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Abstract Individual dietary specialization, where individuals occupy a subset of a population’s wider dietary niche, is a key factor determining a species resilience against environmental change. However, the ontogeny of individual specialization, as well as associated underlying social learning, genetic, and environmental drivers, remain poorly understood. Using a multigenerational dataset of female European brown bears (Ursus arctos) followed since birth, we discerned the relative contributions of environmental similarity, genetic heritability, maternal effects, and offspring social learning from the mother to individual specialization. Individual specialization accounted for 43% of phenotypic variation and spanned half a trophic position, with individual diets ranging from omnivorous to carnivorous. The main determinants of dietary specialization were social learning during rearing (13%), environmental similarity (5%), maternal effects (11%), and permanent between-individual effects (9%), whereas the contribution of genetic heritability (3%) was negligible. The trophic position of offspring closely resembled the trophic position of their mothers during the first 3–4 years of independence, but waned with increasing time since separation. Our study shows that social learning and maternal effects were more important for individual dietary specialization than environmental composition. We propose a tighter integration of social effects into studies of range expansion and habitat selection under global change.

Abstract We study the anomalous magnetic moment of the muon, $$g_\mu - 2 \equiv 2 a_\mu $$ g μ - 2 ≡ 2 a μ , in the context of supersymmetric models beyond the CMSSM, where the unification of either the gaugino masses $$M_{1,2,3}$$ M 1 , 2 , 3 or sfermion and Higgs masses is relaxed, taking into account the measured mass of the Higgs boson, $$m_H$$ m H , the cosmological dark matter density and the direct detection rate. We find that the model with non-unified gaugino masses can make a contribution $$\Delta a_\mu \sim 20 \times 10^{-10}$$ Δ a μ ∼ 20 × 10 - 10 to the anomalous magnetic moment of the muon, for example if $$M_{1,2} \sim 600\; \textrm{GeV}$$ M 1 , 2 ∼ 600 GeV and $$M_3\sim 8 \; \textrm{TeV}$$ M 3 ∼ 8 TeV . The model with non-universal sfermion and Higgs masses can provide even larger $$\Delta a_\mu \sim 24 \times 10^{-10}$$ Δ a μ ∼ 24 × 10 - 10 if the sfermion masses for the first and the second generations are $$ \sim 400 \; \textrm{GeV}$$ ∼ 400 GeV and that of the third is $$ \sim 8 \; \textrm{TeV}$$ ∼ 8 TeV . We discuss the prospects for collider searches for supersymmetric particles in specific benchmark scenarios illustrating these possibilities, focusing in particular on the prospects for detecting the lighter smuon and the lightest neutralino.

Abstract Background The growing concern for player safety in rugby has led to an increased focus on head impacts. Previous laboratory studies have shown that rugby headgear significantly reduces peak linear and rotational accelerations compared to no headgear. However, these metrics may have limited relevance in assessing the effectiveness of headgear in preventing strain-based brain injuries like concussions. This study used an instantaneous deep-learning brain injury model to quantify regional brain strain mitigation of rugby headgear during drop tests. Tests were conducted on flat and angled impact surfaces across different heights, using a Hybrid III headform and neck. Results Headgear presence generally reduced the peak rotational velocities, with some headgear outperforming others. However, the effect on peak regional brain strains was less consistent. Of the 5 headgear tested, only the newer models that use open cell foams at densities above 45 kg/m3 consistently reduced the peak strain in the cerebrum, corpus callosum, and brainstem. The 3 conventional headgear that use closed cell foams at or below 45 kg/m3 showed no consistent reduction in the peak strain in the cerebrum, corpus callosum, and brainstem. Conclusions The presence of rugby headgear may be able to reduce the severity of head impact exposure during rugby. However, to understand how these findings relate to brain strain mitigation in the field, further investigation into the relationship between the impact conditions in this study and those encountered during actual gameplay is necessary.

Background: Intraoperative physiologic parameters could offer predictive utility in evaluating risk of adverse postoperative events yet are not included in current standard risk models. This study examined whether the inclusion of continuous intraoperative data improved machine learning model predictions for multiple outcomes after coronary artery bypass grafting, including 30-day mortality, renal failure, reoperation, prolonged ventilation, and combined morbidity and mortality (MM). Methods: The Society of Thoracic Surgeons (STS) database features and risk scores were combined with retrospectively gathered continuous intraoperative data from patients. Risk models were developed for each outcome by training a logistic regression classifier on intraoperative data using 5-fold cross-validation. STS risk scores were included as offset terms in the models. Results: Compared with the STS Risk Calculator, models developed using a combination of the intraoperative features and the STS preoperative risk score had improved mean area under the receiver operating characteristic curve for prolonged ventilation (0.750 [95% CI, 0.690-0.809] vs 0.800 [95% CI, 0.750-0.851]) and MM (0.695 [95% CI, 0.644-0.746] vs 0.724 [95% CI, 0.673-0.775]). Additionally, models developed using intraoperative features had improved calibration, measured with Brier score, for prolonged ventilation (0.060 [95% CI, 0.050-0.070] vs 0.055 [95% CI, 0.045-0.065]) and MM (0.092 [95% CI, 0.081-0.103] vs 0.087 [95% CI, 0.075-0.098]). Conclusions: The inclusion of time series intraoperative data in risk models may improve early postoperative care by identifying patients who require closer monitoring postoperatively.

Societal Impact Statement Increasing crop productivity is often proposed as a key goal for meeting the food security demands of a growing global population. However, achieving high crop yields alone without meeting end‐use quality requirements is counter to this objective and can lead to negative environmental and sustainability issues. High yielding feed wheat crops in the United Kingdom are a typical example of this. The historical context of UK agricultural industrialisation, developments in plant breeding and wheat end‐use processing are examined. We then outline how employing innovations in plant breeding methods offer the potential to redress the balance between wheat quantity and quality. Summary Bread wheat (Triticum aestivum L.) has historically been an important crop for many human civilisations. Today, variability in wheat supply and trade has a large influence on global economies and food security. The United Kingdom is an example of an industrialised country that achieves high wheat yields through intensive cropping systems and a favourable climate. However, only a minority of the wheat grain produced is of suitable end‐use quality for modern bread baking methods and most wheat produced is fed to livestock. A large agricultural land area and input use dedicated to producing grain for animal rather than human food has wide‐ranging negative impacts for environmental sustainability and domestic food production. Here we present an historical perspective of agricultural and economic changes that have resulted in UK production primarily focussing on wheat quantity over quality. Agricultural intensification, liberalisation of free trade in agricultural commodities, innovations in the milling and baking sector, developments in scientific understanding of genetics and plant breeding, and geopolitical changes have all played a role. We propose that wheat breeding plays a crucial role in influencing these issues and although wheat breeders in the United Kingdom have historically applied the most‐up‐to‐date scientific advances, recent advances in genomics tools and quantitative genetics present a unique opportunity for breeders to redress the balance between quantity and quality.

