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The axillary lymph node status remains an important prognostic factor in breast cancer, and nodal staging using sentinel lymph node biopsy (SLNB) is routine. Randomized clinical trials provide evidence supporting de-escalation of axillary surgery and omission of SLNB in patients at low risk. However, identifying sentinel lymph node macrometastases (macro-SLNMs) is crucial for planning treatment tailored to the individual patient. This study is the first to explore the capacity of deep learning (DL) models to identify macro-SLNMs based on preoperative clinicopathological characteristics. We trained and validated five multivariable models using a population-based cohort of 18,185 patients. DL models outperform logistic regression, with Transformer showing the strongest results, under the constraint that the sensitivity is no less than 90%, reflecting the sensitivity of SLNB. This highlights the feasibility of noninvasive macro-SLNM prediction using DL. Feature importance analysis revealed that patients with similar characteristics exhibited different nodal status predictions, indicating the need for additional predictors for further improvement. [ABSTRACT FROM AUTHOR]

Helicobacter pylori disturbs the stomach lining during long-term colonization of its human host, with sequelae including ulcers and gastric cancer1,2. Numerous H. pylori virulence factors have been identified, showing extensive geographic variation1. Here we identify a ‘Hardy’ ecospecies of H. pylori that shares the ancestry of ‘Ubiquitous’ H. pylori from the same region in most of the genome but has nearly fixed single-nucleotide polymorphism differences in 100 genes, many of which encode outer membrane proteins and host interaction factors. Most Hardy strains have a second urease, which uses iron as a cofactor rather than nickel3, and two additional copies of the vacuolating cytotoxin VacA. Hardy strains currently have a limited distribution, including in Indigenous populations in Siberia and the Americas and in lineages that have jumped from humans to other mammals. Analysis of polymorphism data implies that Hardy and Ubiquitous coexisted in the stomachs of modern humans since before we left Africa and that both were dispersed around the world by our migrations. Our results also show that highly distinct adaptive strategies can arise and be maintained stably within bacterial populations, even in the presence of continuous genetic exchange between strains.‘Hardy’ Helicobacterpylori ecospecies shares the ancestry of ‘Ubiquitous’ H. pylori from the same region in most of the genome but has nearly fixed single-nucleotide polymorphism differences in 100 genes. [ABSTRACT FROM AUTHOR]

Let X be a reduced complex space of pure dimension. We consider divergent integrals of certain forms on X that are singular along a subvariety defined by the zero set of a holomorphic section of some holomorphic vector bundle E → X . Given a choice of Hermitian metric on E we define a finite part of the divergent integral. Our main result is an explicit formula for the dependence on the choice of metric of the finite part. [ABSTRACT FROM AUTHOR]

The intensive nutrient requirements needed to sustain T cell activation and proliferation, combined with competition for nutrients within the tumor microenvironment, raise the prospect that glucose availability may limit CAR-T cell function. Here, we seek to test the hypothesis that stable overexpression (OE) of the glucose transporter GLUT1 in primary human CAR-T cells would improve their function and antitumor potency. We observe that GLUT1OE in CAR-T cells increases glucose consumption, glycolysis, glycolytic reserve, and oxidative phosphorylation, and these effects are associated with decreased T cell exhaustion and increased Th17 differentiation. GLUT1OE also induces broad metabolic reprogramming associated with increased glutathione-mediated resistance to reactive oxygen species, and increased inosine accumulation. When challenged with tumors, GLUT1OE CAR-T cells secrete more proinflammatory cytokines and show enhanced cytotoxicity in vitro, and demonstrate superior tumor control and persistence in mouse models. Our collective findings support a paradigm wherein glucose availability is rate limiting for effector CAR-T cell function and demonstrate that enhancing glucose availability via GLUT1OE could augment antitumor immune function. T cell activation is a process that requires extra nutrients, which could be difficult to source from the tumor microenvironment in competition with tumor cells. Here authors increase the metabolic fitness of CAR-T cells by stable overexpression of the glucose transporter GLUT1, which allows them to increase their glucose intake and enhances their antitumour function. [ABSTRACT FROM AUTHOR]

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

Climbing fibers, connecting the inferior olive and Purkinje cells, form the nervous system's strongest neural connection. These fibers activate after critical events like motor errors or anticipation of rewards, leading to bursts of excitatory postsynaptic potentials (EPSPs) in Purkinje cells. The number of EPSPs is a crucial variable when the brain is learning a new motor skill. Yet, we do not know what determines the number of EPSPs. Here, we measured the effect of nucleo-olivary stimulation on periorbital elicited climbing fiber responses through in-vivo intracellular Purkinje cell recordings in decerebrated ferrets. The results show that while nucleo-olivary stimulation decreased the probability of a response occurring at all, it did not reduce the number of EPSPs. The results suggest that nucleo-olivary stimulation does not influence the number of EPSPs in climbing fiber bursts. [ABSTRACT FROM AUTHOR]

To better assess the pathology of neurodegenerative disorders and the efficacy of neuroprotective interventions, it is necessary to develop biomarkers that can accurately capture age-related biological changes in the human brain. Brain serotonin 2A receptors (5-HT2AR) show a particularly profound age-related decline and are also reduced in neurodegenerative disorders, such as Alzheimer's disease. This study investigates whether the decline in 5-HT2AR binding, measured in vivo using positron emission tomography (PET), can be used as a biomarker for brain aging. Specifically, we aim to (1) predict brain age using 5-HT2AR binding outcomes, (2) compare 5-HT2AR-based predictions of brain age to predictions based on gray matter (GM) volume, as determined with structural magnetic resonance imaging (MRI), and (3) investigate whether combining 5-HT2AR and GM volume data improves prediction. We used PET and MR images from 209 healthy individuals aged between 18 and 85 years (mean = 38, std = 18) and estimated 5-HT2AR binding and GM volume for 14 cortical and subcortical regions. Different machine learning algorithms were applied to predict chronological age based on 5-HT2AR binding, GM volume, and the combined measures. The mean absolute error (MAE) and a cross-validation approach were used for evaluation and model comparison. We find that both the cerebral 5-HT2AR binding (mean MAE = 6.63 years, std = 0.74 years) and GM volume (mean MAE = 6.95 years, std = 0.83 years) predict chronological age accurately. Combining the two measures improves the prediction further (mean MAE = 5.54 years, std = 0.68). In conclusion, 5-HT2AR binding measured using PET might be useful for improving the quantification of a biomarker for brain aging. [ABSTRACT FROM AUTHOR]

Purpose: For children with Esophageal atresia who have to wait for reconstructive surgery, long hospital stay, delayed introduction of oral feeds and hampered oro-motor function has traditionally been draw-backs for this treatment as the patients have minimal training of oro-motor function while waiting for surgery. In this paper, we present the concept of sham-feed at home awaiting reconstructive surgery with the aim to obliviate these problems. The aim was to describe the characteristics of patients with Esophageal atresia waiting for reconstructive surgery sham-feeding at home by their parents and further describe adverse events that arose. Methods: The study is a retrospective descriptive single center study on all children with a delayed reconstruction of Esophageal atresia who was sham-fed by their parents at home before reconstructive surgery between January 2010 and January 2023 at the Karolinska University Hospital, Stockholm. Results: Nine patients where home waiting for reconstructive surgery for a median of 72 days. No adverse events were reported related to the sham-feed procedure at home. The children had reconstructive surgery at a median 120 days of age. Five of the children ate full meals orally day 8–27 after surgery. Two children ate fully before 1 year after surgery. Two children had surgery less than 1 year ago and were not eating fully orally at the time of data collection. Conclusion: Sham-feeding at home by the parents was safe and feasible with the benefits of a prolonged time out of hospital awaiting reconstructive surgery. [ABSTRACT FROM AUTHOR]

