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This design document proposes an interface to support the parallel features of Fortran, named the Parallel Runtime Interface for Fortran (PRIF). PRIF is a proposed solution in which the runtime library is responsible for coarray allocation, deallocation and accesses, image synchronization, atomic operations, events, and teams. In this interface, the compiler is responsible for transforming the invocation of Fortran-level parallel features into procedure calls to the necessary PRIF procedures. The interface is designed for portability across shared- and distributed-memory machines, different operating systems, and multiple architectures. Implementations of this interface are intended as an augmentation for the compiler's own runtime library. With an implementation-agnostic interface, alternative parallel runtime libraries may be developed that support the same interface. One benefit of this approach is the ability to vary the communication substrate. A central aim of this document is to define a parallel runtime interface in standard Fortran syntax, which enables us to leverage Fortran to succinctly express various properties of the procedure interfaces, including argument attributes.

While quinones are essential for respiratory microorganisms, their importance for microbes that rely on fermentation metabolism is not understood. This gap in knowledge hinders our understanding of anaerobic microbial habitats, such in mammalian digestive tracts and fermented foods. We show that Lactiplantibacillus plantarum, a model fermentative lactic acid bacteria species abundant in human, animal, and insect microbiomes and fermented foods, uses multiple exogenous, environmental quinones as electron shuttles for a hybrid metabolism involving EET. Interestingly, quinones both stimulate this metabolism as well as cause oxidative stress when extracellular electron acceptors are absent. We also found that quinone-producing, lactic acid bacteria species commonly enriched together with L. plantarum in food fermentations accelerate L. plantarum growth and medium acidification through a mainly quinone- and EET-dependent mechanism. Thus, our work provides evidence of quinone cross-feeding as a key ecological feature of anaerobic microbial habitats.

Abstract During the last glaciation, the northern hemisphere experienced profound millennial-scale changes (termed Dansgaard-Oeschger (DO) events) in atmospheric and oceanic temperatures. In the North Atlantic, the fluctuations resulted in extremely unstable bottom water conditions with bottom water temperatures (BWT) varying up to > 5 °C. We have studied these changes in a core from 1,300 m water depth at Vestnesa Ridge, northwestern Svalbard margin to investigate a possible connection between BWT and seepage of methane from the seafloor covering the period ~ 50–6 ka. Beneath Vestnesa Ridge, gas hydrates containing vast amounts of methane are kept stable due to the high pressure and low temperatures. Release of gas is shown by numerous pockmarks on the seafloor. The pockmarks at 1,300 m water depth are presently inactive, but they bear witness of earlier activity. Our study shows that from ~ 50–6 ka, the core site experienced repeated increases in BWT and in the emissions of gas, both following the pattern of the DO events. This correspondence in time scale indicates that BWT was the primary forcing factor for the variability in methane release. However, the releases were delayed by up to > 1,000 years compared to the initial increase in BWT.

Abstract Background Plasma levels of d-dimer are elevated in patients with thromboembolisms. Here we investigated the existence of interfering antibodies as a potential cause for elevated d-dimer levels. Case presentation A 42-year-old white Caucasian woman with a prior history of pulmonary embolism during her first pregnancy (treated with heparin therapy for 6 weeks postnatally) and hypothyroidism had a persistent elevated d-dimer without any clinical or ultrasound-based signs of thromboembolic conditions during her second pregnancy. We obtained informed consent and plasma was obtained from the patient. d-dimer levels were measured using two different assays. We also tested for the presence of rheumatoid factor, performed dilution series, and finally used an antibody depletion strategy. The two d-dimer assays performed similarly. Using our antibody depletion technique, we observed that ~ 1/3 of the increased plasma levels of d-dimer may be attributed to interfering antibodies. Conclusions Our results identify interfering antibodies as a potential contributor to an increased d-dimer in this patient. Our case highlights the potential of heterophilic interference for increased d-dimer and provides a procedure to determine this analytically.

Abstract For taxonomy based classification of metagenomics assembled contigs, current methods use sequence similarity to identify their most likely taxonomy. However, in the related field of metagenomic binning, contigs are routinely clustered using information from both the contig sequences and their abundance. We introduce Taxometer, a neural network based method that improves the annotations and estimates the quality of any taxonomic classifier using contig abundance profiles and tetra-nucleotide frequencies. We apply Taxometer to five short-read CAMI2 datasets and find that it increases the average share of correct species-level contig annotations of the MMSeqs2 tool from 66.6% to 86.2%. Additionally, it reduce the share of wrong species-level annotations in the CAMI2 Rhizosphere dataset by an average of two-fold for Metabuli, Centrifuge, and Kraken2. Futhermore, we use Taxometer for benchmarking taxonomic classifiers on two complex long-read metagenomics data sets where ground truth is not known. Taxometer is available as open-source software and can enhance any taxonomic annotation of metagenomic contigs.

