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Abstract Background Atypical teratoid rhabdoid tumors (ATRT) are incurable high-grade pediatric brain tumors. Despite intensive research efforts, the prognosis for ATRT patients under currently established treatment protocols is poor. While novel therapeutic strategies are urgently needed, the generation of molecular-driven treatment concepts is a challenge mainly due to the absence of actionable genetic alterations. Results We here use a functional genomics approach to identify genetic dependencies in ATRT, validate selected hits using a functionally instructed small molecule drug library, and observe preferential activity in ATRT cells without subgroup-specific selectivity. CDK4/6 inhibitors are among the most potent drugs and display anti-tumor efficacy due to mutual exclusive dependency on CDK4 or CDK6. Chemogenetic interactor screens reveal a broad spectrum of G1 phase cell cycle regulators that differentially enable cell cycle progression and modulate response to CDK4/6 inhibition in ATRT cells. In this regard, we find that the ubiquitin ligase substrate receptor AMBRA1 acts as a context-specific inhibitor of cell cycle progression by regulating key components of mitosis including aurora kinases. Conclusions Our data provide a comprehensive resource of genetic and chemical dependencies in ATRTs, which will inform further preclinical evaluation of novel targeted therapies for this tumor entity. Furthermore, this study reveals a unique mechanism of cell cycle inhibition as the basis for tumor suppressive functions of AMBRA1.

Abstract The protective effects of time spent outdoors emphasize the major role of daylight in myopia. Based on the pathophysiology of myopia, the impact of blue light stimulation on the signaling cascade, from melanopsin at the blind spot to clinically relevant biomarkers for myopia, was investigated. Parameters and site of light stimulation are mainly defined by the photopigment melanopsin, that is sensitive to blue light with a peak wavelength of 480 nm and localized on the intrinsically photosensitive retinal ganglion cells (ipRGC) whose axons converge to the optic disc, corresponding to the physiological blind spot. Blue light at the blind spot (BluSpot) stimulation provides the opportunity to activate the vast majority of ipRGC and avoids additional involvement of rods and cones which may exert incalculable effects on the signaling cascade. Experimental studies have applied anatomical, histochemical, electrophysiological, imaging, and psychophysical methods to unravel the mode of action of BluSpot stimulation. Results indicate activation of melanopsin, improvement of contrast sensitivity, gain in electrical retinal activity, and increase of choroidal thickness following BluSpot stimulation. Short-term changes of clinically relevant biomarkers lead to the hypothesis that BluSpot stimulation may exert antimyopic effects with long-term application.

Abstract Air traveler numbers are predicted to reach 4.0 billion in 2024. Between 1/15,000–50,000 passengers will experience acute medical problems inflight with cardiac arrests requiring cardiopulmonary resuscitation (CPR) accounting for 0.3% of medical emergencies. Hypoxia in airplane cabins could impair oxygenation and physical performance of caregivers. We conducted a randomized controlled, double-blind study to test the hypothesis that hypoxia decreases the effectiveness in performing CPR. We randomized 24 healthcare professionals to two different study arms, each consisting of two conditions: arm (1) ‘hypoxia (FiO2 15%, equivalent to 2400 m altitude)’ versus ‘normoxia’; arm (2) ‘hypoxia + supplemental oxygen’ versus ‘normoxia + supplemental oxygen’. The order of conditions was counterbalanced and a minimum wash-out period of 24 h was granted between conditions. In each condition participants performed a 5-min cardiac compression only CPR (CCO-CPR) using a full-body manikin after one, three and six hours in an altitude chamber. Mixed ANOVAs with post-hoc false-discovery-rate adjusted pairwise comparisons indicated that although compression frequency was maintained, the number of compressions with correct depth was decreased at all times during hypoxia compared to normoxia (all p

Abstract Fibroblast heterogeneity is increasingly recognised across cancer conditions. Given their important contribution to disease progression, mapping fibroblasts’ heterogeneity is critical to devise effective anti-cancer therapies. Cancer-associated fibroblasts (CAFs) represent the most abundant cell population in pancreatic ductal adenocarcinoma (PDAC). Whether CAF phenotypes are differently specified by PDAC cell lineages remains to be elucidated. Here, we reveal an important role for the MAPK signalling pathway in defining PDAC CAF phenotypes. We show that epithelial MAPK activity promotes the myofibroblastic differentiation of CAFs by sustaining the expression and secretion of TGF-β1. We integrate single-cell profiling of post-perturbation transcriptional responses from mouse models with cellular and spatial profiles of human tissues to define a MAPKhigh CAF (mapCAF) phenotype. We show that this phenotype associates with basal-like tumour cells and reduced frequency of CD8+ T cells. In addition to elevated MAPK activity, this mapCAF phenotype is characterized by TGF-β signalling, hypoxia responsive signatures, and immunoregulatory gene programs. Furthermore, the mapCAF signature is enriched in myofibroblastic CAFs from various cancer conditions and correlates with reduced response to immune checkpoint inhibition in melanoma. Altogether, our data expand our knowledge on CAF phenotype heterogeneity and reveal a potential strategy for targeting myofibroblastic CAFs in vivo.

Abstract Background Worldwide, the prevalence of childhood overweight and obesity increases. Children with low socioeconomic status (SES) are more often affected by overweight and obesity. SES is also associated with health behaviours. In order to avoid health disparities, school-based health promotion programmes such as “Join the Healthy Boat” can help. Intervention outcomes can differ by SES; therefore, the purpose of this study was to investigate whether the intervention had equal or differential effects both on weight status and health-related behaviours in children from high and low SES. Methods One thousand six hundred twenty children’s data (7.1 ± 0.6 years; 50.6% male) was analysed; anthropometric data was taken on-site, other health-related parameters, such as physical activity, nutrition, and screen media use, as well as SES were assessed subjectively. Logistic regression models and GEEs were calculated. Results Comparisons by SES show that there were significant differences in children’s characteristics and health behaviours such as migration background, height, weight, BMI percentiles, weight status, family education level, household income, physical activity behaviour, screen media use, soft drink intake and breakfast skipping. After one year, there were no intervention effects for overweight status, physical activity, or screen media use, but children with high SES in the intervention group skipped breakfast significantly less often than in the control group (5.34 [1.44;19.85], p = 0.01). Parental education level and household income were also assessed separately, with similar results. Interaction analysis revealed no significant effects apart from an interaction effect for breakfast behaviour (p = 0.02). Conclusions The health-promotion programme “Join the Healthy Boat” has the potential to promote children’s health via a school-based intervention and therefore, reach all children independent from their background. This study shows vast gaps between several health behaviours of primary school children depending on their SES, favouring those children coming from more privileged families. A longer implementation may possibly show more effects. Trial registration DRKS00000949.

Background Pregnancy vulnerability contributes to poor perinatal mental health. Proper cross-sectoral collaboration may mitigate perinatal mental health problems. General practitioners (GPs) often face barriers when assessing pregnancy vulnerability, but little is known about GPs’ perceived barriers to the cross-sectoral collaboration on vulnerable pregnant women.Objective To explore GPs’ barriers to cross-sectoral collaboration on pregnant women with vulnerabilities, and how barriers are associated with the organization of antenatal care (ANC) and general practice characteristics.Design, setting and subjects A cross-sectional questionnaire study among Danish GPs (n = 3465).Main outcome measures Descriptive statistics according to the Theoretical Domains Framework describes the barriers to collaboration. Analytical statistics with ordered logistic regression models demonstrate associations between selected barriers (the main outcome measures) and organization of ANC, GP and practice, characteristics.Results A total of 760 GPs (22%) participated. Perceived GP barriers to collaboration were lacking knowledge of ANC levels relevant to vulnerable pregnant women, insufficient information on vulnerability indicators from collaborating parties, heavy workload and insufficient remuneration for collaborative meetings. Being young were associated with insufficient GP knowledge of ANC levels. Old age was associated with less likelihood of experiencing heavy workload as a barrier.Conclusions Barriers to collaboration on vulnerable pregnant women were associated with some GP-organizational characteristics including low experience in collaborating with partners in ANC, and GP characteristics, such as age. Reducing general practice workload, e.g. by reorganizing priority areas, releasing more time to vulnerable patients, and improving cross-sectoral information sharing on vulnerability might improve collaboration on vulnerable pregnant women.