We report high resolution measurements of the stable water isotope ratios (δ18O, δD) from the Mount Brown South ice core (MBS, 69.11° S 86.31° E). The record covers the period 873 - 2009 CE with sub-annual temporal resolution. Preliminary analyses of surface cores have shown the Mount Brown South site has relatively high annual snowfall accumulation (0.3 metres ice equivalent) with a seasonal bias toward lower snowfall during austral summer. Precipitation at the site is frequently related to intense, short term synoptic scale events from the mid-latitudes of the southern Indian Ocean. Higher snowfall regimes are associated with easterly winds, while lower snowfall regimes are associated with south-easterly winds. Isotope ratios are measured with Infra-Red Cavity Ring Down Spectroscopy, calibrated on the VSMOW/SLAP scale and reported on the MBS2023 time scale interpolated accordingly. We provide estimates for measurement precision and internal accuracy for δ18O and δD. [ABSTRACT FROM AUTHOR]

Background: Chemotherapy has limited efficacy in advanced digestive high-grade neuroendocrine neoplasms (HG-NEN) and prognosis is dismal. Predictive markers for palliative chemotherapy are lacking, and prognostic markers are limited. Methods: Digestive HG-NEN patients (n = 229) were prospectively included 2013–2017. Pathological re-assessment revealed 188 neuroendocrine carcinomas (NEC) and 41 neuroendocrine tumours (NET G3). Tumour-DNA was sequenced across 360 cancer-related genes, assessing mutations (mut) and copy number alterations. We linked sequencing results to clinical information and explored potential markers for first-line chemotherapy efficacy and survival. Results: In NEC given cis/carboplatin and etoposide (PE), TP53mut predicted inferior response rate in multivariate analyses (p = 0.009) and no BRAFmut NEC showed response. In overall assessment of PE-treated NEC, no genetic alterations were prognostic for OS. For small-cell NEC, TP53mut were associated with longer OS (p = 0.011) and RB1 deletions predicted lack of immediate-progression (p = 0.003). In non-small cell NEC, APC mut were associated with immediate-progression and shorter PFS (p = 0.008/p = 0.004). For NET G3, ATRXmut, ARID1A- and ERS1 deletions were associated with shorter PFS. Conclusion: Correlations between genetic alterations and response/immediate-progression to PE were frequent in NEC but affected PFS or OS only when subdividing for cell-type. The classification of digestive NEC into large- and small-cell seems therefore molecularly and clinically relevant. [ABSTRACT FROM AUTHOR]

Purpose: To analyse the reliability and validity of the Swedish indicator 'Drugs that should be avoided in older people'. Methods: From a previous study that included consecutive primary care patients ≥ 65 years of age, all patients ≥ 75 years of age were analysed. Two physicians independently screened their medication lists and medical records, applying the Swedish indicator which includes potentially inappropriate medications (PIMs): long-acting benzodiazepines, drugs with anticholinergic action, tramadol, propiomazine, codeine, and glibenclamide. The clinical relevance of identified PIMs was independently assessed. Thereafter, the physicians determined in consensus whether some medical action related to the drug treatment was medically justified and prioritised before the next regular visit. If so, the drug treatment was considered inadequate, and if not, adequate. Results: A total of 1,146 drugs were assessed in 149 patients (75‒99 years, 62% female, 0‒20 drugs per patient). In 29 (19%) patients, at least one physician identified ≥ 1 PIM according to the indicator at issue; 24 (16%) patients were concordantly identified with ≥ 1 such PIM (kappa: 0.89). Of 26 PIMs concordantly identified, the physicians concordantly assessed four as clinically relevant and 12 as not clinically relevant (kappa: 0.17). After the consensus discussion, six (4%) patients had ≥ 1 PIM according to the studied indicator that merited action. Using the area under the receiver operating characteristic (ROC) curve, the indicator did not outperform chance in identifying inadequate drug treatment: 0.56 (95% confidence interval: 0.46 to 0.66). Conclusion: The Swedish indicator has strong reliability regarding PIM detection but does not validly reflect the adequacy of drug treatment. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the effect of aging and resistance training with a moderate load on the size and mechanical properties of the patellar (PT) and Achilles tendon (AT) and their associated aponeuroses; medial gastrocnemius (MG) and vastus lateralis (VL). Young (Y55; 24.8 ± 3.8 yrs, n = 11) and old men (O55; 70.0 ± 4.6 yrs, n = 13) were assigned to undergo a training program (12 weeks; 3 times/week) of moderate slow resistance training [55% of one repetition maximum (RM)] of the triceps surae and quadriceps muscles. Tendon dimensions were assessed using 1.5 T magnetic resonance imaging before and after 12 weeks. AT and PT cross sectional area (CSA) were determined every 10% of tendon length. Mechanical properties of the free AT, MG aponeurosis, PT, and VL aponeurosis were assessed using ultrasonography (deformation) and tendon force measurements. CSA of the AT but not PT was greater in O55 compared with Y55. At baseline, mechanical properties were generally lower in O55 than Y55 for AT, MG aponeurosis and VL aponeurosis (Young's modulus) but not for PT. CSA of the AT and PT increased equally in both groups following training. Further, for a given force, stiffness and Young's modulus also increased equally for VL aponeurosis and AT, for boths groups. The present study highlights that except for the PT, older men have lower tendon (AT, MG aponeurosis, and VL aponeurosis) mechanical properties than young men and 12-weeks of moderate slow resistance training appears sufficient to improve tendon size and mechanical adaptations in both young and older men. New and Noteworthy: These novel findings suggest that short-term moderate slow resistance training induces equal improvements in tendon size and mechanics regardless of age. [ABSTRACT FROM AUTHOR]

Lay people are now able to obtain one-lead electrocardiograms (ECG) using smartwatches, which facilitates documentation of arrhythmias. The accuracy of smartwatch derived ECG intervals has not been validated in children though. Home-based monitoring of ECG intervals using a smartwatch could improve monitoring of children, e.g. when taking QTc prolonging medications. The aim of this study was to validate the ECG intervals measured by smartwatch in comparison to standard 12-lead ECGs in children and adolescents. Prospective study of children (age 5—17 years) at the outpatient clinic of a national pediatric heart center. Patients underwent a smartwatch ECG (ScanWatch, Withings) and a simultaneous standard 12-lead ECG. ECG intervals were measured both automatically and manually from the smartwatch ECG and the 12-lead ECG. Intraclass correlation coefficients and Bland–Altman plots were performed. 100 patients (54% male, median age 12.9 (IQR 8.7–15.6) were enrolled. The ICC calculated from the automated smartwatch and automated 12-lead ECG were excellent for heart rate (ICC 0.97, p < 0.001), good for the PR and QT intervals (ICC 0.86 and 0.8, p < 0.001), and moderate for the QRS duration and QTc interval (ICC 0.7 and 0.53, p < 0.001). When using manual measurements for the smartwatch ECG, validity was improved for the PR interval (ICC 0.93, p < 0.001), QRS duration (ICC 0.92, p < 0.001), QT (ICC 0.95, p < 0.001) and QTc interval (ICC 0.84, p < 0.001). Conclusion: Automated smartwatch intervals are most reliable measuring the heart rate. The automated smartwatch QTc intervals are less reliable, but this may be improved by manual measurements. What is Known: In adults, smartwatch derived ECG intervals measured manually have previously been shown to be accurate, though agreement for automated QTc may be fair. What is New: In children, automated smartwatch QTc intervals are less reliable than RR, PR, QRS and uncorrected QT interval. Accuracy of the QTc can be improved by peroforming manual measurements. [ABSTRACT FROM AUTHOR]

