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Abstract Machine learning is increasingly applied to Earth Observation (EO) data to obtain datasets that contribute towards international accords. However, these datasets contain inherent uncertainty that needs to be quantified reliably to avoid negative consequences. In response to the increased need to report uncertainty, we bring attention to the promise of conformal prediction within the domain of EO. Unlike previous uncertainty quantification methods, conformal prediction offers statistically valid prediction regions while concurrently supporting any machine learning model and data distribution. To support the need for conformal prediction, we reviewed EO datasets and found that only 22.5% of the datasets incorporated a degree of uncertainty information, with unreliable methods prevalent. Current open implementations require moving large amounts of EO data to the algorithms. We introduced Google Earth Engine native modules that bring conformal prediction to the data and compute, facilitating the integration of uncertainty quantification into existing traditional and deep learning modelling workflows. To demonstrate the versatility and scalability of these tools we apply them to valued EO applications spanning local to global extents, regression, and classification tasks. Subsequently, we discuss the opportunities arising from the use of conformal prediction in EO. We anticipate that accessible and easy-to-use tools, such as those provided here, will drive wider adoption of rigorous uncertainty quantification in EO, thereby enhancing the reliability of downstream uses such as operational monitoring and decision-making.

The electrochemical corrosion mechanisms of Mg alloys were extensively studied in previous investigations of different chemical compositions, modified surface states and various electrolyte conditions. However, recent research focused on the active state of Mg dissolution, leading to unresolved effects of secondary phases adjacent to a stable α-solid solution passive layer. The present study investigates the fundamental electrochemical corrosion mechanisms of three different Laves phases with varying phase morphologies and phase fractions in the passive state of Mg-Al-Ca alloys. The microstructure was characterized by (transmission-) electron microscopy and synchrotron-based transmission X-ray microscopy. The electrochemical corrosion resistance was determined with a standard three-electrode setup and advanced in-situ flow cell measurements. A new electrochemical activity sequence (C15>C36>α-Mg>C14) was obtained, as a result of a stable passive layer formation on the α-solid solution. Furthermore, nm-scale Mg-rich precipitates were identified within the Laves phases, which tend to inhibit the corrosion kinetics.

Abstract SDS22 forms an inactive complex with nascent protein phosphatase PP1 and Inhibitor-3. SDS22:PP1:Inhibitor-3 is a substrate for the ATPase p97/VCP, which liberates PP1 for binding to canonical regulatory subunits. The exact role of SDS22 in PP1-holoenzyme assembly remains elusive. Here, we show that SDS22 stabilizes nascent PP1. In the absence of SDS22, PP1 is gradually lost, resulting in substrate hyperphosphorylation and a proliferation arrest. Similarly, we identify a female individual with a severe neurodevelopmental disorder bearing an unstable SDS22 mutant, associated with decreased PP1 levels. We furthermore find that SDS22 directly binds to Inhibitor-3 and that this is essential for the stable assembly of SDS22:PP1: Inhibitor-3, the recruitment of p97/VCP, and the extraction of SDS22 during holoenzyme assembly. SDS22 with a disabled Inhibitor-3 binding site co-transfers with PP1 to canonical regulatory subunits, thereby forming non-functional holoenzymes. Our data show that SDS22, through simultaneous interaction with PP1 and Inhibitor-3, integrates the major steps of PP1 holoenzyme assembly.

Abstract Esophageal adenocarcinoma (EAC) is one of the deadliest tumor entities worldwide, with a 5-year survival rate of less than 25%. Unlike other tumor entities, personalized therapy options are rare, partly due to the lack of knowledge about specific subgroups. In this publication, we demonstrate a subgroup of patients with EAC in a large screening cohort of 826 patients, characterized by specific morphological and immunohistochemical features. This subgroup represents approximately 0.7% (6/826) of the total cohort. Morphological features of this subgroup show a striking clear cytoplasm of the tumour cells and the parallel existence of rare growth patterns like yolk sac-like differentiation and enteroblastic differentiation. Immunohistochemistry reveals expression of the fetal gut cell-like proteins Sal-like protein 4 (SALL4), claudin-6, and glypican 3. Interestingly, we find a correlation with alterations of SWI/SNF-complex associated genes, which are supposed to serve as tumor suppressor genes in various tumour entities. Our results suggest a possible implication of rare tumour subtypes in the WHO classification for EACs according to the classification for gastric cancer. Furthermore, claudin-6 positive tumors have shown promising efficacy of CAR T cell therapy in the recently published BNT-211-01 trial (NCT04503278). This represents a personalized therapeutic option for this tumor subtype.