Throughout the tree of life RNA-binding proteins play important roles, but they are poorly characterized in cyanobacteria. Overexpression of the predicted RNA-binding protein Ssr1238 in the cyanobacterium Synechocystis 6803 for 24 h led to higher levels of RNase P RNA, tRNAs, and stress-related mRNAs. Co-immunoprecipitation of proteins followed by MS analysis and sequencing of UV crosslinked, co-immunoprecipitated RNA samples identified potential interaction partners of Ssr1238. The most enriched transcript was RNase P RNA, and RnpA, the protein component of RNase P, was among the most highly enriched proteins. A second highly enriched transcript is derived from gene ssl3177, which encodes a central enzyme in cell wall remodelling during cell division. The data also showed a strong connection to the RNA maturation and modification system indicated by co-precipitation of RNA modifying enzymes, riboendonuclease E and enolase. Surprisingly, cyanophycin synthetase and urease were highly enriched as well. In conclusion, Ssr1238 specifically binds to two different transcripts and could be involved in the coordination of RNA maturation, translation, cell division, and aspects of nitrogen metabolism. Our results are consistent with recent findings that the B. subtilis YlxR protein functions as an RNase P modulator (RnpM), extending its proposed role to the phylum cyanobacteria, and suggesting additional functionalities.

Background and objective: Urosymphyseal fistula (UF) and pubic osteomyelitis (PO) are rare and often poorly recognized long-term complications of treatment for localized prostate cancer. Our aim was to describe UF/PO in prostate cancer survivors. Methods: We performed a retrospective review of 26 patients treated for UF/PO after localized prostate cancer treatment at University Hospitals Leuven (1996–2021). We analyzed data for demographic characteristics, history, urethral manipulations (UMs), diagnostic and therapeutic approaches, microbiology, and treatment success. Key findings and limitations: Before diagnosis, 80.8% of the patients had undergone RP, 88.5% received radiotherapy, and 84.6% had at least one UM. The median time from radiotherapy (RT), the last UM, and the first symptoms to diagnosis were 102 mo, 4 mo, and 43 d, respectively. Treatment included cystectomy (n = 19), bladder-sparing interventions (n = 5), and conservative treatment (n = 2). Pubic debridement was required in 21 patients. All cystectomy patients had a history of RT. Imaging-detected UF led to cystectomy in 94.1% of cases. Full conservative treatment succeeded only in non-irradiated patients. Bone cultures were positive in 95% of cases and discordant with urine cultures in 82.4%. Reinterventions and severe complications affected 56.5% of patients; all were UF/PO-free after up to four treatment attempts. Our study is limited by the small sample size, retrospective nature, and possible information and referral bias. Conclusions and clinical implications: UF/PO can occur years after local prostate cancer treatment. Risk factors include RT and UMs. Conservative treatment rarely succeeds, particularly in irradiated patients with persistent UF. Most patients require multidisciplinary treatment involving cystectomy and pubic debridement. A perioperative bone culture to guide postoperative antibiotic treatment is crucial because of discordance with urine cultures. Postoperative complications are common, often requiring reintervention. Caution with UMs is advised after pelvic RT. Patient summary: We looked at data for patients with a rare complication that can occur after treatment for localized prostate cancer that involves a small tunnel between the lower urinary tract and the pubic bone, and infection in the pubic bone. Diagnosis occurred years after pelvic radiotherapy and shortly after a procedure performed through the urethra, typically surgery for narrowing of the urethra. Most patients needed removal of their bladder and surgical cleaning of the pubic bone, followed by long-term antibiotics. The bacteria found in bone were often different from those found in the patient’s urine, which is important in guiding antibiotic treatment after surgery.

Background: After pylorus-resecting pancreatoduodenectomy (PrPD), delayed gastric emptying (DGE) might partially be attributed to biliary reflux. We investigated whether the incidence of primary DGE is reduced after Roux-en-Y instead of Billroth-II reconstruction. Methods: Patients undergoing PrPD from 2016 to 2019 at a high-volume center were identified. Excluding causes of secondary DGE, we matched patients with Roux-en-Y and Billroth-II reconstruction in a 1:2 ratio and compared primary DGE. Results: In 24 vs. 48 (Roux-en-Y vs. Billroth-II) patients, DGE (grade B/C) incidence (20.8 % vs. 18.8 %; P = 1.000), nasogastric tube requirement (median 2 vs. 2 days; P = 0.844) and time to solid food intake (7 vs. 7 days; P = 0.933) were comparable. Univariable logistic regression showed no association between DGE and Roux-en-Y reconstruction (OR 1.47; P = 0.524), in contrast to age (1.08; P = 0.030) and pancreatic biochemical leak (4.98; P = 0.007). Conclusions: Primary DGE did not differ between Roux-en-Y and Billroth-II reconstruction after PrPD. Instead, age and postoperative pancreatic biochemical leak were associated with higher DGE risk.

Vertical profiles of salinity, and isotopic abundance ratios of hydrogen (δ2H) and oxygen (δ18O) of 18 landfast ice cores, collected along the northeast coast of James Bay in March 2019, and one ice core collected in Belcher Islands, were used to obtain the winter timeseries of the spatiotemporal evolution of the under-ice plume of La Grande River (LGR), the dominant river in the area. Variability in the isotopic composition and salinity of the ice cores indicated changes to the water source composition at the ice–water interface when the ice layers formed. The increased presence of river water beneath the ice during January–March was marked by more negative isotopic ratios in the lower portion of the ice as river discharge was increased for hydroelectric production. River water was the source of ∼43% of the ice in our ice core samples (n = 320) with the interquartile range from 16% to 71%. The river water fractions incorporated into the ice indicate that LGR under-ice plume extended more than 75 km north and at least 30 km south of the river mouth for ∼3 months. These findings correspond well with more challenging to obtain hydrographic observations. End-of-winter ice core sampling and analysis for isotopic abundance has potential as a tool to monitor dispersal of LGR discharge into the ice-covered coastal environment.

Indigenous-driven and community-partnered research projects seeking to develop salient, legitimate, and credible knowledge bases for environmental decision-making require a multiple knowledge systems approach. When involving partners in addition to communities, diverging perspectives and priorities may arise, making the pathways to engaging in principled research while generating actionable knowledge unclear to disciplinarily-trained natural science researchers. Here, we share insights from the Eeyou Coastal Habitat Comprehensive Research Project (CHCRP), an interdisciplinary, Cree-driven community-academic partnership. This project brought together Cree community members, regional organizations, industry (Hydro-Québec), and academics from seven universities across Canada to address the unprecedented loss of seagrass Zostera marina (eelgrass), the concurrent decline in migratory Canada geese and its impact on fall goose harvest activities in Eeyou Istchee. After describing the history and context of the project, we discuss the challenges, complexities, and benefits of the collaborative approach balancing saliency, legitimacy, and credibility of the knowledge produced. We suggest the paper may be of use to researchers and partners seeking to engage in principled and actionable research related to environmental change including impacts of past development.

