Search

Knowing the genes involved in quantitative traits provides an entry point to understanding the biological bases of behavior, but there are very few examples where the pathway from genetic locus to behavioral change is known. To explore the role of specific genes in fear behavior, we mapped three fear-related traits, tested fourteen genes at six quantitative trait loci (QTLs) by quantitative complementation, and identified six genes. Four genes, Lamp, Ptprd, Nptx2, and Sh3gl, have known roles in synapse function; the fifth, Psip1, was not previously implicated in behavior; and the sixth is a long non-coding RNA, 4933413L06Rik, of unknown function. Variation in transcriptome and epigenetic modalities occurred preferentially in excitatory neurons, suggesting that genetic variation is more permissible in excitatory than inhibitory neuronal circuits. Our results relieve a bottleneck in using genetic mapping of QTLs to uncover biology underlying behavior and prompt a reconsideration of expected relationships between genetic and functional variation.

Cough is a common and commonly ignored symptom of lung disease. Cough is often perceived as difficult to quantify, frequently self-limiting, and non-specific. However, cough has a central role in the clinical detection of many lung diseases including tuberculosis (TB), which remains the leading infectious disease killer worldwide. TB screening currently relies on self-reported cough which fails to meet the World Health Organization (WHO) accuracy targets for a TB triage test. Artificial intelligence (AI) models based on cough sound have been developed for several respiratory conditions, with limited work being done in TB. To support the development of an accurate, point-of-care cough-based triage tool for TB, we have compiled a large multi-country database of cough sounds from individuals being evaluated for TB. The dataset includes more than 700,000 cough sounds from 2,143 individuals with detailed demographic, clinical and microbiologic diagnostic information. We aim to empower researchers in the development of cough sound analysis models to improve TB diagnosis, where innovative approaches are critically needed to end this long-standing pandemic.

Abstract Background Persons living with dementia and their care partners encounter many challenges within the health and social care system, including lack of information, support, counselling, and access to community services, as well as significant staff turnover in home care services. The objective of this study was to work with multiple stakeholders to formulate relevant and feasible recommendations to improve care for persons living with dementia and their care partners in Quebec, Canada. Methods We conducted deliberative dialogues in the context of a large mixed methods study on the care of persons living with dementia and care partners. First, we organized two deliberative dialogues with care partners to formulate recommendations informed by the quantitative and qualitative results of the large study. These recommendations were further discussed in a third deliberative dialogue focused on the prioritization of relevant and feasible recommendations by clinicians, health project managers, and decision-makers. We performed a thematic analysis of the data using a multi-level framework: structural, organizational, provider, and patient perspectives. Results Participants formulated 14 recommendations. Two structural-level recommendations included fighting ageism and ensuring the same access to services in the whole province. Three organizational-level recommendations involved improving interdisciplinarity collaboration, improving access and follow-up in primary care, and adapting emergency departments. Additionally, two organizational-level recommendations were specific to healthcare crisis management (such as the COVID-19 pandemic): ensuring both the regular communication and the flexibility of implemented rules. Four provider-level recommendations encompassed providing more training on dementia, offering more training on levels of care, reviewing the relationship-based approach in training programs, and revising and optimizing medications. There were three patient-level recommendations including strengthening partnerships with persons living with dementia and care partners, guaranteeing personalized services and care, and reinforcing support for care partners. Conclusion The deliberative dialogues enabled us to formulate relevant recommendations based on research evidence, the lived experience of care partners, and the expertise of clinicians, health project managers and decision-makers. The results revealed several recommendations that will help mitigate the challenges faced by persons living with dementia and care partners in the health and social care system by informing policies and practices.