Abstract Introduction Nivolumab plus ipilimumab (NIVO + IPI) and pembrolizumab plus axitinib (PEM + AXI) are first-line (1L) treatments for advanced or metastatic renal cell carcinoma (aRCC), although the long-term trends in their associated real-world healthcare costs are not well defined. We compared the real-world healthcare costs of patients with aRCC who received 1L NIVO + IPI or PEM + AXI over 24 months. Methods Adults with RCC and secondary malignancy who initiated 1L NIVO + IPI or PEM + AXI were identified in the Merative MarketScan Commercial and Medicare Supplemental Databases (01/01/2004 to 09/30/2021). All-cause and RCC-related healthcare costs (unadjusted and adjusted) were assessed per patient per month (PPPM) at 6-month intervals post-treatment initiation (index date) up to 24 months, and differences between the NIVO + IPI and PEM + AXI cohorts were compared. Results Of 325 patients with aRCC, 219 received NIVO + IPI and 106 received PEM + AXI as the 1L treatment. According to patients’ follow-up length, the analyses for months 7–12 included 210 patients in the NIVO + IPI cohort and 103 in the PEM + AXI cohort; months 13–18 included 119 and 48 patients, respectively; and months 19–24 included 81 and 25 patients. PPPM unadjusted all-cause total costs were $46,348 for NIVO + IPI and $38,097 for PEM + AXI in months 1–6; $26,840 versus $27,983, respectively, in months 7–12; $22,899 versus $25,137 in months 13–18; and $22,279 versus $27,947 in months 19–24. PPPM unadjusted RCC-related costs were $44,059 for NIVO + IPI and $36,456 for PEM + AXI in months 1–6; $25,144 versus $26,692, respectively, in months 7–12; $21,645 versus $23,709 in months 13–18; and $20,486 versus $25,515 in months 19–24. PPPM costs declined more rapidly for patients receiving NIVO + IPI compared to those receiving PEM + AXI, resulting in significantly lower all-cause costs associated with NIVO + IPI during months 19–24 (difference − $10,914 [95% confidence interval − $21,436, − $1091]) and RCC-related costs during months 7–12 (− $4747 [(− $8929, − $512]) and 19–24 (− $10,261 [− $20,842, − $421]) after adjustment. Cost savings for NIVO + IPI versus PEM + AXI were driven by differences in drug costs which, after adjustment, were significantly lower in months 7–12 (difference − $5555 [all-cause], − $5689 [RCC-related]); 13–18 (− $7217 and − $6870, respectively); and 19–24 (− $16,682 and − $16,125). Conclusion Although the real-world PPPM healthcare costs of 1L NIVO + IPI were higher compared with PEM + AXI in the first 6 months of treatment, the costs associated with NIVO + IPI rapidly declined thereafter, resulting in significantly lower costs vs. PEM + AXI from months 7 to 24.

Abstract Background Leveraging Alzheimer’s disease (AD) imaging biomarkers and longitudinal cognitive data may allow us to establish evidence of cognitive resilience (CR) to AD pathology in-vivo. Here, we applied latent class mixture modeling, adjusting for sex, baseline age, and neuroimaging biomarkers of amyloid, tau and neurodegeneration, to a sample of cognitively unimpaired older adults to identify longitudinal trajectories of CR. Methods We identified 200 Harvard Aging Brain Study (HABS) participants (mean age = 71.89 years, SD = 9.41 years, 59% women) who were cognitively unimpaired at baseline with 2 or more timepoints of cognitive assessment following a single amyloid-PET, tau-PET and structural MRI. We examined latent class mixture models with longitudinal cognition as the dependent variable and time from baseline, baseline age, sex, neocortical Aβ, entorhinal tau, and adjusted hippocampal volume as independent variables. We then examined group differences in CR-related factors across the identified subgroups from a favored model. Finally, we applied our favored model to a dataset from the Alzheimer’s Disease Neuroimaging Initiative (ADNI; n = 160, mean age = 73.9 years, SD = 7.6 years, 60% women). Results The favored model identified 3 latent subgroups, which we labelled as Normal (71% of HABS sample), Resilient (22.5%) and Declining (6.5%) subgroups. The Resilient subgroup exhibited higher baseline cognitive performance and a stable cognitive slope. They were differentiated from other groups by higher levels of verbal intelligence and past cognitive activity. In ADNI, this model identified a larger Normal subgroup (88.1%), a smaller Resilient subgroup (6.3%) and a Declining group (5.6%) with a lower cognitive baseline. Conclusion These findings demonstrate the value of data-driven approaches to identify longitudinal CR groups in preclinical AD. With such an approach, we identified a CR subgroup who reflected expected characteristics based on previous literature, higher levels of verbal intelligence and past cognitive activity.

Abstract The intestinal epithelium dynamically controls cell cycle, yet no experimental platform exists for directly analyzing cell cycle phases in non-immortalized human intestinal epithelial cells (IECs). Here, we present two reporters and a complete platform for analyzing cell cycle phases in live primary human IECs. We interrogate the transcriptional identity of IECs grown on soft collagen, develop two fluorescent cell cycle reporter IEC lines, design and 3D print a collagen press to make chamber slides for optimal imaging while supporting primary human IEC growth, live image cell cycle dynamics, then assemble a computational pipeline building upon free-to-use programs for semi-automated analysis of cell cycle phases. The PIP-FUCCI construct allows for assigning cell cycle phase from a single image of living cells, and our PIP-H2A construct allows for semi-automated direct quantification of cell cycle phase lengths using our publicly available computational pipeline. Treating PIP-FUCCI IECs with oligomycin demonstrates that inhibiting mitochondrial respiration lengthens G1 phase, and PIP-H2A cells allow us to measure that oligomycin differentially lengthens S and G2/M phases across heterogeneous IECs. These platforms provide opportunities for future studies on pharmaceutical effects on the intestinal epithelium, cell cycle regulation, and more.

The automated soft matter indenter (ASMI) is a platform for rapidly performing mechanical characterization of samples with elastic moduli in the range 7 kPa to 67 MPa with a sample acquisition time between 1 and 10 min. It is a low-cost system based upon open-source software, a modified mill, and an educational force sensor with a total bill of materials

Background Despite achieving endoscopic remission, over 20% of inflammatory bowel disease (IBD) patients experience chronic abdominal pain. Visceral pain and the microbiome exhibit sex-dependent interactions, while visceral pain in IBD shows a sex bias. Our aim was to evaluate whether post-inflammatory microbial perturbations contribute to visceral hypersensitivity in a sex-dependent manner.Methods Males, cycling females, ovariectomized, and sham-operated females were given dextran sodium sulfate to induce colitis and allowed to recover. Germ-free recipients received sex-appropriate and cross-sex fecal microbial transplants (FMT) from post-inflammatory donor mice. Visceral sensitivity was assessed by recording visceromotor responses to colorectal distention. The composition of the microbiota was evaluated via 16S rRNA gene V4 amplicon sequencing, while the metabolome was assessed using targeted (short chain fatty acids – SCFA) and semi-targeted mass spectrometry.Results Post-inflammatory cycling females developed visceral hyperalgesia when compared to males. This effect was reversed by ovariectomy. Both post-inflammatory males and females exhibited increased SCFA-producing species, but only males had elevated fecal SCFA content. FMT from post-inflammatory females transferred visceral hyperalgesia to both males and females, while FMT from post-inflammatory males could only transfer visceral hyperalgesia to males.Conclusions Female sex, hormonal status as well as the gut microbiota play a role in pain modulation. Our data highlight the importance of considering biological sex in the evaluation of visceral pain.

ABSTRACTPesticides are crucial for increasing agricultural productivity, but they have also been linked to a range of health and environmental risks. In this paper, we used nationally representative data from 557 agro-dealers in Uganda to assess the role of agro-dealer certification in improving knowledge and practices related to environmentally-friendly pest control. We found that almost half of the sampled agro-dealers were not certified or accredited by regulatory bodies, even though this is a prerequisite for selling pesticides in the country. Results further showed that only 16% of the agro-input shops were selling biopesticide products, largely due to a lack of awareness, access and demand from farmers. Regression results showed that certified agro-dealers were 9–12 percentage points more likely to know about biopesticides and integrated pest management, and 8–10 percentage points more likely to sell biopesticide products, compared to their non-certified counterparts. Our findings imply that agro-dealer certification courses can play an important role in raising knowledge and stimulating the supply of environmentally-benign pest control products. We identified regulatory enforcement, a decentralized certification system and agro-dealer associations as some of the potential pathways for incentivising compliance with certification requirements, thereby promoting lower-risk pest control products and strategies.

