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•Largest and most diverse genetic study of plasma fibrinogen identifies 54 regions (18 novel), housing 69 distinct variants (20 novel).•Links to (1) liver enzyme, blood cell, and lipid genetic signals, (2) liver regulatory elements, and (3) thrombotic and inflammatory disease.

Contamination with tropane alkaloids in cereals is expected to increase globally. However, current identification tools (e.g., liquid chromatography–mass spectrometry) for tropane alkaloids are time-consuming and expensive. Furthermore, their miniaturized alternatives lack sensitivity and robustness. Therefore, there is a pressing need for inexpensive and effective screening methods. Here, an on-site applicable modular workflow for tropane alkaloid detection in buckwheat is presented. The modular workflow combines paper microfluidics and interconnectable 3D-printed sample preparation tools and was evaluated for different tropane alkaloids, including atropine and scopolamine. Furthermore, integration with an indirect competitive lateral flow immunoassay (icLFIA) for atropine detection at relevant levels was demonstrated. In the modular workflow, to minimize matrix coextraction, tropane alkaloids were extracted from the milled buckwheat cereals by a mixture of alkaline aqueous and immiscible organic solvents (extraction recoveries: 66–79%). The tropane alkaloids were subsequently concentrated with a newly developed paper-immobilized liquid-phase microextraction (PI-LPME, extraction recoveries: 34–60%, concentration factor to immobilized solution in paper: 60–108×). After the PI-LPME, with an integrated 3D-printed setup, the tropane alkaloids were directly eluted (elution recoveries: 83–93%) and detected with the icLFIA. Digital read-out of the icLFIA, by employing a hand-held reader, enabled semiquantification of atropine (IC50= 0.56 ng mL–1in standard solutions). The modular workflow was validated by analyzing 24 blank and spiked buckwheat cereal samples with 5 and 10 μg kg–1atropine. A cutoff value was established with an estimated false negative rate of 1% and estimated false positive rate of 0.68%. Therefore, the modular workflow can aid in fast, inexpensive, and on-site atropine detection by nonexperts, and when integrated with a scopolamine-specific icLFIA expanded toward scopolamine detection. Moreover, the developed sample extraction and concentration method (PI-LPME) is suitable for the analysis of many other compounds with pH-dependent polarity.

AbstractAd creativity, based on the originality, meaningfulness, and craftsmanship of a brand message, is widely studied as an important mechanism of advertising success. These studies are based on practitioners’ and consumers’ creativity assessments. The purpose of this study is to evaluate the creativity assessments of these two groups against empirical standards in terms of intercoder reliability, stability, criterion validity, and predictive validity. To address this aim, sixty Instagram brand messages from the top-100 most interactive Instagram brand accounts were assessed by practitioners, consumers, and trained advertising researchers (for examining criterion validity). The results showed that practitioners and consumers can produce stable creativity assessments provided that the number of coders is large enough. Moreover, the results showed that assessments of both groups differed in terms of criterion validity. Examining the predictive validity showed that both groups yielded different outcome measures. These results (1) confirm that the creativity assessments of practitioners and consumers differ and (2) show that the quality of these assessments are contingent on the group of assessors (practitioners or consumers), sample size, and the assessed creativity dimensions. These findings have important implications for the design, evaluation, and comparability of creativity studies.

Cooling environments are a pervasive need in our society, with conventional air conditioners being the most popular approach. However, air conditioners rely heavily on electricity and Freon, a chemical that depletes ozone and contributes to greenhouse gas effects. To address this issue, passive daytime radiative coolers (PDRCs) have been proposed to achieve cooling by simultaneously reflecting sunlight and allowing internal heat to escape without electricity. Despite their potential, most high-performance PDRCs are composed of thick polymer films, which increases material costs during PDRC preparation and limits thermal transport. In this work, we introduced an economical and scalable solvent evaporation-based method to prepare a relatively thin hierarchically micro- and nanostructured poly(vinylidene fluoride-trifluoroethylene) via crystallinity alteration. Particularly, we find that the key to generating nanosized pores is to remove the water residual within the film without sample annealing, which significantly enhances the scattering efficiency across the solar spectrum. With our design, we demonstrate effective cooling of the outdoor environment, achieving a cooling temperature of Δ2.5 °C, with a film thickness of only 215 μm. Furthermore, our model suggested that applying this material could lead to annual energy savings of up to ∼39% in warmer climates across the country and up to 715 GJ nationwide. Developing effective PDRCs with reduced material thickness, such as the one discussed here, is imperative for implementing sustainable cooling solutions and reducing our carbon footprint.

