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Human induced pluripotent stem cell (iPSC) lines are a powerful tool for studying development and disease, but the considerable phenotypic variation between lines makes it challenging to replicate key findings and integrate data across research groups. To address this issue, we sub-cloned candidate human iPSC lines and deeply characterized their genetic properties using whole genome sequencing, their genomic stability upon CRISPR-Cas9-based gene editing, and their phenotypic properties including differentiation to commonly used cell types. These studies identified KOLF2.1J as an all-around well-performing iPSC line. We then shared KOLF2.1J with groups around the world who tested its performance in head-to-head comparisons with their own preferred iPSC lines across a diverse range of differentiation protocols and functional assays. On the strength of these findings, we have made KOLF2.1J and its gene-edited derivative clones readily accessible to promote the standardization required for large-scale collaborative science in the stem cell field.

PurposeSustained minimal residual disease (MRD) negativity is associated with long-term survival in multiple myeloma. The gut microbiome is affected by diet, and in turn can modulate host immunity, for example through production of short-chain fatty acids including butyrate. We hypothesized that dietary factors affect the microbiome (abundance of butyrate-producing bacteria or stool butyrate concentration) and may be associated with multiple myeloma outcomes.Experimental designWe examined the relationship of dietary factors (via a food frequency questionnaire), stool metabolites (via gas chromatography-mass spectrometry), and the stool microbiome (via 16S sequencing - α-diversity and relative abundance of butyrate-producing bacteria) with sustained MRD negativity (via flow cytometry at two timepoints 1 year apart) in myeloma patients on lenalidomide maintenance. The Healthy Eating Index 2015 score and flavonoid nutrient values were calculated from the food frequency questionnaire. The Wilcoxon rank sum test was used to evaluate associations with two-sided P < 0.05 considered significant.ResultsAt 3 months, higher stool butyrate concentration (P = 0.037), butyrate producers (P = 0.025), and α-diversity (P = 0.0035) were associated with sustained MRD negativity. Healthier dietary proteins, (from seafood and plants), correlated with butyrate at 3 months (P = 0.009) and sustained MRD negativity (P = 0.05). Consumption of dietary flavonoids, plant nutrients with antioxidant effects, correlated with stool butyrate concentration (anthocyanidins P = 0.01, flavones P = 0.01, and flavanols P = 0.02).ConclusionsThis is the first study to demonstrate an association between a plant-based dietary pattern, stool butyrate production, and sustained MRD negativity in multiple myeloma, providing rationale to evaluate a prospective dietary intervention.

Rationale and objectivesOsteoporosis affects 9% of individuals over 50 in the United States and 200 million women globally. Spinal osteoporotic compression fractures (OCFs), an osteoporosis biomarker, are often incidental and under-reported. Accurate automated opportunistic OCF screening can increase the diagnosis rate and ensure adequate treatment. We aimed to develop a deep learning classifier for OCFs, a critical component of our future automated opportunistic screening tool.Materials and methodsThe dataset from the Osteoporotic Fractures in Men Study comprised 4461 subjects and 15,524 spine radiographs. This dataset was split by subject: 76.5% training, 8.5% validation, and 15% testing. From the radiographs, 100,409 vertebral bodies were extracted, each assigned one of two labels adapted from the Genant semiquantitative system: moderate to severe fracture vs. normal/trace/mild fracture. GoogLeNet, a deep learning model, was trained to classify the vertebral bodies. The classification threshold on the predicted probability of OCF outputted by GoogLeNet was set to prioritize the positive predictive value (PPV) while balancing it with the sensitivity. Vertebral bodies with the top 0.75% predicted probabilities were classified as moderate to severe fracture.ResultsOur model yielded a sensitivity of 59.8%, a PPV of 91.2%, and an F1 score of 0.72. The areas under the receiver operating characteristic curve (AUC-ROC) and the precision-recall curve were 0.99 and 0.82, respectively.ConclusionOur model classified vertebral bodies with an AUC-ROC of 0.99, providing a critical component for our future automated opportunistic screening tool. This could lead to earlier detection and treatment of OCFs.

IceCube, a cubic-kilometer array of optical sensors built to detect atmospheric and astrophysical neutrinos between 1 GeV and 1 PeV, is deployed 1.45 km to 2.45 km below the surface of the ice sheet at the South Pole. The classification and reconstruction of events from the in-ice detectors play a central role in the analysis of data from IceCube. Reconstructing and classifying events is a challenge due to the irregular detector geometry, inhomogeneous scattering and absorption of light in the ice and, below 100 GeV, the relatively low number of signal photons produced per event. To address this challenge, it is possible to represent IceCube events as point cloud graphs and use a Graph Neural Network (GNN) as the classification and reconstruction method. The GNN is capable of distinguishing neutrino events from cosmic-ray backgrounds, classifying different neutrino event types, and reconstructing the deposited energy, direction and interaction vertex. Based on simulation, we provide a comparison in the 1 GeV-100 GeV energy range to the current state-of-the-art maximum likelihood techniques used in current IceCube analyses, including the effects of known systematic uncertainties. For neutrino event classification, the GNN increases the signal efficiency by 18% at a fixed background rate, compared to current IceCube methods. Alternatively, the GNN offers a reduction of the background (i.e. false positive) rate by over a factor 8 (to below half a percent) at a fixed signal efficiency. For the reconstruction of energy, direction, and interaction vertex, the resolution improves by an average of 13%-20% compared to current maximum likelihood techniques in the energy range of 1 GeV-30 GeV. The GNN, when run on a GPU, is capable of processing IceCube events at a rate nearly double of the median IceCube trigger rate of 2.7 kHz, which opens the possibility of using low energy neutrinos in online searches for transient events.