Despite often being referred to as a ‘coolhouse climate’, the climate during the Miocene (23.03–5.33 Ma) was overall humid, warm and temperate. It was paced by orbitally driven cooler periods (the Oligocene–Miocene Transition and Mi-events) overprinted by a climatic optimum. Global cooling during the Late Miocene brought more arid conditions with climate seasonality, which varied across western Eurasia. Sedimentary archives from onshore Denmark comprise shallow marine siliciclastic deposits and discrete brown coal layers. Hence, they allow us to infer past climates and environments using both marine and terrestrial fossils. The backbone for Miocene stratigraphy and palaeoclimate reconstruction in the eastern North Sea Basin (present-day Denmark) is the Sønder (Sdr.) Vium sediment core, which penetrates a shallow marine succession and spans an interval from c. 22 to 8 Ma. Here, we present an improved age model for the core. During the Miocene, forested lowlands predominated in the eastern North Sea Basin. Coastal areas included rich riparian landscapes and delta areas of lignite-forming swamp forest. Compilations of existing proxy records (pollen, spores, leaves, plant fragments and the organic biomarkers alkenones and membrane lipids) collectively show that the climate here was warm and moist during the Early and Middle Miocene, while the Late Miocene was characterised by climate cooling and modernisation of the vegetation. The interval preceding the Miocene Climatic Optimum was already warm and moist, and the onset was not characterised by a significant increase in temperature and precipitation. Instead, the palynoflora indicates homogeneous vegetation and only a weak signal of warming shown by a minor increase of, for example, sabaloid palms and Mastixiaceae.

Background: Pregnancy-associated plasma protein-A (PAPP-A) regulates bioavailability of insulin-like growth factor 1 (IGF1) in various tissues by proteolytic cleavage of a subset of IGF-binding proteins (IGFBPs). Pre-clinical studies have established a role of PAPP-A in atherosclerosis and proposed that targeting the proteolytic activity of PAPP-A has therapeutic value.This study aimed to investigate whether human atherosclerotic plaques contain proteolytically active PAPP-A, a prerequisite for further considering PAPP-A as a therapeutic target in patients. Methods: We obtained carotid (n = 9) and femoral (n = 11) atherosclerotic plaques from patients undergoing vascular surgery and incubated freshly harvested plaque tissue in culture media for 24 h. Subsequently, conditioned media were assayed for PAPP-A, STC2, IGFBP4, and IGF1 using immunoassays. Enzymatic activity of PAPP-A was assessed by its ability to process recombinant IGFBP4-IGF1 complexes - a specific substrate of PAPP-A - by Western blotting. Results: PAPP-A and STC2 were detectable in conditioned media from both carotid and femoral plaques, with higher STC2 concentrations in eluates from carotid plaque incubations (p = 0.02). IGFBP4 and IGF1 were undetectable. Conditioned media from all 20 plaques exhibited PAPP-A proteolytic activity. However, no correlation between PAPP-A concentration and its proteolytic activity was observed, whereas the PAPP-A: STC2 molar ratio correlated with PAPP-A activity (R2 = 0.25, p = 0.03). Conclusion: This study provides evidence for the presence of enzymatically active PAPP-A in atherosclerotic plaques and underscores the need for further investigating potential beneficial effects associated with targeting PAPP-A in atherosclerotic cardiovascular disease.

This article presents the C-grid implementation of the CICE sea ice model, including the C-grid discretization of the momentum equation, the boundary conditions (BCs), and the modifications to the code required to use the incremental remapping transport scheme. To validate the new C-grid implementation, many numerical experiments were conducted and compared to the B-grid solutions. In idealized experiments, the standard advection method (incremental remapping with C-grid velocities interpolated to the cell corners) leads to a checkerboard pattern. A modal analysis demonstrates that this computational noise originates from the spatial averaging of C-grid velocities at corners. The checkerboard pattern can be eliminated by adjusting the departure regions to match the divergence obtained from the solution of the momentum equation. We refer to this novel approach as the edge flux adjustment (EFA) method. The C-grid discretization with edge flux adjustment allows for transport in channels that are one grid cell wide – a capability that is not possible with the B-grid discretization nor with the C-grid and standard remapping advection. Simulation results match the predicted values of a novel analytical solution for one-grid-cell-wide channels.

Abstract Ribosomal DNA (rDNA) encodes the ribosomal RNA genes and represents an intrinsically unstable genomic region. However, the underlying mechanisms and implications for genome integrity remain elusive. Here, we use Bloom syndrome (BS), a rare genetic disease characterized by DNA repair defects and hyper-unstable rDNA, as a model to investigate the mechanisms leading to rDNA instability. We find that in Bloom helicase (BLM) proficient cells, the homologous recombination (HR) pathway in rDNA resembles that in nuclear chromatin; it is initiated by resection, replication protein A (RPA) loading and BRCA2-dependent RAD51 filament formation. However, BLM deficiency compromises RPA-loading and BRCA1/2 recruitment to rDNA, but not RAD51 accumulation. RAD51 accumulates at rDNA despite depletion of long-range resection nucleases and rDNA damage results in micronuclei when BLM is absent. In summary, our findings indicate that rDNA is permissive to RAD51 accumulation in the absence of BLM, leading to micronucleation and potentially global genomic instability.