Lena-Karin Gustafsson,1 Els-Marie Anbacken,2 Gunnel Östlund,2 Anna Bondesson,1 Tina Pettersson,1 Viktoria Zander3 1Division of Caring Science, School of Health, Care and Social Welfare, Mälardalens University, Eskilstuna, Sweden; 2Division of Social Work, School of Health, Care and Social Welfare, Mälardalens University, Eskilstuna, Sweden; 3Division of Health and Welfare Technology, School of Health, Care and Social Welfare, Mälardalens University, Eskilstuna, SwedenCorrespondence: Lena-Karin Gustafsson, Division of Caring Science, School of Health, Care and Social Welfare, Mälardalens University, Eskilstuna, Sweden, Tel +46 70 7874420, Email lena-karin.gustafsson@mdu.seAim: This study aims to describe experiences of the implementation of a new integrated healthcare model for older adults with complex care needs due to multimorbidity, living at home, from a health and welfare personnel perspective. The goal was to diminish hospitalization and still carry out high quality care at home for older adults living with multimorbidity. The model was implemented by two organizations working in cooperation, the municipality, and the region that handles interprofessional social care and healthcare in people’s homes.Materials and Method: Open-ended group interviews with personnel were carried out, three of the group interviews pre-implementations of the model, and three of the group interviews post-implementation. The interviews were audiotaped and analysed according to the procedure of thematic analysis.Results: The quality of the integrated care model was based on care-chain cooperation, shared professionalism, and creating relations with the patient including closeness to next of kin, which was underlined by the participants. Unencumbered time gave the professionals the possibility to develop quality in integrated healthcare as part of integrated and person-centred care. The coproduction of education, research interviews and the follow-up meeting identified successes in diminishing hospitalization rates according to the participants’ experiences of the post-implementation interviews. An identified failure was, however, that shared professionalism was not developed over time, rather the different responsibilities were accentuated according to the information retrieved at the follow-up meeting.Conclusion: Quality aspects of the model were identified in the present study. However, when implementation of a new model is completed, the organizations always have their own interpretation of how to further understand the model in question.Plain language summary: The intention of the present study was to follow the process of working with a new model of providing care at home, thus preventing increased numbers of hospital readmissions, based on the professionals´ point of view of what quality care is for older adults with complex care needs due to multimorbidity, living in their own home. The professionals were interviewed in group settings on several occasions during the implementation.The result showed hopeful expectations expressed by the professionals before the new model was implemented, such as a hope for getting more time for high-quality care for the older adults with multimorbidity. During the teamwork, the conversation within the team members was praised as a key factor that included shared professionalism from professionals with different levels of education and focus on their work. According to the staff, unnecessary hospital stays were reduced, while the interprofessional care-chain cooperation was improved through the work of the integrated care team. For many team members, the positive difference in both work and care satisfaction was highlighted in comparison to regular home care as they were able to use their multi-disciplinary skills and support.Keywords: integrated-care model, multi-morbidity, interprofessional care, home-based care, person-centred integrated care

Summary The base excess value (BE, mmol/L), not standard base excess (SBE), correctly calculated including pH, pCO2 (mmHg), sO2 (%) and cHb (g/dl) is a diagnostic tool for several in vivo events, e.g., mortality after multiple trauma or shock, acidosis, bleeding, clotting, artificial ventilation. In everyday clinical practice a few microlitres of blood (arterial, mixed venous or venous) are sufficient for optimal diagnostics of any metabolic acidosis or alkalosis. The same applies to a therapeutic tool—then referred to as potential base excess (BEpot)—for several in vitro assessments, e.g., solutions for infusion, sodium bicarbonate, blood products, packed red blood cells, plasma. Thus, BE or BEpot has been a parameter with exceptional clinical significance since 2007.