Along their long propagation from production to detection, neutrinos undergo flavour conversions that convert their types or flavours1,2. High-energy astrophysical neutrinos propagate unperturbed over a billion light years in vacuum3 and are sensitive to small effects caused by new physics. Effects of quantum gravity4 are expected to appear at the Planck energy scale. Such a high-energy universe would have existed only immediately after the Big Bang and is inaccessible by human technologies. On the other hand, quantum gravity effects may exist in our low-energy vacuum5–8, but are suppressed by inverse powers of the Planck energy. Measuring the coupling of particles to such small effects is difficult via kinematic observables, but could be observable through flavour conversions. Here we report a search with the IceCube Neutrino Observatory, using astrophysical neutrino flavours9,10 to search for new space–time structure. We did not find any evidence of anomalous flavour conversion in the IceCube astrophysical neutrino flavour data. We apply the most stringent limits of any known technologies, down to 10−42 GeV−2 with Bayes factor greater than 10 on the dimension-six operators that parameterize the space–time defects. We thus unambiguously reach the parameter space of quantum-gravity-motivated physics.

Gamma-ray bursts (GRBs) are considered as promising sources of ultra-high-energy cosmic rays (UHECRs) due to their large power output. Observing a neutrino flux from GRBs would offer evidence that GRBs are hadronic accelerators of UHECRs. Previous IceCube analyses, which primarily focused on neutrinos arriving in temporal coincidence with the prompt gamma-rays, found no significant neutrino excess. The four analyses presented in this paper extend the region of interest to 14 days before and after the prompt phase, including generic extended time windows and targeted precursor searches. GRBs were selected between 2011 May and 2018 October to align with the data set of candidate muon-neutrino events observed by IceCube. No evidence of correlation between neutrino events and GRBs was found in these analyses. Limits are set to constrain the contribution of the cosmic GRB population to the diffuse astrophysical neutrino flux observed by IceCube. Prompt neutrino emission from GRBs is limited to 21% of the observed diffuse neutrino flux, and emission on timescales up to 104 s is constrained to 24% of the total diffuse flux.

We present a search for an unstable sterile neutrino by looking for a resonant signal in eight years of atmospheric ν_{μ} data collected from 2011 to 2019 at the IceCube Neutrino Observatory. Both the (stable) three-neutrino and the 3+1 sterile neutrino models are disfavored relative to the unstable sterile neutrino model, though with p values of 2.8% and 0.81%, respectively, we do not observe evidence for 3+1 neutrinos with neutrino decay. The best-fit parameters for the sterile neutrino with decay model from this study are Δm_{41}^{2}=6.7_{-2.5}^{+3.9}  eV^{2}, sin^{2}2θ_{24}=0.33_{-0.17}^{+0.20}, and g^{2}=2.5π±1.5π, where g is the decay-mediating coupling. The preferred regions of the 3+1+decay model from short-baseline oscillation searches are excluded at 90% C.L.

Epilepsy genetics is a rapidly developing field, in which novel disease-associated genes, novel mechanisms associated with epilepsy, and precision medicine approaches are continuously being identified. In the past decade, advances in genomic knowledge and analysis platforms have begun to make clinical genetic testing accessible for, in principle, people of all ages with epilepsy. For this reason, the Genetics Commission of the International League Against Epilepsy (ILAE) presents this update on clinical genetic testing practice, including current techniques, indications, yield of genetic testing, recommendations for pre- and post-test counseling, and follow-up after genetic testing is completed. We acknowledge that the resources vary across different settings but highlight that genetic diagnostic testing for epilepsy should be prioritized when the likelihood of an informative finding is high. Results of genetic testing, in particular the identification of causative genetic variants, are likely to improve individual care. We emphasize the importance of genetic testing for individuals with epilepsy as we enter the era of precision therapy.

The majority of astrophysical neutrinos have undetermined origins. The IceCube Neutrino Observatory has observed astrophysical neutrinos but has not yet identified their sources. Blazars are promising source candidates, but previous searches for neutrino emission from populations of blazars detected in ≳ GeV gamma rays have not observed any significant neutrino excess. Recent findings in multimessenger astronomy indicate that high-energy photons, coproduced with high-energy neutrinos, are likely to be absorbed and reemitted at lower energies. Thus, lower-energy photons may be better indicators of TeV-PeV neutrino production. This paper presents the first time-integrated stacking search for astrophysical neutrino emission from MeV-detected blazars in the first Fermi Large Area Telescope low energy (1FLE) catalog using ten years of IceCube muon-neutrino data. The results of this analysis are found to be consistent with a background-only hypothesis. Assuming an E-2 neutrino spectrum and proportionality between the blazars MeV gamma-ray fluxes and TeV-PeV neutrino flux, the upper limit on the 1FLE blazar energy-scaled neutrino flux is determined to be 1.64 × 10-12 TeV cm-2 s-1 at 90% confidence level. This upper limit is approximately 1% of IceCube's diffuse muon-neutrino flux measurement.

Galaxy clusters have the potential to accelerate cosmic rays (CRs) to ultrahigh energies via accretion shocks or embedded CR acceleration sites. The CRs with energies below the Hillas condition will be confined within the cluster and eventually interact with the intracluster medium gas to produce secondary neutrinos and gamma rays. Using 9.5 yr of muon neutrino track events from the IceCube Neutrino Observatory, we report the results of a stacking analysis of 1094 galaxy clusters with masses ≳1014 Me and redshifts between 0.01 and ∼1 detected by the Planck mission via the Sunyaev–Zel’dovich effect. We find no evidence for significant neutrino emission and report upper limits on the cumulative unresolved neutrino flux from massive galaxy clusters after accounting for the completeness of the catalog up to a redshift of 2, assuming three different weighting scenarios for the stacking and three different power-law spectra. Weighting the sources according to mass and distance, we set upper limits at a 90% confidence level that constrain the flux of neutrinos from massive galaxy clusters (≳1014 Me) to be no more than 4.6% of the diffuse IceCube observations at 100 TeV, assuming an unbroken E−2.5 power-law spectrum.