ABSTRACTRandomized controlled trials have reported psychoanalytic psychotherapy to improve longer-term post-treatment outcomes in patients with treatment-resistant depression. In this case study, we examine the therapy process of a female trial participant diagnosed with treatment-resistant depression. Structured clinical assessments indicated that the patient's level of depression remained unchanged during and after treatment. Over the course of the therapy, she repeatedly broke away from important others and finally also from the therapy itself, which we linked to the impact of earlier experiences of abandonment on her internal world. In the discussion, we present a variety of reflections that were put forward by the authors during a series of case discussion meetings. Some of these reflections relate to how the inner world of this patient might have triggered a negative therapeutic reaction and a destructive pattern of repetition. The interpretative stance, in which the therapist interpreted this reaction as indicative of a psychic conflict and linked this conflict to the therapeutic relationship, seemed to be experienced by the patient as unhelpful and persecutory. Other elements that were brought up include basic distrust, lack of symbolization and trauma in the patient, as well as the constraints of the research context.

The prevalence of comorbidities in individuals with neurodevelopmental disorders (NDDs) is not well understood, yet these are important for accurate diagnosis and prognosis in routine care and for characterizing the clinical spectrum of NDD syndromes. We thus developed PhenomAD-NDD, an aggregated database containing the comorbid phenotypic data of 51,227 individuals with NDD, all harmonized into Human Phenotype Ontology (HPO), with in total 3,054 unique HPO terms. We demonstrate that almost all congenital anomalies are more prevalent in the NDD population than in the general population, and the NDD baseline prevalence allows for an approximation of the enrichment of symptoms. For example, such analyses of 33 genetic NDDs show that 32% of enriched phenotypes are currently not reported in the clinical synopsis in the Online Mendelian Inheritance in Man (OMIM). PhenomAD-NDD is open to all via a visualization online tool and allows us to determine the enrichment of symptoms in NDD.

Personalized news experiences powered by recommender systems permeate our lives and have the potential to influence not only our opinions, but also our decisions. At the same time, the content and viewpoints contained within news recommendations are driven by multiple factors, including both personalization and editorial selection. Explanations could help users gain a better understanding of the factors contributing to the news items selected for them to read. Indeed, recent works show that explanations are essential for users of news recommenders to understand their consumption preferences and set intentions in line with their goals, such as goals for knowledge development and increased diversity of content or viewpoints. We give examples of such works on explanation and interactive interface interventions which have been effective in influencing readers' consumption intentions and behaviors in news recommendations. However, the state‐of‐the‐art in news recommender systems currently fall short in terms of evaluating such interventions in live systems, limiting our ability to measure their true impact on user behavior and opinions. To help understand the true benefit of these interfaces, we therefore call for improving the realism of studies for news.

This intervention study examined the effectiveness of instructional support tailored toward two techniques (i.e., random associations and constraint identification) to strengthen children's creative problem‐solving skills within upper‐elementary science education. Five inquiry‐based science lessons with ample opportunity for creative problem‐solving (i.e., divergent and convergent thinking) were provided. Children were assigned to a condition with instructional support (n= 107) or without (n= 134). Domain‐general and specific measures of divergent and convergent thinking were included, and reading comprehension as well as mathematical ability were taken into account. Repeated measures multivariate analyses of covariance revealed how all children improved in terms of domain‐general convergent thinking, with a larger increase for children who performed better in mathematics. This shows a promising premise for future research focusing on the domain generality of convergent thinking and for the potential of transfer across domains. No additional improvement based on instructional support was found and children did not improve in terms of divergent thinking. The constraint identification and random associations technique might not be suitable for elementary school children, yet future research is necessary to validate such claims. Meanwhile, teachers could possibly support convergent thinking by simply providing exercises for divergent and convergent thinking.

Shortening of the long finger flexors (Flexor Digitorum Profundus, FDPs) in Duchenne Muscular Dystrophy (DMD) causes reduced hand function. Until now, longitudinal studies on the natural course of the shortening of the FDPs are lacking, which impedes recommendations on timing and evaluation of preventive measures. To investigate the longitudinal course of the FDP length during different disease stages focusing on symmetry, timing, and decline of the FDP length. A retrospective, longitudinal multicenter study was conducted in the Radboud university medical center and the Leiden university medical center. The FDP outcome was measured using goniometry and gross motor function was assessed using the Brooke score. Longitudinal mixed model analyses were used to describe the course of the FDP outcome, and to investigate symmetry in both hands. Data on 534 visits of 197 males (age ranged 4–48 years) showed that in the ambulatory stages the FDP outcome was within a normal range. The mean decline in FDP outcome is 3.5 degrees per year, the biggest decline was seen in Brooke 5 (>15 degrees per year). In Brooke 4, 41% of the FDP outcome was < 40 degrees. No significant differences were found between right and left. This study supports the consideration of preventive measures to delay shortening of the FDPs in DMD patients transitioning to a Brooke scale of 4 or higher. Besides, natural history of FDP outcome has been established, which provides a base to evaluate (preventive) interventions.