Thinning sea ice cover and earlier melt in the Arctic impact primary producer (PP) phenology, causing earlier ice algal bloom termination and phytoplankton bloom commencement. However, logistic constraints limit capturing the complete seasonal evolution of PPs and their physical drivers. Here, we combine spectral irradiance data from subsurface oceanographic moorings with synthetic aperture radar backscatter and meteorological variables to study light in Dease Strait, investigating its relation to timing and magnitude of surface PPs for 2017 and 2019. Ice algal blooms in 2017 and 2019 lasted 66 and 84 days, respectively, peaking within 2 days of snow melt onset. In 2019, lower temperatures and a deeper snowpack before snow melt extended the ice algal bloom. Melt pond formation increased light transmission, enabling a short, 6–7-day under-ice phytoplankton bloom in both years that was likely nutrient-limited. The 2019 phytoplankton bloom was less productive, possibly due to the longer ice algal bloom depleting surface nutrients. After ice break-up in 2019, a 31-day late-summer bloom occurred via wind-driven mixing. Our findings suggest that the combined remote sensing technique has novel applicability in other settings, providing insights into the changing state of PP phenology, and the need for long-term Arctic observations to discern regional climate change effects.

Abstract Structure predictions have become invaluable tools, but viral proteins are absent from the EMBL/DeepMind AlphaFold database. Here, we provide proteome-wide structure predictions for all nine human herpesviruses and analyze them in depth with explicit scoring thresholds. By clustering these predictions into structural similarity groups, we identified new families, such as the HCMV UL112-113 cluster, which is conserved in alpha- and betaherpesviruses. A domain-level search found protein families consisting of subgroups with varying numbers of duplicated folds. Using large-scale structural similarity searches, we identified viral proteins with cellular folds, such as the HSV-1 US2 cluster possessing dihydrofolate reductase folds and the EBV BMRF2 cluster that might have emerged from cellular equilibrative nucleoside transporters. Our HerpesFolds database is available at https://www.herpesfolds.org/herpesfolds and displays all models and clusters through an interactive web interface. Here, we show that system-wide structure predictions can reveal homology between viral species and identify potential protein functions.

Abstract The collective dynamics of self-organised systems emerge from the decision rules agents use to respond to each other and to external forces. This is evident in groups of animals under attack from predators, where understanding collective escape patterns requires evaluating the risks and rewards associated with particular social rules, prey escape behaviour, and predator attack strategies. Here, we find that the emergence of the ‘fountain effect’, a common collective pattern observed when animal groups evade predators, is the outcome of rules designed to maximise individual survival chances given predator hunting decisions. Using drone-based empirical observations of schooling sardine prey (Sardinops sagax caerulea) attacked by striped marlin (Kajikia audax), we first find the majority of attacks produce fountain effects, with the dynamics of these escapes dependent on the predator’s attack direction. Then, using a spatially-explicit agent-based model of predator-prey dynamics, we show that fountain manoeuvres can emerge from combining an optimal individual prey escape angle with social interactions. The escape rule appears to prioritise maximising the distance to the predator and creates conflict in the effectiveness of predators’ attacks and the prey’s avoidance, explaining the empirically observed predators’ attack strategies and the fountain evasions produced by prey. Overall, we identify the proximate and ultimate explanations for fountain effects and more generally highlight that the collective patterns of self-organised predatory-prey systems can be understood by considering both social escape rules and attack strategies.

Abstract Background Neurofibromatosis type 1 (NF1) is a genetic condition characterized by various somatic manifestations and cognitive impairments, but the latter are sparsely described in adults. This study aimed at characterizing potential impairments of neurocognitive functions using neuropsychological tests as well as a self-report questionnaire. Methods In a nationwide, population-based study including 103 adults with NF1 and 38 age- and gender-matched NF1-free comparisons, we used a comprehensive neurocognitive test battery to assess intelligence and visual short-term memory, immediate visuospatial recall, reaction time, sustained attention, motor speed, planning, planning time, working memory as well as multitasking and a questionnaire to assess executive functions. Descriptive statistics, multivariate analysis of variance (MANOVA), and general linear models with repeated measure analysis of variance (ANOVA) were used. Results We observed a statistically significant difference in overall performance-based cognitive functioning. Adults with NF1 showed significant, moderate-to-severe impairments in intelligence, visual short-term memory, immediate visuospatial recall, sustained attention (p

Abstract Background Understanding environmental correlates of sedentary behaviour (SB) among young people is important as such data can identify approaches to limit sedentary time. This paper estimates associations of parent-reported neighbourhood and adolescent-reported home environments with SB among adolescents aged 11–19 years from 14 countries. Methods In the International Physical activity and the Environment Network (IPEN) Adolescent Study (an observational, cross-sectional multi-country study), adolescents wore a triaxial accelerometer for seven days that assessed sedentary time (ST). Adolescents completed survey measures of sedentary behaviour (SB) related to recreational screen time and sitting time in motor vehicles. Parents and adolescents completed surveys assessing neighbourhood and home environments. Accelerometer based ST was available in 3,982 adolescents while survey data were available for 6,302 dyads. We estimated the total and direct effects of each environmental attribute on ST and SB. Sex of the adolescent and city/country were examined as moderators. Results The average ST in adolescents from 14 countries ranged from 7.8 to 10.5 h/day. Personal social media was the only significant correlate of total ST across both sexes. With respect to self-reported SB, adolescents accumulated an average of 3.8 h of non-school screen time per day and nearly 40 min of transport-related sitting time. Screen time was associated with all home environment variables, including social media account, as well as land use mix—diversity, traffic safety, and crime safety. Transport-related sitting time was related to land use mix—diversity, recreation facilities, walking facilities, and pedestrian infrastructure, but no home environment variables. City/country and sex were significant moderators of several associations. Conclusions Both home and neighbourhood environment features were related to ST and SB. Having social media accounts emerged as a major contributor towards sedentarism in adolescents.

Abstract Background Long-axial field-of-view (LAFOV) Positron Emission Tomography (PET) scanners provide high sensitivity, but throughput is limited because of time-consuming patient positioning. To enhance throughput, a novel Walk-Through PET (WT-PET) scanner has been developed, allowing patients to stand upright, supported by an adjustable headrest and hand supports. This study evaluates the degree of motion in the WT-PET system and compares it with the standard PET-CT. Methods Three studies were conducted with healthy volunteers to estimate motion. The first two studies assessed motion in the WT-PET’s Design I (Study 1) and Design II (Study 2), while the third study compared motion on a standard PET-CT scanner bed (Study 3). Infrared markers placed on the head, shoulders, chest, and abdomen were tracked and processed using image-processing techniques involving thresholding and connected component analysis. Videos were recorded for normal breathing and breath-holding conditions, and 2D centroids were transformed into 3D coordinates using depth information. Results The results shows a significant reduction in motion during breath-holding, especially for the abdomen. Mean motion distances decreased from 2.63 mm to 2.18 mm in Study 1 and from 2.42 mm to 1.67 mm in Study 2. Statistical analysis revealed notable differences in motion between the WT-PET and mCT scanners. The Shapiro-Wilk test indicated non-normal motion distributions in the head, right shoulder, and abdomen for both systems, leading to the use of the Wilcoxon signed-rank test for all markers. Significant differences were found in the right shoulder (p = 0.0266), left shoulder (p = 0.0004) and chest (p < 0.0001) but no significant differences were observed in the head (p = 0.1327) and abdomen (p = 0.8404). Conclusion This study provides a comprehensive analysis of patient motion in a WT-PET scanner with respect to the standard PET. The findings highlight a significant increase in shoulder and chest motion, while the head and abdomen regions showed more stability.