Abstract Background Existing frameworks of older persons’ experiences in health and social care systems are usually based on single stakeholder perspectives and focused on limited aspects that are independent from one another. This study aimed to describe such experiences from the perspective of diverse stakeholders and develop a comprehensive experience-based framework for actionable priorities to enhance Canada’s health and social care system. Methods We adapted a nominal group technique with a qualitative approach. We formed four groups of stakeholders (4 older persons, 7 clinicians, 5 managers, 4 decision-makers) in the province of Quebec. First, participants individually completed a questionnaire to rank the six domains of an international set of metrics of quality of care for older persons in terms of their importance. Then, we conducted a remote discussion with each stakeholder group, obtained consensus on the priority domains, and explored personal/professional experiences explaining prioritization processes and what changes are needed. An inductive-deductive thematic analysis was conducted to develop a framework for actionable health and social care priorities. Results The framework included six key categories revolving around a core category of ‘health equity’. (1) ‘Access to services and care’ focused on improved accessibility of healthcare navigators, primary and home care services, and end-of life care. (2) ‘Respect for older persons’ involved individuality and uniqueness, daily needs, advocacy in defence of vulnerability, and decision-making valuing care preferences. (3) ‘Involvement of family and friends’ encompassed formal recognition, responsibilities, and trajectories associated with caregiving. (4) ‘Communication and education’ consisted of adaptive communication between older persons, caregivers, and professionals and societal-level education and awareness-raising. (5) ‘Coordination and integration of care’ comprised health and social services organization, cross-sectoral approaches, and interdisciplinary collaboration. (6) ‘Responsiveness to evolving needs’ of older persons involved timely response to health transitions and promoting holistic approaches. Conclusions This study illustrates the complex challenges of caring for older persons. The framework suggests several areas for improvement in care practices and policies for older persons and caregivers. Proposed intervention targets include public healthcare system navigators, standardized goals of care practices respecting persons’ wishes, formal recognition of caregiver contributions, society-level education, cross-sectoral initiatives, and holistic approaches.

A recent study assessed the ability of 4 feed evaluation models to predict milk protein yield (MPY) in a commercial context, with data of 541 cows from 23 dairy herds in the province of Québec, Canada. However, the recently published Nutrient Requirements of Dairy Cattle from the National Academies of Sciences, Engineering, and Medicine (NASEM, 2021) was not released at that time. Thus, the current study evaluated NASEM using the same dataset. To be consistent with the previous study, predicted DMI was used. Therefore, MPY was predicted using the 2 estimations of DMI proposed by NASEM: one based on animal characteristics only (DMIAo) and one also including ration characteristics (DMIA&R). For each type of DMI estimates, 2 MPY predictions were made, using (1) the multivariate equation directly published in NASEM and (2) a variable efficiency of utilization of MP predicted using inputs and outputs from NASEM, published a posteriori. With the 2 approaches, multivariate and variable efficiency, the DMIA&R yielded the best MPY predictions. The multivariate equation showed a regression bias between observed and predicted MPY with both DMI estimations. The estimated variable efficiency allowed for MPY predictions without mean and regression biases. With DMIA&R, concordance correlation coefficients (CCC) were 0.72 and 0.78 for MPY predicted using the multivariate and variable efficiency equations, respectively. In comparison, DMIAo CCC were 0.60 and 0.71, respectively. In conclusion, on commercial farms, where dairy rations are usually optimized for a group of cows, estimates of DMI based on animal and rations characteristics yielded the best MPY predictions. The multivariate equation from NASEM predicted MPY with a regression bias, whereas the variable efficiency of utilization of MP based on MP and energy supplies resulted in no bias in MPY predictions.