Abstract Foams are versatile by nature and ubiquitous in a wide range of applications, including padding, insulation, and acoustic dampening. Previous work established that foams 3D printed via Viscous Thread Printing (VTP) can in principle combine the flexibility of 3D printing with the mechanical properties of conventional foams. However, the generality of prior work is limited due to the lack of predictable process‐property relationships. In this work, a self‐driving lab is utilized that combines automated experimentation with machine learning to identify a processing subspace in which dimensionally consistent materials are produced using VTP with spatially programmable mechanical properties. In carrying out this process, an underlying self‐stabilizing characteristic of VTP layer thickness is discovered as an important feature for its extension to new materials and systems. Several complex exemplars are constructed to illustrate the newly enabled capabilities of foams produced via VTP, including 1D gradient rectangular slabs, 2D localized stiffness zones on an insole orthotic and living hinges, and programmed 3D deformation via a cable‐driven humanoid hand. Predictive mapping models are developed and validated for both thermoplastic polyurethane (TPU) and polylactic acid (PLA) filaments, suggesting the ability to train a model for any material suitable for material extrusion (ME) 3D printing.

BackgroundEmployment plays an important role in the maintenance of mental and physical health. Losing a job creates emotional distress, which can, in turn, interfere with effective job seeking. Thus, a program for job seekers that provides support for both the logistics of job seeking as well as emotional distress may help people find employment and improve emotional well-being. ObjectiveThis study aims to test the efficacy of the 6-week intervention for job seekers in a randomized controlled trial. MethodsThis is a parallel-assignment randomized control trial comparing a 6-week return-to-work intervention versus job seeking as usual for a stratified sample of job seekers (n=150). The intervention will be delivered through a mobile phone app and scheduled video counseling sessions with a job coach. Assessments will be taken weekly during the intervention as well as 8 and 16 weeks later. The intervention and control group procedures will be administered remotely, allowing the study to take place in several regions of the United States. Eligible participants will be adults aged 18 to 65 years, currently unemployed, and actively searching for work. Participants will be recruited from 7 major metropolitan areas in the United States using online advertisements on Craigslist. The primary outcome measure is the Job Search Behavior Scale, which has 2 subscales, preparatory job search behavior and active job search behavior. Employment status will also be assessed throughout the trial. A mixed-model regression analysis will be used to compare job searching behavior in the intervention group versus the control group. A time-to-event analysis (ie, survival analysis) will be used to compare employment status in the 2 experimental groups. Secondary outcomes will also be evaluated, including job search self-efficacy and mental health-related outcomes such as anxiety and depression. ResultsThis study started on August 7, 2023, and as of June 2024, we have enrolled 140 participants. Enrollment began in August 2023 and will conclude by October 2024. Half of the participants (75/150, 50%) will be assigned to the intervention arm while the other half (75/150, 50%) will be assigned to the control arm, job seeking as usual. ConclusionsThe findings from this study will determine the efficacy of a mobile app–based intervention that uses both job training and psychological techniques on job seeking and employment outcomes. This first trial of Distress Return-to-Work Intervention (DRIVEN) will provide important information about blended support techniques for unemployed individuals, determine the usefulness of mobile apps to address large-scale mental health outcomes, and improve our understanding of the relationship between depression and unemployment status. Trial RegistrationClinicalTrials.gov NCT06026280; https://clinicaltrials.gov/study/NCT06026280 International Registered Report Identifier (IRRID)DERR1-10.2196/62715

Extramammary Paget disease (EMPD) is a rare dermatologic malignancy with a high rate of recurrence and increased risk for developing secondary malignancies. We present a 74-year-old male with previously resected primary EMPD who presented with widespread PSMA-avid lesions without prostatic uptake, an elevated PSA >100, and a negative prostate biopsy. Based on this and immunohistological staining, recurrent EMPD was suspected. However, after additional staining and reexamining their clinical presentation, metastatic prostate cancer without a detected primary lesion is more probable. This case highlights the diagnostic challenge variable expression of shared biomarkers found in EMPD and prostate cancer present to clinicians.

We examined the feeding ecology of planktonic crustaceans at three waterbodies situated across a latitudinal gradient in Europe (Croatia, Poland, Lithuania) using stable isotope measurements (δ13C, δ15N) in animal tissues. Relative, lake-specific values of δ15N showed that in all lakes, calanoid copepods occupied the highest trophic position, while Daphnia sp. and Diaphanosoma sp. were located closer to primary producers with Cyclopoid copepods located between these groups. We found a negative correlation between C:N ratio (proxy for lipid content) and δ15N, which indicates lipid content declined with the trophic level of the animals. Employment of stable isotope-based approach allows better recognition of trophic linkages than could be inferred from classical methods, and therefore our results contribute improvement of management strategies developed for aquatic ecosystems.

Objective To examine the likelihood of head acceleration events (HAEs) as a function of previously identified risk factors: match time, player status (starter or substitute) and pitch location in elite-level men’s and women’s rugby union matches.Methods Instrumented mouthguard data were collected from 179 and 107 players in the men’s and women’s games and synchronised to video-coded match footage. Head peak resultant linear acceleration (PLA) and peak resultant angular acceleration were extracted from each HAE. Field location was determined for HAEs linked to a tackle, carry or ruck. HAE incidence was calculated per player hour across PLA recording thresholds with 95% CIs estimated. Propensity was calculated as the percentage of contact events that caused HAEs across PLA recording thresholds, with a 95% CI estimated. Significance was assessed by non-overlapping 95% CIs.Results 29 099 and 6277 HAEs were collected from 1214 and 577 player-matches in the men’s and women’s games. No significant differences in match quarter HAE incidence or propensity were found. Substitutes had higher HAE incidence than starters at lower PLA recording thresholds for men but similar HAE propensity. HAEs were more likely to occur in field locations with high contact event occurrence.Conclusion Strategies to reduce HAE incidence need not consider match time or status as a substitute or starter as HAE rates are similar throughout matches, without differences in propensity between starters and substitutes. HAE incidence is proportional to contact frequency, and strategies that reduce either frequency or propensity for contact to cause head contact may be explored.

Abstract Background Autopsy work indicates that the widely-projecting noradrenergic pontine locus coeruleus (LC) is among the earliest regions to accumulate hyperphosphorylated tau, a neuropathological Alzheimer’s disease (AD) hallmark. This early tau deposition is accompanied by a reduced density of LC projections and a reduction of norepinephrine’s neuroprotective effects, potentially compromising the neuronal integrity of LC’s cortical targets. Previous studies suggest that lower magnetic resonance imaging (MRI)-derived LC integrity may signal cortical tissue degeneration in cognitively healthy, older individuals. However, whether these observations are driven by underlying AD pathology remains unknown. To that end, we examined potential effect modifications by cortical beta-amyloid and tau pathology on the association between in vivo LC integrity, as quantified by LC MRI signal intensity, and cortical neurodegeneration, as indexed by cortical thickness. Methods A total of 165 older individuals (74.24 ± 9.72 years, ~ 60% female, 10% cognitively impaired) underwent whole-brain and dedicated LC 3T-MRI, Pittsburgh Compound-B (PiB, beta-amyloid) and Flortaucipir (FTP, tau) positron emission tomography. Linear regression analyses with bootstrapped standard errors (n = 2000) assessed associations between bilateral cortical thickness and i) LC MRI signal intensity and, ii) LC MRI signal intensity interacted with cortical FTP or PiB (i.e., EC FTP, IT FTP, neocortical PiB) in the entire sample and a low beta-amyloid subsample. Results Across the entire sample, we found a direct effect, where lower LC MRI signal intensity was associated with lower mediolateral temporal cortical thickness. Evaluation of potential effect modifications by FTP or PiB revealed that lower LC MRI signal intensity was related to lower cortical thickness, particularly in individuals with elevated (EC, IT) FTP or (neocortical) PiB. The latter result was present starting from subthreshold PiB values. In low PiB individuals, lower LC MRI signal intensity was related to lower EC cortical thickness in the context of elevated EC FTP. Conclusions Our findings suggest that LC-related cortical neurodegeneration patterns in older individuals correspond to regions representing early Braak stages and may reflect a combination of LC projection density loss and emergence of cortical AD pathology. This provides a novel understanding that LC-related cortical neurodegeneration may signal downstream consequences of AD-related pathology, rather than being exclusively a result of aging.