The Cancer of Unknown Primary (CUP) syndrome is characterized by identifiable metastases while the primary tumor remains hidden. In recent years, various data-driven approaches have been suggested to predict the location of the primary tumor (LOP) in CUP patients promising improved diagnosis and outcome. These LOP prediction approaches use high-dimensional input data like images or genetic data. However, leveraging such data is challenging, resource-intensive and therefore a potential translational barrier. Instead of using high-dimensional data, we analyzed the LOP prediction performance of low-dimensional data from routine medical care. With our findings, we show that such low-dimensional routine clinical information suffices as input data for tree-based LOP prediction models. The best model reached a mean Accuracy of 94% and a mean Matthews correlation coefficient (MCC) score of 0.92 in 10-fold nested cross-validation (NCV) when distinguishing four types of cancer. When considering eight types of cancer, this model achieved a mean Accuracy of 85% and a mean MCC score of 0.81. This is comparable to the performance achieved by approaches using high-dimensional input data. Additionally, the distribution pattern of metastases appears to be important information in predicting the LOP.

Ensuring a crisis-proof food supply has become a key political issue. In Germany, official spatial planning allows the use of priority and reserved areas to secure land for agricultural use and regional food supply. The focus should be particularly on climate-resilient areas that also have a stable yield potential in the future. This paper supplements widely used, static approaches for determining priority and reserved areas with a dynamic bio-economic analysis that takes future climate scenarios into account. The results for the German federal state of Brandenburg show a high area equivalence between the static and dynamic approaches. In the case of data gaps, for example, static approaches such as soil quality indices can serve as an adequate proxy for future yield potentials. However, not all climate-robust areas can be classified as potential reserved or priority areas. Furthermore, areas that show low yield potential under future conditions are not released for other land uses. Feedback from stakeholders involved in the study showed that the use of the dynamic approach and a target value using the results of a foodshed model lead to broad acceptance. The method developed here can make a valuable contribution to climate change adaptation in spatial planning instruments.

Stereotype threat (ST) is a potential explanation for inequalities in language competencies observed between students from different language backgrounds. Language competencies are an important prerequisite for educational success, wherefore the significance for investigation arises. While ST effects on achievement are empirically well documented, little is known about whether ST also impairs learning. Thus, we investigated vocabulary learning in language minority elementary school students, also searching for potential moderators. In a pre-post design, 240 fourth-grade students in Germany who were on average 10 years old (M[subscript Age] = 9.92, SD = 0.64; 49.8% female) were randomly assigned to one of four experimental conditions: implicit ST, explicit ST without threat removal before posttest, explicit ST with threat removal before posttest, and a control group. Results showed that learning difficult vocabulary from reading two narrative texts was unaffected by ST. Neither students' identification with their culture of residence and culture of origin nor stereotyped domain of reading were moderators. The findings are discussed with regard to content and methodological aspects such that a motivation effect might have undermined a possible ST effect. Implications for future research include examining the question at what age children become susceptible to ST and whether students have internalized negative stereotypes about their own group, which could increase the likelihood of ST effects occurring.