We discuss about the lower semicontinuity of set-valued maps, which is a crucial concept in parametric optimization and game theory. The focus is on the intersection of set-valued maps and the preservation of lower semicontinuity under this operation. We present new results based on some minimal properties that ensure the lower semicontinuity of the intersection with other lower semicontinuous maps. Additionally, the lower semicontinuity of the intersection of an infinite family of set-valued maps is considered, which has not been studied in the literature. We provide two examples to illustrate the applications of this concept in bilevel games, including a single-leader multi-follower game with robust followers and a secured multi-leader-follower game. [ABSTRACT FROM AUTHOR]

X-ray computed tomography (CT) is utilised in some sawmills today, primarily for enhancing value yield and for process automation, which includes log sorting and sawing optimisation. Nevertheless, there is a scarcity of recent research utilising CT to assess the local cutting process. As a preliminary study, this paper addresses this gap by using CT to investigate the connections between local cutting force and local wood properties including density, knots, and annual ring width. Workpieces of Scots pine (Pinus sylvestris L.), from Sweden and Poland, were CT-scanned in laboratory conditions. Quasi-linear cutting tests were then performed on both clear and knotty regions of the workpieces using a custom-made laboratory stand with a Stellite-tipped tooth mounted on piezoelectric sensors. It was found that density influences cutting forces for both clear and knotty wood, and this effect increased noticeably with increasing uncut chip thickness. Changes in wood density, such as between sapwood and heartwood or between clear wood and knot, caused dynamic changes in cutting forces and temporary disturbances to the stability of the system. Normalisation of cutting forces by local density allowed the conclusion that density is not the only property affecting cutting forces. Other structural properties, e.g. annual ring width and latewood–earlywood proportion may affect the cutting process as well, which requires deeper analysis in the future research. This preliminary study demonstrates the feasibility and usefulness of coupling CT data with cutting force measurements and suggests further research on the relationship between cutting force and wood properties. [ABSTRACT FROM AUTHOR]

We consider the CH–KP-I equation. For this equation, we prove the existence of steady solutions, which are solitary in one horizontal direction and periodic in the other. We show that such waves bifurcate from the line solitary wave solutions, i.e. solitary wave solutions to the Camassa–Holm equation, in a dimension-breaking bifurcation. This is achieved through reformulating the problem as a dynamical system for a perturbation of the line solitary wave solutions, where the periodic direction takes the role of time, then applying the Lyapunov–Iooss theorem. [ABSTRACT FROM AUTHOR]

Hypervirulent Klebsiella pneumoniae (HvKP) is an emerging bacterial pathogen causing invasive infection in immune-competent humans. The hypervirulence is strongly linked to the overproduction of hypermucoviscous capsule, but the underlying regulatory mechanisms of hypermucoviscosity (HMV) have been elusive, especially at the post-transcriptional level mediated by small noncoding RNAs (sRNAs). Using a recently developed RNA interactome profiling approach iRIL-seq, we interrogate the Hfq-associated sRNA regulatory network and establish an intracellular RNA-RNA interactome in HvKP. Our data reveal numerous interactions between sRNAs and HMV-related mRNAs, and identify a plethora of sRNAs that repress or promote HMV. One of the strongest HMV repressors is ArcZ, which is activated by the catabolite regulator CRP and targets many HMV-related genes including mlaA and fbp. We discover that MlaA and its function in phospholipid transport is crucial for capsule retention and HMV, inactivation of which abolishes Klebsiella virulence in mice. ArcZ overexpression drastically reduces bacterial burden in mice and reduces HMV in multiple hypervirulent and carbapenem-resistant clinical isolates, indicating ArcZ is a potent RNA inhibitor of bacterial pneumonia with therapeutic potential. Our work unravels a novel CRP-ArcZ-MlaA regulatory circuit of HMV and provides mechanistic insights into the posttranscriptional virulence control in a superbug of global concern. By performing a global RNA-RNA interactome analysis in hypervirulent Klebsiella pneumoniae, the authors identify the small RNA ArcZ targets many capsule genes and a key virulence factor MlaA, inhibiting Klebsiella infection and pathogenesis in mice. [ABSTRACT FROM AUTHOR]

Resonant inelastic x-ray scattering (RIXS) is a widely used spectroscopic technique, providing access to the electronic structure and dynamics of atoms, molecules, and solids. However, RIXS requires a narrow bandwidth x-ray probe to achieve high spectral resolution. The challenges in delivering an energetic monochromated beam from an x-ray free electron laser (XFEL) thus limit its use in few-shot experiments, including for the study of high energy density systems. Here we demonstrate that by correlating the measurements of the self-amplified spontaneous emission (SASE) spectrum of an XFEL with the RIXS signal, using a dynamic kernel deconvolution with a neural surrogate, we can achieve electronic structure resolutions substantially higher than those normally afforded by the bandwidth of the incoming x-ray beam. We further show how this technique allows us to discriminate between the valence structures of Fe and Fe2O3, and provides access to temperature measurements as well as M-shell binding energies estimates in warm-dense Fe compounds. The authors combine differentiable physics modelling and neural networks to extract high-resolution electronic density of states of warm dense materials from resonant inelastic x-ray scattering spectra. With this approach, they identify distinctive features in the valence structures of warm dense Fe and Fe2O3, also estimating their temperature and M-shell binding energies. [ABSTRACT FROM AUTHOR]

As a new class of organic photocatalysts, polymer dots show a potential application in photocatalytic hydrogen peroxide production coupled with chemical oxidation such as methanol oxidation. However, the poor methanol oxidation ability by polymer dots still inhibits the overall photocatalytic reaction occurring in the neutral condition. In this work, an organic molecular catalyst 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl radical is covalently linked to a fluorene unit in a polymer skeleton, eventually enabling photocatalytic hydrogen peroxide production coupled with methanol oxidation in the neutral condition. By conducting various spectroscopic measurements, charge transfer between components in this molecular catalyst-immobilized polymer dots system is studied and found to be very efficient for hydrogen peroxide production coupled with alcohol oxidation. This work proves a strategy for designing polymer dots photocatalysts with molecular catalysts, facilitating their future development and potential applications in other fields such as water splitting, CO2 reduction, photoredox catalysis and photodynamic therapy. A strategy of covalently grafting molecular catalysts to polymer backbones in polymer dots photocatalysts is proposed in this work, realizing a groundbreaking photocatalytic oxidation of various alcohols in neutral conditions. [ABSTRACT FROM AUTHOR]