Abstract The transformation of the energy system towards sustainable energy sources is characterized by an increase in weather dependent distributed energy resources (DER). This adds a layer of uncertainty in energy generation on top of already uncertain load distribution. At the same time, many households are fitted with renewable generation units and storage systems. The increased intermittent generation in the distribution grid leads to new challenges for the commitment and economic dispatch of DER. The main challenge addressed in this work is to decide which available resources to select for a given task. To solve this, we introduce Stochastic Resource Optimization (SRO), a general purpose, combinatorial, chance-constrained optimization model for the short-term economic selection of stochastic DER. It incorporates correlations between stochastic resources are using copula theory. The contributions of this paper are twofold: First, we validate the applicability of the SRO formulation on a simplified congestion management use-case in a small neighbourhood grid comprised of prosumer households. Second, we provide an analysis of the performance of different solving algorithms for SRO problems and their run-times. Our results show that a fast metaheuristic algorithm can provide high quality solutions in acceptable time on the evaluated problem sets.

Abstract Geochemical proxies are frequently utilized in the reconstruction of past ocean temperatures. Due to resource constraints, these reconstructions typically rely on a single sediment core, raising questions about the local and regional representativeness of paleotemperature records. To address this, we analyzed four sediment cores located within a 10-km radius in the northern Okinawa Trough (OT), which share the same climatic forcing and thus should reflect similar climate variations. We compiled published data and generated new paleotemperature estimates based on three widely used geochemical proxies (foraminiferal Mg/Ca, $${\text{U}}_{37}^{{{\text{K}}^{\prime}}}$$ U 37 K ′ , $${\text{TEX}}_{86}$$ TEX 86 ). Analysis of the mean absolute deviations for nearby records based on the same proxy revealed that $${\text{U}}_{37}^{{{\text{K}}^{\prime}}}$$ U 37 K ′ has the highest reproducibility, followed by Mg/Ca and $${\text{TEX}}_{86}$$ TEX 86 . However, inconsistencies in inter-proxy offsets among nearby sites suggest the presence of noise in the proxy records, likely stemming from instrumental errors and sediment heterogeneity. Furthermore, the Mg/Ca and $${\text{U}}_{37}^{{{\text{K}}^{\prime}}}$$ U 37 K ′ paleotemperature records agree within uncertainty when accounting for inter-site variability and calibration uncertainties, challenging previous interpretations of temperature signals from different seasons. All proxies indicate similar glacial-interglacial trends, albeit with varying magnitudes of temperature change. Both Mg/Ca and $${\text{U}}_{37}^{{{\text{K}}^{\prime}}}$$ U 37 K ′ records suggest a glacial cooling of ~ 3 °C, whereas $${\text{TEX}}_{86}$$ TEX 86 sea surface temperature (SST) data indicate a stronger glacial cooling of approximately ~ 6–8 °C. Modern observations indicate a subsurface $${\text{TEX}}_{86}$$ TEX 86 recording depth of 50–100 m, coinciding with the thermocline. However, the $${\text{TEX}}_{86}$$ TEX 86 subsurface temperature (subT) record does not resemble the Mg/Ca records of thermocline-dwelling foraminifera species. Instead, there is a better agreement with benthic foraminiferal Mg/Ca records of Uvigerina spp. (~ 700 m) and the intermediate temperature record derived from radiolarian assemblages (~ 500 m), pointing to a $${\text{TEX}}_{86}$$ TEX 86 recording depth that is deeper than the thermocline. In summary, our findings show that proxy noise can impact inter-proxy comparisons of paleotemperature records, but not the direction of glacial-interglacial shifts. Future research should prioritize constraining the recording depth of paleotemperature proxies and reducing calibration uncertainty for more precise and reliable quantitative paleotemperature reconstruction.

Abstract Introduction Nasal high flow (NHF) is a popular technique to provide support in respiratory failure in different conditions. Recently published bench studies have hypothesized that airway pressure can be increased by using different cannula sizes and corresponding prongs resulting in a range of prong-nare ratios. We conducted this study to verify these experimental findings in clinical practice. Methods We characterized prong size and flow rate dependent changes in ventilation parameters and changes in hypercapnia in an interventional clinical setting. Outcome parameters included changes in mean airway pressure, tidal volume (TV), respiratory rate (RR), minute volume (MV) and decrease in pCO2. The ventilatory parameters were determined at 20, 30, 40 and 50 l/min with 3 different prong sizes. 20 and 40 l/min and the 3 different prong sizes were used to document the changes in pCO2. Results In this study we demonstrate changes in ventilation with increasing flow rates of NHF. A significant increase in mean airway pressure was seen with every 10 l/min increase in flow rate. Respiratory rate and minute volume (using large prongs) changed significantly with larger increases in flow rate, while tidal volume was not significantly altered. When the flow rate was increased by 20 l/min (i.e. from 20 l/min to 40 l/min) capillary pCO2 decreased significantly. None of the measured values were significantly altered by the prong size used. Conclusion In summary, we presented strong indications that different prong sizes have no influence on essential respiratory parameters or the elimination of pCO2 when using NHF in COPD patients.

Abstract Current legislation and market dynamics require and encourage systems to become more open and interoperable. Given this shift, the challenge arises as to how service providers can navigate such environments and whether and how known platform economics are affected by that change. In this context, our work investigates behavior when users interact with services in highly interoperable environments, examining the influence of service attributes and platform economics on service selection and switching decisions, with a focus on the role of transaction cost and time, onboarding time, privacy, ownership, and community. For this purpose, we designed and conducted an extensive survey study with more than 500 respondents that combined a conjoint study with an experimental part on switching scenarios. Our findings suggest that transaction features such as cost, time, and privacy are the main factors in service selection with part-worth utilities being 2.1 to 14.7 times higher than non-transactional features. Additionally, building a strong community and offering ownership opportunities to users are effective strategies for customer retention. Further, we observe that rational choice theory does not explain switching decisions in many cases. Our study has important implications for both industry practitioners and policymakers. Practitioners can use our results to carefully manage effective customer retention strategies, while policymakers can use them to better regulate digital markets.

Abstract The Cyprus Biobank collects biosamples, medical and lifestyle information with the aim of reaching 16,500 Cypriots aged ≥ 18-years, by year 2027, as part of a multitasked EU funded project. Volunteers are both from the general population and from disease cohorts of focused research projects, who amongst others will contribute to canvas the architecture of the Cyprus human genome and study the healthy and morbid anatomy of Cypriots. The Cyprus Biobank is a research infrastructure pillar of the biobank.cy Center of Excellence in Biobanking and Biomedical Research. Within 3-years (November 2019–October 2022), 1348 participants of the general population who represent a subset of the Cyprus Biobank recruited individuals, were enrolled in the pilot study. The study did not include individuals from separate disease-specific cohorts. Extensive information was collected from each participant, including biochemistry, complete blood count, physiological, anthropometric, socio-demographic, diet, and lifestyle characteristics. Prevalent health conditions along with medication use and family history were recorded, including 58 biomarkers based on blood and urine samples. With a systematic recruitment campaign, the Biobank is continuously increasing the number of individuals in the general population cohort and is developing separate disease cohorts of the Cypriot population. The pilot study enrolled 579 men and 769 women, aged between 18 and 85 years (median 48-years). The enrollment takes 40 min on average, including the collection of biological samples and phenotypic information. More than half (n = 733, 55%) of the participants are educated to college level or above. Statistically significant differences were found between men and women regarding their education level (p