Abstract Rapid, high-resolution volumetric imaging without moving heavy objectives or disturbing delicate samples remains challenging. Pupil-matched remote focusing offers a promising solution for high NA systems, but the fluorescence signal’s incoherent and unpolarized nature complicates its application. Thus, remote focusing is mainly used in the illumination arm with polarized laser light to improve optical coupling. Here, we introduce a novel optical design that can de-scan the axial focus movement in the detection arm of a microscope. Our method splits the fluorescence signal into S and P-polarized light, lets them pass through the remote focusing module separately, and combines them with the camera. This allows us to use only one focusing element to perform aberration-free, multi-color, volumetric imaging without (a) compromising the fluorescent signal and (b) needing to perform sample/detection-objective translation. We demonstrate the capabilities of this scheme by acquiring fast dual-color 4D (3D space + time) image stacks with an axial range of 70 μm and camera-limited acquisition speed. Owing to its general nature, we believe this technique will find its application in many other microscopy techniques that currently use an adjustable Z-stage to carry out volumetric imaging, such as confocal, 2-photon, and light sheet variants.

Abstract Tabular data analysis is a critical task in various domains, enabling us to uncover valuable insights from structured datasets. While traditional machine learning methods can be used for feature engineering and dimensionality reduction, they often struggle to capture the intricate relationships and dependencies within real-world datasets. In this paper, we present Multi-representation DeepInsight (MRep-DeepInsight), a novel extension of the DeepInsight method designed to enhance the analysis of tabular data. By generating multiple representations of samples using diverse feature extraction techniques, our approach is able to capture a broader range of features and reveal deeper insights. We demonstrate the effectiveness of MRep-DeepInsight on single-cell datasets, Alzheimer's data, and artificial data, showcasing an improved accuracy over the original DeepInsight approach and machine learning methods like random forest, XGBoost, LightGBM, FT-Transformer and L2-regularized logistic regression. Our results highlight the value of incorporating multiple representations for robust and accurate tabular data analysis. By leveraging the power of diverse representations, MRep-DeepInsight offers a promising new avenue for advancing decision-making and scientific discovery across a wide range of fields.

Abstract Background Autopsy work reported that neuronal density in the locus coeruleus (LC) provides neural reserve against cognitive decline in dementia. Recent neuroimaging and pharmacological studies reported that left frontoparietal network functional connectivity (LFPN-FC) confers resilience against beta-amyloid (Aβ)-related cognitive decline in preclinical sporadic and autosomal dominant Alzheimer’s disease (AD), as well as against LC-related cognitive changes. Given that the LFPN and the LC play important roles in attention, and attention deficits have been observed early in the disease process, we examined whether LFPN-FC and LC structural health attenuate attentional decline in the context of AD pathology. Methods 142 participants from the Harvard Aging Brain Study who underwent resting-state functional MRI, LC structural imaging, PiB(Aβ)-PET, and up to 5 years of cognitive follow-ups were included (mean age = 74.5 ± 9.9 years, 89 women). Cross-sectional robust linear regression associated LC integrity (measured as the average of five continuous voxels with the highest intensities in the structural LC images) or LFPN-FC with Digit Symbol Substitution Test (DSST) performance at baseline. Longitudinal robust mixed effect analyses examined associations between DSST decline and (i) two-way interactions of baseline LC integrity (or LFPN-FC) and PiB or (ii) the three-way interaction of baseline LC integrity, LFPN-FC, and PiB. Baseline age, sex, and years of education were included as covariates. Results At baseline, lower LFPN-FC, but not LC integrity, was related to worse DSST performance. Longitudinally, lower baseline LC integrity was associated with a faster DSST decline, especially at PiB > 10.38 CL. Lower baseline LFPN-FC was associated with a steeper decline on the DSST but independent of PiB. At elevated PiB levels (> 46 CL), higher baseline LFPN-FC was associated with an attenuated decline on the DSST, despite the presence of lower LC integrity. Conclusions Our findings demonstrate that the LC can provide resilience against Aβ-related attention decline. However, when Aβ accumulates and the LC’s resources may be depleted, the functioning of cortical target regions of the LC, such as the LFPN-FC, can provide additional resilience to sustain attentional performance in preclinical AD. These results provide critical insights into the neural correlates contributing to individual variability at risk versus resilience against Aβ-related cognitive decline.

Abstract We explore possible extensions of the Weak Gravity Conjecture (WGC) to scalar field theories. To avoid charged black hole remnants, the WGC requires the existence of a particle with a mass m ≤ gqM P , with charge q and U(1) gauge coupling g, allowing the decay to shed the black hole charge. Although there is no obvious problem that arises in the absence of a U(1) charge, it has been postulated that gravity must remain the weakest force even when extended to scalar interactions. Quantifying this conjecture may be done by comparing scalar and gravitational amplitudes, or as we advocate here by comparing scattering cross sections. In theories with non-trivial field space geometries, by working out examples with perturbation theory around arbitrary field values and performing tadpole resummations, we argue that the conjecture must be applied only at extrema of the scalar potential (when expressed in locally canonical coordinates). We consider several toy models in the context of no-scale supergravity and also consider examples of inflationary models.

Abstract Energy absorbing efficiency is a key determinant of a structure’s ability to provide mechanical protection and is defined by the amount of energy that can be absorbed prior to stresses increasing to a level that damages the system to be protected. Here, we explore the energy absorbing efficiency of additively manufactured polymer structures by using a self-driving lab (SDL) to perform >25,000 physical experiments on generalized cylindrical shells. We use a human-SDL collaborative approach where experiments are selected from over trillions of candidates in an 11-dimensional parameter space using Bayesian optimization and then automatically performed while the human team monitors progress to periodically modify aspects of the system. The result of this human-SDL campaign is the discovery of a structure with a 75.2% energy absorbing efficiency and a library of experimental data that reveals transferable principles for designing tough structures.

Abstract Background Surgical patients are at risk of postoperative complications, which may lead to increased morbidity, mortality, hospital length-of-stay and healthcare costs. Enhanced Recovery After Surgery (ERAS®) protocols are evidence-based and have demonstrated effectiveness in decreasing complications and associated consequences. However, their adoption in Australia has been limited and the reason for this is unclear. This study aimed to describe clinicians’ perceptions of ERAS protocols in Australia. Methods A national online survey of anaesthetists, surgeons and nurses was undertaken. Invitations to participate were distributed via emails from professional colleges. The 30-item survey captured respondent characteristics, ERAS perceptions, beliefs, education and learning preferences and future planning considerations. The final question was open-ended for elaboration of perceptions of ERAS. Descriptive and inferential statistics were used to describe and compare group differences across disciplines relative to perceptions of ERAS. Results The sample included 178 responses (116 nurses, 65.2%; 36 surgeons, 20.2%; 26 anaesthetists, 14.6%) across six states and two territories. More than half (n = 104; 58.8%) had used ERAS protocols in patient care, and most perceived they were ‘very knowledgeable’ (n = 24; 13.6%) or ‘knowledgeable’ (n = 71; 40.3%) of ERAS. However, fewer nurses had cared for a patient using ERAS (p

Abstract β-N-Acetylgalactosamine-containing glycans play essential roles in several biological processes, including cell adhesion, signal transduction, and immune responses. β-N-Acetylgalactosaminidases hydrolyze β-N-acetylgalactosamine linkages of various glycoconjugates. However, their biological significance remains ambiguous, primarily because only one type of enzyme, exo-β-N-acetylgalactosaminidases that specifically act on β-N-acetylgalactosamine residues, has been documented to date. In this study, we identify four groups distributed among all three domains of life and characterize eight β-N-acetylgalactosaminidases and β-N-acetylhexosaminidase through sequence-based screening of deep-sea metagenomes and subsequent searching of public protein databases. Despite low sequence similarity, the crystal structures of these enzymes demonstrate that all enzymes share a prototype structure and have diversified their substrate specificities (oligosaccharide-releasing, oligosaccharide/monosaccharide-releasing, and monosaccharide-releasing) through the accumulation of mutations and insertional amino acid sequences. The diverse β-N-acetylgalactosaminidases reported in this study could facilitate the comprehension of their structures and functions and present evolutionary pathways for expanding their substrate specificity.