ObjectivesPhysical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using genotype, may be causally associated with breast cancer risk overall, pre/post-menopause, and by case-groups defined by tumour characteristics.MethodsWe performed two-sample inverse-variance-weighted MR using individual-level Breast Cancer Association Consortium case-control data from 130 957 European-ancestry women (69 838 invasive cases), and published UK Biobank data (n=91 105-377 234). Genetic instruments were single nucleotide polymorphisms (SNPs) associated in UK Biobank with wrist-worn accelerometer-measured overall physical activity (nsnps=5) or sedentary time (nsnps=6), or accelerometer-measured (nsnps=1) or self-reported (nsnps=5) vigorous physical activity.ResultsGreater genetically-predicted overall activity was associated with lower breast cancer overall risk (OR=0.59; 95% confidence interval (CI) 0.42 to 0.83 per-standard deviation (SD;~8 milligravities acceleration)) and for most case-groups. Genetically-predicted vigorous activity was associated with lower risk of pre/perimenopausal breast cancer (OR=0.62; 95% CI 0.45 to 0.87,≥3 vs. 0 self-reported days/week), with consistent estimates for most case-groups. Greater genetically-predicted sedentary time was associated with higher hormone-receptor-negative tumour risk (OR=1.77; 95% CI 1.07 to 2.92 per-SD (~7% time spent sedentary)), with elevated estimates for most case-groups. Results were robust to sensitivity analyses examining pleiotropy (including weighted-median-MR, MR-Egger).ConclusionOur study provides strong evidence that greater overall physical activity, greater vigorous activity, and lower sedentary time are likely to reduce breast cancer risk. More widespread adoption of active lifestyles may reduce the burden from the most common cancer in women.

Low-dose human interleukin-2 (hIL-2) treatment is used clinically to treat autoimmune disorders due to the cytokine's preferential expansion of immunosuppressive regulatory T cells (Tregs). However, off-target immune cell activation and short serum half-life limit the clinical potential of IL-2 treatment. Recent work showed that complexes comprising hIL-2 and the anti-hIL-2 antibody F5111 overcome these limitations by preferentially stimulating Tregs over immune effector cells. Although promising, therapeutic translation of this approach is complicated by the need to optimize dosing ratios and by the instability of the cytokine/antibody complex. We leverage structural insights to engineer a single-chain hIL-2/F5111 antibody fusion protein, termed F5111 immunocytokine (IC), which potently and selectively activates and expands Tregs. F5111 IC confers protection in mouse models of colitis and checkpoint inhibitor-induced diabetes mellitus. These results provide a roadmap for IC design and establish a Treg-biased immunotherapy that could be clinically translated for autoimmune disease treatment.

Modern targeted prophylaxis is recommended for patients with hereditary angioedema (HAE), but many remain on attenuated androgens. EMJ spoke to two HAE experts who explain how they help patients to make the switch.

Abstract Background Service readiness tools are important for assessing hospital capacity to provide quality small and sick newborn care (SSNC). Lack of summary scoring approaches for SSNC service readiness means we are unable to track national targets such as the Every Newborn Action Plan targets. Methods A health facility assessment (HFA) tool was co-designed by Newborn Essential Solutions and Technologies (NEST360) and UNICEF with four African governments. Data were collected in 68 NEST360-implementing neonatal units in Kenya, Malawi, Nigeria, and Tanzania (September 2019-March 2021). Two summary scoring approaches were developed: a) standards-based, including items for SSNC service readiness by health system building block (HSBB), and scored on availability and functionality, and b) level-2 + , scoring items on readiness to provide WHO level-2 + clinical interventions. For each scoring approach, scores were aggregated and summarised as a percentage and equally weighted to obtain an overall score by hospital, HSBB, and clinical intervention. Results Of 1508 HFA items, 1043 (69%) were included in standards-based and 309 (20%) in level-2 + scoring. Sixty-eight neonatal units across four countries had median standards-based scores of 51% [IQR 48–57%] at baseline, with variation by country: 62% [IQR 59–66%] in Kenya, 49% [IQR 46–51%] in Malawi, 50% [IQR 42–58%] in Nigeria, and 55% [IQR 53–62%] in Tanzania. The lowest scoring was family-centred care [27%, IQR 18–40%] with governance highest scoring [76%, IQR 71–82%]. For level-2 + scores, the overall median score was 41% [IQR 35–51%] with variation by country: 50% [IQR 44–53%] in Kenya, 41% [IQR 35–50%] in Malawi, 33% [IQR 27–37%] in Nigeria, and 41% [IQR 32–52%] in Tanzania. Readiness to provide antibiotics by culture report was the highest-scoring intervention [58%, IQR 50–75%] and neonatal encephalopathy management was the lowest-scoring [21%, IQR 8–42%]. In both methods, overall scores were low ( 75%. Discussion Two scoring approaches reveal gaps in SSNC readiness with no neonatal units achieving high scores (> 75%). Government-led quality improvement teams can use these summary scores to identify areas for health systems change. Future analyses could determine which items are most directly linked with quality SSNC and newborn outcomes.