Purpose: Traumatic brain injury is the main reason for the emergency department visit of up to 3% of the patients and a major worldwide cause for morbidity and mortality. Current emergency management guidelines recommend close attention to patients taking oral anticoagulation but not patients on antiplatelet therapy. Recent studies have begun to challenge this. The aim of this study was to determine the impact of antiplatelet therapy and oral anticoagulation on traumatic intracranial hemorrhage. Methods: Medical records of adult patients triaged with "head injury" as the main reason for emergency care were retrospectively reviewed from January 1, 2017, to December 31, 2017, and January 1, 2020, to December 31, 2021. Patients ≥ 18 years with head trauma were included. Odds ratio was calculated, and multiple logistic regression was performed. Results: A total of 4850 patients with a median age of 70 years were included. Traumatic intracranial hemorrhage was found in 6.2% of the patients. The risk ratio for traumatic intracranial hemorrhage in patients on antiplatelet therapy was 2.25 (p < 0.001, 95% confidence interval 1.73–2.94) and 1.38 (p = 0.002, 95% confidence interval 1.05–1.84) in patients on oral anticoagulation compared to patients without mediations that affect coagulation. In binary multiple regression, antiplatelet therapy was associated with intracranial hemorrhage, but oral anticoagulation was not. Conclusion: This study shows that antiplatelet therapy is associated with a higher risk of traumatic intracranial hemorrhage compared to oral anticoagulation. Antiplatelet therapy should be given equal or greater consideration in the guidelines compared to anticoagulation therapy. Further studies on antiplatelet subtypes within the context of head trauma are recommended to improve the guidelines' diagnostic accuracy. [ABSTRACT FROM AUTHOR]

In the period between 5,300 and 4,900 calibrated years before present (cal. bp), populations across large parts of Europe underwent a period of demographic decline1,2. However, the cause of this so-called Neolithic decline is still debated. Some argue for an agricultural crisis resulting in the decline3, others for the spread of an early form of plague4. Here we use population-scale ancient genomics to infer ancestry, social structure and pathogen infection in 108 Scandinavian Neolithic individuals from eight megalithic graves and a stone cist. We find that the Neolithic plague was widespread, detected in at least 17% of the sampled population and across large geographical distances. We demonstrate that the disease spread within the Neolithic community in three distinct infection events within a period of around 120 years. Variant graph-based pan-genomics shows that the Neolithic plague genomes retained ancestral genomic variation present in Yersinia pseudotuberculosis, including virulence factors associated with disease outcomes. In addition, we reconstruct four multigeneration pedigrees, the largest of which consists of 38 individuals spanning six generations, showing a patrilineal social organization. Lastly, we document direct genomic evidence for Neolithic female exogamy in a woman buried in a different megalithic tomb than her brothers. Taken together, our findings provide a detailed reconstruction of plague spread within a large patrilineal kinship group and identify multiple plague infections in a population dated to the beginning of the Neolithic decline.Population-scale ancient genomics are used to infer ancestry, social structure and pathogen infection in 108 Scandinavian Neolithic individuals from eight megalithic graves and a stone cist, showing that Neolithic plague was widespread. [ABSTRACT FROM AUTHOR]

Introduction: This study aims to evaluate the use of CT-based whole kidney parenchyma (WKP) segmentation in 177Lu-DOTATATE dosimetry. Specifically, it investigates whether WKP volumes change during treatment and evaluates the accuracy of applying a single delineated WKP volume for dosimetry. Furthermore, it aims to determine the cause of WKP volume changes—whether caused by radiation or amino acid infusion—by comparing them with spleen volume changes as a marker for radiation-induced alterations. Methods: SPECT/CT images of 18 patients were acquired over the abdomen approximately 4 h (h) (D0), 24 h (D1), 48 h (D2) and 168 h (D7) post-administration of 177Lu-DOTATATE. CT guided WKP volumes were measured before (baseline) and during treatment. Kidney activity concentrations at each time point were derived from CT-segmented WKP overlaid on SPECT scans. The accuracy of using WKP segmentation from a single CT for all time points was assessed against the gold standard of segmenting each WKP individually. Time-integrated activity calculations were based on a tri-exponential curve fit of the kidney activity concentration over time. Kidney absorbed doses were estimated under the assumption of local energy deposition. Additionally, the impact of various partial volume correction methods on dosimetry was evaluated. Results: Whole-kidney parenchyma (WKP) volumes, ranging from 31 to 243 mL, showed a gradual increase from baseline (mean ± SD = 130.6 ± 46.1 mL) at the initial time points D0 (138.5 ± 44.7 mL) and D1 (139.4 ± 41.6 mL), followed by a slight decrease at D2 (132.8 ± 44.5 mL) and a further decrease at D7 (129.2 ± 42.7 mL). The volume increase at D0 and D1 was statistically significant. Spleen volume did not change during treatment, suggesting that amino acid infusion rather than irradiation effects caused WKP volume changes. Bland-Altman analysis revealed WKP volume biases of 8.77% (D0 vs. BL), 10.77% (D1 vs. BL), 1.10% (D2 vs. BL), and 1.10% (D7 vs. BL), with corresponding uncertainties of 24.4%, 23.6%, 25.4%, and 25.4%, respectively. When WKP segmentation from a single CT is applied across all SPECTs, these WKP volume changes could overestimate the activity concentration and mean absorbed doses up to 4.3% and 2.5%, respectively. The absorbed dose uncertainties using a recovery coefficient (RC) of 0.85 for single-time-point WKP delineation increase the absorbed dose uncertainty by 4% compared to the use of patient-specific RCs and time specific segmentation of WKP volumes. Conclusions: Kidney volume exhibited significant variation form D0 to D7, affecting the precision of dosimetry calculation, primarily due to errors in whole-kidney parenchyma (WKP) delineation. Notably, using WKP segmentation from a single CT scan applied to sequential SPECT images introduce further uncertainty and may lead to an overestimation of the absorbed dose. The fluctuations in kidney volume are most likely attributable to amino acid infusion. [ABSTRACT FROM AUTHOR]

Minimal hepatic encephalopathy (MHE) is common in liver cirrhosis and is identified by psychometric tests. The portosystemic hepatic encephalopathy score (PHES) is the most widely used and serves as an inter-study comparator. PHES has not been standardised for use in the Danish population, where German normal values have been applied until now based on the notion that the populations are comparable. This study aimed to evaluate if German PHES normal values can be applied in the Danish population and establish Danish normal values if needed. 200 Danish and 217 German healthy persons underwent Number Connection Test A and B (NCT), Line Tracing Test (LTT), Digit Symbol Test (DST), and Serial Dotting Test (SDT), and based on performance, PHES was calculated. German and Danish PHES performance declined with age in all subtests but more rapidly in Danes. Both German and Danish norms were impacted by gender and education, but to a different extent in the single tests of the test battery. Accordingly, there was a need for specific Danish normal values, which are presented here. Applying the new Danish normal values instead of the German in patients with cirrhosis yielded a lower percentage of out-of-norm performances (58% vs. 66%) and, hence, a lower prevalence of MHE. Danes and Germans perform differently on PHES, and therefore, normal German values cannot be used in Danish patients. Danish normal values are presented here and yield a lower number of 'out of norm' performances. [ABSTRACT FROM AUTHOR]