Abstract Background To meaningfully understand outcomes of gender-affirming care, patient-reported outcome measures (PROMs) that are grounded in what matters to individuals seeking care are urgently needed. The objective of this study was to develop a comprehensive PROM to assess outcomes of gender-affirming care in clinical practice, research, and quality initiatives (the GENDER-Q). Methods Internationally established guidelines for PROM development were used to create a field test version of the GENDER-Q. In-depth interviews were conducted from December 2018 to March 2020 with youth and adults aged 16 years and older who were seeking or had received gender-affirming care at outpatient clinics providing gender-affirming care located within tertiary care centers or communities in Canada, Denmark, the Netherlands or the US. Data were analyzed and used to develop a conceptual framework and an item pool, which was used to develop preliminary scales. Between February 2021 to November 2021, iterative feedback was sought from clinicians and patient participants on the scales and used to refine or develop new scales. The revised scales were pilot-tested using a crowd-sourcing platform between February 2022 and April 2022. Results Data from interviews with 84 participants (aged 34 ± 14 years) resulted in a conceptual framework of the GENDER-Q with 13 domains measuring health-related quality of life, sexual, urination, gender practices, voice, hair, face and neck, body, breasts, genital feminization, chest, genital masculinization, and experience of care. Preliminary versions of 44 scales were developed covering most concepts in the conceptual framework. Iterative feedback was obtained from clinician experts (4 to 37 experts per scale; response rate, 67%) and 7–14 patient participants (depending on scale). All scales were refined, and 15 new scales were developed, resulting in 55 scales in the field test version of the GENDER-Q. In total, 601 transgender and gender diverse (TGD) people (aged 25 ± 6 years) participated in the pilot field test and the data were used to make changes to the field test survey. Conclusion The GENDER-Q was developed using extensive input from TGD individuals and clinician experts and represents the most comprehensive set of independently functioning scales that are available to date. An international field test of the GENDER-Q was completed in 2024 and the GENDER-Q is available for use in patient care, clinical research and quality improvement efforts.

Abstract Germinal center (GC) formation, which is an integrant part of humoral immunity, involves energy-consuming metabolic reprogramming. Rag-GTPases are known to signal amino acid availability to cellular pathways that regulate nutrient distribution such as the mechanistic target of rapamycin complex 1 (mTORC1) pathway and the transcription factors TFEB and TFE3. However, the contribution of these factors to humoral immunity remains undefined. Here, we show that B cell-intrinsic Rag-GTPases are critical for the development and activation of B cells. RagA/RagB deficient B cells fail to form GCs, produce antibodies, and to generate plasmablasts during both T-dependent (TD) and T-independent (TI) humoral immune responses. Deletion of RagA/RagB in GC B cells leads to abnormal dark zone (DZ) to light zone (LZ) ratio and reduced affinity maturation. Mechanistically, the Rag-GTPase complex constrains TFEB/TFE3 activity to prevent mitophagy dysregulation and maintain mitochondrial fitness in B cells, which are independent of canonical mTORC1 activation. TFEB/TFE3 deletion restores B cell development, GC formation in Peyer’s patches and TI humoral immunity, but not TD humoral immunity in the absence of Rag-GTPases. Collectively, our data establish the Rag GTPase-TFEB/TFE3 pathway as a likely mTORC1 independent mechanism to coordinating nutrient sensing and mitochondrial metabolism in B cells.

Abstract Non-homologous end joining (NHEJ) is the predominant pathway that repairs DNA double-stranded breaks (DSBs) in vertebrates. However, due to challenges in detecting DSBs in living cells, the repair capacity of the NHEJ pathway is unknown. The DNA termini of many DSBs must be processed to allow ligation while minimizing genetic changes that result from break repair. Emerging models propose that DNA termini are first synapsed ~115 Å apart in one of several long-range synaptic complexes before transitioning into a short-range synaptic complex that juxtaposes DNA ends to facilitate ligation. The transition from long-range to short-range synaptic complexes involves both conformational and compositional changes of the NHEJ factors bound to the DNA break. Importantly, it is unclear how NHEJ proceeds in vivo because of the challenges involved in analyzing recruitment of NHEJ factors to DSBs over time in living cells. Here, we develop an approach to study the temporal and compositional dynamics of NHEJ complexes using live cell single-molecule imaging. Our results provide direct evidence for stepwise maturation of the NHEJ complex, pinpoint key regulatory steps in NHEJ progression, and allowed us to estimate the overall repair capacity of the NHEJ pathway in living cells.

Abstract Background Metastatic prostate cancer remains a therapeutic challenge. Based on data of the STAMPEDE trial, patients with a low metastatic burden showed prolonged failure-free and overall survival when treated with prostate radio therapy (RT) in addition to standard of care (SOC). The objective of this study was to determine the cost-effectiveness of additional prostate RT compared to SOC alone for following subgroups: non-regional lymph node (NRLN) metastases, up to three bone metastases and four or more bone metastases. Methods A partitioned survival model was implemented with clinical data from STAMPEDE trial. Analyses were performed from a United States healthcare system perspective. Costs for treatment and adverse events were derived from Medicare coverage. Utilities for health states were derived from public databases and literature. Outcome measurements included incremental costs, effectiveness, and cost-effectiveness ratio. The willingness-to-pay threshold was set to USD 100,000 per quality-adjusted life year (QALY). Results Additional RT led to 0.92 incremental QALYs with increased costs of USD 26,098 with an incremental cost-effectiveness ratio (ICER) of USD 28,452/QALY for patients with only NRLN metastases and 3.83 incremental QALYs with increased costs of USD 153,490 with an ICER of USD 40,032/QALY for patients with up to three bone metastases. Sensitivity analysis showed robustness of the model regarding various parameters. In probabilistic sensitivity analysis using Monte Carlo simulation with 10,000 iterations, additional RT was found as the cost-effective strategy in over 96% for both subgroups iterations at a willingness-to-pay threshold of USD 100,000/QALYs. Conclusions Additional RT is cost-effective in patients with only NRLN metastases and up to three metastases compared to SOC.

Abstract A central building block of many quantum algorithms is the diagonalization of Pauli operators. Although it is always possible to construct a quantum circuit that simultaneously diagonalizes a given set of commuting Pauli operators, only resource-efficient circuits can be executed reliably on near-term quantum computers. Generic diagonalization circuits, in contrast, often lead to an unaffordable SWAP gate overhead on quantum devices with limited hardware connectivity. A common alternative is to exclude two-qubit gates altogether. However, this comes at the severe cost of restricting the class of diagonalizable sets of Pauli operators to tensor product bases (TPBs). In this article, we introduce a theoretical framework for constructing hardware-tailored (HT) diagonalization circuits. Our framework establishes a systematic and highly flexible procedure for tailoring diagonalization circuits with ultra-low gate counts. We highlight promising use cases of our framework and – as a proof-of-principle application – we devise an efficient algorithm for grouping the Pauli operators of a given Hamiltonian into jointly-HT-diagonalizable sets. For several classes of Hamiltonians, we observe that our approach requires fewer measurements than conventional TPB approaches. Finally, we experimentally demonstrate that HT circuits can improve the efficiency of estimating expectation values with cloud-based quantum computers.

Abstract Robust spin-photon interfaces with optical transitions in the telecommunication band are essential for quantum networking technologies. Erbium (Er) ions are the ideal candidate with environmentally protected transitions in telecom-C band. Finding the right technologically compatible host material to enable long-lived spins remains a major hurdle. We introduce a new platform based on Er ions in cerium dioxide (CeO2) as a nearly-zero nuclear spin environment (0.04%) epitaxially grown on silicon, offering silicon compatibility for opto-electrical devices. Our studies focus on Er3+ ions and show a narrow homogeneous linewidth of 440 kHz with an optical coherence time of 0.72 μs at 3.6 K. The reduced nuclear spin noise enables a slow spin-lattice relaxation with a spin relaxation time up to 2.5 ms and an electron spin coherence time of 0.66 μs (in the isolated ion limit) at 3.6 K. These findings highlight the potential of Er3+:CeO2 platform for quantum networks applications.

Abstract Parkinson’s disease, an aging-associated neurodegenerative disorder, is characterised by nigrostriatal pathway dysfunction caused by the gradual loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain. Human in vitro models are enabling the study of the dopaminergic neurons’ loss, but not the dysregulation within the dopaminergic network in the nigrostriatal pathway. Additionally, these models do not incorporate aging characteristics which potentially contribute to the development of Parkinson’s disease. Here we present a nigrostriatal pathway model based on midbrain-striatum assembloids with inducible aging. We show that these assembloids can develop characteristics of the nigrostriatal connectivity, with catecholamine release from the midbrain to the striatum and synapse formation between midbrain and striatal neurons. Moreover, Progerin-overexpressing assembloids acquire aging traits that lead to early neurodegenerative phenotypes. This model shall help to reveal the contribution of aging as well as nigrostriatal connectivity to the onset and progression of Parkinson’s disease.