Abstract Background Each year an estimated 2.3 million newborns die in the first 28 days of life. Most of these deaths are preventable, and high-quality neonatal care is fundamental for surviving and thriving. Service readiness is used to assess the capacity of hospitals to provide care, but current health facility assessment (HFA) tools do not fully evaluate inpatient small and sick newborn care (SSNC). Methods Health systems ingredients for SSNC were identified from international guidelines, notably World Health Organization (WHO), and other standards for SSNC. Existing global and national service readiness tools were identified and mapped against this ingredients list. A novel HFA tool was co-designed according to a priori considerations determined by policymakers from four African governments, including that the HFA be completed in one day and assess readiness across the health system. The tool was reviewed by > 150 global experts, and refined and operationalised in 64 hospitals in Kenya, Malawi, Nigeria, and Tanzania between September 2019 and March 2021. Results Eight hundred and sixty-six key health systems ingredients for service readiness for inpatient SSNC were identified and mapped against four global and eight national tools measuring SSNC service readiness. Tools revealed major content gaps particularly for devices and consumables, care guidelines, and facility infrastructure, with a mean of 13.2% (n = 866, range 2.2–34.4%) of ingredients included. Two tools covered 32.7% and 34.4% (n = 866) of ingredients and were used as inputs for the new HFA tool, which included ten modules organised by adapted WHO health system building blocks, including: infrastructure, pharmacy and laboratory, medical devices and supplies, biomedical technician workshop, human resources, information systems, leadership and governance, family-centred care, and infection prevention and control. This HFA tool can be conducted at a hospital by seven assessors in one day and has been used in 64 hospitals in Kenya, Malawi, Nigeria, and Tanzania. Conclusion This HFA tool is available open-access to adapt for use to comprehensively measure service readiness for level-2 SSNC, including respiratory support. The resulting facility-level data enable comparable tracking for Every Newborn Action Plan coverage target four within and between countries, identifying facility and national-level health systems gaps for action.

Commercial deployment of nuclear microreactors presents an opportunity for the industry to rethink its approach to manufacturing, siting, operation and maintenance, and fuel cycle management as certain principles used in grid-scale nuclear projects are not applicable to a decentralized microreactor economy. The success of this nascent industry is dependent on its ability to reduce infrastructure, logistical, regulatory and lifecycle costs. A utility-like ‘Central Facility’ that consolidates the services required and responsibilities borne by vendors into one or a few centralized locations will be necessary to support the deployment of a fleet of microreactors. This paper discusses the requirements for a Central Facility, its implications on the cost structures of owners and suppliers of microreactors, and the impact of the facility for the broader microreactor industry. In addition, this paper discusses the pre-requisites for eligibility as well as the opportunities for a Central Facility host site. While there are many suitable locations for such a capability across the U.S., this paper considers a facility co-located with the Vogtle Nuclear Power Plant and Savannah River Sites to illustrate how a Central Facility can leverage the existing infrastructure and stimulate a local ecosystem.

Abstract Background Patagonian toothfish (Dissostichus eleginoides) is an economically and ecologically important fish species in the family Nototheniidae. Juveniles occupy progressively deeper waters as they mature and grow, and adults have been caught as deep as 2500 m, living on or in just above the southern shelves and slopes around the sub-Antarctic islands of the Southern Ocean. As apex predators, they are a key part of the food web, feeding on a variety of prey, including krill, squid, and other fish. Despite its importance, genomic sequence data, which could be used for more accurate dating of the divergence between Patagonian and Antarctic toothfish, or establish whether it shares adaptations to temperature with fish living in more polar or equatorial climes, has so far been limited. Results A high-quality D. eleginoides genome was generated using a combination of Illumina, PacBio and Omni-C sequencing technologies. To aid the genome annotation, the transcriptome derived from a variety of toothfish tissues was also generated using both short and long read sequencing methods. The final genome assembly was 797.8 Mb with a N50 scaffold length of 3.5 Mb. Approximately 31.7% of the genome consisted of repetitive elements. A total of 35,543 putative protein-coding regions were identified, of which 50% have been functionally annotated. Transcriptomics analysis showed that approximately 64% of the predicted genes (22,617 genes) were found to be expressed in the tissues sampled. Comparative genomics analysis revealed that the anti-freeze glycoprotein (AFGP) locus of D. eleginoides does not contain any AFGP proteins compared to the same locus in the Antarctic toothfish (Dissostichus mawsoni). This is in agreement with previously published results looking at hybridization signals and confirms that Patagonian toothfish do not possess AFGP coding sequences in their genome. Conclusions We have assembled and annotated the Patagonian toothfish genome, which will provide a valuable genetic resource for ecological and evolutionary studies on this and other closely related species.

Abstract Introduction Clinical practice guidelines recommend against the routine use of psychotropic medications in residential aged care facilities (RACFs). Knowledge brokers are individuals or groups who facilitate the transfer of knowledge into practice. The objective of this trial is to evaluate the effectiveness and cost-effectiveness of using knowledge brokers to translate Australia’s new Clinical Practice Guidelines for the Appropriate Use of Psychotropic Medications in People Living with Dementia and in Residential Aged Care. Methods and analysis The Evidence-based Medication knowledge Brokers in Residential Aged CarE (EMBRACE) trial is a helix-counterbalanced randomised controlled trial. The 12-month trial will be conducted in up to 19 RACFs operated by four Australian aged care provider organisations in Victoria, New South Wales, Western Australia and Queensland. RACFs will be randomised to receive three levels of implementation strategies (knowledge broker service, pharmacist-led quality use of medications education activities and distribution of the Guidelines and supporting materials) across three medication contexts (antipsychotics, benzodiazepines and antidepressants). Implementation strategies will be delivered by an embedded on-site aged care pharmacist working at a system level across each participating RACF. All RACFs will receive all implementation strategies simultaneously but for different medication contexts. The primary outcome will be a composite dichotomous measure of 6-month RACF-level concordance with Guideline recommendations and good practice statements among people using antipsychotics, benzodiazepines and antidepressants for changed behaviours. Secondary outcomes will include proportion of residents with Guideline concordant use of antipsychotics, benzodiazepines and antidepressants measured at the RACF-level and proportion of residents with psychotropic medication use, hospitalisation, falls, falls with injury, polypharmacy, quality of life, activities of daily living, medication incidents and behavioural incidents measured at the RACF-level. Discussion The EMBRACE trial investigates a novel guideline implementation strategy to improve the safe and effective use of psychotropic medications in RACFs. We anticipate that the findings will provide new information on the potential role of knowledge brokers for successful and cost-effective guideline implementation. Trial registration Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12623001141639. Registered 6 November 2023 — retrospectively registered, https://www.anzctr.org.au/TrialSearch.aspx .