This study focuses on the performance of the elastic–viscous–plastic (EVP) dynamical solver within the sea ice model, CICE v6.5.1. The study has been conducted in two steps. First, the standard EVP solver was extracted from CICE for experiments with refactored versions, which are used for performance testing. Second, one refactored version was integrated and tested in the full CICE model to demonstrate that the new algorithms do not significantly impact the physical results. The study reveals two dominant bottlenecks, namely (1) the number of Message Parsing Interface (MPI) and Open Multi-Processing (OpenMP) synchronization points required for halo exchanges during each time step combined with the irregular domain of active sea ice points and (2) the lack of single-instruction, multiple-data (SIMD) code generation. The standard EVP solver has been refactored based on two generic patterns. The first pattern exposes how general finite differences on masked multi-dimensional arrays can be expressed in order to produce significantly better code generation by changing the memory access pattern from random access to direct access. The second pattern takes an alternative approach to handle static grid properties. The measured single-core performance improvement is more than a factor of 5 compared to the standard implementation. The refactored implementation of strong scales on the Intel® Xeon® Scalable Processors series node until the available bandwidth of the node is used. For the Intel® Xeon® CPU Max series, there is sufficient bandwidth to allow the strong scaling to continue for all the cores on the node, resulting in a single-node improvement factor of 35 over the standard implementation. This study also demonstrates improved performance on GPU processors.

Nontuberculous mycobacteria (NTM) are emerging as notable causative agents of opportunistic infections. To examine clinical significance, species distribution, and temporal trends of NTM in Denmark, we performed a nationwide register-based study of all unique persons with NTM isolated in the country during 1991–2022. We categorized patients as having definite disease, possible disease, or isolation by using a previously validated method. The incidence of pulmonary NTM increased throughout the study period, in contrast to earlier findings. Mycobacterium malmoense, M. kansasii, M. szulgai, and M. avium complex were the most clinically significant species based on microbiologic findings; M. avium dominated in incidence. This study shows the need for surveillance for an emerging infection that is not notifiable in most countries, provides evidence to support clinical decision-making, and highlights the importance of not considering NTM as a single entity.

ABSTRACT: An increasing number of countries are investigating options to stop the spread of the emerging zoonotic infection Salmonella Dublin (S. Dublin), which mainly spreads among bovines and with cattle manure. Detailed surveillance and cattle movement data from an 11-yr period in Denmark provided an opportunity to gain new knowledge for mitigation options through a combined social network and simulation modeling approach. The analysis revealed similar network trends for noninfected and infected cattle farms despite stringent cattle movement restrictions imposed on infected farms in the national control program. The strongest predictive factor for farms becoming infected was their cattle movement activities in the previous month, with twice the effect of local transmission. The simulation model indicated an endemic S. Dublin occurrence, with peaks in outbreak probabilities and sizes around observed cattle movement activities. Therefore, pre- and postmovement measures within a 1-mo time window may help reduce S. Dublin spread.

ABSTRACT: An economic simulation was carried out over 183 milk-producing countries to estimate the global economic impacts of 12 dairy cattle diseases and health conditions: mastitis (subclinical and clinical), lameness, paratuberculosis (Johne's disease), displaced abomasum, dystocia, metritis, milk fever, ovarian cysts, retained placenta, and ketosis (subclinical and clinical). Estimates of disease impacts on milk yield, fertility, and culling were collected from the literature, standardized, meta-analyzed using a variety of methods ranging from simple averaging to random-effects models, and adjusted for comorbidities to prevent overestimation. These comorbidity-adjusted disease impacts were then combined with a set of country-level estimates for lactational incidence or prevalence or both, herd characteristics, and price estimates within a series of Monte Carlo simulations that estimated and valued the economic losses due to these diseases. It was estimated that total annual global losses are US$65 billion (B). Subclinical ketosis, clinical mastitis, and subclinical mastitis were the costliest diseases modeled, resulting in mean annual global losses of approximately US$18B, US$13B, and US$9B, respectively. Estimated global annual losses due to clinical ketosis, displaced abomasum, dystocia, lameness, metritis, milk fever, ovarian cysts, paratuberculosis, and retained placenta were estimated to be US$0.2B, US$0.6B, US$0.6B, US$6B, US$5B, US$0.6B, US$4B, US$4B, and US$3B, respectively. Without adjustment for comorbidities, when statistical associations between diseases were disregarded, mean aggregate global losses would have been overestimated by 45%. Although annual losses were greatest in India (US$12B), the United States (US$8B), and China (US$5B), depending on the measure of losses used (losses as a percentage of gross domestic product, losses per capita, losses as a percentage of gross milk revenue), the relative economic burden of these dairy cattle diseases across countries varied markedly.

Abstract Introduction This study reports our experiences with systematic retinal screening in Denmark through optometrists with access to tele-ophthalmological services before, during, and after the COVID-19 pandemic. Methods We evaluated an optometrist-based retinal screening system with a referral option for tele-ophthalmological service by a consultant ophthalmologist within the time period of August 1, 2018 to September 30, 2023. The optometrist collected patient history, refraction, best-corrected visual acuity, intraocular pressure, basic slit-lamp examination, 4-in-1 visual field report, and retinal imaging using color fundus 45° photography. Tele-ophthalmological services were provided by consultant ophthalmologists. Within pre-defined periods of pre-COVID-19, COVID-19, and post-COVID-19, we evaluated the rate of referrals to the tele-ophthalmological service, diagnoses made, and referrals to the public healthcare system. Results A total of 1,142,028 unique individuals, which corresponded to 19.1% of the entire population of Denmark, underwent screening by the optometrists; 50,612 (4.4%) of these individuals were referred to the tele-ophthalmological examination by consultant ophthalmologists. A referral for further ophthalmic examination, either at hospital or at an ophthalmic practice, was made for 10,300 individuals (20.4% of those referred for tele-ophthalmology, corresponding to 0.9% of the population screened). The referral rate from the screening to the tele-ophthalmological service increased from before COVID-19 (3.4%) to during COVID-19 (4.3%) and further after COVID-19 (6.4%). This increase coincided with an increasing prevalence of conditions seen in the tele-ophthalmological service. Conclusion During a period of 5 years, 19.1% of the entire population of Denmark underwent retinal screening. This provided an adjunctive health service during a period of severe strain on the public healthcare system, while limiting the number of excessive referrals to the public healthcare system. Temporal trends illustrated an increased pattern of use of a large-scale tele-ophthalmological system.