Abstract Lassa virus (LASV) is a rodent-borne mammarenavirus that causes tens to hundreds of thousands of human infections annually in Western Africa. Approximately 20% of these infections progress to Lassa fever (LF), an acute disease with case–fatality rates from ≈20–70%. Currently, there are no approved vaccines or specific therapeutics to prevent or treat LF. The LASV genome consists of a small (S) segment that has two genes, GP and NP, and a large (L) segment that has two genes, L and Z. In both segments, the two genes are separated by non-coding intergenic regions (IGRs). Recombinant LASVs (rLASVs), in which the L segment IGR was replaced with the S segment IGR or in which the GP gene was codon-deoptimized, lost fitness in vitro, were highly attenuated in vivo, and, when used as vaccines, protected domesticated guinea pigs from otherwise lethal LASV exposure. Here, we report the generation of rLASV/IGR-CD, which includes both determinants of attenuation and further enhances the safety of the vaccine compared with its predecessors. rLASV/IGR-CD grew to high titers in Vero cells, which are approved for human vaccine production, but did not cause signs of disease or pathology in guinea pigs. Importantly, guinea pigs vaccinated with rLASV/IGR-CD were completely protected from disease and death after a typically lethal exposure to wild-type LASV. Our data support the development of rLASV/IGR-CD as a live-attenuated LF vaccine with stringent safety features.

Abstract Background Injection of autologous adipose-derived regenerative cells (ADRCs) combined with lipotransfer has been suggested to alleviate symptoms in diseases including breast cancer-related lymphedema (BCRL). We recently performed a randomized controlled trial injecting lipoaspirate with ADRCs into the axilla of BCRL patients, and here we aimed in the intervention group to define in an unbiased fashion whether ADRC injection was linked to the clinical outcome. Methods 39 BCRL patients received lipotransfer assisted with autologous ADRCs (4.20 × 107 ± 1.75 × 107 cells) whereas 41 BCRL patients were included for placebo treatment. At 12 month follow-up, we assessed quality of life, lymphangiography, and bioimpedance enclosing 59 outcome parameters. Multifactorial analysis of clinical outcomes was used to define responders and non-responders to the intervention, and collected ADRCs from these patient groups were analyzed by single cell RNA sequencing (scRNAseq). Results Unbiased multifactorial analysis ranked and defined the clinical outcomes (Sf36 physical change, L-Dex Lymph Change, ICG mdanderson change) with the highest effect on BCRL patients. The 10 patients with the highest- and lowest effect (five responders and five non-responders) were included in the study. No difference between non-responders and responders were observed for injected ADRC number/size/viability (p > 0.05). In scRNAseq, we did not find any major difference (p > 0.05) between groups in ADRC composition regarding adipose derived stem cells, endothelial-, smooth muscle-, T-, B-, mast cells as well as macrophages, which was verified by flow cytometry. Differential subcluster gene expression between groups were for 92.5% of genes, including those encoding secretory proteins, below the threshold of 1.5, and thus neglible. Together this suggested that the ADRC phenotype was indistinguishable between BCRL responders and non-responders to the intervention. Conclusion Our data suggest that the ADRC injection and ADRC phenotype or heterogeneity have no effect on the clinical outcomes on BCRL, and ADRC assisted lipotranfer for BCRL should therefore not be considered currently.

Abstract Background There are several strategies used to assess involvement in their healthcare across service providers. However, there is no consensus on the most appropriate measurement tool to use when evaluating patient involvement initiatives. This qualitative study aimed to explore the perspectives of stakeholders from micro, meso, and macro levels within the Danish healthcare system on measuring patient involvement in their healthcare. Methods This descriptive, explorative study employed semi-structured interviews with open-ended questions to elicit participants’ views and experiences of patient involvement and measurement tools. A purposeful sample of participants was identified, to include decision makers, researchers, and health professionals (n = 20) with experiences of measuring patient involvement in healthcare at micro, meso, and macro levels across Danish organizations. Data underwent reflexive thematic analysis. Results Three main themes were identified: 1) Determining the purpose of patient involvement practices and measurement alignment; 2) Reflecting on the qualities, fit, and usefulness of measures; 3) Recognizing conflicting stakeholder paradigms. Despite the interest in and positive attitudes toward patient involvement innovations, views on the meaning and value of evaluating involvement varied; in part, this was attributable to challenges in selecting criteria, methods, and measures for evaluation. Conclusion The findings indicate the need to integrate the perspectives of all key stakeholders in designing the evaluation of patient involvement initiatives. The application of a multiple stakeholder approach and co-production of a multidimensional evaluation may provide some common ground for selecting evaluation criteria and measurement tools in the healthcare setting. Trial registration Danish Data Protection Agency (1–16-02–400-21) 15 October 2021.

Abstract Participant management in a lung cancer screening (LCS) depends on the assigned Lung Imaging Reporting and Data System (Lung-RADS) category, which is based on reliable detection and measurement of pulmonary nodules. The aim of this study was to compare the agreement of two AI-based software tools for detection, quantification and categorization of pulmonary nodules in an LCS program in Northern Germany (HANSE-trial). 946 low-dose baseline CT-examinations were analyzed by two AI software tools regarding lung nodule detection, quantification and categorization and compared to the final radiologist read. The relationship between detected nodule volumes by both software tools was assessed by Pearson correlation (r) and tested for significance using Wilcoxon signed-rank test. The consistency of Lung-RADS classifications between Software tool 1 (S1, Aview v2.5, Coreline Soft, Seoul, Korea) and Software tool 2 (S2, Prototype ‘’ChestCTExplore’’, software version ToDo, Siemens Healthineers, Forchheim, Germany) was evaluated by Cohen’s kappa (κ) and percentual agreement (PA).The derived volumes of true positive nodules were strongly correlated (r > 0.95), the volume derived by S2 was significantly higher than by S1 (P

Abstract Circulating tumor cell separation has been the focus of numerous studies owing to its importance in the diagnosis, prognosis, and therapy of cancer. This study reports a highly efficient microfluidic device that integrates a specialized dielectrophoresis configuration, namely the facing-electrode configuration dielectrophoresis (FEC-DEP) structure, to isolate circulating tumor cells (CTCs) from various blood components, including red blood cells, white blood cells, and platelets. The FEC-DEP design features a bottom-slanted electrode array positioned parallel to a basic rectangular top electrode. A non-homogeneous electric field is produced between these parallel electrodes, generating dielectrophoretic forces acting on cells. Consequently, when the FEC-DEP is integrated into a flow, it can direct various biological objects in the flow along separate trajectories. As a result, cells with comparable characteristics might move together within a similar path. This configuration may simplify the microfabrication process and lessen dependency on particle position within the microchannel. The separation process was numerically analyzed using the finite element method, and device parameters were optimized to obtain high-efficiency and high-purity cell separation. The simulations show that the microfluidic device may effectively enrich tumor cells in a label-free and non-invasive manner, with a high-efficiency rate of almost 80%.