Abstract Background Medicare provides significant funding to improve, encourage and coordinate better practices in primary care. Medicare-rebated Chronic Disease Management (CDM) plans are a structured approach to managing chronic diseases in Australia. These chronic disease care plans are intended to be a vehicle to deliver guideline-based / evidence-based care.. However, recommended care is not always provided, and health outcomes are often not achieved. This scoping review aimed to identify the specific components of CDM plans that are most effective in promoting self-management, as well as the factors that may hinder or facilitate the implementation of these plans in general practice settings in Australia. Method A comprehensive search was conducted using multiple electronic databases, considering inclusion and exclusion criteria. Two reviewers independently screened the titles and abstracts of the identified studies via Covidence, and the full texts of eligible studies were reviewed for inclusion. A data extraction template was developed based on the Cochrane Effective Practice and Organization of Care Group (EPOC) to classify the intervention methods and study outcomes. A narrative synthesis approach was used to summarize the findings of the included studies. The quality of the included studies was assessed using the JBI Critical Appraisal Checklist. Results Seventeen articles were included in the review for analysis and highlighted the effectiveness of CDM plans on improving patient self-management. The findings demonstrated that the implementation of CDM plans can have a positive impact on patient self-management. However, the current approach is geared towards providing care to patients, but there are limited opportunities for patients to engage in their care actively. Furthermore, the focus is often on achieving the outcomes outlined in the CDM plans, which may not necessarily align with the patient’s needs and preferences. The findings highlighted the significance of mutual obligations and responsibilities of team care for patients and healthcare professionals, interprofessional collaborative practice in primary care settings, and regular CDM plan reviews. Conclusion Self-management support remains more aligned with a patient-centred collaboration approach and shared decision-making and is yet to be common practice. Identifying influential factors at different levels of patients, healthcare professionals, and services affecting patients’ self-management via CDM plans can be crucial to developing the plans.

Abstract Bone marrow stromal cells (BMSCs) have immunomodulatory activities in numerous species and have been used in clinical trials. BMSCs also make antibacterial agents. Since hepcidin is known to have antimicrobial effects in fish, we wondered if it might also be used as an antimicrobial agent by mammalian BMSCs. In the present study, we show hepcidin expression in both mouse (mBMSC) and human BMSCs (hBMSC). We observed a hBMSC hepcidin-dependent degradation of ferroportin in HEK-293 reporter cells in vitro. In human and mouse bone marrows (BM) we detected hepcidin-positive BMSCs in close proximity to hematopoietic progenitors. The conditioned culture medium of hBMSCs significantly reduced bacterial proliferation that was partially blocked by a hepcidin-neutralizing antibody. Similarly, medium in which hepcidin-deficient (Hamp −/− ) mouse BMSCs had been grown was significantly less effective in reducing bacterial counts than the medium of wild-type cells. In a zymosan-induced peritonitis mouse model we found that mBMSC-derived hepcidin reduced the number of invading polymorphonuclear (PMN) cells in the peritoneal cavity. Our results show that BMSC-derived hepcidin has antimicrobial properties in vitro and also reduces inflammation in vivo. We conclude that hepcidin should be added to the expanding arsenal of agents available to BMSCs to fight infections and inflammation.

Abstract While evidence abounds that motor synchrony is a powerful form of ‘social glue’ for those involved, we have yet to understand how observers perceive motor synchrony: can observers estimate the degree of synchrony accurately? Is synchrony aesthetically pleasing? In two preregistered experiments (n = 161 each), we assess how accurately observers can estimate the degree of synchrony in dyads playing the mirror game, and how much observers enjoy watching these movements. We further assess whether accuracy and enjoyment are influenced by individual differences in self-reported embodied expertise (ability to reproduce movements, body awareness, body competence), psychosocial resources (extraversion, self-esteem), or social competencies (empathy, autistic traits), while objectively controlling for the degree of measured synchrony and complexity. The data revealed that observers’ estimated synchrony with poor accuracy, showing a tendency to underestimate the level of synchrony. Accuracy for low synchrony improved with increasing body competence, while accuracy for high synchrony improved with increasing autistic traits. Observers’ enjoyment of dyadic movements correlated positively with the degree of measured synchrony, the predictability of the movements, and the observer’s empathy. Furthermore, very low enjoyment was associated with increased body perception. Our findings indicate that accuracy in perceiving synchrony is closely linked to embodiment, while aesthetic evaluations of action hinge on individual differences.