ABSTRACTData from whole-class discussions in Dutch upper primary school show that teachers occasionally explicitly take downgraded epistemic stances through epistemic disclaimers such as ‘ik weet het niet’ (English: I don’t know (it)), which contrasts with their institutionally assigned epistemic authority. In the current study, we have collected turns in which such epistemic disclaimers occur, and analysed them using conversation analysis. In our analyses, we focused on the positions of the turns in which epistemic disclaimers occur, and on the varying ways in which these turns influence the subsequent course of interaction. We have found that teachers’ epistemic disclaimers occur in initiating turns, facilitating student participation, but also in responsive turns. The latter vary in the extent to which they facilitate participation, ranging from facilitating student participation in a similar way to the initiating turns, to blocking further student contributions altogether. This study furthermore demonstrates that teachers employ epistemic disclaimers to navigate two teacher roles, namely those of a teacher with epistemic authority, and of a facilitator of whole class-discussions.

Enzalutamide is een sterke remmer van de androgeenreceptor. Behandeling met enzalutamide is effectief bij verschillende stadia van prostaatkanker. De behandeling kan echter gepaard gaan met bijwerkingen, zoals vermoeidheid, cognitieve achteruitgang en depressie, die een grote impact kunnen hebben op de kwaliteit van leven. In dit onderzoek werd gekeken of een gereduceerde dosis enzalutamide (1 dd 120 mg) leidt tot minder bijwerkingen ten opzichte van de standaarddosis enzalutamide (1 dd 160 mg) bij kwetsbare patiënten met prostaatkanker. Hiervoor zijn 52 patiënten gerandomiseerd tussen beide doseringen. Patiënten die de gereduceerde dosering kregen waren significant minder vermoeid na 24 weken vergeleken met degenen die behandeld werden met de standaarddosis (verschil FACIT-Fatigue-vragenlijst 6,2; 95%-BI 1,4–11,0; p= 0,01). Patiënten met de standaarddosis ervaarden meer vermoeidheid, cognitieve bijwerkingen en depressieve symptomen na 24 weken behandeling dan voor de start van de behandeling. Bij patiënten die behandeld werden met de gereduceerde dosis bleven deze symptomen over de tijd stabiel. Geconcludeerd wordt dat een gereduceerde dosis enzalutamide resulteert in minder vermoeidheid, cognitieve bijwerkingen en depressieve symptomen bij kwetsbare patiënten met prostaatkanker, zonder aanwijzingen van verlies van effectiviteit.

Ferroptosis is an iron-dependent, non-apoptotic form of cell death initiated by oxidative stress and lipid peroxidation. Recent evidence has linked ferroptosis to the action of the transcription factor Nuclear factor erythroid-2 derived,-like-1 (NFE2L1). NFE2L1 regulates proteasome abundance in an adaptive fashion, maintaining protein quality control to secure cellular homeostasis, but the regulation of NFE2L1 during ferroptosis and the role of the ubiquitin-proteasome system (UPS) herein are still unclear. In the present study, using an unbiased proteomic approach charting the specific ubiquitylation sites, we show that induction of ferroptosis leads to recalibration of the UPS. RSL3-induced ferroptosis inhibits proteasome activity and leads to global hyperubiquitylation, which is linked to NFE2L1 activation. As NFE2L1 resides in the endoplasmic reticulum tethered to the membrane, it undergoes complex posttranslational modification steps to become active and induce the expression of proteasome subunit genes. We show that proteolytic cleavage of NFE2L1 by the aspartyl protease DNA-damage inducible 1 homolog 2 (DDI2) is a critical step for the ferroptosis-induced feed-back loop of proteasome function. Cells lacking DDI2 cannot activate NFE2L1 in response to RSL3 and show global hyperubiquitylation. Genetic or chemical induction of ferroptosis in cells with a disrupted DDI2-NFE2L1 pathway diminishes proteasomal activity and promotes cell death. Also, treating cells with the clinical drug nelfinavir, which inhibits DDI2, sensitized cells to ferroptosis. In conclusion, our results provide new insight into the importance of the UPS in ferroptosis and highlight the role of the DDI2-NFE2L1 as a potential therapeutic target. Manipulating DDI2-NFE2L1 activity through chemical inhibition might help sensitizing cells to ferroptosis, thus enhancing existing cancer therapies.