Millennial-scale climate variations during the last glacial period, such as Dansgaard–Oeschger (DO) cycles and Heinrich events, have been extensively studied using ice core and marine proxy records. However, there is a limited understanding of the magnitude of these temperature fluctuations in continental regions, and questions remain about the seasonal signal of these climate events. This study presents a 60 000-year-long temperature reconstruction based on branched glycerol dialkyl glycerol tetraethers (brGDGTs) extracted from lake sediments from the Eifel Volcanic Field, Germany. brGDGTs are bacterial membrane-spanning lipids that are known to have a strong relationship with temperature, making them suitable for temperature reconstructions. We test several temperature calibration models on modern samples taken from soils and multiple maar lakes. We find a negative bias in brGDGT-based temperature estimates associated with water depth and anoxic conditions that can be corrected for by accounting for a brGDGT isomer that is only produced in anoxic conditions. The corrected temperature reconstruction correlates with proxy and climate model estimates of temperature spanning the same time period, validating the calibration approach we selected. However, millennial-scale variability is significantly dampened in the brGDGT record, and in contrast to other Northern Hemisphere climate records, during several Heinrich stadials, temperatures actually increase. We demonstrate that these apparent discrepancies can be explained by the unique seasonal response of the brGDGT paleothermometer to temperatures of months above freezing (TMAF). Our data support the view that warm-season temperatures in Europe varied minimally during the last glacial period and that abrupt millennial-scale events were defined by colder, longer winters. Our continuous high-resolution temperature reconstruction provides important information about the magnitude of seasonal climate variability during the last glacial period that can be used to test climate models and inform studies of paleoecological change.

Abstract Background Fibroblast activation protein (FAP) is expressed in the tumor microenvironment (TME) of various cancers. In our analysis, we describe the impact of dual-tracer imaging with Gallium-68-radiolabeled inhibitors of FAP (FAPI-46-PET/CT) and fluorodeoxy-D-glucose (FDG-PET/CT) on the radiotherapeutic management of primary esophageal cancer (EC). Methods 32 patients with EC, who are scheduled for chemoradiation, received FDG and FAPI-46 PET/CT on the same day (dual-tracer protocol, 71%) or on two separate days (29%) We compared functional tumor volumes (FTVs), gross tumor volumes (GTVs) and tumor stages before and after PET-imaging. Changes in treatment were categorized as “minor” (adaption of radiation field) or “major” (change of treatment regimen). Immunohistochemistry (IHC) staining for FAP was performed in all patients with available tissue. Results Primary tumor was detected in all FAPI-46/dual-tracer scans and in 30/32 (93%) of FDG scans. Compared to the initial staging CT scan, 12/32 patients (38%) were upstaged in nodal status after the combination of FDG and FAPI-46 PET scans. Two lymph node metastases were only visible in FAPI-46/dual-tracer. New distant metastasis was observed in 2/32 (6%) patients following FAPI-4 -PET/CT. Our findings led to larger RT fields (“minor change”) in 5/32 patients (16%) and changed treatment regimen (“major change”) in 3/32 patients after FAPI-46/dual-tracer PET/CT. GTVs were larger in FAPI-46/dual-tracer scans compared to FDG-PET/CT (mean 99.0 vs. 80.3 ml, respectively (p

Abstract Background Colorectal cancer (CRC) frequently involves mutations in the KRAS gene, impacting therapeutic strategies and prognosis. The occurrence of KRAS mutations typically precludes the presence of RET fusions, with current medical literature suggesting a mutual exclusivity between these two genetic alterations. We present a unique case that challenges this notion. Case Presentation An 85-year-old female with metastatic CRC was found to have a combination of genetic anomalies that is to the best of our knowledge not yet described in the medical literature: a KRAS p.G12C mutation, associated with oncogenesis and treatment resistance, and an ANK3::RET fusion, an infrequent but targetable mutation in CRC. This molecular profile was uncovered through comprehensive genomic sequencing after the patient experienced metachronous tumor dissemination. The presence of both genetic events complicates the treatment approach. Conclusions The identification of both a KRAS p.G12C mutation and an ANK3::RET fusion in the same CRC patient adds a new layer to the oncogenic landscape and treatment considerations for CRC. It highlights the intricate decision-making required in the era of precision medicine, where targeted therapies must be carefully chosen and potentially combined to combat complex genetic profiles. The case emphasizes the urgency of investigating the clinical effects of concurrent or sequential use of KRAS p.G12C and RET inhibitors to inform future therapeutic guidelines and improve patient outcomes in similar cases.