Abstract Background Retrospective and descriptive molecular epidemiology studies have shown that Mycobacterium tuberculosis whole genome sequencing can identify outbreaks and disease transmission events with higher resolution than conventional epidemiological investigations. Those studies have strengthened our understanding of genomic polymorphisms correlating with person-to-person transmission and helped resolve putative transmission clusters. To date, systematic genomic surveillance programs implemented for M. tuberculosis were only implemented in low-incidence settings. The purpose of this study is to determine whether there is an impact of routine M. tuberculosis whole genome sequencing on tuberculosis case detection in a high-incidence setting. Methods A cluster randomized controlled trial will be performed. Forty-eight rural village groups (or Fokontany) in the Vohibato district of Madagascar will be randomized to one of three interventions arms. Arm 1 (standard of care) involves healthcare facility-based passive case detection with smear microscopy testing. Arm 2 (best practice) consists of active case finding and Xpert MTB/RIF Ultra PCR testing followed by household contact investigations. Arm 3 (novel intervention) includes the same interventions as arm 2, with addition of sputum culture and M. tuberculosis whole genome sequencing for all newly diagnosed cases. In arm 3, molecular suggested putative outbreaks are investigated, and additional TB suspects are appropriately tested. The intervention observational period will be 2 years. The primary outcome will be the number of detected cases/100,000/year in each arm after 1 year of intervention. Discussion This study is designed to determine whether there is an impact of prospective whole genome sequencing-based molecular typing on tuberculosis case detection in high-incidence settings. Investigating potential outbreaks and focusing active case finding in spatiotemporal settings where disease transmission is suggested by genomic typing is hypothesized to improve case detection in rural communities. Trial registration ClinicalTrials.gov NCT05406453 . Retrospectively registered on June 6, 2022.

Abstract Cough is a common and commonly ignored symptom of lung disease. Cough is often perceived as difficult to quantify, frequently self-limiting, and non-specific. However, cough has a central role in the clinical detection of many lung diseases including tuberculosis (TB), which remains the leading infectious disease killer worldwide. TB screening currently relies on self-reported cough which fails to meet the World Health Organization (WHO) accuracy targets for a TB triage test. Artificial intelligence (AI) models based on cough sound have been developed for several respiratory conditions, with limited work being done in TB. To support the development of an accurate, point-of-care cough-based triage tool for TB, we have compiled a large multi-country database of cough sounds from individuals being evaluated for TB. The dataset includes more than 700,000 cough sounds from 2,143 individuals with detailed demographic, clinical and microbiologic diagnostic information. We aim to empower researchers in the development of cough sound analysis models to improve TB diagnosis, where innovative approaches are critically needed to end this long-standing pandemic.

Background and Context: Current programming learning research often compares novices and experienced programmers, leaving early learning stages and emotional and cognitive states under-explored. Objective: Our study investigates relationships between cognitive and emotional states and learning performance in early stage programming learners with varying expertise (12 novices and 11 beginners; N = 23). Method: Measures such as electrodermal activity, automated facial emotion recognition, and pupil diameter were collected to study cognitive and emotional states during a programming task. We examined how these states correlated with performance and the influence of expertise on these correlations. Findings: Multiple regression analysis on panel data (n = 690 observations) suggested fear negatively impacts programming performance, irrespective of expertise level. Meanwhile, programming expertise positively moderated cognitive effort applied to the task. Implications: Our findings highlight the importance for educators to design early programming experiences that anticipate and reduce fear and cognitive overload, promoting better learning outcomes.

Abstract Background Implementation strategies targeting individual healthcare professionals and teams, such as audit and feedback, educational meetings, opinion leaders, and reminders, have demonstrated potential in promoting evidence-based nursing practice. This systematic review examined the effects of the 19 Cochrane Effective Practice and Organization Care (EPOC) healthcare professional-level implementation strategies on nursing practice and patient outcomes. Methods A systematic review was conducted following the Cochrane Handbook, with six databases searched up to February 2023 for randomized studies and non-randomized controlled studies evaluating the effects of EPOC implementation strategies on nursing practice. Study selection and data extraction were performed in Covidence. Random-effects meta-analyses were conducted in RevMan, while studies not eligible for meta-analysis were synthesized narratively based on the direction of effects. The quality of evidence was assessed using GRADE. Results Out of 21,571 unique records, 204 studies (152 randomized, 52 controlled, non-randomized) enrolling 36,544 nurses and 340,320 patients were included. Common strategies (> 10% of studies) were educational meetings, educational materials, guidelines, reminders, audit and feedback, tailored interventions, educational outreach, and opinion leaders. Implementation strategies as a whole improved clinical practice outcomes compared to no active intervention, despite high heterogeneity. Group and individual education, patient-mediated interventions, reminders, tailored interventions and opinion leaders had statistically significant effects on clinical practice outcomes. Individual education improved nurses’ attitude, knowledge, perceived control, and skills, while group education also influenced perceived social norms. Although meta-analyses indicate a small, non-statistically significant effect of multifaceted versus single strategies on clinical practice, the narrative synthesis of non-meta-analyzed studies shows favorable outcomes in all studies comparing multifaceted versus single strategies. Group and individual education, as well as tailored interventions, had statistically significant effects on patient outcomes. Conclusions Multiple types of implementation strategies may enhance evidence-based nursing practice, though effects vary due to strategy complexity, contextual factors, and variability in outcome measurement. Some evidence suggests that multifaceted strategies are more effective than single component strategies. Effects on patient outcomes are modest. Healthcare organizations and implementation practitioners may consider employing multifaceted, tailored strategies to address local barriers, expand the use of underutilized strategies, and assess the long-term impact of strategies on nursing practice and patient outcomes. Trial registration PROSPERO CRD42019130446.