IntroductionTo reduce the appeal of tobacco, the European Union (EU) banned menthol as a characterising flavour in cigarettes in May 2020. This pre/post-study evaluated the impact of the menthol ban on smoking cessation outcomes among a representative cohort of Dutch smokers.MethodsAdult (18+ years) smokers were recruited at wave 1 (pre-ban) of the International Tobacco Control Netherlands Surveys (February–March 2020) and followed post-ban at wave 2 (September–November 2020) and wave 3 (June–July 2021) (N=1326 participated in all three waves). Weighted bivariate, logistic regression and generalised estimating equation model analyses were conducted.ResultsUsual menthol use decreased from pre-ban (7.8%) to post-ban (4.0% at wave 2 and 4.4% at wave 3) (p<0.001). Pre-ban menthol smokers had greater odds of making a post-ban quit attempt than non-menthol smokers (66.9% vs 49.6%, adjusted OR (aOR)=1.89, 95% CI: 1.13 to 3.16). Compared with pre-ban non-menthol smokers, a higher proportion of menthol smokers quit by wave 2 (17.8% vs 10.2%, p=0.025) and by wave 3 (26.1% vs 14.1%, p=0.002), although this was not significant after adjusting for other factors. Female pre-ban menthol smokers had greater odds of quitting by wave 3 than female non-menthol smokers (aOR=2.23, 95% CI: 1.10 to 4.51). Most pre-ban menthol smokers (n=99) switched to non-menthol cigarettes (40.0%) or reported that they continued to smoke menthol cigarettes (33.0%) at wave 3.ConclusionsThe EU menthol ban was effective in reducing menthol use and in increasing quit attempts and quitting among pre-ban menthol smokers. Impact could be maximised by closing gaps that allow post-ban menthol cigarette use.

Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease.

Background: Hypertensive disorders of pregnancy (HDP), including pregnancy-induced hypertension (PIH), Preeclampsia (PE), Hemolysis Elevated Liver enzymes and Low Platelets (HELLP) and chronic hypertension, are leading causes of maternal and perinatal morbidity and mortality. Although the pathophysiology of HDP is complex, preconceptional weight reduction in obese women might reduce these complications. We conducted a systematic review and meta-analysis to investigate the effectiveness of preconceptional weight loss by lifestyle intervention or bariatric surgery in overweight and obese women and the reduction of the risk of HDP. Methods and results: Databases are searched until September 2019 resulting in 2547 articles: 110 full-text analysis and 29 detailed analysis. Reduced risks were shown for HDP in seven articles (n= 4381) of weight loss after lifestyle intervention or bariatric surgery (OR range 0.10–0.64), for PIH in four articles (n= 46,976) (OR range 0.14–0.79), and for PE in seven articles (n= 169,734) (OR range 0.14–0.84). The stratified analysis of weight loss after lifestyle intervention and bariatric surgery shows comparable results. The meta-analysis of 20 studies of the effectiveness of lifestyle intervention and bariatric surgery revealed reduced risks of HDP (OR 0.45 (95% CI 0.32–0.63)), PIH (OR 0.61 (95%CI 0.44–0.85)) and PE (OR 0.67 (95%CI 0.51–0.88)). Conclusions: Preconceptional weight loss after lifestyle intervention or bariatric surgery is effective in reducing risks of HDP, PIH and PE, and emphasizes the need to optimize weight in overweight and obese women with a child wish. More research is recommended to investigate short-term and long-term beneficial and harmful side-effects of these interventions on maternal and offspring health.

The 10th edition of the Joint Workshop on Interfaces and Human Decision Making for Recommender Systems was held as part of the 17th ACM Conference on Recommender Systems (RecSys), the premier international forum for the presentation of new research results, systems and techniques in the broad field of recommender systems. The workshop was organized as a hybrid event: the physical session took place on September 18th at the venue of the main conference, Singapore, with the possibility for authors to present remotely. The IntRS workshop brings together an interdisciplinary community of researchers and practitioners who share research on new recommender systems (informed by psychology), including new design technologies and evaluation methodologies, and aim to identify critical challenges and emerging topics in the field. This year we focused particularly on topics related to Human-Centered AI, Explainability of decision-making models, User-adaptive XAI systems, which are becoming more and more popular in the last years, especially in domains where recommended options might have ethical and legal impacts on users. The integration of XAI with recommender systems is crucial for enhancing their transparency, interpretability, and accountability. This topic attracted a lot of interest from the community, as demonstrated by the fact that several workshop papers proposed methods for recommendation explanations. Date: 18 September 2023. Website: https://intrs2023.wordpress.com. [ABSTRACT FROM AUTHOR]

AbstractIntroductionPerineal bowel evisceration is a rare complication after extralevator abdominoperineal excision (ELAPE). This surgical technique is used to resect low rectal and anal cancer, with a lower likelihood of positive surgical margins, but resulting in a larger perineal defect. A vertical rectus abdominis myocutaneous (VRAM) flap allows filling of the empty pelvic space and closure of the defect in the pelvic floor.Case presentationA 77-year-old woman, with a hysterectomy in her medical history, underwent an ELAPE followed by reconstruction of the perineal defect with a VRAM flap after neoadjuvant radiotherapy for a moderately differentiated invasive adenocarcinoma of the distal rectum. The postoperative course was complicated with a herniation of the perineal wound and evisceration of a bowel loop.ConclusionClosure of the perineal defect after ELAPE remains a challenge, especially in cases where several risk factors for delayed wound healing, flap failure and perineal herniation are present.