Abstract FOXO transcription factors modulate aging-related pathways and influence longevity in multiple species, but the transcriptional targets that mediate these effects remain largely unknown. Here, we identify an evolutionarily conserved FOXO target gene, Oxidative stress-responsive serine-rich protein 1 (OSER1), whose overexpression extends lifespan in silkworms, nematodes, and flies, while its depletion correspondingly shortens lifespan. In flies, overexpression of OSER1 increases resistance to oxidative stress, starvation, and heat shock, while OSER1-depleted flies are more vulnerable to these stressors. In silkworms, hydrogen peroxide both induces and is scavenged by OSER1 in vitro and in vivo. Knockdown of OSER1 in Caenorhabditis elegans leads to increased ROS production and shorter lifespan, mitochondrial fragmentation, decreased ATP production, and altered transcription of mitochondrial genes. Human proteomic analysis suggests that OSER1 plays roles in oxidative stress response, cellular senescence, and reproduction, which is consistent with the data and suggests that OSER1 could play a role in fertility in silkworms and nematodes. Human studies demonstrate that polymorphic variants in OSER1 are associated with human longevity. In summary, OSER1 is an evolutionarily conserved FOXO-regulated protein that improves resistance to oxidative stress, maintains mitochondrial functional integrity, and increases lifespan in multiple species. Additional studies will clarify the role of OSER1 as a critical effector of healthy aging.

Abstract Vast amounts of pathogen genomic, demographic and spatial data are transforming our understanding of SARS-CoV-2 emergence and spread. We examined the drivers of molecular evolution and spread of 291,791 SARS-CoV-2 genomes from Denmark in 2021. With a sequencing rate consistently exceeding 60%, and up to 80% of PCR-positive samples between March and November, the viral genome set is broadly whole-epidemic representative. We identify a consistent rise in viral diversity over time, with notable spikes upon the importation of novel variants (e.g., Delta and Omicron). By linking genomic data with rich individual-level demographic data from national registers, we find that individuals aged 75 years had a lower contribution to molecular change (i.e., branch lengths) compared to other age groups, but similar molecular evolutionary rates, suggesting a lower likelihood of introducing novel variants. Similarly, we find greater molecular change among vaccinated individuals, suggestive of immune evasion. We also observe evidence of transmission in rural areas to follow predictable diffusion processes. Conversely, urban areas are expectedly more complex due to their high mobility, emphasising the role of population structure in driving virus spread. Our analyses highlight the added value of integrating genomic data with detailed demographic and spatial information, particularly in the absence of structured infection surveys.

Niklas Kahr Rasmussen,1 Birgitte Berg,2 Anne Sia Louise Christiansen,3 Jesper Skov Neergaard,1 Gitte Ter-Borch,2 Emily A Hildebrand,4 Maya Gonczi,4 Thomas Sparre1 1Medical & Science Innovation, Novo Nordisk A/S, Søborg, Denmark; 2Clinical Operations, Novo Nordisk A/S, Søborg, Denmark; 3Biostatistics, Novo Nordisk A/S, Søborg, Denmark; 4Research Collective LLC, Tempe, AZ, USACorrespondence: Niklas Kahr Rasmussen, Medical & Science Innovation, Novo Nordisk A/S, Søborg, Denmark, Tel +45 3075 5040, Email NKHR@novonordisk.comIntroduction: Concizumab is a once-daily prophylactic treatment developed for patients with hemophilia A or B (HA/HB) with or without inhibitors. It is the first treatment for hemophilia patients to be delivered subcutaneously using a pre-filled, multi-dose pen-injector with a 4 mm, 32 G needle.Aim: To investigate patient and caregiver handling and preference for the concizumab pen-injector compared with current injection systems used to treat hemophilia.Methods: This preference and handling study was conducted in accordance with authority guidelines for approval of new devices and included adults and adolescents with HA/HB with or without inhibitors and caregivers currently administering factor replacement therapy or factor VIII mimetic (emicizumab) therapy. All participants underwent a training session, followed by a test session during which participants independently administered a single pen-injection into an injection pad or manikin. Time to train, time to prepare and inject, and number of complete independent injections handling the pen were assessed. Participants evaluated handling and preference via the Hemophilia Device Handling and Preference Assessment Questionnaire.Results: 80 participants (44 adults, 21 adolescents, 15 caregivers) currently using factor replacement therapy (n=41, 51%) or emicizumab (n=39, 49%) participated. Average training time and time to complete an injection were 7 min 49s and 1 min 21s. In total, 98% of independent complete injections were achieved at first attempt. 98% (n=78; 95% confidence interval [CI] 91– 100%) of participants assessed the pen-injector as either “easy” or “very easy” to use. 88% of participants preferred the pen-injector (n=70; 95% CI 78– 94%) over their current injection system, and 9% (n=7) reported “no preference”.Conclusion: Participants found the concizumab pen-injector easy to learn and easy to use and preferred it over their current injection systems.Plain Language Summary: People with hemophilia lack clotting factors that help stop bleeding after an injury. If left untreated, it can lead to life-threatening bleeding episodes. Treatment such as replacement therapy with clotting factors needs to be administered at regular intervals to prevent bleeding. The administration of intravenous (inside the vein) medication can be challenging due to the required skills, injection pain and availability of a good vein to inject into. Factor VIII mimetic therapy now allows people to inject medication under the skin (subcutaneously). However, using vials and syringes still poses challenges with the time to prepare and inject medication. Pen-injectors have been developed to address these challenges and provide additional benefits, including increased dose accuracy, portability, reduced discomfort, and less administration time. Concizumab is a medication developed for once-daily subcutaneous injection for people with hemophilia A or hemophilia B, with or without inhibitors, using a pen-injector. The objective of this preference and handling study was to understand patient and caregiver pen-injector handling experiences, and device preferences compared to their existing devices. In this study, most participants found it easy to learn to use the pen-injector. 98% of participants reported that the pen-injector was easy or very easy to use compared with their current device. 88% of participants reported a preference for the concizumab pen-injector over their current device. This shows that the pen-injector can easily and effectively be used to inject concizumab, providing more control and independence in patients’ treatment while reducing the burden caused by intravenous modes of administration.Keywords: concizumab, pen-injector, subcutaneous, preference and handling study, questionnaire