Genetically-encoded dopamine (DA) sensors enable high-resolution imaging of DA release, but their ability to detect a wide range of extracellular DA levels, especially tonic versus phasic DA release, is limited by their intrinsic affinity. Here we show that a human-selective dopamine receptor positive allosteric modulator (PAM) can be used to boost sensor affinity on-demand. The PAM enhances DA detection sensitivity across experimental preparations (in vitro, ex vivo and in vivo) via one-photon or two-photon imaging. In vivo photometry-based detection of optogenetically-evoked DA release revealed that DETQ administration produces a stable 31 minutes window of potentiation without effects on animal behavior. The use of the PAM revealed region-specific and metabolic state-dependent differences in tonic DA levels and enhanced single-trial detection of behavior-evoked phasic DA release in cortex and striatum. Our chemogenetic strategy can potently and flexibly tune DA imaging sensitivity and reveal multi-modal (tonic/phasic) DA signaling across preparations and imaging approaches. Dopamine regulates multiple brain functions through coexisting tonic and phasic release modalities. Here, the authors describe an approach for monitoring tonic and phasic dopamine release simultaneously via on-demand chemogenetic tuning of a dopamine sensor. [ABSTRACT FROM AUTHOR]

Deep learning-based approaches for generating novel drug molecules with specific properties have gained a lot of interest in the last few years. Recent studies have demonstrated promising performance for string-based generation of novel molecules utilizing reinforcement learning. In this paper, we develop a unified framework for using reinforcement learning for de novo drug design, wherein we systematically study various on- and off-policy reinforcement learning algorithms and replay buffers to learn an RNN-based policy to generate novel molecules predicted to be active against the dopamine receptor DRD2. Our findings suggest that it is advantageous to use at least both top-scoring and low-scoring molecules for updating the policy when structural diversity is essential. Using all generated molecules at an iteration seems to enhance performance stability for on-policy algorithms. In addition, when replaying high, intermediate, and low-scoring molecules, off-policy algorithms display the potential of improving the structural diversity and number of active molecules generated, but possibly at the cost of a longer exploration phase. Our work provides an open-source framework enabling researchers to investigate various reinforcement learning methods for de novo drug design. [ABSTRACT FROM AUTHOR]

Background: For dosimetry, the demand for whole-body SPECT/CT imaging, which require long acquisition durations with dual-head Anger cameras, is increasing. Here we evaluated sparsely acquired projections and assessed whether the addition of deep-learning-generated synthetic intermediate projections (SIPs) could improve the image quality while preserving dosimetric accuracy. Methods: This study included 16 patients treated with 177Lu-DOTATATE with SPECT/CT imaging (120 projections, 120P) at four time points. Deep neural networks (CUSIPs) were designed and trained to compile 90 SIPs from 30 acquired projections (30P). The 120P, 30P, and three different CUSIP sets (30P + 90 SIPs) were reconstructed using Monte Carlo-based OSEM reconstruction (yielding 120P_rec, 30P_rec, and CUSIP_recs). The noise levels were visually compared. Quantitative measures of normalised root mean square error, normalised mean absolute error, peak signal-to-noise ratio, and structural similarity were evaluated, and kidney and bone marrow absorbed doses were estimated for each reconstruction set. Results: The use of SIPs visually improved noise levels. All quantitative measures demonstrated high similarity between CUSIP sets and 120P. Linear regression showed nearly perfect concordance of the kidney and bone marrow absorbed doses for all reconstruction sets, compared to the doses of 120P_rec (R2 ≥ 0.97). Compared to 120P_rec, the mean relative difference in kidney absorbed dose, for all reconstruction sets, was within 3%. For bone marrow absorbed doses, there was a higher dissipation in relative differences, and CUSIP_recs outperformed 30P_rec in mean relative difference (within 4% compared to 9%). Kidney and bone marrow absorbed doses for 30P_rec were statistically significantly different from those of 120_rec, as opposed to the absorbed doses of the best performing CUSIP_rec, where no statistically significant difference was found. Conclusion: When performing SPECT/CT reconstruction, the use of SIPs can substantially reduce acquisition durations in SPECT/CT imaging, enabling acquisition of multiple fields of view of high image quality with satisfactory dosimetric accuracy. [ABSTRACT FROM AUTHOR]

Like for many bacteria, flagella are crucial for Campylobacter jejuni motility and virulence. Biogenesis of the flagellar machinery requires hierarchical transcription of early, middle (RpoN-dependent), and late (FliA-dependent) genes. However, little is known about post-transcriptional regulation of flagellar biogenesis by small RNAs (sRNAs). Here, we characterized two sRNAs with opposing effects on C. jejuni filament assembly and motility. We demonstrate that CJnc230 sRNA (FlmE), encoded downstream of the flagellar hook protein, is processed from the RpoN-dependent flgE mRNA by RNase III, RNase Y, and PNPase. We identify mRNAs encoding a flagella-interaction regulator and the anti-sigma factor FlgM as direct targets of CJnc230 repression. CJnc230 overexpression upregulates late genes, including the flagellin flaA, culminating in longer flagella and increased motility. In contrast, overexpression of the FliA-dependent sRNA CJnc170 (FlmR) reduces flagellar length and motility. Overall, our study demonstrates how the interplay of two sRNAs post-transcriptionally fine-tunes flagellar biogenesis through balancing of the hierarchically-expressed components. Koenig et al. describe two Campylobacter small RNAs (FlmE and FlmR) that are co-regulated within the flagellar transcriptional cascade and together post-transcriptionally fine-tune expression of components during flagellar biogenesis. [ABSTRACT FROM AUTHOR]

This study examines the psychometric structure and properties of the Swedish version of the Super-Brief Pathological Narcissism Inventory (SB-PNI) among adolescents. In order to ensure the validity and feasibility of the measure, we examined the factor structure, measurement invariance across gender, age and ethnicity, and construct validity in relation to a number of correlates of narcissism in adolescence. Data were drawn from a large cross-sectional survey conducted in 35 schools in southern Sweden. The sample consisted of N = 5313 adolescents (Mage = 16.10 SD = 1.55) with 52.2% girls, 45.9% boys and 1.8% adolescents with unspecified gender, from compulsory and upper secondary schools in southern Sweden. The results showed that the measure holds a two-factor structure, suggesting the use of the subscales grandiosity and vulnerability separately, rather than as a unidimensional measure. The correlated factors grandiosity and vulnerability yielded full configural and metric invariance across gender, age, and ethnicity. Both grandiosity and vulnerability were correlated with externalizing and internalizing symptoms, as well as with low self-esteem. The study provides evidence for the utility of the SB-PNI among Swedish adolescents and indicates that the measure can be used across male and female adolescents of different ages and ethnic groups. [ABSTRACT FROM AUTHOR]

Calmodulin transduces [Ca2+] information regulating the rhythmic Ca2+ cycling between the sarcoplasmic reticulum and cytoplasm during contraction and relaxation in cardiac and skeletal muscle. However, the structural dynamics by which calmodulin modulates the sarcoplasmic reticulum Ca2+ release channel, the ryanodine receptor, at physiologically relevant [Ca2+] is unknown. Using fluorescence lifetime FRET, we resolve different structural states of calmodulin and Ca2+-driven shifts in the conformation of calmodulin bound to ryanodine receptor. Skeletal and cardiac ryanodine receptor isoforms show different calmodulin-ryanodine receptor conformations, as well as binding and structural kinetics with 0.2-ms resolution, which reflect different functional roles of calmodulin. These FRET methods provide insight into the physiological calmodulin-ryanodine receptor structural states, revealing additional distinct structural states that complement cryo-EM models that are based on less physiological conditions. This technology will drive future studies on pathological calmodulin-ryanodine receptor interactions and dynamics with other important ryanodine receptor bound modulators. Calmodulin (CaM) modulates the sarcoplasmic reticulum Ca2+ release channel, the ryanodine receptor (RyR), to facilitate Ca2+ cycling in muscle contraction and release. Using fluorescence lifetime FRET with native sarcoplasmic reticulum from skeletal and cardiac muscle, the authors resolve calcium-driven structural states and kinetics of CaM binding to RyR isoforms one and two. [ABSTRACT FROM AUTHOR]