Abstract We present the very first constraints on the number of Standard Model (SM) copies with an additional Dirac right-handed neutrino. From cosmology, we are able to pose strong limits on large regions of the parameter space. Moreover, we show that it is possible to account for the right dark matter density in form of stable particles from the dark sectors.

Objectives: The primary aim of this study was to investigate the incidence of segmental aneuploidies (full vs. mosaic) in embryos biopsied for Preimplantation Genetic Testing with Aneuploidy (PGT-A) screening using low-coverage whole genome sequencing (WGS). The secondary aim was to investigate factors that may be associated with segmental aneuploidy rates, including blastocyst developmental stage and quality. Methods: This study involved a retrospective analysis of cycle and PGT-A data from 8,153 blastocysts biopsied from 2,522 patients at four Monash IVF Victorian clinics between January 2015 and June 2021. All biopsies were processed using the Veriseq PGS Kit (Illumina) and analyzed using Bluefuse Multi software (Illumina) with a conclusive PGT-A result. Segmental aneuploidy was reported with a minimum resolution of greater than or equal to 10[Formula: see text]Mb. The reporting range for mosaicism was 20%–70% loss/gain in copy number. Statistical significance was established at a P-value of less than 0.05. Results: Segmental aneuploidies (full and/or mosaic) were reported in 682/8,153 (8.4%) biopsied embryos. Analysis of the types of segmental aneuploidy showed a higher proportion of deletions (423/8,153; 5.2%) compared to duplications (210/8,153; 2.6% [[Formula: see text]] plus a small portion with both duplications and deletions detected 49/8153; 0.6% [[Formula: see text]]). The incidence of segmental aneuploidies appeared to increase in correlation with chromosome size. Segregation of embryos by blastocyst stage indicated an increase in the incidence of segmental aneuploidies in early blastocysts (9/64; 14.1%) compared with expanding/expanded (39/475, 8.2%, [[Formula: see text]] and hatching/hatched blastocysts [634/7614, 8.3%; [Formula: see text]]). Furthermore, the incidence of segmental aneuploidies significantly increased as blastocyst overall grade decreased (Grade A 71/1,429, 5.0%; Grade B 298/3,764, 7.9%; Grade C 313/2,960, 10.6%; [Formula: see text]). Of the segmental aneuploidies detected, 425/682 (62.3%) were present at a mosaic level. Conclusions: Segmental aneuploidy rates varied between blastocyst stage and grades, with a significant proportion of segmental aneuploidies being detected at the mosaic level. Our data highlights that segmental aneuploidies, both at the full and mosaic level, are associated with lower blastocyst quality and poorer embryo development.

Background: Hyaluronan (HA) sperm selection, utilizing the affinity of mature sperm for HA, has emerged as a technique to enhance the selection of sperm for intracytoplasmic sperm injection (ICSI). However, conflicting evidence exists regarding the impact of HA-ICSI on clinical outcomes including fertilization, embryo utilization, and pregnancy rates. The study aimed to compare clinical outcomes including fertilization, utilization, and pregnancy rates between paired ICSI and HA-ICSI cycles within patients, particularly for male factor and low utilization subgroups. Methods: A retrospective study from 3,988 ICSI treatment cycles was conducted between January 2018 and March 2022. A HA-ICSI cycle was paired with the preceding ICSI cycle from the same patient. Fertilization, utilization, and clinical pregnancy rates were compared based on infertility diagnosis and utilization rate (UR) from the initial ICSI cycle. Results: There were no differences in fertilization, utilization, embryo quality, euploidy, or pregnancy rates between ICSI and HA-ICSI in all paired cycles. However, for patients with male factor infertility UR increased from 25.0% to 38.5% in their HA-ICSI cycle ([Formula: see text]). There was no difference observed for female factor infertility patients. HA-ICSI use was of particular benefit for male factor infertility patients with low ([Formula: see text]) embryo utilization in their initial ICSI cycle, evident by an increased utilization from 14.3% to 25.0% in their HA cycle ([Formula: see text]). Conclusions: This is the first study to focus on the impact of HA-ICSI on embryo utilization, particularly in patients with male factor infertility. The efficacy of HA-ICSI as a sperm selection tool appears to be limited to improving UR in patients with male factor infertility, particularly those with low utilization in a previous ICSI cycle, with no significant effect on fertilization or pregnancy rates. Conclusion: HA-ICSI may be useful for sperm selection at the time of ICSI for a select subgroup of patients. Male factor infertility patients, who have previously undertaken an ICSI cycle with less than 40% utilization, should be considered as candidates for treatment.