Abstract Background Multiple myeloma often presents with vague and non-specific symptoms. Many patients are diagnosed in unplanned rather than elective (planned) diagnostic pathways. This study investigates the diagnosis of multiple myeloma in unplanned pathways and the association with patient characteristics, disease profile, and survival. Methods We conducted a nationwide register-based study, including all patients diagnosed with multiple myeloma in Denmark in 2014–2018. Patients were categorised as diagnosed in an unplanned pathway if registered with an acute admission within 30 days prior to the multiple myeloma diagnosis and no other previously registered pathway to this diagnosis. Unplanned pathways were compared to all other pathways combined. Results We included 2,213 patients diagnosed with multiple myeloma, hereof 32% diagnosed in an unplanned pathway. Comorbidity, no prior cancer diagnosis, a history of few visits to the general practitioner (GP), multiple myeloma complications at diagnosis, high-risk cytogenetics, and advanced cancer stage were associated with a higher probability of being diagnosed in an unplanned pathway. For example, 24.4% (95% confidence interval (CI): 21.8–27.0) of patients with low comorbidity (Charlson Comorbidity Index (CCI) score 0) were diagnosed in an unplanned pathway as were 50.9% (95% CI: 45.6–56.1) of patients with high comorbidity (CCI score 3+). For patients with dialysis need at the time of diagnosis the probability was 66.0% (95% CI 54.2–77.8) and 30.9% (95% CI: 28.9–32.9) for patients with no dialysis need. Patients diagnosed in an unplanned pathway had inferior survival (hazard ratio 1.44 (95% CI: 1.26–1.64)). However, this association was not seen in analyses restricted to patients surviving for more than three years. Conclusions High comorbidity level, few usual GP visits, advanced disease status at diagnosis, and complications were associated with diagnosis in an unplanned pathway. Further, patients diagnosed in an unplanned pathway had inferior survival. Promoting earlier diagnosis and preventing unplanned pathways may help improve survival in multiple myeloma.

Abstract Background With the development of immune checkpoint inhibitors for the treatment of non-small cell lung cancer, the need for new functional imaging techniques and early response assessments has increased to account for new response patterns and the high cost of treatment. The present study was designed to assess the prognostic impact of dynamic contrast-enhanced computed tomography (DCE-CT) on survival outcomes in non-small cell lung cancer patients treated with immune checkpoint inhibitors. Methods Thirty-three patients with inoperable non-small-cell lung cancer treated with immune checkpoint inhibitors were prospectively enrolled for DCE-CT as part of their follow-up. A single target lesion at baseline and subsequent follow-up examinations were enclosed in the DCE-CT. Blood volume deconvolution (BVdecon), blood flow deconvolution (BFdecon), blood flow maximum slope (BFMax slope) and permeability were assessed using overall survival (OS) and progression-free survival (PFS) as endpoints in Kaplan Meier and Cox regression analyses. Results High baseline Blood Volume (BVdecon) (> 12.97 ml × 100 g−1) was associated with a favorable OS (26.7 vs 7.9 months; p = 0.050) and PFS (14.6 vs 2.5 months; p = 0.050). At early follow-up on day seven a higher relative increase in BFdecon (> 24.50% for OS and > 12.04% for PFS) was associated with an unfavorable OS (8.7 months vs 23.1 months; p