Peatland pools are unvegetated, inundated depressions that cover up to 30 % of the surface of many temperate and boreal peatlands and that are net carbon (C) sources within C-accumulating ecosystems. The emission of carbon dioxide (CO2) and methane (CH4) from peatland pools comes from the degradation of organic matter (OM) that comprises the surrounding matrix. It is, however, not clear how decomposition rates in pools, which define their function and distinguish them from other aquatic ecosystems, vary spatially and what mechanisms drive these variations. We first quantified rates of OM decomposition from fresh litter at different depths in six pools of distinct morphological characteristics in a temperate ombrotrophic peatland using litterbags of Sphagnum capillifolium and Typha latifolia over a 27-month period. Rates of decomposition were faster for T. latifolia than S. capillifolium and, overall, faster at the pool surface and decreased with increasing depth. We then measured potential CO2 and CH4 production from the sediments of the same six pools by performing 35 d laboratory incubations. Pool sediment chemistry was variable among pools and influenced the production of CH4 and CO2 from sediments, with decreasing CO2 production with increasing OM humification and decreasing CH4 production with increasing nitrogen-to-phosphorus ratio. Both CH4 production and CO2 production from pool sediments were higher in the 1 m deep pools but similar in the shallow < 1 and the > 1.5 m deep pools. When combining both experiments, our results indicate that OM decomposition in peatland pools is highly variable and mostly related to the environmental conditions in which it occurs as a function of general pool depth rather than to OM chemistry. Overall, we show that OM degradation and C emissions in peatland open-water pools may increase over time in warmer and drier climate conditions.

Quantification of potassium (K) excretion in dairy cattle is important to understand the environmental impact of dairy farming. To improve and monitor the environmental impact of dairy cows, there is a need for a simple, inexpensive, and less laborious method to quantify K excretion on dairy farms. The adoption of empirical mathematical models has been shown to be a promising tool to address this issue. Thus, the current study aimed to develop empirical predictive models for K excretion in dairy cattle from urine and feces that can help evaluate efficiency and monitor the environmental impact of milk production. To develop urine K (KUr, g/d) and fecal K (KFa, g/d) excretion prediction models, published literature that involved 45 and 54 treatment means from 10 and 14 studies, respectively, were used. Some studies reported either urinary or fecal K excretion or both, but in total, treatment means used to develop the models were from 17 studies. The linear mixed models were fitted with the fixed effect of K intake, DMI, dietary K content, urine volume, milk yield, and water intake, and the random effect of study weighted according to the number of observations. Leave-one-study out cross-validation was used to evaluate the performance of the proposed models and the best model was based on the lowest root mean square prediction error as a percentage of the observed mean values (RMSPE%) and highest concordance correlation coefficient (CCC). As expected, most daily K excretion was through urine (202.5 ± 92.1 g/d) than through feces (43.5 ± 21.0 g/d), and among the proposed models, the model including dietary K concentration showed poor predictive ability for both KUr and KFa with the lowest CCC values (−0.15 and −0.02, respectively) and systematic bias. The model developed using DMI to predict KFa excretion showed reasonable accuracy, as indicated by RMSPE, CCC, and R2marginal of 46.6%, 0.42, and 48%, respectively. Among the proposed models for KUr and KFa, the model with K intake demonstrated better predictive performance, showing minimal systematic bias and random errors due to data variability of >92%. While these proposed models suggested that reducing K intake can lead to a decrease in K excretion, it is important to ensure that dairy cows receive adequate amounts of this nutrient to maintain optimal health and productivity, especially during periods of heat stress.