Positron emission tomography (PET) imaging of tau aggregation in Alzheimer's disease (AD) is helping to map and quantify the in vivo progression of AD pathology. To date, no high-affinity tau-PET radiopharmaceutical has been optimized for imaging non-AD tauopathies. Here we show the properties of analogues of a first-in-class 4R-tau lead, [18F]OXD-2115, using ligand-based design. Over 150 analogues of OXD-2115 were synthesized and screened in post-mortem brain tissue for tau affinity against [3H]OXD-2115, and in silico models were used to predict brain uptake. [18F]OXD-2314 was identified as a selective, high-affinity non-AD tau PET radiotracer with favorable brain uptake, dosimetry, and radiometabolite profiles in rats and non-human primate and is being translated for first-in-human PET studies. [18F]OXD-2314 is a brain penetrant positron emission tomography radiotracer with high affinity for tau aggregates in Alzheimer's disease (AD) and non-AD tauopathies based on in vitro and in vivo studies, and is suitable for first-in-human use. [ABSTRACT FROM AUTHOR]

Squirrels traded for pets or consumption have the potential to be vectors for zoonotic disease transmission and to establish themselves as invasive species. Callosciurus spp. (Greek for beautiful squirrel) are popular in the pet trade due to their medium size and many colour variants, though several feral populations have established themselves in various parts of the world and these wild-caught individuals can carry and spread infectious diseases. Here, we investigate the live trade in Prevost's squirrels (C. prevosti) in Indonesia where they are naturally found on the islands of Sumatra, Bangka and Borneo. Between 2016 and 2024, we recorded 284 Prevost's squirrels for sale, viz., 115 in the physical markets and 169 online. We detected the species for sale in Sumatra (13 individuals), Bangka (7) and Borneo (3), i.e. within their natural range, but also on Java (242) and Bali (4). The mean asking price per individual was US$63, and younger individuals commanded higher prices than older ones. Asking prices were not higher in cities further away from the species' native range nor in cities with higher purchasing power. All individuals were wild-caught, and with a domestic quota of five individuals allowed to be traded as pets per year (45 over the study period) most of this trade is illegal under Indonesian law. This is distinctly different from trade in Prevost's squirrels in for instance Europe or the USA where legally captive-bred individuals are offered for sale. In Indonesia the illegal trade happens in the open and despite the risk of the spread of zoonotic diseases wherever it is traded there appears to be little incentive on the side of the authorities to curb this trade. Their widespread availability on Java and Bali risks the accidental or deliberate introduction on these two islands. Better coordination is needed between the Indonesian authorities, online sales sites, pet traders and consumers to stop the sale of illegally obtained Prevost's squirrels to limit the risk of them becoming invasive species or contributing to the spread of emerging infectious diseases. [ABSTRACT FROM AUTHOR]

Investigating the collective impact of psychometric properties and sleep quality on pain sensitivity in temporomandibular disorder (TMD) patients could improve clinical management strategies. Objective: Assessing whether combined psychometric properties and sleep quality impact painful mechanical sensitivity and pain modulation in TMD patients. Materials and methods: A cross-sectional study using secondary data analysis of 77 TMD patients and 101 controls. All participants completed questionnaires characterizing their psychometric profile (anxiety, depression, stress and catastrophizing) and sleep quality, alongside psychophysical tests for painful mechanical sensory (mechanical pain threshold (MPT), pressure pain threshold (PPT), and wind-up ratio (WUR)) and conditioned pain modulation (CPM). Participants were grouped into "High distress" or "Low distress" categories based on psychometric properties and sleep quality using hierarchical cluster and k-means analyses. Multiple linear regression evaluated the influence of TMD, age, and the distress cluster on MPT, WUR, PPT, and CPM in masseter and thenar muscles. Differences were statistically significant when p < 0.05. Results: The presence of TMD was the strongest predictor of mechanical painful sensitivity in the trigeminal region (MPT[F(3,174) = 51.902;p <.001;R2 =.463]; TMD presence (β = -.682) / PPT[F(3,174) = 15.573;p <.001;R2 =.198] TMD presence (β = -.452), and extra-trigeminal (MPT[F(3,174) = 35.897;p <.001;R2 =.382] TMD (β = -.647) / CPM [F(3,174) = 4.106;p <.05;R2 =.050] TMD presence (β =.197). Furthermore, neither the high distress group nor the low distress group were able to significantly influence the variation of the values of any of the psychophysical variables evaluated (p >.05). Conclusions: There is not a significant influence of impairment clusters based on psychological variables and sleep quality on painful mechanical sensitivity and pain modulation, regardless of the presence of TMD. Clinical relevance: This outcome suggests that psychosocial factors and sleep quality may not play a decisive role in the sensory-discriminative aspect of pain, particularly concerning painful TMD. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: The aim of this study was to investigate whether higher dietary intake of marine n-3 fatty acids during pregnancy is associated with a lower risk of type 1 diabetes in children. Methods: The Danish National Birth Cohort (DNBC) and the Norwegian Mother, Father and Child Cohort Study (MoBa) together include 153,843 mother–child pairs with prospectively collected data on eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) intake during pregnancy from validated food frequency questionnaires. Type 1 diabetes diagnosis in children (n=634) was ascertained from national diabetes registries. Results: There was no association between the sum of EPA and DHA intake during pregnancy and risk of type 1 diabetes in offspring (pooled HR per g/day of intake: 1.00, 95% CI 0.88, 1.14), with consistent results for both the MoBa and the DNBC. Robustness analyses gave very similar results. Conclusions/interpretation: Initiation of a trial of EPA and DHA during pregnancy to prevent type 1 diabetes in offspring should not be prioritised. [ABSTRACT FROM AUTHOR]

We study how sourcing of applied and basic knowledge is related to the likelihood and speed at which inventions become innovations as well as their profitability. By using a patent database with unique commercialization information, we reveal that inventions strongly based on applied knowledge lead to innovations more quickly, while inventions embedding basic knowledge lead to more profitable innovations. Sourcing both applied and basic knowledge (i.e., their combination effect) is negatively related to innovation speed. Explanations include the notion that inventions based on applied knowledge follow more established technological trajectories. Hence, such inventions relatively easily turn into innovations, but due to hard competitive pressure, profits are modest. Conversely, inventions embedding basic knowledge likely depart from conventional technological trajectories and market logic and are more difficult and/or riskier to transform into innovations. However, if such innovations are launched, the gains could be significant because of their improved performance and distinctiveness. Finally, recombining applied and basic knowledge may become too complex to handle, thus hampering innovation speed. From a managerial perspective, managers who seek to innovate quickly should exploit inventions embodying applied knowledge; however, those who seek increased profitability should exploit inventions embodying basic knowledge even if this may be more difficult and riskier. From a policy perspective, actions aiming to lessen the risks associated with commercializing inventions based on basic knowledge should be implemented. [ABSTRACT FROM AUTHOR]