Developmental Transformations (DvT), a practice involving interactive, improvisational play in pairs or groups, has gained international appeal as a therapeutic intervention for different populations in a variety of health, care and recreational contexts. However, a rigorous review of the benefits of DvT has not been conducted. The purpose of this study was to review extant literature for the observed benefits of DvT, identify gaps in the literature and make recommendations concerning future research including identifying possible areas for outcome measurement for preliminary studies. The authors, who each completed training in this approach, conducted a scoping review of English-language, published, peer-reviewed and grey DvT literature through 2021. From an initial 745 records retrieved through databases and a manual search, 51 publications met criteria, which, when analysed using in-vivo and pattern coding, resulted in a total of seventeen categories of observed benefits ascribed to DvT. These included six general categories – relational, emotional, social, cognitive, behavioural and physical benefits – and eleven complex categories of benefits to participants across the lifespan. In addition to benefits for participants, benefits of DvT were also observed and reported for facilitators, therapists, teachers and supervisors engaged in this practice. This review revealed inconsistencies regarding the reporting of practitioner training, frequency, format, population, intended goals, assessment measures and outcomes. Future studies with increased experimental rigor, standardized outcome measures and consistent reporting are recommended.

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Platooning is a cooperative driving technology for driving in a longitudinal formation. Vehicle-to-vehicle (V2V) communication is the key enabling technology. Platooning is considered to be a closed application between well-known participants that use V2V data for their operation. For the deployment of platooning, multi-brand, i.e. interoperable, solutions are paramount. To achieve this, the European ENSEMBLE (ENabling SafE Multi-Brand pLatooning for Europe) project has been conducted. In this project, multi-brand specifications have been harmonized to a set of common specifications and requirements for a generic Platooning Support Function (PSF). Part of the specifications is a common interaction protocol, which also encompasses security features. A reference design has been developed to initially check the specifications. It consists of a detailed design of the common functionality and includes software and communication sub-system hardware prototypes. This reference design has also been used as benchmark for brand-specific implementations, e.g. in communication plug tests. Daimler Truck included the reference design directly in their PSF implementation, which gave the opportunity to continuously develop the reference design during the project. In this paper, the ‘final’ reference design is described as implemented in the Daimler truck, which took part in the verification, validation and demonstration of multi-brand platooning together with six other truck manufacturers.

Metabolic dysfunction and cachexia are associated with poor cancer prognosis. With no pharmacological treatments, it is crucial to define the molecular mechanisms causing cancer‐induced metabolic dysfunction and cachexia. Adenosine monophosphate‐activated protein kinase (AMPK) connects metabolic and muscle mass regulation. As AMPK could be a potential treatment target, it is important to determine the function for AMPK in cancer‐associated metabolic dysfunction and cachexia. We therefore established AMPK's roles in cancer‐associated metabolic dysfunction, insulin resistance and cachexia. In vastus lateralis muscle biopsies from n= 26 patients with non‐small cell lung cancer (NSCLC), AMPK signalling and protein content were examined by immunoblotting. To determine the role of muscle AMPK, male mice overexpressing a dominant‐negative AMPKα2 (kinase‐dead [KiDe]) specifically in striated muscle were inoculated with Lewis lung carcinoma (LLC) cells (wild type [WT]: n= 27, WT + LLC: n= 34, mAMPK‐KiDe: n= 23, mAMPK‐KiDe + LLC: n= 38). Moreover, male LLC‐tumour‐bearing mice were treated with (n= 10)/without (n= 9) 5‐aminoimidazole‐4‐carboxamide ribonucleotide (AICAR) to activate AMPK for 13 days. Littermate mice were used as controls. Metabolic phenotyping of mice was performed via indirect calorimetry, body composition analyses, glucose and insulin tolerance tests, tissue‐specific 2‐[3H]deoxy‐d‐glucose (2‐DG) uptake and immunoblotting. Patients with NSCLC presented increased muscle protein content of AMPK subunits α1, α2, β2, γ1 and γ3 ranging from +27% to +79% compared with control subjects. In patients with NSCLC, AMPK subunit protein content correlated with weight loss (α1, α2, β2 and γ1), fat‐free mass (α1, β2 and γ1) and fat mass (α1 and γ1). Tumour‐bearing mAMPK‐KiDe mice presented increased fat loss and glucose and insulin intolerance. LLC in mAMPK‐KiDe mice displayed lower insulin‐stimulated 2‐DG uptake in skeletal muscle (quadriceps: −35%, soleus: −49%, extensor digitorum longus: −48%) and the heart (−29%) than that in non‐tumour‐bearing mice. In skeletal muscle, mAMPK‐KiDe abrogated the tumour‐induced increase in insulin‐stimulated TBC1D4thr642phosphorylation. The protein content of TBC1D4 (+26%), pyruvate dehydrogenase (PDH; +94%), PDH kinases (+45% to +100%) and glycogen synthase (+48%) was increased in skeletal muscle of tumour‐bearing mice in an AMPK‐dependent manner. Lastly, chronic AICAR treatment elevated hexokinase II protein content and normalized phosphorylation of p70S6Kthr389(mTORC1 substrate) and ACCser212(AMPK substrate) and rescued cancer‐induced insulin intolerance. Protein contents of AMPK subunits were upregulated in skeletal muscle of patients with NSCLC. AMPK activation seemed protectively inferred by AMPK‐deficient mice developing metabolic dysfunction in response to cancer, including AMPK‐dependent regulation of multiple proteins crucial for glucose metabolism. These observations highlight the potential for targeting AMPK to counter cancer‐associated metabolic dysfunction and possibly cachexia.