Abstract Introduction Food security and nutrition have been severely impacted during the COVID-19 pandemic, particularly in low- and middle-income countries (LMICs). We aimed to quantify the impacts of the pandemic on food security and diet diversity within Chilanga District in Zambia and identify target areas for high-impact social protection and safety net programs. Methods We conducted a cross-sectional study in Chilanga district immediately after the Omicron variant surge in February 2022. Diet quality and food security were assessed based on a household diet questionnaire and a Minimum Dietary Diversity-Women (MDD-W) score was calculated. A paired t-test was used to determine whether there was a statistically significant change in the MDD-W score and McNemar test was used to investigate the change in food security between the pre- and peri-COVID-19 period. Results Compared to the pre-COVID-19 period, there were increases in food prices across the board in the peri-COVID-19 period and decreased consumption of key food categories including legumes, dairy and vitamin A rich foods. Despite high rates of food insecurity, only 6.6% of surveyed households received any cash or in-kind assistance from a government agency, non-profit, or other organization in the post-COVID-19 period. Conclusion The COVID-19 pandemic had significant impacts on food security and dietary diversity in Chilanga district. This is particularly relevant in the low-income communities that we surveyed, which had pre-existing challenges with food security. Additional resources must be invested in Chilanga District and similarly affected areas to address this gap in access to food and promote national equity. Trial Registration N/A.

Background: Although studies have documented higher rates of chronic pain among women Veterans compared to men Veterans, there remains a lack of comprehensive information about potential contributors to these disparities. Materials and Methods: This study examined gender differences in chronic pain and its contributors among 419 men and 392 women Veterans, enrolled in a mindfulness trial for chronic pain. We conducted descriptive analyses summarizing distributions of baseline measures, obtained by survey and through the electronic health record. Comparisons between genders were conducted using chi-square tests for categorical variables and t-tests for continuous measures. Results: Compared to men, women Veterans were more likely to have chronic overlapping pain conditions and had higher levels of pain interference and intensity. Women had higher prevalence of psychiatric and sleep disorder diagnoses, greater levels of depression, anxiety, post-traumatic stress disorder, fatigue, sleep disturbance, stress and pain catastrophizing, and lower levels of pain self-efficacy and participation in social roles and activities. However, women were less likely to smoke or have a substance abuse disorder and used more nonpharmacological pain treatment modalities. Conclusion: Among Veterans seeking treatment for chronic pain, women differed from men in their type of pain, had greater pain intensity and interference, and had greater prevalence and higher levels of many known biopsychosocial contributors to pain. Results point to the need for pain treatment that addresses the comprehensive needs of women Veterans. Clinical Trial Registration Number: NCT04526158. Patient enrollment began on December 4, 2020.

This research presents a novel game theory based model for femtocell power management, engineered to significantly enhance the Signal-to-Interference-plus-Noise Ratio (SINR) while optimizing energy consumption across wireless communication networks. Femtocells, as a solution to the increasing demand for high-quality indoor network coverage, face challenges in power management and interference mitigation. Our proposed model addresses these issues, providing a sophisticated algorithmic approach that ensures high SINR levels without a proportional increase in power usage. Through a series of simulations, the model’s performance was evaluated against existing power management techniques. The results, delineated across several tables, revealed that the proposed model consistently achieved and often surpassed targeted SINR levels with modest power consumption increments, even at high targets. Notably, at a SINR target of 20, the model sustained a high SINR of 23.62 while maintaining a reasonable energy profile. Additionally, the model exhibited exceptional operational efficiency, characterized by low execution times and rapid convergence rates, across varying network conditions. This responsiveness is essential for adapting to user mobility and varying traffic patterns, particularly in dense urban settings and during peak usage periods.

Abstract Background High quality endoscopy is key for detecting and removing precursor lesions to colorectal cancer (CRC). Adenoma detection rates (ADRs) measure endoscopist performance. Improving other components of examinations could increase adenoma detection. Aims To investigate how endoscopist performance at flexible sigmoidoscopy (FS) affects adenoma detection and CRC incidence. Methods Among 34,139 participants receiving FS screening by the main endoscopist at one of 13 centres in the UK FS Screening Trial, median follow-up was 17 years. Factors examined included family history of CRC, bowel preparation quality, insertion and withdrawal time, bowel segment reached, patient pain and ADR. Odds ratios (OR) for distal adenoma detection were estimated by logistic regression. Hazard ratios (HR) for distal CRC incidence were estimated by Cox regression. Results At screening, 4,104 participants had distal adenomas detected and 168 participants developed distal CRC during follow-up. In multivariable models, a family history of CRC (yes vs. no: OR 1.40, 95%CI 1.21–1.62), good or adequate bowel preparation quality (vs. excellent: OR 0.84, 95%CI 0.74–0.95; OR 0.56, 95%CI 0.49–0.65, respectively) and longer insertion and withdrawal times (≥ 4.00 vs.

Abstract Background Schoolteachers are often the first to respond when a student presents with a mental health issue in the classroom. This places a burden on schools that impacts school staff, healthcare workers and teachers. More broadly, it places a responsibility on the education system to address students’ mental health. This study examines Australian teachers’ classroom experiences and the training areas identified by teachers as necessary to manage these issues. Method Interviews were undertaken with 18 in-service teachers between 2020 and 2021 from Catholic, Independent and Public schools. Data were gathered via multiple interviews and analysed using thematic content analysis. Results The major mental health issues identified by teachers related to mental disorders, depression, anxiety, and a complex range of negative emotional states. Teachers requested training in child and adolescent mental health, counselling skills, early detection and intervention, and training skills to manage the complex relationship with parents and external health and community personnel. Teachers also reported the need to access mental health resources, support and training, which were differentially accessed along socioeconomic status and postcodes. Conclusion The data show that teachers are often placed as first responders when a student has a mental health issue but feel inadequately trained to manage these issues in the classroom. We identified mental health issues presenting in Australian classrooms and documented critical features of mental-health training asked for by teachers in order to address those issues. Given the increasing demands on teachers to address the mental health of children and adolescents, we argue that an urgent review of mental health training for teachers is needed.