Abstract Axially swept light-sheet microscope in conjunction with tissue clearing enables three-dimensional morphological investigation of millimeter-scaled tissues at isotropic sub-micron resolution. However, these microscopes suffer from low detection signal and slow imaging speed. Here we report a simple and efficient imaging platform that employs precise control of two fixed distant light-sheet foci for axial sweeping. This enables full field of view imaging at 40 frames per second, a four-fold improvement over the current state-of-the-art. In addition, in a particular frame rate, our method doubles the signal compared to the existing techniques. To augment the overall imaging performance, we also developed a deep learning based tissue information classifier that enables faster determination of tissue boundary. We demonstrated the performance of our imaging platform on various cleared tissue samples and delineated its robustness over a wide range of clearing protocols.

Background & Objectives Trial Emulation methods can be applied to Population-Scale Linked Electronic Health Records (EHR) to generalise the results of Randomised Controlled Trials (RCTs) to a broader patient population. However, the Data Generating Mechanisms (DGMs) associated with EHR data mean that there is a need to adjust for informative observations, i.e. worse prognosis patients may have more observations. Approach Using the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA) as a case study: a RCT of a calcium-channel blocker-based regimen versus a β-blocker-based regimen, an emulated trial was created from population-scale, individual-level, linked anonymized EHR data curated as part of the Wales Multimorbidity e-cohort (WMC) for individuals who would have been eligible for ASCOT-BPLA but who also had Multiple Long-Term Conditions (MLTCs). Outcomes were systolic and diastolic blood pressure estimated/predicted at treatment initiation, 6 weeks, 3 months, and 6 monthly until 4 years. Methods & Results Predictions were made using a fully probabilistic Bayesian joint model which allowed for dropout due to death and which either did or did not also adjust for the frequency of blood pressure observations available. In previous simulation studies such a joint modelling approach has been shown to out-perform other adjustment methods in terms of bias and coverage. Conclusions & Implications Whilst EHR data offer an attractive platform in which to evaluate interventions in people living with MLTCs, the inherent DGMs associated with them need to be taken into account, and the use of a joint modelling approach is an attractive way to achieve this.

Background and Objectives Healthcare decision-making has previously focused on developing recommendations for single conditions. This research aimed to develop a modeling framework to estimate the effects of multi-indication treatment in people living with multiple long-term conditions. Approach Using a case study in type 2 diabetes mellitus [T2DM], chronic kidney disease [CKD], and heart failure [HF], age-adjusted multistate models were used to estimate the effect of sodium-glucose cotransporter-2 (SGLT2) inhibitors as a multi-indication treatment. Baseline hazards were estimated using population-scale, individual-level, linked anonymized electronic health record (EHR) data for 613,195 individuals aged 55 to 85 years in Wales over a 20-year period. Hazard ratios for treatment effects compared to standard of care were obtained from randomized controlled trials for combinations of multiple-long term conditions and incorporated in a patient-level simulation. Results SGLT2 inhibitors increased the estimated mean life expectancy from 0.02 (95% Confidence Interval (CI): -0.02, 0.05) to 1.44 (95% CI: 1.12, 1.74) years in people living with coexisting T2DM, CKD, and HF. The estimated gain in life expectancy was less than 0.5 years for individuals with T2DM, CKD, and HF in different temporally ordered sequences. The estimated mean time to develop HF increased by 3.1 (95% CI: 3.00, 3.24) and 1.34 (95% CI: 1.12, 1.56) years in individuals with CKD, and in those with CKD followed by T2DM. Conclusions and Implications There is an ever increasing need to appraise interventions in people living with multiple long-term conditions to identify optimal treatment strategies and reduce polypharmacy. Multistate models applied to linked EHRs allow for a more rigorous assessment of treatment effects to inform healthcare policy.

Group activities and connection with nature are associated with improved well-being for older adults. This quasi-experiment tests the effectiveness of RASCALs , an innovative program of group activities using nature-focused livestream broadcasts. Assisted living residents in the experimental group ( n = 16) lived in buildings that received RASCALs programming twice a week for 3 months. Compared to residents in the comparison group ( n = 17) who received regular group activity programming, they experienced significant positive change in the Positive Relations with Others domain of well-being (β = .873, p = .008). Combining nature-focused livestream broadcasts with groups activities for older adults in assisted living communities may be an innovative and effective way to overcome barriers to accessing nature and improve residents’ well-being.

Over the last two decades, there have been numerous initiatives to improve undergraduate student outcomes in STEM. One model for scalable reform is the inclusive Research Education Community (iREC). In an iREC, STEM faculty from colleges and universities across the nation are supported to adopt and sustainably implement course-based research – a form of science pedagogy that enhances student learning and persistence in science. In this study, we used pathway modeling to develop a qualitative description that explicates the HHMI Science Education Alliance (SEA) iREC as a model for facilitating the successful adoption and continued advancement of new curricular content and pedagogy. In particular, outcomes that faculty realize through their participation in the SEA iREC were identified, organized by time, and functionally linked. The resulting pathway model was then revised and refined based on several rounds of feedback from over 100 faculty members in the SEA iREC who participated in the study. Our results show that in an iREC, STEM faculty organized as a long-standing community of practice leverage one another, outside expertise, and data to adopt, implement, and iteratively advance their pedagogy. The opportunity to collaborate in this manner and, additionally, to be recognized for pedagogical contributions sustainably engages STEM faculty in the advancement of their pedagogy. Here, we present a detailed pathway model of SEA that, together with underpinning features of an iREC identified in this study, offers a framework to facilitate transformations in undergraduate science education.

Summary: Background: Given the rapidly growing burden of cardiovascular disease (CVD) in Asia, this study forecasts the CVD burden and associated risk factors in Asia from 2025 to 2050. Methods: Data from the Global Burden of Disease 2019 study was used to construct regression models predicting prevalence, mortality, and disability-adjusted life years (DALYs) attributed to CVD and risk factors in Asia in the coming decades. Findings: Between 2025 and 2050, crude cardiovascular mortality is expected to rise 91.2% despite a 23.0% decrease in the age-standardised cardiovascular mortality rate (ASMR). Ischaemic heart disease (115 deaths per 100,000 population) and stroke (63 deaths per 100,000 population) will remain leading drivers of ASMR in 2050. Central Asia will have the highest ASMR (676 deaths per 100,000 population), more than three-fold that of Asia overall (186 deaths per 100,000 population), while high-income Asia sub-regions will incur an ASMR of 22 deaths per 100,000 in 2050. High systolic blood pressure will contribute the highest ASMR throughout Asia (105 deaths per 100,000 population), except in Central Asia where high fasting plasma glucose will dominate (546 deaths per 100,000 population). Interpretation: This forecast forewarns an almost doubling in crude cardiovascular mortality by 2050 in Asia, with marked heterogeneity across sub-regions. Atherosclerotic diseases will continue to dominate, while high systolic blood pressure will be the leading risk factor. Funding: This was supported by the NUHS Seed Fund (NUHSRO/2022/058/RO5+6/Seed-Mar/03), National Medical Research Council Research Training Fellowship (MH 095:003/008-303), National University of Singapore Yong Loo Lin School of Medicine's Junior Academic Fellowship Scheme, NUHS Clinician Scientist Program (NCSP2.0/2024/NUHS/NCWS) and the CArdiovascular DiseasE National Collaborative Enterprise (CADENCE) National Clinical Translational Program (MOH-001277-01).