IMPORTANCE: Quantification of bilirubin in blood is essential for early diagnosis and timely treatment of neonatal hyperbilirubinemia. Handheld point-of-care (POC) devices may overcome the current issues with conventional laboratory-based bilirubin (LBB) quantification. OBJECTIVE: To systematically evaluate the reported diagnostic accuracy of POC devices compared with LBB quantification. DATA SOURCES: A systematic literature search was conducted in 6 electronic databases (Ovid MEDLINE, Embase, Web of Science Core Collection, Cochrane Central Register of Controlled Trials, CINAHL, and Google Scholar) up to December 5, 2022. STUDY SELECTION: Studies were included in this systematic review and meta-analysis if they had a prospective cohort, retrospective cohort, or cross-sectional design and reported on the comparison between POC device(s) and LBB quantification in neonates aged 0 to 28 days. Point-of-care devices needed the following characteristics: portable, handheld, and able to provide a result within 30 minutes. This study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline. DATA EXTRACTION AND SYNTHESIS: Data extraction was performed by 2 independent reviewers into a prespecified, customized form. Risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 tool. Meta-analysis was performed of multiple Bland-Altman studies using the Tipton and Shuster method for the main outcome. MAIN OUTCOMES AND MEASURES: The main outcome was mean difference and limits of agreement in bilirubin levels between POC device and LBB quantification. Secondary outcomes were (1) turnaround time (TAT), (2) blood volumes, and (3) percentage of failed quantifications. RESULTS: Ten studies met the inclusion criteria (9 cross-sectional studies and 1 prospective cohort study), representing 3122 neonates. Three studies were considered to have a high risk of bias. The Bilistick was evaluated as the index test in 8 studies and the BiliSpec in 2. A total of 3122 paired measurements showed a pooled mean difference in total bilirubin levels of −14 μmol/L, with pooled 95% CBs of −106 to 78 μmol/L. For the Bilistick, the pooled mean difference was −17 μmol/L (95% CBs, −114 to 80 μmol/L). Point-of-care devices were faster in returning results compared with LBB quantification, whereas blood volume needed was less. The Bilistick was more likely to have a failed quantification compared with LBB. CONCLUSIONS AND RELEVANCE: Despite the advantages that handheld POC devices offer, these findings suggest that the imprecision for measurement of neonatal bilirubin needs improvement to tailor neonatal jaundice management.

The tendency of organic contaminants (OCs) to partition between different phases is a key set of properties that underlie their human and ecological health impacts and the success of remediation efforts. A significant challenge associated with these efforts is the need for accurate partitioning data for an ever-expanding list of OCs and breakdown products. All-atom molecular dynamics (MD) simulations have the potential to help generate these data, but existing studies have applied these techniques only to a limited variety of OCs. Here, we use established MD simulation approaches to examine the partitioning of 82 OCs, including many compounds of critical concern, at the water–air interface. Our predictions of the Henry’s law constant (KH) and interfacial adsorption coefficients (Kiw, Kia) correlate strongly with experimental results, indicating that MD simulations can be used to predict KH, Kiw, and Kiavalues with mean absolute deviations of 1.1, 0.3, and 0.3 logarithmic units after correcting for systematic bias, respectively. A library of MD simulation input files for the examined OCs is provided to facilitate future investigations of the partitioning of these compounds in the presence of other phases.

