11, 95% CI 0.97–1.26, p = 0.13). Conclusions: The benefit of neoadjuvant radiotherapy for upper third rectal tumors is not certain, and surgery alone for patients with potentially curative disease at preoperative staging may be sufficient. [ABSTRACT FROM AUTHOR]

The post-harvest processing of strawberries generates considerable amounts of by-products that consist of the inedible parts of the fruit (sepal, calyx, stem, and non-marketable portion of the fruit), which is an environmental problem for local producers and industries. This study aimed to revalue these kinds of tissues through identifying and quantifying the genotype influence on the total phenolic content, phenolic profile, and the antioxidant activity of the by-products from three strawberry cultivars: 'Festival' (FE), 'San Andreas ' (SA), and 'Camino Real' (CR). The total phenolic content was determined by the Folin–Ciocalteu method, in-vitro antioxidant activity by the DPPH* radical scavenging method and the phenolic profile by PAD–HPLC. The different genotypes showed significant differences (p < 0.05) in total phenolic content (TPC), FE being the one with the highest TPC (14.97 g of gallic acid equivalents < GAE > /Kg of by-product < R >), followed by SA and CR cultivars. The antioxidant capacity of the SA and FE tissues were similar (p > 0.05) and higher (15.1–16.3 mmol Trolox equivalents < TE > /Kg R) than CR. Eight main phenolic compounds were identified and quantified on the three cultivars. Agrimoniin was the principal polyphenol (0.38–1.56 g/Kg R), and the cultivar FE had the highest concentration. This compound showed the highest correlation coefficient with the antioxidant capacity (R2 0.87; p < 0.001). This study highlighted the impact of the multi-cultivar systems in strawberry production on the bioactive potential and the diversity of secondary metabolites obtained from strawberry agro-industrial by-products at a low cost. [ABSTRACT FROM AUTHOR]