Background The extent to which differences in results from Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) and Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial (ROCKET) atrial fibrillation (AF)—the landmark trials for the approval of apixaban and rivaroxaban, respectively, for non-valvular AF—were influenced by differences in their protocols is debated. The potential influence of selection criteria on trial results was assessed by emulating these trials in data from the Global Anticoagulant Registry in the Field (GARFIELD)-AF registry.Methods Vitamin K antagonist (VKA) and non-vitamin K oral antagonist (NOAC) users from GARFIELD-AF were selected according to eligibility for the original ARISTOTLE or ROCKET AF trials. A propensity score overlap weighted Cox model was used to emulate trial randomisation between treatment groups. Adjusted HRs for stroke or systemic embolism (SE) within 2 years of enrolment were calculated for each NOAC versus VKA.Results Among patients on apixaban, rivaroxaban and VKA, 2570, 3560 and 8005 were eligible for ARISTOTLE, respectively, and 1612, 2005 and 4368, respectively, for ROCKET AF. When selecting for ARISTOTLE criteria, apixaban users had significantly lower stroke/SE risk versus VKA (HR 0.57; 95% CI 0.34 to 0.94) while no reduction was observed with rivaroxaban (HR 0.98; 95% CI 0.68 to 1.40). When selecting for ROCKET AF criteria, safety and efficacy versus VKA were similar across the NOACs.Conclusion Apixaban and rivaroxaban showed similar results versus VKA in high-risk patients selected according to ROCKET AF criteria, whereas differences emerged when selecting for the more inclusive ARISTOTLE criteria. Our results highlight the importance of trial selection criteria in interpreting trial results and underline the problems faced in comparing treatments across rather than within clinical trials.

Abstract INTRODUCTION Sleep is crucial for memory consolidation and the clearance of toxic proteins associated with Alzheimer's disease (AD). We examined the association between sleep characteristics and imaging biomarkers of early amyloid beta (Aβ) and tau pathology as well as neurodegeneration in brain regions known to be affected in the incipient stages of AD. METHODS Thirty‐nine cognitively unimpaired (CU) participants of the Harvard Aging Brain Study underwent at‐home polysomnography as well as tau positron emission tomography (flortaucipir‐PET), amyloid PET (Pittsburgh compound B [PiB]‐PET), and magnetic resonance imaging–derived assessment of cortical thickness (CT). RESULTS Increased N1 sleep was associated with a higher tau PET signal (β = 0.009, p = 0.001) and lower CT in the temporal composite region of interest (β = –0.017, p = 0.007). Decreased slow‐wave sleep (SWS) was associated with higher tau burden in the temporal composite (β = –0.008, p = 0.005) and lower CT (β = 0.008, p = 0.002), even after controlling for global PiB‐PET. DISCUSSION In CU older adults, lower SWS and higher N1 sleep were associated with higher tau burden and lower CT in brain regions associated with early tau deposition and vulnerable to AD‐related neurodegeneration through mechanisms dissociable from amyloid deposition. Highlights We report the results of an observational study, which leveraged ‐a well‐characterized cohort of healthy aging (Harvard Aging Brain Study) by adding in‐home full polysomnograms. By adding at‐home polysomnograms to this unique and deeply phenotyped cohort, we examined variations in sleep architecture that are associated with Alzheimer's disease (AD) pathologic changes. Our results confirmed the association of sleep changes with early tau and cortical neurodegenerative changes that were independent of amyloid. The results will be of importance in monitoring sleep‐related variations in relation to the natural history of AD pathology and in designing sleep‐focused clinical trials.

ABSTRACT The occurrence of cyanobacterial harmful algal blooms (cyanoHABs) is related to their physical and chemical environment. However, less is known about their associated microbial interactions and processes. In this study, cyanoHABs were analyzed as a microbial ecosystem, using 1 year of 16S rRNA sequencing and 70 metagenomes collected during the bloom season from Lake Okeechobee (Florida, USA). Biogeographical patterns observed in microbial community composition and function reflected ecological zones distinct in their physical and chemical parameters that resulted in bloom “hotspots” near major lake inflows. Changes in relative abundances of taxa within multiple phyla followed increasing bloom severity. Functional pathways that correlated with increasing bloom severity encoded organic nitrogen and phosphorus utilization, storage of nutrients, exchange of genetic material, phage defense, and protection against oxidative stress, suggesting that microbial interactions may promote cyanoHAB resilience. Cyanobacterial communities were highly diverse, with picocyanobacteria ubiquitous and oftentimes most abundant, especially in the absence of blooms. The identification of novel bloom-forming cyanobacteria and genomic comparisons indicated a functionally diverse cyanobacterial community with differences in its capability to store nitrogen using cyanophycin and to defend against phage using CRISPR and restriction-modification systems. Considering blooms in the context of a microbial ecosystem and their interactions in nature, physiologies and interactions supporting the proliferation and stability of cyanoHABs are proposed, including a role for phage infection of picocyanobacteria. This study displayed the power of “-omics” to reveal important biological processes that could support the effective management and prediction of cyanoHABs.IMPORTANCECyanobacterial harmful algal blooms pose a significant threat to aquatic ecosystems and human health. Although physical and chemical conditions in aquatic systems that facilitate bloom development are well studied, there are fundamental gaps in the biological understanding of the microbial ecosystem that makes a cyanobacterial bloom. High-throughput sequencing was used to determine the drivers of cyanobacteria blooms in nature. Multiple functions and interactions important to consider in cyanobacterial bloom ecology were identified. The microbial biodiversity of blooms revealed microbial functions, genomic characteristics, and interactions between cyanobacterial populations that could be involved in bloom stability and more coherently define cyanobacteria blooms. Our results highlight the importance of considering cyanobacterial blooms as a microbial ecosystem to predict, prevent, and mitigate them.

Endoplasmic reticulum stress occurs due to large amounts of misfolded proteins, hypoxia, nutrient deprivation, and more. The unfolded protein is a complex intracellular signaling network designed to operate under this stress. Composed of three individual arms, inositol-requiring enzyme 1, protein kinase RNA-like ER kinase, and activating transcription factor-6, the unfolded protein response looks to resolve stress and return to proteostasis. The CD8+ T cell is a critical cell type for the adaptive immune system. The unfolded protein response has been shown to have a wide-ranging spectrum of effects on CD8+ T cells. CD8+ T cells undergo cellular stress during activation and due to environmental insults. However, the magnitude of the effects this response has on CD8+ T cells is still understudied. Thus, studying these pathways is important to unraveling the inner machinations of these powerful cells. In this review, we will highlight the recent literature in this field, summarize the three pathways of the unfolded protein response, and discuss their roles in CD8+ T cell biology and functionality.

ABSTRACT Escherichia coli is the leading cause of urinary tract infections (UTIs) in children and adults. The gastrointestinal tract is the primary reservoir of uropathogenic E. coli, which can be acquired from a variety of environmental exposures, including retail meat. In the current study, we used a novel statistical-genomic approach to estimate the proportion of pediatric UTIs caused by foodborne zoonotic E. coli strains. E. coli urine isolates were collected from DC residents aged 2 months to 17 years from the Children’s National Medical Center Laboratory, 2013–2014. During the same period, E. coli isolates were collected from retail poultry products purchased from 15 sites throughout DC. A total of 52 urine and 56 poultry isolates underwent whole-genome sequencing, core genome phylogenetic analysis, and host-origin prediction by a Bayesian latent class model that incorporated data on the presence of mobile genetic elements (MGEs) among E. coli isolates from multiple vertebrate hosts. A total of 56 multilocus sequence types were identified among the isolates. Five sequence types—ST10, ST38, ST69, ST117, and ST131—were observed among both urine and poultry isolates. Using the Bayesian latent class model, we estimated that 19% (10/52) of the clinical E. coli isolates in our population were foodborne zoonotic strains. These data suggest that a substantial portion of pediatric UTIs in the Washington DC region may be caused by E. coli strains originating in food animals and likely transmitted via contaminated poultry meat.IMPORTANCEEscherichia coli UTIs are a heavy public health burden and can have long-term negative health consequences for pediatric patients. E. coli has an extremely broad host range, including humans, chickens, turkeys, pigs, and cattle. E. coli derived from food animals is a frequent contaminant of retail meat products, but little is known about the risk these strains pose to pediatric populations. Quantifying the proportion of pediatric UTIs caused by food-animal-derived E. coli, characterizing the highest-risk strains, and identifying their primary reservoir species could inform novel intervention strategies to reduce UTI burden in this vulnerable population. Our results suggest that retail poultry meat may be an important vehicle for pediatric exposure to zoonotic E. coli strains capable of causing UTIs. Vaccinating poultry against the highest-risk strains could potentially reduce poultry colonization, poultry meat contamination, and downstream pediatric infections.