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People with HIV generally have more ageing-associated comorbidities than those without HIV. We aimed to establish whether the difference in comorbidities and their disease burden changes with ageing.

Missense and truncating variants in the X-chromosome-linked CLCN4gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopusoocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a “shift” of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.

Truck platooning is the linking of two or more trucks in convoy, using connectivity technology and automated driving support systems. For the wide deployment of platooning, multi-brand, i.e. interoperable, solutions are paramount. To achieve this, the European ENSEMBLE (ENabling SafE Multi-Brand pLatooning for Europe) project has been conducted. In this project, amongst others, all European truck manufacturers worked together to define harmonized multi-brand specifications for two different levels of platooning: a Platooning Support Function (PSF) and a Platooning Autonomous Function (PAF). The PSF aims towards fast deployment, whereas the PAF gives an outlook on the future of platooning when more advanced automated driving technologies become available. This paper describes the definition and specifications for the first level of platooning, the Platooning Support Function. It comprises a set of use cases, specifications and requirements for the common functionality. Part of the specifications is an interaction protocol, which also encompasses a security framework. To verify the definitions and to expedite standardization, all truck manufacturers implemented the PSF and this was tested in several multi-brand settings to conclude that the specifications result in technically feasible solutions.

An efficient technique is presented for 3-D finite element modeling of large-scale periodic excited bulk acoustic resonator (XBAR) resonators in the time-harmonic domain. In this technique, a domain decomposition scheme is used to decompose the computational domain into many small subdomains whose FE subsystems can be factorized with a direct sparse solver at a low cost. Transmission conditions (TCs) are enforced to interconnect adjacent subdomains, and a global interface system is formulated and solved iteratively. To accelerate the convergence, a second-order TC (SOTC) is designed to make the subdomain interfaces transparent for propagating and evanescent waves. An effective forward–backward preconditioner is constructed that when combined with the SOTC significantly reduce the number of iterations at no additional cost. Numerical results are given to demonstrate the accuracy, efficiency, and capability of the proposed algorithm.

Background: Pubertal growth patterns correlate with future health outcomes. However, the genetic mechanisms mediating growth trajectories remain largely unknown. Here, we modeled longitudinal height growth with Super-Imposition by Translation And Rotation (SITAR) growth curve analysis on ~ 56,000 trans-ancestry samples with repeated height measurements from age 5 years to adulthood. We performed genetic analysis on six phenotypes representing the magnitude, timing, and intensity of the pubertal growth spurt. To investigate the lifelong impact of genetic variants associated with pubertal growth trajectories, we performed genetic correlation analyses and phenome-wide association studies in the Penn Medicine BioBank and the UK Biobank. Results: Large-scale growth modeling enables an unprecedented view of adolescent growth across contemporary and 20th-century pediatric cohorts. We identify 26 genome-wide significant loci and leverage trans-ancestry data to perform fine-mapping. Our data reveals genetic relationships between pediatric height growth and health across the life course, with different growth trajectories correlated with different outcomes. For instance, a faster tempo of pubertal growth correlates with higher bone mineral density, HOMA-IR, fasting insulin, type 2 diabetes, and lung cancer, whereas being taller at early puberty, taller across puberty, and having quicker pubertal growth were associated with higher risk for atrial fibrillation. Conclusion: We report novel genetic associations with the tempo of pubertal growth and find that genetic determinants of growth are correlated with reproductive, glycemic, respiratory, and cardiac traits in adulthood. These results aid in identifying specific growth trajectories impacting lifelong health and show that there may not be a single “optimal” pubertal growth pattern.

ABSTRACTIn this conversation analytic study, we investigate requests for assistance in the third-age (65+) language classroom. Seven Dutch seniors participated in a one-month course of English as a foreign language. We found that these seniors asked many language-related questions which fell into one of three categories: (1) production-oriented questions, (2) comprehension-oriented questions and (3) wonderment questions. These questions differ in the ways the sequences are shaped: (a) what precedes the request for assistance, (b) the person who is recruited to provide the assistance, (c) the person who offers the assistance, and (d) the response to the provided assistance and the subsequent interaction. We found wonderment questions to be the most prevalent category. Our findings suggest that the senior learners in our data show clear ownership and agency over their own learning process, demonstrated by their active participation and frequent (wonderment) questions in the classroom.