Abstract While Early Live Adversity (ELA) is a known risk factor for mental and physical diseases, the investigation into the mechanisms behind this connection is ongoing. In the present study, we investigated whether ELA blunts the relaxation response in healthy adults. Using a within-subjects design, we employed a paced breathing exercise (four seconds inhale, six seconds exhale) and a 360° nature video as relaxation interventions while measuring physiological relaxation using heart rate variability and subjective relaxation using the Relaxation State Questionnaire. A total of 103 participants (63.11% female; agemean = 22.73 ± 3.43 years) completed the Parental Bonding Instrument and the Childhood Trauma Questionnaire to assess ELA retrospectively. For subjective relaxation, a blunted relaxation reaction was associated with lower scores of paternal care and higher scores of paternal overprotection, physical abuse, physical neglect, and emotional abuse. For heart rate variability emotional abuse in interaction with nicotine consumption was related to a blunted relaxation response. This indicates that experiencing ELA negatively affects the relaxation capability in a healthy sample and emphasizes the importance of assessing relaxation at a physiological and subjective level.

Abstract Decline in mitochondrial function is linked to decreased muscle mass and strength in conditions like sarcopenia and type 2 diabetes. Despite therapeutic opportunities, there is limited and equivocal data regarding molecular cues controlling muscle mitochondrial plasticity. Here we uncovered that the mitochondrial mRNA-stabilizing protein SLIRP, in complex with LRPPRC, is a PGC-1α target that regulates mitochondrial structure, respiration, and mtDNA-encoded-mRNA pools in skeletal muscle. Exercise training effectively counteracts mitochondrial defects caused by genetically-induced LRPPRC/SLIRP loss, despite sustained low mtDNA-encoded-mRNA pools, by increasing mitoribosome translation capacity and mitochondrial quality control. In humans, exercise training robustly increases muscle SLIRP and LRPPRC protein across exercise modalities and sexes, yet less prominently in individuals with type 2 diabetes. SLIRP muscle loss reduces Drosophila lifespan. Our data points to a mechanism of post-transcriptional mitochondrial regulation in muscle via mitochondrial mRNA stabilization, offering insights into how exercise enhances mitoribosome capacity and mitochondrial quality control to alleviate defects.

Abstract The cognitive reserve (CR) hypothesis posits that individuals can differ in how their brain function is disrupted by pathology associated with aging and neurodegeneration. Here, we test this hypothesis in the continuum from cognitively normal to at-risk stages for Alzheimer’s Disease (AD) to AD dementia using longitudinal data from 490 participants of the DELCODE multicentric observational study. Brain function is measured using task fMRI of visual memory encoding. Using a multivariate moderation analysis, we identify a CR-related activity pattern underlying successful memory encoding that moderates the detrimental effect of AD pathological load on cognitive performance. CR is mainly represented by a more pronounced expression of the task-active network encompassing deactivation of the default mode network (DMN) and activation of inferior temporal regions including the fusiform gyrus. We devise personalized fMRI-based CR scores that moderate the impact of AD pathology on cognitive performance and are positively associated with years of education. Furthermore, higher CR scores attenuate the effect of AD pathology on cognitive decline over time. Our findings primarily provide evidence for the maintenance of core cognitive circuits including the DMN as the neural basis of CR. Individual brain activity levels of these areas during memory encoding have prognostic value for future cognitive decline.

Abstract The discovery of fibroblast activation protein inhibitor positron emission tomography (FAPI-PET) has paved the way for a new class of PET tracers that target the tumor microenvironment (TME) rather than the tumor itself. Although 18F-fluorodeoxyglucose (FDG) is the most common PET tracer used in clinical imaging of cancer, multiple studies have now shown that the family of FAP ligands commonly outperform FDG in detecting cancers, especially those known to have lower uptake on FDG-PET. Moreover, FAPI-PET will have applications in benign fibrotic or inflammatory conditions. Thus, even while new FAPI-PET tracers are in development and applications are yet to enter clinical guidelines, a significant body of literature has emerged on FAPI-PET, suggesting it will have important clinical roles. This article summarizes the current state of clinical FAPI-PET imaging as well as potential uses as a theranostic agent.

Abstract The response of European precipitation variability to climate change is still poorly understood. Here we present a high-resolution speleothem record of Eastern Central European (ECE) autumn/winter precipitation to study decadal to centennial hydroclimatic variations in the European-Atlantic sector since the Last Glacial Maximum. The Cloşani Cave δ18O record shows that the reorganization of the North Atlantic jet following the demise of the Northern Hemispheric ice sheets lasted until c. 6000 to 5000 years before present. Trace element-derived semi-quantitative autumn/winter precipitation amount reveals that the late Glacial and the early to mid-Holocene experienced about 20–30% higher precipitation than present. During the deglaciation, we detect an increased decadal to centennial precipitation variability decoupled from millennial-scale North Atlantic temperature changes. The findings suggest that dynamic (rather than thermodynamic) processes determine regional precipitation variability and the probability of extreme precipitation events in ECE, highlighting the importance of understanding such dynamics for future predictions.

Abstract Deep brain stimulation (DBS) is an established treatment for motor disorders like Parkinson’s disease, but its mechanisms and effects on neurons and networks are not fully understood, limiting research-driven progress. This review presents a framework that combines neurophysiological insights and translational research to enhance DBS therapy, emphasizing biomarkers, device technology, and symptom-specific neuromodulation. It also examines the role of animal research in improving DBS, while acknowledging challenges in clinical translation.

Abstract Postnatal care immediately after birth is a crucial component to save lives of mothers and the newborns. A paucity of evidence indicated that women’s unwillingness to receive care after birth is a remained challenge in resource-limited settings in general and in Ethiopia in particular. This study aimed to assess the utilization of postnatal care within 48 h after birth and its determinants in northwest Ethiopia. A community-based cross-sectional study was conducted from October to November 2020. A total of 811 women who had birth within the last one year were involved in the study. Both random and fixed effects were reported using an adjusted odds ratio with a 95% confidence interval and p value of 0.05. The study revealed that 13.3% (95% CI 10.9–15.7%) of women attended postnatal care visits within 48 h after birth. Attending secondary and above education (AOR = 2.39; 95% CI 1.18, 4.84); health extension workers home visiting during pregnancy (AOR = 1.74; 95% CI 1.08, 2.82); birth order (AOR = 2.07; 95% CI 1.03, 4.14); place of delivery (AOR = 7.49; 95% CI 3.73, 15.06); and short distance to health facility (AOR = 4.19; 95% CI 1.64, 10.70) were significantly associated with postnatal care utilization within 48 h after birth. Postnatal care utilization within 48 h is low in rural northwest Ethiopia compared to findings from most resource-limited settings. The existing health system should consider multilevel intervention strategies focusing on maternal health education, engaging community health workers in health promotion, and ensuring physical accessibility of healthcare facilities to be more effective in improving postnatal care utilization within 48 h.

Abstract Precise means of characterizing analog quantum simulators are key to developing quantum simulators capable of beyond-classical computations. Here, we precisely estimate the free Hamiltonian parameters of a superconducting-qubit analog quantum simulator from measured time-series data on up to 14 qubits. To achieve this, we develop a scalable Hamiltonian learning algorithm that is robust against state-preparation and measurement (SPAM) errors and yields tomographic information about those SPAM errors. The key subroutines are a novel super-resolution technique for frequency extraction from matrix time-series, tensorESPRIT, and constrained manifold optimization. Our learning results verify the Hamiltonian dynamics on a Sycamore processor up to sub-MHz accuracy, and allow us to construct a spatial implementation error map for a grid of 27 qubits. Our results constitute an accurate implementation of a dynamical quantum simulation that is precisely characterized using a new diagnostic toolkit for understanding, calibrating, and improving analog quantum processors.

Abstract Materials exhibiting electronic inhomogeneities at the nanometer scale have enormous potential for applications. Magnetic polarons are one such type of inhomogeneity which link the electronic, magnetic and lattice degrees of freedom in correlated matter and often give rise to colossal magnetoresistance. Here, we investigate single crystals of Eu5In2Sb6 by thermal expansion and magnetostriction along different crystallographic directions. These data provide compelling evidence for the formation of magnetic polarons in Eu5In2Sb6 well above the magnetic ordering temperature. More specifically, our results are consistent with anisotropic polarons with varying extent along the different crystallographic directions. A crossover revealed within the magnetically ordered phase can be associated with a surprising stabilization of ferromagnetic polarons within the global antiferromagnetic order upon decreasing temperature. These findings make Eu5In2Sb6 a rare example of such coexisting and competing magnetic orders and, importantly, shed new light on colossal magnetoresistive behavior beyond manganites.