Background Golf carts (GCs) and all-terrain vehicles (ATVs) are popular forms of personal transport. Although ATVs are considered adventurous and dangerous, GCs are perceived to be safer. Anecdotal experience suggests increasing numbers of both GC and ATV injuries, as well as high severity of GC injuries in children. This multicenter study examined GC and ATV injuries and compared their injury patterns, resource utilization, and outcomes.Methods Pediatric trauma centers in Florida submitted trauma registry patients age

Abstract This letter demonstrates the potential of novel cryptic proteins resulting from TAR DNA-binding protein 43 (TDP-43) dysfunction as markers of TDP-43 pathology in neurodegenerative diseases.

Abstract Respiratory syncytial virus (RSV) is the leading cause of hospitalisation for respiratory infection in young children. RSV disease severity is known to be age-dependent and highest in young infants, but other correlates of severity, particularly the presence of additional respiratory pathogens, are less well understood. In this study, nasopharyngeal swabs were collected from two cohorts of RSV-positive infants 100 pathogens, including all common respiratory viruses and bacteria, from samples collected from 433 infants, that burden of additional viruses is common (111/433, 26%) but only modestly correlates with RSV disease severity. In contrast, there is strong evidence in both cohorts and across age groups that presence of Haemophilus bacteria (194/433, 45%) is associated with higher severity, including much higher rates of hospitalisation (odds ratio 4.25, 95% CI 2.03–9.31). There is no evidence for association between higher severity and other detected bacteria, and no difference in severity between RSV genotypes. Our findings reveal the genomic diversity of additional pathogens during RSV infection in infants, and provide an evidence base for future causal investigations of the impact of co-infection on RSV disease severity.

Abstract Background Primary health care (PHC) has historically led and implemented successful immunization programs, driven by strong relationships with patients and communities. During the COVID-19 pandemic, Canada began its vaccination strategy with mass immunizations that later included local efforts with PHC providers. This study seeks to understand how PHC contributed to the different phases of the COVID-19 vaccination rollouts in Ontario, Canada’s most populous province. Methods We conducted a descriptive qualitative study with focus groups consisting of PHC providers, administrators, and staff in Ontario. Eight focus groups were held with 39 participants representing geographic diversity across the six Ontario Health regions. Participants reflected a diverse range of clinical, administrative, and leadership roles. Each focus group was audio-recorded and transcribed with transcriptions analyzed using thematic analysis. Results With respect to understanding PHC teams’ participation in the different phases of the COVID-19 vaccination rollouts, we identified five themes: (i) supporting long-term care, (ii) providing leadership in mass vaccinations, (iii) integrating vaccinations in PHC practice sites, (iv) reaching those in need through outreach activities; and (v) PHC’s contributions being under-recognized. Conclusions PHC was instrumental in supporting COVID-19 vaccinations in Ontario, Canada across all phases of the rollout. The flexibility and adaptability of PHC allowed teams to participate in both large-scale and small-scale vaccination efforts.

Abstract Background Phytochemicals have become a growing source of alternative medicine in developing countries due to the poor prognosis, high cost of conventional pharmaceuticals, and undesirable effects associated with mainstream cancer treatment. Objective This study was aimed at investigating the anticancer effect of some selected Nigerian medicinal plants used in cancer treatment. These include ethanol extracts of Dialium guineense root (DGR), Dialium guineense leaves (DGL), Jateorhiza macrantha leaves (JML), Musanga cecropioides leaves (MCL), Musanga cecropioides stembark (MCSB), Piptadeniastrum africanum stembark (PASB), Piptadeniastrum africanum root (PAR), Pupalia lappacea flower tops (PLF), Raphiostylis beninensis root (RBR), Raphiostylis beninensis leaves (RBL), Ritchiea capparoides leaves (RCL), Ritchiea capparoides stembark (RCSB), and Triplochiton scleroxylon stembark (TSB). Methods The cytotoxic activity of the extracts was examined using a brine shrimp lethality assay and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay against three cancer cell lines, including MCF-7, HUH-7, and HeLa. The selectivity of all extracts towards cancer cells was investigated using normal lung fibroblasts (MRC-5). Cell migration and colony-forming assays of active extracts against MCF-7 cells were also performed. Additionally, the total polyphenolic contents of the active extracts were estimated using standard methods. Results The extract of PASB had the highest cytotoxicity (LC50 = 1.58 μg/mL) on the brine shrimps compared to vincristine sulphate (LC50 = 2.24 μg/mL). In the cell viability assay, all the extracts produced significant (p

Abstract Background Strategic action plans around newborn health evaluation are needed, to address the high neonatal mortality rate in Nepal. Surveillance systems, like Newborn Metabolic Screening (NBS), could reveal unrecognized drivers of neonatal death. NBS is not routinely performed in Nepal. Our objective was to determine the feasibility of establishing NBS, and its acceptability among healthcare providers and parents, in Nepal. Methods This prospective cohort study was conducted between November 2021 and May 2022 in term/late preterm infants born at Paropakar Maternity Hospital, Kathmandu, screening for 6 disorders that can be confirmed and managed locally. Staff were trained on dried-blood spot collection and transport protocols, performance metrics were established, and assays were performed at an accredited laboratory in Bangalore, India. Surveys were developed to determine acceptability among health-care providers and parents. Results Of 835 parents approached for the study, 825 (98.8%) consented. Parental surveys showed that 92% considered “no cost” option most important in choosing to participate in the study. Samples were transported to laboratories in Kathmandu and Bangalore in 36 ± 24 h, and 4.75 ± 1 days, which exceeded expected metrics of 24 and 48 h, respectively. Results were communicated to parents by 9.5 ± 2 days, which was within the expected metric window of 14 days. Abnormalities were reported in 13 infants and included 5 hemoglobinopathy traits (4 Hb E and 1 Hb D), 3 congenital hypothyroidism, 2 glucose-6-phosphate dehydrogenase deficiency, 1 congenital adrenal hyperplasia, 1 elevated acylcarnitine, and 1 biotinidase deficiency. Healthcare providers surveyed (n = 116) showed that 67% reported a moderate understanding of NBS; all indicated that screening would be beneficial. Most cited early diagnosis and treatment, as well as, providing risk to future pregnancies as significant benefits. 90% thought screening should be routinely performed. Conclusions We demonstrate that it is feasible to introduce NBS in Nepal. Transport metrics were longer than expected due to COVID pandemic travel restrictions; however, it was possible to deliver results to families within 2 weeks of birth. Parents overwhelmingly considered “no cost” option as the most important in choosing to screen. A government-sponsored program will be a key factor in establishing NBS in Nepal.

In this study, a 1 MW double-rotor flux switching machine is designed for high-power density electric motors in all-electric aircraft. The motor features an air core stator that accommodates armature windings and field coils. Armature conductors utilize aluminum Litz wire at T = 20K, while YBCO superconducting tapes are employed for the field coils operating at T = 20 K. The inner and outer rotors are constructed with laminated Hiperco 50. Most notably, superconducting magnetic shields are positioned between the two rotor teeth to minimize leakage flux and guide magnetizing flux on a pre-determined path. This new motor is shown to have widely superior power density and efficiency. The motor design is evaluated across different pole/slot combinations, revealing that higher pole numbers increase power density. Specifically, a 20-pole/15-slot double rotor flux switching motor with a shield achieves a power density exceeding 100 kW/kg, with efficiency reaching up to 99.5%. This was twice the power density of a comparable design without the shield. The thermal management system has been designed for the proposed motor. The result is a machine that satisfies requirements for electric aviation propulsion applications.