The complexity and uncertainty of the COVID‐19 pandemic highlights the need to change training of public health professionals in higher education by shifting from siloed specialisations to interdisciplinary collaboration. At the end of 2020 and 2021, public health professionals collaboratively designed and delivered, a week‐long intensive course—Public Health in Pandemics. The aim of this research study was to understand whether the use of systems thinking in the design and delivery of the course enabled students to grasp the interdisciplinary nature of contemporary health promotion and public health practice. Two focus group interviews (n= 5 and 3/47) and a course opinion survey (n= 11/47) were utilised to gather information from students regarding experiences and perceptions of course design and delivery, and to determine if students felt better able to understand the complex nature of pandemics and pandemic responses. Students provided positive feedback on the course and believed that the course design and delivery assisted in understanding the complex nature of health problems and the ways in which health promotion and public health practitioners need to work across sectors with diverse disciplines for pandemic responses. The use of an integrated interdisciplinary approach to course design and delivery enabled students used systems thinking to understand the complexity in preparing for and responding to a pandemic. This approach may have utility in preparing an agile, iterative and adaptive health promotion and public health workforce more capable of facing the challenges and complexity in public health.

The incretin hormone glucagon-like peptide 1 (GLP-I) promotes glucose homeostasis and enhances B-cell function. GLP-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, which inhibit the physiological inactivation of endogenous GLP-1, are used for the treatment of type 2 diabetes. Using the Metabochip, we identified three novel genetic loci with large effects (30-40%) on GLP-1-stimulated insulin secretion during hyperglycemic clamps in nondiabetic Caucasian individuals (TMEM114; CHST3 and CTRB1/2; n = 232; all P ≤ 8.8 x [10.sup.-7]). rs7202877 near CTRB1/2, a known diabetes risk locus, also associated with an absolute 0.51 ± 0.16% (5.6 ± 1.7 mmo/mol) lower A1C response to DPP-4 inhibitor treatment in G-allele carriers, but there was no effect on GLP-1 RA treatment in type 2 diabetic patients (n = 527). Furthermore, in pancreatic tissue, we show that rs7202877 acts as expression quantitative trait locus for CTRB1 and CTRB2, encoding chymotrypsinogen, and increases fecal chymotrypsin activity in healthy carriers. Chymotrypsin is one of the most abundant digestive enzymes in the gut where it cleaves food proteins into smaller peptide fragments. Our data identify chymotrypsin in the regulation of the incretin pathway, development of diabetes, and response to DPP-4 inhibitor treatment., The incretin hormone glucagon-like peptide 1 (GLP-1) is released after a meal by L cells in the distal parts of the gastrointestinal tract, and it potentiates glucose-dependent insulin secretion by [...]

Research on context effects has demonstrated a link between program-induced involvement and recall of commercials broadcast in breaks. However, the effect of program-induced involvement on recall of advertising embedded in the program itself has been understudied. In addition, little consideration has been given to the antecedents of program involvement. The present study aims to address these gaps. Results from a naturalistic field study show an attention spillover effect on both embedded and successive advertising. The results further demonstrate that program involvement is a function of various personal factors, related to enduring topic involvement and social viewing environment., Sports events traditionally attract large television audiences, and have therefore become popular vehicles for advertisers desiring substantial reach in an era of growing media clutter and audience fragmentation. Next to [...]

Background. Longitudinal research on musculoskeletal disorders often makes use of a single measure of recovery, despite the large variation in reported recovery that exists. Patients with an acute ankle sprain often experience no pain or functional disability following treatment, yet report not being fully recovered, or vice versa. Objective. The purpose of this study was to find explanatory variables for reporting recovery by analyzing the extent to which different outcomes (eg, pain intensity) were associated with recovery and how baseline scores of different variables influence this association in adult patients after acute lateral ankle sprain. Design. This was a cohort study based on data collected in a randomized controlled trial (RCT). Methods. This study was constructed within the framework of an RCT. One hundred two patients who incurred an acute ankle sprain were included. Recovery, pain intensity, giving way of the ankle, and Ankle Function Score (AFS) were assessed during the RCT at baseline and at 4 weeks, 8 weeks, 3 months, and 12 months postinjury. Mean differences were calculated between baseline and follow-up. Associations were calculated using linear mixed models, and the influence of baseline scores on these associations was determined using linear regression with interaction. Results. Associations were found between recovery and the mean differences of pain during running on flat and rough surfaces (4 and 8 weeks, 3 months) and between recovery and the mean difference of giving way of the ankle during walking on a rough surface (8 weeks, 3 months). Limitations. This study used data collected from an RCT. Therefore, the study was limited to the outcomes measured in that trial, and some explanatory factors easily could have been missed. Conclusions. This study is the first to identify explanatory variables for reporting recovery in adults after ankle sprain. Pain intensity and giving way of the ankle measured during high ankle load activities make it easier to measure and to generalize recovery in this population and should be the primary outcome measures of interest. This study indicates the huge need to reach consensus about primary outcome measures for research in patients sustaining ankle sprains., Longitudinal research on musculoskeletal disorders often makes use of a single measure of recovery. (1-4) Consequently, an increased emphasis is placed on the patient's serf-reported perceived recovery as an outcome [...]