Background: Thyroid autoimmunity (TAI) may be present in 1–17% of pregnant women. Monitoring of thyroid function in euthyroid pregnant women positive for anti-thyroperoxidase antibodies (TPOAb+) is recommended. Objective: To determine the prevalence and possible clinical and biological risk factors of biochemical progression (rise in serum thyroid-stimulating hormone (TSH) > 2.5 mU/L) at second blood sampling during pregnancy, in euthyroid women (TSH ≤ 2.5 mU/L) according to their TPOAb status. Methods: This study included demographic and biological data from two previously published cohorts (n = 274 women from August 1996 to May 1997 Copenhagen cohort, and n = 66 women from January 2013 to December 2014 Brussels cohort) having at least two measurements of TSH and free thyroxine (FT4) and at least one of TPOAb during spontaneously achieved singleton pregnancies. Results: The majority of women studied did not show biochemical progression. Only 4.2% progressed, significantly more frequently among TPOAb+ women, as compared to TPOAb− group (9.4 vs 2.7%, P = 0.015). No rise in serum TSH > 4 mU/L at 2nd sampling was observed. Higher baseline TSH levels were associated with biochemical progression in both TPOAb+ (P = 0.05) and TPOAb− women (P < 0.001), whereas maternal age, BMI, multiparity, smoking, FT4, and TPOAb concentrations were not significantly different between women with and without progression. Conclusions: Only a minority of euthyroid women with thyroid autoimmunity presented biochemical progression and none with a TSH > 4 mU/L. Larger studies are needed to better target the subset of women who would benefit most from repeated thyroid function monitoring during pregnancy.

Abstract Background Due to increasing older populations worldwide, injuries, disabilities and deaths caused by falls among the elderly represent a growing human and societal problem. We aimed to improve health among men of at least 70 years of age with low‐normal to low testosterone and mobility problems by using testosterone undecanoate (TU) injections, progressive strength training, and oral supplements of vitamin D, calcium and protein. Methods This was a single‐centre, randomized, placebo‐controlled, double‐blind trial with 148 older men with a median age of 77 (73–81) years, testosterone levels at median 8 (5–9) nmol/L (full range from 1.1 to 12.9 nmol/L) and mobility problems, recruited at University Hospital of Copenhagen, Herlev Hospital, Denmark. Participants were randomized into four arms for 20 weeks: (1) TU therapy (n = 37); (2) progressive resistance training with supplements of calcium, vitamin D and protein (n = 36); (3) both interventions combined (n = 36); or (4) no intervention (n = 39). The main outcome measure was the 30‐s chair stand test, due to test performance correlating with the risk of serious fall injuries and lower extremity muscle strength. Outcome measurements were performed at baseline and after 20 weeks. Results After the intervention, the combination group receiving progressive resistance training, TU and supplements achieved a median score of 13 (11–15) compared to the control group at 10 (0–14) in the 30‐s chair stand test (P = 0.003). This median improvement of 3.0 was clinically important. Compared to the control group, participants in the combination group also increased quality of life (P

The work of early childhood educators is conducted in highly regulated environments in many Western nations. This is due to managerialism, the right arm of neoliberal-inspired policies. To explore educators' work within these contexts, our international study highlights the impacts of these systems on educators and the children they teach. This paper presents findings from five countries, namely, Australia, Canada, Denmark, Georgia and Italy. The results reveal the experiences of educators in these countries, impacted by neoliberal-inspired policies that are manifested in two different ways. They are dealing with increased managerial regulation or with the neglect of the sector in the pursuit of higher profits. Educators' job satisfaction is impacted when they perceive they are not able to adequately educate and support children due to these constraints. Using a critical neoliberal framework, we employed a mixed-method approach. The participants were educators with various roles and qualifications in a variety of service types. To analyse the numerical/closed answer data we used cross tabulation. Thematic analysis was used to analyse the qualitative data. Despite their difficulties, educators provided many ideas on the ways their government can better support their work so that they can focus on supporting children's learning through play. This study will be of interest to researchers, educators, policymakers and teacher educators.

The implementation of large-scale intervention and development projects is often problematic, and the impacts of such projects usually fall somewhat short of what was expected. Additionally, the rationalities of intervention projects are not carried over into classroom teaching as directly as expected. This problem is generally known, but comprehensive explanations continue to elude the research community at large. Using the theory of cultural-historical activity theory (CHAT), we propose that the heart of the problem lies in the "expansive learning process" that teachers undergo. This process is driven by unrecognised contradictions in terms of cultural and historical origin, which are fundamentally different from the processes governing the projects. We analyze two cases taken from two large Danish professional development projects. In each case, we focus on a teacher as part of two activity systems ('the project' and 'the classroom') and how the contradictions within and between these shape learning through epistemic actions. The results indicate the importance of making these contradictions apparent and accessible to everyone in the activity systems. Because of these various contradictions, the agency conferred upon teachers leads to unintended outcomes.

The purpose of this article is to present an instructional innovation called the Structure-Culture Alignment Activity, which leads students through the process of aligning cultural values pertaining to diversity, equity, and inclusiveness (DEI) to two important structural elements, formalization and centralization. Using decision making, team cooperation, reflection of preferences, and practice in decision-making skills, students create a part of a strategic plan for a new organization. In this article, we offer detailed instructions, learning objectives, debrief questions, extensions, and variations for the Structure-Culture Alignment Activity. We also offer our suggestions from lived experience in running the Structure-Culture Alignment Activity as well as the findings from our statistical analysis. Our findings contribute to management education literature and suggest that participation in the Structure-Culture Alignment Activity improves knowledge pertaining to structural elements, diversity value attitudes, and attitudes towards aligning organizational structural elements with DEI cultural values in an undergraduate management class.