Electromagnetic interference poses enormous challenges for feedback-controlled systems, especially at medium-voltage levels. As power converters are increasingly utilized for medium- and high-voltage applications, optically-based measurement methods must be explored. This paper investigates current measurement via electroluminescence from silicon carbide semiconductor devices. A SiC half-bridge MOSFET module, provided by Powerex, is manufactured with fiber optic cables placed against the semiconductor junctions. The new fiber ports are employed to characterize the light spectrum as a function of conducted current and junction temperature for the body diodes. Most of the light energy is concentrated around peaks at 390 nm and 500 nm. It is observed that although the energy at the 390 nm peak increases with rising temperature, the energy at the 500 nm peak decreases. Therefore, the total light output is seen to only slightly vary with temperature and mostly depends on conducted current. A function is fitted to the light transducer output as a in relation to the on-state current. This function is utilized in a microprocessor that implements feedback current control in a buck converter. This type of control forms the basis of torque regulation in a motor drive or an “inner-current loop” of motor drive speed control or converter voltage control. The new electroluminescence control was demonstrated in the laboratory on a prototype system where the current command is stepped from 0 to 25A, showcasing the effectiveness of the new optical sensing method.

Abstract Upcoding in Medicare has been a topic of interest to economists and policy makers for nearly 40 years. While upcoding is generally understood as “billing for services at higher level of complexity than the service actually pro- vided or documented,” it has a wide range of definitions within the literature. This is largely because the financial incentives across programs and aspects under the coding control of billing specialists and providers are different, and have evolved substantially over time, as has the published literature. Arguably, the primary importance of analyzing upcoding in different parts of Medicare is to inform policy makers on the magnitude of the process and to suggest approaches to mitigate the level of upcoding. Financial estimates for upcoding in traditional Medicare (Medicare Parts A and B), are highly variable, in part reflecting differences in methodology for each of the services covered. To resolve this variability, we used summaries of audit data from the Comprehensive Error Rate Testing program for the period 2010–2019. This program uses the same methodology across all forms of service in Medicare Parts A and B, allowing direct comparisons of upcoding magnitude. On average, upcoding for hospitalization under Part A represents $656 million annually (or 0.53% of total Part A annual expenditures) during our sample period, while up- coding for physician services under Part B is $2.38 billion annually (or 2.43% of Part B annual expenditures). These numbers compare to the recent consistent estimates from multiple different entities putting upcoding in Medicare Part C at $10–15 billion annually (or approximately 2.8–4.2% of Part C annual expenditures). Upcoding for hospitalization under Medicare Part A is small, relative to overall upcoding expenditures.

Abstract β-cells are a type of endocrine cell found in pancreatic islets that synthesize, store and release insulin. In type 1 diabetes (T1D), T-cells of the immune system selectively destroy the insulin-producing β-cells. Destruction of these cells leads to a lifelong dependence on exogenous insulin administration for survival. Consequently, there is an urgent need to identify novel therapies that stimulate β-cell growth and induce β-cell function. We and others have shown that pancreatic ductal progenitor cells are a promising source for regenerating β-cells for T1D owing to their inherent differentiation capacity. Default transcriptional suppression is refractory to exocrine reaction and tightly controls the regenerative potential by the EZH2 methyltransferase. In the present study, we show that transient stimulation of exocrine cells, derived from juvenile and adult T1D donors to the FDA-approved EZH2 inhibitors GSK126 and Tazemetostat (Taz) influence a phenotypic shift towards a β-like cell identity. The transition from repressed to permissive chromatin states are dependent on bivalent H3K27me3 and H3K4me3 chromatin modification. Targeting EZH2 is fundamental to β-cell regenerative potential. Reprogrammed pancreatic ductal cells exhibit insulin production and secretion in response to a physiological glucose challenge ex vivo. These pre-clinical studies underscore the potential of small molecule inhibitors as novel modulators of ductal progenitor differentiation and a promising new approach for the restoration of β-like cell function.

Abstract Background Ehlers-Danlos syndrome Type IV (aka Vascular Ehlers Danlos, or vEDS) is a dominantly inherited mutation in the Collagen 3A1 gene (COL3A1). The disease is characterized by tissue friability and age-related susceptibility to arterial aneurysm, dissection and rupture as well as uterine and bowl tears. These clinical manifestations result in major surgical intervention and decreased life expectancy. Understanding how mutations in COL3A1 impact the structure and function of the extracellular matrix (ECM) is important to managing the disease and finding treatments. Results Skin fibroblasts from vEDS subjects heterozygous for the p.G588S pathogenic variant in the COL3A1 gene and a normal individual were cultured and studied. Proteomics analysis identified dozens of upregulated proteins related to extracellular matrix dysregulation that is characteristic of fibrosis. Gene expression libraries from cultured primary fibroblasts were screened for messenger RNA (mRNA) markers of ECM degradation. The proteomics and targeted gene expression array results were largely consistent with dysregulation of the extracellular matrix in vEDS. The data show upregulation of multiple Collagen proteins and genes, other ECM components, and enzymes related to ECM processing and turn-over. vEDS fibroblasts expressed significantly more cross linked C-Telopeptide of Collagen III (CTXIII) than normal fibroblasts, indicative of Collagen III degradation and turn-over. Further, the expression and activity of Lysyl Oxidase (LOX), an enzyme that initiates covalent cross-linking of soluble collagen and elastin into protease resistant fibers, is elevated in vEDS fibroblasts compared to normal fibroblasts. Conclusion Together, these findings suggest dysregulated ECM deposition and processing, reminiscent of a state of fibrosis. Therapeutics that target the dysregulated ECM proteins or help replace damaged tissue may improve clinical outcomes.

Abstract Electroweak loop corrections to the matrix elements for the spin-independent scattering of cold dark matter particles on nuclei are generally small, typically below the uncertainty in the local density of cold dark matter. However, as shown in this paper, there are instances in which the electroweak loop corrections are relatively large, and change significantly the spin-independent dark matter scattering rate. An important example occurs when the dark matter particle is a wino, e.g., in anomaly-mediated supersymmetry breaking (AMSB) and pure gravity mediation (PGM) models. We find that the one-loop electroweak corrections to the spin-independent wino LSP scattering cross section generally interfere constructively with the tree-level contribution for AMSB models with negative Higgsino mixing, $$\mu < 0$$ μ < 0 , and in PGM-like models for both signs of $$\mu $$ μ , lifting the cross section out of the neutrino fog and into a range that is potentially detectable in the next generation of direct searches for cold dark matter scattering.

We demonstrate that the absorption of femtosecond hard x-ray pulses excites quasispherical, high-amplitude, and high-wave-vector coherent acoustic phonon wave packets using an all hard-x-ray pump-probe scattering experiment. The time- and momentum-resolved diffuse scattering signal is consistent with an ensemble of 3D strain wave packets induced by the rapid electron cascade dynamics following photoionization at uncorrelated excitation centers. We quantify key parameters of this process, including the localization size of the stress field and the photon energy conversion efficiency into elastic energy. The parameters are determined by the photoelectron and Auger electron cascade dynamics, as well as the electron-phonon interaction. In particular, we obtain the localization size of the observed strain wave packet to be 1.5 and 2.5 nm for bulk SrTiO_{3} and KTaO_{3} single crystals, respectively. The results provide crucial information on the mechanism of x-ray energy deposition into matter and shed light on the shortest collective length scales accessible to coherent acoustic phonon generation using x-ray excitation.