Abstract Cholesterol‐dependent cytolysins (CDCs) are essential virulence factors for many human pathogens like Streptococcus pneumoniae (pneumolysin, PLY), Streptococcus pyogenes (streptolysin O, SLO), and Listeria monocytogenes (Listeriolysin, LLO) and induce cytolysis and inflammation. Recently, we identified that pneumococcal PLY interacts with the mannose receptor (MRC‐1) on specific immune cells thereby evoking an anti‐inflammatory response at sublytic doses. Here, we identified the interaction sites between MRC‐1 and CDCs using computational docking. We designed peptides from the CTLD4 domain of MRC‐1 that binds to PLY, SLO, and LLO, respectively. In vitro, the peptides blocked CDC‐induced cytolysis and inflammatory cytokine production by human macrophages. Also, they reduced PLY‐induced damage of the epithelial barrier integrity as well as blocked bacterial invasion into the epithelium in a 3D lung tissue model. Pre‐treatment of human DCs with peptides blocked bacterial uptake via MRC‐1 and reduced intracellular bacterial survival by targeting bacteria to autophagosomes. In order to use the peptides for treatment in vivo, we developed calcium phosphate nanoparticles (CaP NPs) as peptide nanocarriers for intranasal delivery of peptides and enhanced bioactivity. Co‐administration of peptide‐loaded CaP NPs during infection improved survival and bacterial clearance in both zebrafish and mice models of pneumococcal infection. We suggest that MRC‐1 peptides can be employed as adjunctive therapeutics with antibiotics to treat bacterial infections by countering the action of CDCs.

Therapeutic antibodies have been developed to target amyloid-beta (Aβ), and some of these slow the progression of Alzheimer’s disease (AD). However, they can also cause adverse events known as amyloid-related imaging abnormalities with edema (ARIA-E). We investigated therapeutic Aβ antibody binding to cerebral amyloid angiopathy (CAA) fibrils isolated from human leptomeningeal tissue to study whether this related to the ARIA-E frequencies previously reported by clinical trials. The binding of Aβ antibodies to CAA Aβ fibrils was evaluated in vitro using immunoprecipitation, surface plasmon resonance, and direct binding assay. Marked differences in Aβ antibody binding to CAA fibrils were observed. Solanezumab and crenezumab showed negligible CAA fibril binding and these antibodies have no reported ARIA-E cases. Lecanemab showed a low binding to CAA fibrils, consistent with its relatively low ARIA-E frequency of 12.6%, while aducanumab, bapineuzumab, and gantenerumab all showed higher binding to CAA fibrils and substantially higher ARIA-E frequencies (25–35%). An ARIA-E frequency of 24% was reported for donanemab, and its binding to CAA fibrils correlated with the amount of pyroglutamate-modified Aβ present. The findings of this study support the proposal that Aβ antibody-CAA interactions may relate to the ARIA-E frequency observed in patients treated with Aβ-based immunotherapies. [ABSTRACT FROM AUTHOR]

Background: Cartilage oligomeric matrix protein (COMP) is a novel regulator of the tumor microenvironment. Studies in colon cancer and pancreatobiliary adenocarcinoma have revealed COMP expression to be associated with decreased infiltration of immune cells in the tumor microenvironment. Herein, the expression of COMP was investigated in gastric and esophageal adenocarcinoma with particular reference to its the relationship with the immune microenvironment. Methods: COMP expression was evaluated in tissue microarrays representing primary tumors from 159 patients with chemo- and radiotherapy naïve esophageal and gastric adenocarcinoma and 67 matched samples of lymph node metastases using immunohistochemistry. Additionally, collagen fibers were stained with Sirius Red and evaluated with the FIJI macro TWOMBLI algorithm. Results: The expression of COMP in cancer cells in the entire cohort was associated with shorter overall survival (OS) (p = 0.013) and recurrence-free survival (RFS) (p = 0.029), while COMP expression in the stroma was correlated with shorter RFS (p = 0.042). Similar correlations were found for patients with gastric adenocarcinoma, whereas COMP expression was not prognostic in esophageal adenocarcinoma. Further, in the entire cohort, the expression of COMP in the stroma was correlated with exclusion of different populations of immune cells (CD8+, CD3+, FoxP3+, CD20+) from the tumor microenvironment. Finally, higher density and alignment of collagen fibers were correlated with the expression of COMP in the stroma. Conclusions: Expression of COMP in gastric and esophageal adenocarcinoma was correlated with shorter OS and RFS. A reduced number of immune cells infiltrated the tumor microenvironment when COMP expression was detected. This phenomenon could be attributed to the denser collagen deposits, a hallmark of tumor fibrosis observed in COMP-expressing tumors. [ABSTRACT FROM AUTHOR]

This document is a call for contributions to a special feature in the journal Sustainability Science. The special feature focuses on sufficiency as a sustainability strategy and explores the intersections of influence between actors and structures in achieving sufficiency goals. The document introduces two conceptual frameworks, "The Intersections of Influence" and the "Sufficiency Dimension Matrix," to analyze actor roles and influences. The special feature aims to provide a more integrated view of actor influence and generate insights on various topics related to sufficiency, such as energy systems and business models. The deadline for abstract submission is March 15, 2024, and the completion of the special issue is expected in December 2025. [Extracted from the article]

In machining, the heat generated during the process deforms the components and the final shape might not meet specified tolerances. There is therefore a need for a compensation strategy which requires knowledge of the workpiece temperature field and the associated thermal distortions. In this work, a methodology is presented for the determination of the heat load for indexable insert drilling of AISI 4140. Compared to previous research, this work has introduced a varying heat load. The heat load is extracted from thermo-mechanical finite element simulations for different nominal chip thicknesses and cutting speeds using the coupled Eulerian-Lagrangian formulation of an orthogonal turning process. The heat load is then transferred to a simplified 2D axisymmetric heat transfer model where the in-process temperature field in the workpiece is predicted. To verify the methodology, the predicted temperatures are compared to the experimentally measured temperatures for various feed rates. It is found that the model is capable of predicting the workpiece temperatures reasonably well. However, the methodology needs to be further explored to validate its applicability. [ABSTRACT FROM AUTHOR]

Poor self-rated health (SRH) is associated with incident arterial cardiovascular disease in both sexes. Studies on the association between SRH and incident venous thromboembolism (VTE) show divergent results in women and no association in men. This study focuses on the association between change in SRH and incident VTE in a cohort of 11,558 men and 6682 women who underwent a baseline examination and assessment of SRH between 1974 and 1992 and a re-examination in 2002–2006. To investigate if changes in SRH over time affect the risk of incident VTE in men and women. During a follow-up time from the re-examination of more than 16 years, there was a lower risk for incident VTE among women if SRH changed from poor at baseline to very good/excellent (HR 0.46, 95% CI 0.28; 0.74) at the re-examination. Stable good SRH (good to very good/excellent at the re-examination, HR 0.60, 95% CI 0.42; 0.89), or change from good SRH at baseline into poor/fair at the re-examination (HR 0.68, 95% CI 0.51; 0.90) were all significantly associated with a reduced risk for VTE. All comparisons were done with the group with stable poor SRH. This pattern was not found among men. Regardless of a decreased or increased SRH during life, having an SRH of very good/excellent at any time point seems to be associated with a decreased risk of VTE among women. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to explore parents' experience of sham feeding their baby born with esophageal atresia at home, waiting for reconstructive surgery. Method: Semi-structured interviews were conducted with parents of six children born with esophageal atresia waiting for delayed reconstruction. The interviews were analyzed using qualitative content analysis. Results: Parents experienced that sham feed reinforced the healthy abilities in their baby. They had faith in their own ability as parents to care for their child as well as to see to their baby's strength to cope with difficulties. Parents expressed that the health care system can hinder as well as be a major support on their way to a more normal life at home while waiting for reconstructive surgery. Conclusion: The experience of sham feeding at home while waiting for reconstructive surgery is characterized by positive aspects both for children born with esophageal atresia and their parents. [ABSTRACT FROM AUTHOR]