Abstract Background Combining multimodal lifestyle interventions and disease-modifying drugs (novel or repurposed) could provide novel precision approaches to prevent cognitive impairment. Metformin is a promising candidate in view of the well-established link between type 2 diabetes (T2D) and Alzheimer’s Disease and emerging evidence of its potential neuro-protective effects (e.g. vascular, metabolic, anti-senescence). MET-FINGER aims to test a FINGER 2.0 multimodal intervention, combining an updated FINGER multidomain lifestyle intervention with metformin, where appropriate, in an APOE ε4-enriched population of older adults (60–79 years) at increased risk of dementia. Methods MET-FINGER is an international randomised, controlled, parallel-group, phase-IIb proof-of-concept clinical trial, where metformin is included through a trial-within-trial design. 600 participants will be recruited at three sites (UK, Finland, Sweden). Participants at increased risk of dementia based on vascular risk factors and cognitive screening, will be first randomised to the FINGER 2.0 intervention (lifestyle + metformin if eligible; active arm) or to receive regular health advice (control arm). Participants allocated to the FINGER 2.0 intervention group at risk indicators of T2D will be additionally randomised to receive metformin (2000 mg/day or 1000 mg/day) or placebo. The study duration is 2 years. The changes in global cognition (primary outcome, using a Neuropsychological Test Battery), memory, executive function, and processing speed cognitive domains; functional status; lifestyle, vascular, metabolic, and other dementia-related risk factors (secondary outcomes), will be compared between the FINGER 2.0 intervention and the control arm. The feasibility, potential interaction (between-groups differences in healthy lifestyle changes), and disease-modifying effects of the lifestyle-metformin combination will be exploratory outcomes. The lifestyle intervention is adapted from the original FINGER trial (diet, physical activity, cognitive training, monitoring of cardiovascular/metabolic risk factors, social interaction) to be consistently delivered in three countries. Metformin is administered as Glucophage®XR/SR 500, (500 mg oral tablets). The metformin/placebo treatment will be double blinded. Conclusion MET-FINGER is the first trial combining a multimodal lifestyle intervention with a putative repurposed disease-modifying drug for cognitive impairment prevention. Although preliminary, its findings will provide crucial information for innovative precision prevention strategies and form the basis for a larger phase-III trial design and future research in this field. Trial registration ClinicalTrials.gov (NCT05109169).

Abstract Copy number alterations (CNAs) are among the most important genetic events in cancer, but their detection from sequencing data is challenging because of unknown sample purity, tumor ploidy, and general intra-tumor heterogeneity. Here, we present CNAqc, an evolution-inspired method to perform the computational validation of clonal and subclonal CNAs detected from bulk DNA sequencing. CNAqc is validated using single-cell data and simulations, is applied to over 4000 TCGA and PCAWG samples, and is incorporated into the validation process for the clinically accredited bioinformatics pipeline at Genomics England. CNAqc is designed to support automated quality control procedures for tumor somatic data validation.

Abstract To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.

As elsewhere in the global ocean, the Gulf of Alaska is experiencing the rapid onset of ocean acidification (OA) driven by oceanic absorption of anthropogenic emissions of carbon dioxide from the atmosphere. In support of OA research and monitoring, we present here a data product of marine inorganic carbon chemistry parameters measured from seawater samples taken during biannual cruises between 2008 and 2017 in the northern Gulf of Alaska. Samples were collected each May and September over the 10 year period using a conductivity, temperature, depth (CTD) profiler coupled with a Niskin bottle rosette at stations including a long-term hydrographic survey transect known as the Gulf of Alaska (GAK) Line. This dataset includes discrete seawater measurements such as dissolved inorganic carbon and total alkalinity, which allows the calculation of other marine carbon parameters, including carbonate mineral saturation states, carbon dioxide (CO2), and pH. Cumulative daily Bakun upwelling indices illustrate the pattern of downwelling in the northern Gulf of Alaska, with a period of relaxation spanning between the May and September cruises. The observed time and space variability impart challenges for disentangling the OA signal despite this dataset spanning a decade. However, this data product greatly enhances our understanding of seasonal and interannual variability in the marine inorganic carbon system parameters. The product can also aid in the ground truthing of biogeochemical models, refining estimates of sea–air CO2 exchange, and determining appropriate CO2 parameter ranges for experiments targeting potentially vulnerable species. Data are available at https://doi.org/10.25921/x9sg-9b08 (Monacci et al., 2023).

Abstract Background Mexico is one of the countries with the greatest excess death due to COVID-19. Chiapas, the poorest state in the country, has been particularly affected. Faced with an exacerbated shortage of health professionals, medical supplies, and infrastructure to respond to the pandemic, the non-governmental organization Compañeros En Salud (CES) implemented a COVID-19 infection prevention and control program to limit the impact of the pandemic in the region. We evaluated CES’s implementation of a community health worker (CHW)-led contact tracing intervention in eight rural communities in Chiapas. Methods Our retrospective observational study used operational data collected during the contract tracing intervention from March 2020 to December 2021. We evaluated three outcomes: contact tracing coverage, defined as the proportion of named contacts that were located by CHWs, successful completion of contact tracing, and incidence of suspected COVID-19 among contacts. We described how these outcomes changed over time as the intervention evolved. In addition, we assessed associations between these three main outcomes and demographic characteristics of contacts and intervention period (pre vs. post March 2021) using univariate and multivariate logistic regression. Results From a roster of 2,177 named contacts, 1,187 (54.5%) received at least one home visit by a CHW and 560 (25.7%) had successful completion of contact tracing according to intervention guidelines. Of 560 contacts with complete contact tracing, 93 (16.6%) became suspected COVID-19 cases. We observed significant associations between sex and coverage (p = 0.006), sex and complete contact tracing (p = 0.049), community of residence and both coverage and complete contact tracing (p