Abstract HIV infection compromises both the peripheral and central immune systems due to its pathogenic and neuropathogenic features. The mechanisms driving HIV-1 pathogenesis and neuropathogenesis involve a series of events, including metabolic dysregulation. Furthermore, HIV-subtype-specific variations, particularly alterations in the amino acid sequences of key viral proteins, are known to influence the severity of clinical outcomes in people living with HIV. However, the impact of amino acid sequence variations in specific viral proteins, such as Viral protein R (Vpr), on metabolites within the Tryptophan (Trp)-kynurenine (Kyn) pathway in people living with HIV remains unclear. Our research aimed to explore the relationship between variations in the Vpr amino acid sequence (specifically at positions 22, 41, 45, and 55, as these have been previously linked to neurocognitive function) and peripheral Trp-Kyn metabolites. Additionally, we sought to clarify the systems biology of Vpr sequence variation by examining the link between Trp-Kyn metabolism and peripheral inflammation, as a neuropathogenic mechanism. In this preliminary study, we analyzed a unique cohort of thirty-two (n = 32) South African cART naïve people living with HIV. We employed Sanger sequencing to ascertain blood-derived Vpr amino acid sequence variations and a targeted LC-MS/MS metabolomics platform to assess Trp-Kyn metabolites, such as Trp, Kyn, kynurenic acid (KA), and quinolinic acid (QUIN). Particle-enhanced turbidimetric assay and Enzyme-linked immunosorbent assays were used to measure immune markers, hsCRP, IL-6, suPAR, NGAL and sCD163. After applying Bonferroni corrections (p =.05/3) and adjusting for covariates (age and sex), only the Vpr G41 and A55 groups was nearing significance for higher levels of QUIN compared to the Vpr S41 and T55 groups, respectively (all p =.023). Multiple regression results revealed that Vpr amino acid variations at position 41 (adj R2 = 0.049, β = 0.505; p =.023), and 55 (adj R2 = 0.126, β = 0.444; p =.023) displayed significant associations with QUIN after adjusting for age and sex. Lastly, the higher QUIN levels observed in the Vpr G41 group were found to be correlated with suPAR (r =.588, p =.005). These results collectively underscore the importance of specific Vpr amino acid substitutions in influencing QUIN and inflammation (specifically suPAR levels), potentially contributing to our understanding of their roles in the pathogenesis and neuropathogenesis of HIV-1.

Abstract This study provides analytic solutions for the magnetic field of coils and magnets that have a non‐axisymmetric cylindrical geometry with a rectangular cross‐section. New analytic solutions are provided for radially magnetized permanent magnet arcs, thin coil disc sectors, and thick coil sectors. If components of the 3D field are not representable in closed‐form or as canonical Legendre elliptic integrals, the exact solution is given in terms of a series of regularized beta functions. The limit and hence spatial convergence is found to these series, giving a well‐defined and fast solving algorithm for computation. The equations can be readily applied to find the magnetostatic field in linear or non‐linear systems that contain a large set of elements. Example applications are provided to demonstrate how the field can be used to calculate forces and benchmark computational efficiency of the equations. A thorough review of the preceding literature and background theory is provided before a detailed methodology obtaining the analytic solutions contained in this compendium, and further related geometries in cylindrical or spherical coordinates. This is the first study to comprehensively solve the field equations for this collection of electromagnetic geometries.