Objectives: This cross-sectional school-based study explored the influence of malocclusion on temporomandibular disorders (TMD) pain complaints, and whether this association would be mediated by sleep bruxism in a representative sample of 7- to 8-year-old children. Methods: Path analysis estimated direct, indirect, and total effects of occlusal features on sleep bruxism and TMD pain in 7- to 8-year-old children. Occlusal features were assessed with Dental Aesthetic Index (DAI), orofacial pain complaints using the TMD pain screener, possible sleep bruxism based on self-reports, and probable sleep bruxism based on self-reports combined with clinical findings. Structural equation modeling analyzed data with confounding factors. Results: From 580 participants, possible sleep bruxism was observed in 136 children (31.5%), probable sleep bruxism in 30 children (6.7%), and TMD pain complaints in 78 children (13.8%). Malocclusion had no direct effect on either possible sleep bruxism [standardized coefficient (SC) 0.000; p = 0.992], or TMD pain complaints (SC – 0.01; p = 0.740). When probable sleep bruxism was set as the mediator of interest, malocclusion did not directly affect probable sleep bruxism (SC 0.01; p = 0.766), nor TMD pain complaints (SC – 0.02; p = 0.515). A direct effect of probable sleep bruxism on TMD pain complaints was observed with an SC of 0.60 (p < 0.001). However, in neither case, malocclusion indirectly affected TMD pain complaints via bruxism. Conclusion: Malocclusion in 7- to 8-year-old children did not directly influence possible or probable sleep bruxism or TMD pain complaints. Instead, probable sleep bruxism was strongly associated with TMD pain complaints. Clinical significance: The impact of occlusal features on TMD pain complaints and bruxism has been a long-standing controversy in dentistry. However, the scientific literature linking this association may be inconsistent, mainly due to biased sample selection methods with inadequate consideration of confounders. Further research should try to identify additional risk factors for TMD pain in addition to probable sleep bruxism in children. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the dopaminergic signaling in human adipose tissue in the context of obesity and type 2 diabetes (T2D) and potential direct implications in adipose tissue metabolism. Methods: mRNA and protein expression of dopamine receptors D1 and D2 (DRD1 and DRD2) were determined in subcutaneous adipose tissue from subjects without or with T2D and with different body weight, and correlated with markers of obesity, hyperglycemia, and insulin resistance. Glucose uptake and lipolysis were measured in adipocytes ex vivo following short-term exposure to dopamine, DRD1 receptor agonist (SKF81297), or DRD2 receptor agonist (bromocriptine). Results: DRD1 and DRD2 gene expression in subcutaneous adipose tissue correlated positively with clinical markers of insulin resistance (e.g. HOMA-IR, insulin, and triglycerides) and central obesity in subjects without T2D. Protein expression of DRD2 in subcutaneous adipose tissue, but not DRD1, is higher in subjects with impaired fasting glucose and T2D and correlated positively with hyperglycemia, HbA1c, and glucose AUC, independent of obesity status. DRD1 and DRD2 proteins were mainly expressed in adipocytes, compared to stromal vascular cells. Dopamine and dopaminergic agonists did not affect adipocyte glucose uptake ex vivo, but DRD1 and DRD2 agonist treatment inhibited isoproterenol-stimulated lipolysis. Conclusion: The results suggest that protein expression of DRD2 in subcutaneous adipose tissue is up-regulated with hyperglycemia and T2D. Whether DRD2 protein levels contribute to T2D development or occur as a secondary compensatory mechanism needs further investigation. Additionally, dopamine receptor agonists inhibit adipocyte beta-adrenergic stimulation of lipolysis, which might contribute to the beneficial effects in lipid metabolism as observed in patients taking bromocriptine. [ABSTRACT FROM AUTHOR]

Greenland ice core records exhibited 100-fold higher dust concentrations during the Last Glacial Maximum (LGM) than during the Holocene, and dust input temporal variability corresponded to different climate states in the LGM. While East Asian deserts, the Sahara, and European loess have been suggested as the potential source areas (PSAs) for Greenland LGM dust, millennial-scale variability in their relative contributions within the LGM remains poorly constrained. Here, we present the morphological, mineralogical, and geochemical characteristics of insoluble microparticles to constrain the provenance of dust in Greenland NEEM ice core samples covering cold Greenland Stadials (GS)-2.1a to GS-3 (~ 14.7 to 27.1 kyr ago) in the LGM. The analysis was conducted on individual particles in microdroplet samples by scanning electron microscopy with energy dispersive X-ray spectroscopy and Raman microspectroscopy. We found that the kaolinite-to-chlorite (K/C) ratios and chemical index of alteration (CIA) values were substantially higher (K/C: 1.4 ± 0.7, CIA: 74.7 ± 2.9) during GS-2.1a to 2.1c than during GS-3 (K/C: 0.5 ± 0.1, CIA: 65.8 ± 2.8). Our records revealed a significant increase in Saharan dust contributions from GS-2.1a to GS-2.1c and that the Gobi Desert and/or European loess were potential source(s) during GS-3. This conclusion is further supported by distinctly different carbon contents in particles corresponding to GS-2.1 and GS-3. These results are consistent with previous estimates of proportional dust source contributions obtained using a mixing model based on Pb and Sr isotopic compositions in NEEM LGM ice and indicate millennial-scale changes in Greenland dust provenance that are probably linked to large-scale atmospheric circulation variabilities during the LGM. [ABSTRACT FROM AUTHOR]

Static form errors due to in-process deflections is a major concern in flank milling of thin-walled parts. To increase both productivity and part geometric accuracy, there is a need to predict and control these form errors. In this work, a modelling framework for prediction of the cutting force-induced form errors, or thickness errors, during flank milling of a thin-walled workpiece is proposed. The modelled workpiece geometry is continuously updated to account for material removal and the reduced stiffness matrix is calculated for nodes in the engagement zone. The proposed modelling framework is able to predict the resulting thickness errors for a thin-walled plate which is cut on both sides. Several cutting strategies and cut patterns using constant z-level finishing are studied. The modelling framework is used to investigate the effect of different cut patterns, machining allowance, cutting tools and cutting parameters on the resulting thickness errors. The framework is experimentally validated for various cutting sequences and cutting parameters. The predicted thickness errors closely correspond to the experimental results. It is shown from numerical evaluations that the selection of an appropriate cut pattern is crucial in order to reduce the thickness error. Furthermore, it is shown that an increased machining allowance gives a decreased thickness error for thin-walled plates. [ABSTRACT FROM AUTHOR]