Abstract Background No single pulmonary function test captures the functional effect of emphysema in idiopathic pulmonary fibrosis (IPF). Without experienced radiologists, other methods are needed to determine emphysema extent. Here, we report the development and validation of a formula to predict emphysema extent in patients with IPF and emphysema. Methods The development cohort included 76 patients with combined IPF and emphysema at the Royal Brompton Hospital, London, United Kingdom. The formula was derived using stepwise regression to generate the weighted combination of pulmonary function data that fitted best with emphysema extent on high-resolution computed tomography. Test cohorts included patients from two clinical trials (n = 455 [n = 174 with emphysema]; NCT00047645, NCT00075998) and a real-world cohort from the Royal Brompton Hospital (n = 191 [n = 110 with emphysema]). The formula is only applicable for patients with IPF and concomitant emphysema and accordingly was not used to detect the presence or absence of emphysema. Results The formula was: predicted emphysema extent = 12.67 + (0.92 x percent predicted forced vital capacity) – (0.65 x percent predicted forced expiratory volume in 1 second) – (0.52 x percent predicted carbon monoxide diffusing capacity). A significant relationship between the formula and observed emphysema extent was found in both cohorts (R2 = 0.25, P

Abstract Background Physique athletes are ranked by a panel of judges against the judging criteria of the corresponding division. To enhance on-stage presentation and performance, competitors in certain categories (i.e. bodybuilding and classic physique) achieve extreme muscle size and definition aided by implementing acute “peaking protocols” in the days before competition. Such practices can involve manipulating nutrition and training variables to increase intramuscular glycogen and water while minimising the thickness of the subcutaneous layer. Carbohydrate manipulation is a prevalent strategy utilised to plausibly induce muscle glycogen supercompensation and subsequently increase muscle size. The relationship between carbohydrate intake and muscle glycogen saturation was first examined in endurance event performance and similar strategies have been adopted by physique athletes despite the distinct physiological dissimilarities and aims between the sports. Objectives The aim of this narrative review is to (1) critically examine and appraise the existing scientific literature relating to carbohydrate manipulation practices in physique athletes prior to competition; (2) identify research gaps and provide direction for future studies; and (3) provide broad practical applications based on the findings and physiological reasoning for coaches and competitors. Findings The findings of this review indicate that carbohydrate manipulation practices are prevalent amongst physique athletes despite a paucity of experimental evidence demonstrating the efficacy of such strategies on physique performance. Competitors have also been observed to manipulate water and electrolytes in conjunction with carbohydrate predicated on speculative physiological mechanisms which may be detrimental for performance. Conclusions Further experimental evidence which closely replicates the nutritional and training practices of physique athletes during peak week is required to make conclusions on the efficacy of carbohydrate manipulation strategies. Quasi-experimental designs may be a feasible alternative to randomised controlled trials to examine such strategies due to the difficulty in recruiting the population of interest. Finally, we recommend that coaches and competitors manipulate as few variables as possible, and experiment with different magnitudes of carbohydrate loads in advance of competition if implementing a peaking strategy.

The IceCube Neutrino Observatory instruments about 1 km3 of deep, glacial ice at the geographic South Pole. It uses 5160 photomultipliers to detect Cherenkov light emitted by charged relativistic particles. An unexpected light propagation effect observed by the experiment is an anisotropic attenuation, which is aligned with the local flow direction of the ice. We examine birefringent light propagation through the polycrystalline ice microstructure as a possible explanation for this effect. The predictions of a first-principles model developed for this purpose, in particular curved light trajectories resulting from asymmetric diffusion, provide a qualitatively good match to the main features of the data. This in turn allows us to deduce ice crystal properties. Since the wavelength of the detected light is short compared to the crystal size, these crystal properties include not only the crystal orientation fabric, but also the average crystal size and shape, as a function of depth. By adding small empirical corrections to this first-principles model, a quantitatively accurate description of the optical properties of the IceCube glacial ice is obtained. In this paper, we present the experimental signature of ice optical anisotropy observed in IceCube light-emitting diode (LED) calibration data, the theory and parameterization of the birefringence effect, the fitting procedures of these parameterizations to experimental data, and the inferred crystal properties.

Balazs Horvath,1,2 Benjamin Kloesel,3 Sarah N Cross4 1Department of Anesthesiology, St. Vincent’s Medical Center, Bridgeport, CT, USA; 2Department of Anesthesiology, University of Minnesota Medical School, Minneapolis, MN, USA; 3Department of Anesthesiology, Children’s Minnesota Hospital, Minneapolis, MN, USA; 4Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USACorrespondence: Balazs HorvathDepartment of Anesthesiology, St. Vincent’s Medical Center, Bridgeport, CT, USA, Tel +612 624-9990, Email bhorvath@umn.eduAbstract: Persistent postpartum pain is common and has a complex etiology. It has both somatic and psychosocial provoking factors and has both functional and psychological ramifications following childbirth. Pain that limits the functional capacity of a person who has the daunting task to take care of all the demands of managing a growing newborn and infant can have debilitating consequences for several people simultaneously. We will review the incidence of persistent postpartum pain, analyze the risk factors, and discuss obstetric, anesthetic, and psychological tools for prevention and management. Based on the current knowledge, early antenatal screening and management is described as the most likely measure to identify patients at risk for persistent postpartum pain. Such antenatal management should be based on the close collaboration between obstetricians, anesthesiologists, and psychologists to tailor peripartum pain management and psychological support-based individual needs.Keywords: persistent pain, postpartum, risk factors, analgesia, labor, delivery