Measurement-based care, an evidence-based practice endorsed by the American Psychological Association, is underpinned by routine assessment supporting a data-driven approach to clinical decision making. Nonetheless, there is a need for brief, nonproprietary measures assessing non-symptom-based outcomes. The present study examined the psychometric properties of the Therapy Progress Scale (TPS), a four-item measure assessing clients' perceived treatment progress in multiple life functioning domains. The sample included 36,420 clients (66% female, 55.5% White, 31.5% Racial/Ethnic Minority) receiving outpatient psychotherapy from a practice-research group of private practitioners. The TPS demonstrated a one-factor solution (X[superscript 2] (2) = 362.08, RMSEA = 0.076, CFI = 0.999, TLI = 0.996) with high reliability estimate (coefficient [alpha] = 0.87). Additionally, the factor structure was consistent across client gender and race/ethnicity. There were moderate negative correlations with symptom-based measures (i.e. PHQ-9 and GAD-7). Test-retest correlation was also strong. Implications for research and practice are provided.

This study analyzes the impact of the Chicago Alliance for Equity in Computer Science (CAFÉCS) Research Practice Partnership (RPP) on the Chicago Public School (CPS) Office of Computer Science (OCS). Using a qualitative analysis drawing on data from leadership team meetings, published articles and presentations, and evaluation reports from 11 years of the partnership, we utilized a framework developed by the CAFÉCS leadership team to document the impact on district (1) Programs, (2) Research, (3) Organizational Structures, and (4) Policies leading to (5) Equitable Results for students, condensed as PROSPER. In particular, we explore the role of the RPP in supporting a 500% increase in graduating students who completed at least one high school computer science (CS) course between 2016 and 2020 in Chicago Public Schools (CPS). This study adds to the existing literature on assessing the impact of RPPs through the development of the PROSPER Framework, which may be a useful tool to help RPPs examine impacts on partner districts.

This study examines podcasts as a pedagogical approach to improve principles-level accounting students' perceptions of course engagement and the relevance of accounting. In each podcast, the course instructor interviews a business professional who describes how he/she uses accounting information in the workplace. Students listen to podcasts periodically throughout the course. Survey results indicate that approximately one-half of study participants perceived the podcasts increased their engagement in the course and two-thirds perceived the podcasts helped them better understand the relevance of accounting for business professionals. Results are significantly stronger for accounting majors and participants expecting to earn higher course grades. Results for non-accounting majors and participants with lower grade expectations remain positive. These findings suggest that podcasts may be used to positively influence perceptions of course engagement and the relevance of accounting, particularly among accounting majors and high performing students.

OBJECTIVES: Both high and low levels of occupational physical activity are associated with back pain. Thus, there might be a “sweet- and sour-spot” of occupational physical activity for back pain. Our aim was to investigate if there exists an occupational physical activity “sweet- (lowest risk) and sour-spot” (highest risk) for back pain. METHODS: A total of 396 eldercare workers from 20 Danish nursing homes participated. Occupational physical activity was measured between 1–4 working days using thigh-worn accelerometry. Back pain intensity was reported monthly on a scale from 0–10 over 1-year. A zero-inflated mixed-effects model was developed regressing occupational physical activity against back pain, adjusted for confounders. The “sweet- and sour-spot” were defined as the occupational physical activity compositions (sitting, standing, light, and moderate-to-vigorous) associated with the 5% lowest and highest risk for back pain, respectively. RESULTS: The composition associated with the lowest risk of back pain – the “sweet-spot”– consisted of 71% worktime spent sitting, 18% spent standing, 5% spent on light physical activity and 6% spent on moderate-to-vigorous physical activity. The composition associated with highest risk for back pain –the “sour-spot”– consisted of 8% worktime spent sitting, 66% spent standing, 4% spent on light physical activity, and 21% spent on moderate-to-vigorous physical activity. CONCLUSIONS: The “sweet-spot” of occupational physical activity for back pain among eldercare workers involves more sitting and light physical activity time, while the “sour-spot” involves more standing and moderate-to-vigorous physical activity time. Research on the occupational physical activity “sweet- and sour-spot” is needed.

Perioperative cardiac arrest (POCA) is a catastrophic complication that requires immediate recognition and correction of the underlying cause to improve patient outcomes. While the hypoxia, hypovolemia, hydrogen ions (acidosis), hypo-/hyperkalemia, and hypothermia (Hs) and toxins, tamponade (cardiac), tension pneumothorax, thrombosis (pulmonary), and thrombosis (coronary) (Ts) mnemonic is a valuable tool for rapid differential diagnosis, it does not cover all possible causes leading to POCA. To address this limitation, we propose using the preload-contractility-afterload-rate and rhythm (PCARR) construct to categorize POCA, which is comprehensive, systemic, and physiologically logical. We provide evidence for each component in the PCARR construct and emphasize that it complements the Hs and Ts mnemonic rather than replacing it. Furthermore, we discuss the significance of utilizing monitored variables such as electrocardiography, pulse oxygen saturation, end-tidal carbon dioxide, and blood pressure to identify clues to the underlying cause of POCA. To aid in investigating POCA causes, we suggest the Anesthetic care, Surgery, Echocardiography, Relevant Check and History (A-SERCH) list of actions. We recommend combining the Hs and Ts mnemonic, the PCARR construct, monitoring, and the A-SERCH list of actions in a rational manner to investigate POCA causes. These proposals require real-world testing to assess their feasibility.