Societal Impact Statement Can modern breeding technologies, such as genome editing, contribute to reduced pesticide usage? This question has been accentuated by a recent legal proposal to exempt genome‐edited plants from the strict regulations applied to classical genetically modified (GM) crops within the European Union (EU). Using official statistics on crop cultivation and pesticide usage for two example crops commonly grown in Sweden, we calculate that cereal farmers collectively could save up to 70 million € in pesticide usage for wheat alone and that a late blight‐resistant potato could reduce pesticide usage by over 80% provided that the EU legislation is amended. Summary The European Commission has set goals to reduce the use of chemical pesticides, and one way to meet these goals in the agricultural sector is to breed disease‐resistant crops. Here, we ask whether modern breeding technologies, for example, genome editing using site‐directed nucleases, can contribute to these goals. This question has been accentuated by recent legal proposals in the European Union (EU) and several other jurisdictions worldwide to exempt genome‐edited plants from the strict regulations often applied to classical genetically modified (GM) crops. Using official statistics on crop cultivation and pesticide usage for two example crops commonly grown in Sweden (wheat and potato), we show that cereal farmers collectively could potentially save up to 70 million € in pesticide usage for wheat alone and that a late blight‐resistant potato could reduce pesticide usage by over 80% provided that the EU legislation is amended. Given the immense potential of genome‐edited crops, we further discuss details in the legal proposal currently being negotiated in the EU on the so‐called new genomic techniques that includes both genome editing and targeted insertions of cisgenes. Although promising, we argue that several technical limitations in the legal proposal will, if implemented, hamper the development of disease‐resistant crops and make the suggested legislation less future‐proof.

For decades micoorganisms have been engineered for the utilization of lignocellulose-based second-generation (2G) feedstocks, but with the concerns of increased levels of atmospheric CO2 causing global warming there is an emergent need to transition from the utilization of 2G feedstocks to third-generation (3G) feedstocks such as CO2 and its derivatives. Here, we established a yeast platform that is capable of simultaneously converting 2G and 3G feedstocks into bulk and value-added chemicals. We demonstrated that by adopting 3G substrates such as CO2 and formate, the conversion of 2G feedstocks could be substantially improved. Specifically, formate could provide reducing power and energy for xylose conversion into valuable chemicals. Simultaneously, it can form a concentrated CO2 pool inside the cell, providing thermodynamically and kinetically favoured amounts of precursors for CO2 fixation pathways, e.g., the Calvin–Benson–Bassham (CBB) cycle. Furthermore, we demonstrated that formate could directly be utilized as a carbon source by yeast to synthesize endogenous amino acids. The engineered strain achieved a one-carbon (C1) assimilation efficiency of 9.2%, which was the highest efficiency observed in the co-utilization of 2G and 3G feedstocks. We applied this strategy for productions of both bulk and value-added chemicals, including ethanol, free fatty acids (FFAs), and longifolene, resulting in yield enhancements of 18.4%, 49.0%, and ∼100%, respectively. The strategy demonstrated here for co-utilization of 2G and 3G feedstocks sheds lights on both basic and applied research for the up-coming establishment of 3G biorefineries.

Background Direct-to-implant breast reconstruction (DIR) is becoming more and more accepted. There is a lack of high-quality studies assessing differences in patient-reported quality of life (QoL) between different implant placement methods. The aim of this randomized controlled (clinical) trial was to compare QoL between women reconstructed by sub- or prepectoral implant placement.

Abstract Background Perivascular space (PVS) enlargement in ageing and Alzheimer’s disease (AD) and the drivers of such a structural change in humans require longitudinal investigation. Elucidating the effects of demographic factors, hypertension, cerebrovascular dysfunction, and AD pathology on PVS dynamics could inform the role of PVS in brain health function as well as the complex pathophysiology of AD. Methods We studied PVS in centrum semiovale (CSO) and basal ganglia (BG) computationally over three to four annual visits in 503 participants (255 females; meanage = 70.78 ± 5.78) of the ongoing observational multicentre “DZNE Longitudinal Cognitive Impairment and Dementia Study” (DELCODE) cohort. We analysed data from subjects who were cognitively unimpaired (n = 401), had amnestic mild cognitive impairment (n = 71), or had AD (n = 31). We used linear mixed-effects modelling to test for changes of PVS volumes in relation to cross-sectional and longitudinal age, as well as sex, years of education, hypertension, white matter hyperintensities, AD diagnosis, and cerebrospinal-fluid-derived amyloid (A) and tau (T) status (available for 46.71%; A-T-/A + T-/A + T + n = 143/48/39). Results PVS volumes increased significantly over follow-ups (CSO: B = 0.03 [0.02, 0.05], p A-T-, p FDR = 0.004) or who were amyloid positive but tau negative (A + T + > A + T-, p FDR = 0.07). CSO-PVS volumes increased at a faster rate with amyloid positivity as compared to amyloid negativity (A + T-/A + T + > A-T-, p FDR = 0.021). Conclusion Our longitudinal evidence supports the relevance of PVS enlargement in presumably healthy ageing as well as in AD pathology. We further discuss the region-specific involvement of white matter hyperintensities and neurotoxic waste accumulation in PVS enlargement and the possibility of additional factors contributing to PVS progression. A comprehensive understanding of PVS dynamics could facilitate the understanding of pathological cascades and might inform targeted treatment strategies. Trial registration German Clinical Trials Register DRKS00007966. Registered 04.05.2015 – retrospectively registered, https://drks.de/search/en/trial/DRKS00007966 .

Abstract Background For over three decades, the concomitance of cortical neurodegeneration and white matter hyperintensities (WMH) has sparked discussions about their coupled temporal dynamics. Longitudinal studies supporting this hypothesis nonetheless remain scarce. Methods We applied global and regional bivariate latent growth curve modelling to determine the extent to which WMH and cortical thickness were interrelated over a four-year period. For this purpose, we leveraged longitudinal MRI data from 451 cognitively unimpaired participants (DELCODE; median age 69.71 [IQR 65.51, 75.50] years; 52.32% female). Participants underwent MRI sessions annually over a four-year period (1815 sessions in total, with roughly four MRI sessions per participant). We adjusted all models for demographics and cardiovascular risk. Results Our findings were three-fold. First, larger WMH volumes were linked to lower cortical thickness (σ = -0.165, SE = 0.047, Z = -3.515, P

Abstract Background An increased number of revisits may signal that the immediate medical needs of patients seeking care at Emergency Departments (EDs) are not being met. The prevalence and characteristics of revisits to the EDs in Sweden among older patients, and its association to frailty, are unknown. We aimed to investigate the prevalence of ED revisits among patients over 65 years of age, living with or without frailty, and its association with rate of admission, and mortality; in the Swedish ED setting. Methods This was a prospective, multicentre study of patients over 65 years of age with an index visit to one of three Swedish EDs during May-Nov 2021. Frailty was assessed in conjunction with standard triage, using the 9-level Clinical Frailty Scale (CFS) with a CFS score of 5 to 8 as cut-off for identifying frailty. For all patients who made a revisit within 90 days of their index visit, we collected information about the revisit, admission, and mortality. Results A total of 1835 patients made an index visit which were included, and out of those, 595 patients made a revisit within 90 days of the index visit. Patients living with frailty (CFS 5 to 8) were more likely to make a revisit to the ED at 8 to 30 days (17% vs. 11%, diff 6%, 95% CI 2–10%, p