OBJECTIVES: This study aimed to examine the intergenerational effects of maternal adverse childhood experiences (ACEs) and child mental health outcomes in rural Uganda, as well as the potentially mediating role of maternal depression in this pathway. Additionally, we sought to test the extent to which maternal social group membership attenuated the mediating effect of maternal depression on child mental health. METHODS: Data come from a population-based cohort of families living in the Nyakabare Parish, a rural district in southwestern Uganda. Between 2016 and 2018, mothers completed surveys about childhood adversity, depressive symptoms, social group membership, and their childrens mental health. Survey data were analyzed using causal mediation and moderated-mediation analysis. RESULTS: Among 218 mother-child pairs, 61 mothers (28%) and 47 children (22%) showed symptoms meeting cutoffs for clinically significant psychological distress. In multivariable linear regression models, maternal ACEs had a statistically significant association with severity of child conduct problems, peer problems, and total child difficulty scores. Maternal depression mediated the relationship between maternal ACEs and conduct problems, peer problems, and total difficulty, but this mediating effect was not moderated by maternal group membership. CONCLUSIONS: Maternal depression may act as a potential mechanism linking maternal childhood adversity with poor child mental health in the next generation. Within a context of elevated rates of psychiatric morbidity, high prevalence of childhood adversity, and limited healthcare and economic infrastructures across Uganda, these results emphasize the prioritization of social services and mental health resources for rural Ugandan families.

Until recently, intronic lariats were regarded as short-lasting splicing byproducts with no apparent function; however, increasing evidence of stable derivatives suggests regulatory roles. Yet little is known about their characteristics, functions, distribution, and expression in healthy and tumor tissue. Here, we profiled and characterized circular stable intronic sequence RNAs (sisRNAs) using total RNA-Seq data from bladder cancer (BC; n = 457, UROMOL cohort), healthy tissue (n = 46), and fractionated cell lines (n = 5). We found that the recently-discovered full-length intronic circles and the stable lariats formed distinct subclasses, with a surprisingly high intronic circle fraction in BC (∼45%) compared to healthy tissues (0-20%). The stable lariats and their host introns were characterized by small transcript sizes, highly conserved BP regions, enriched BP motifs, and localization in multiple cell fractions. Additionally, circular sisRNAs showed tissue-specific expression patterns. We found nine circular sisRNAs as differentially expressed across early-stage BC patients with different prognoses, and sisHNRNPK expression correlated with progression-free survival. In conclusion, we identify distinguishing biological features of circular sisRNAs and point to specific candidates (incl. sisHNRNPK, sisWDR13 and sisMBNL1) that were highly expressed, had evolutionary conserved sequences, or had clinical correlations, which may facilitate future studies and further insights into their functional roles.

Einsteins general theory of relativity from 19151 remains the most successful description of gravitation. From the 1919 solar eclipse2 to the observation of gravitational waves3, the theory has passed many crucial experimental tests. However, the evolving concepts of dark matter and dark energy illustrate that there is much to be learned about the gravitating content of the universe. Singularities in the general theory of relativity and the lack of a quantum theory of gravity suggest that our picture is incomplete. It is thus prudent to explore gravity in exotic physical systems. Antimatter was unknown to Einstein in 1915. Diracs theory4 appeared in 1928; the positron was observed5 in 1932. There has since been much speculation about gravity and antimatter. The theoretical consensus is that any laboratory mass must be attracted6 by the Earth, although some authors have considered the cosmological consequences if antimatter should be repelled by matter7-10. In the general theory of relativity, the weak equivalence principle (WEP) requires that all masses react identically to gravity, independent of their internal structure. Here we show that antihydrogen atoms, released from magnetic confinement in the ALPHA-g apparatus, behave in a way consistent with gravitational attraction to the Earth. Repulsive antigravity is ruled out in this case. This experiment paves the way for precision studies of the magnitude of the gravitational acceleration between anti-atoms and the Earth to test the WEP.

This guidance updates 2021 GRADE (Grading of Recommendations Assessment, Development and Evaluation) recommendations regarding immediate allergic reactions following coronavirus disease 2019 (COVID-19) vaccines and addresses revaccinating individuals with first-dose allergic reactions and allergy testing to determine revaccination outcomes. Recent meta-analyses assessed the incidence of severe allergic reactions to initial COVID-19 vaccination, risk of mRNA-COVID-19 revaccination after an initial reaction, and diagnostic accuracy of COVID-19 vaccine and vaccine excipient testing in predicting reactions. GRADE methods informed rating the certainty of evidence and strength of recommendations. A modified Delphi panel consisting of experts in allergy, anaphylaxis, vaccinology, infectious diseases, emergency medicine, and primary care from Australia, Canada, Europe, Japan, South Africa, the United Kingdom, and the United States formed the recommendations. We recommend vaccination for persons without COVID-19 vaccine excipient allergy and revaccination after a prior immediate allergic reaction. We suggest against >15-minute postvaccination observation. We recommend against mRNA vaccine or excipient skin testing to predict outcomes. We suggest revaccination of persons with an immediate allergic reaction to the mRNA vaccine or excipients be performed by a person with vaccine allergy expertise in a properly equipped setting. We suggest against premedication, split-dosing, or special precautions because of a comorbid allergic history.