Abstract Tuberculosis, caused by Mycobacterium tuberculosis, remains a major public health concern, demanding new antibiotics with innovative therapeutic principles due to the emergence of resistant strains. Benzothiazinones (BTZs) have been developed to address this problem. However, an unprecedented in vivo biotransformation of BTZs to hydride-Meisenheimer complexes has recently been discovered. Herein, we present a study of the influence of electron-withdrawing groups on the propensity of HMC formation in whole cells for a series of C-6-substituted BTZs obtained through reductive fluorocarbonylation as a late-stage functionalization key step. Gibbs free energy of reaction and Mulliken charges and Fukui indices on C-5 at quantum mechanics level were found as good indicators of in vitro HMC formation propensity. These results provide a first blueprint for the evaluation of HMC formation in drug development and set the stage for rational pharmacokinetic optimization of BTZs and similar drug candidates.

Chronic myelomonocytic leukemia (CMML) is a severe myeloid malignancy with limited therapeutic options. Single-cell analysis of clonal architecture demonstrates early clonal dominance with few residual WT hematopoietic stem cells. Circulating myeloid cells of the leukemic clone and the cytokines they produce generate a deleterious inflammatory climate. Our hypothesis is that therapeutic control of the inflammatory component in CMML could contribute to stepping down disease progression. The present study explored the contribution of immature granulocytes (iGRANs) to CMML progression. iGRANs were detected and quantified in the peripheral blood of patients by spectral and conventional flow cytometry. Their accumulation was a potent and independent poor prognostic factor. These cells belong to the leukemic clone and behaved as myeloid-derived suppressor cells. Bulk and single-cell RNA-Seq revealed a proinflammatory status of iGRAN that secreted multiple cytokines of which CXCL8 was at the highest level. This cytokine inhibited the proliferation of WT but not CMML hematopoietic stem and progenitor cells (HSPCs) in which CXCL8 receptors were downregulated. CXCL8 receptor inhibitors and CXCL8 blockade restored WT HSPC proliferation, suggesting that relieving CXCL8 selective pressure on WT HSPCs is a potential strategy to slow CMML progression and restore some healthy hematopoiesis., Introduction Chronic myelomonocytic leukemia (CMML) is a myeloid malignancy defined by overlapping features of both myeloproliferative and myelodysplastic neoplasms (1). CMML diagnosis is based on sustained absolute and relative peripheral [...]

To identify addiction genes, we evaluate intravenous self-administration of cocaine or saline in 84 inbred and recombinant inbred mouse strains over 10 days. We integrate the behavior data with brain RNA-seq data from 41 strains. The self-administration of cocaine and that of saline are genetically distinct. We maximize power to map loci for cocaine intake by using a linear mixed model to account for this longitudinal phenotype while correcting for population structure. A total of 15 unique significant loci are identified in the genome-wide association study. A transcriptome-wide association study highlights the Trpv2 ion channel as a key locus for cocaine self-administration as well as identifying 17 additional genes, including Arhgef26, Slc18b1, and Slco5a1. We find numerous instances where alternate splice site selection or RNA editing altered transcript abundance. Our work emphasizes the importance of Trpv2, an ionotropic cannabinoid receptor, for the response to cocaine.

Mendelian randomization (MR) has emerged as a powerful approach to leverage genetic instruments to infer causality between pairs of traits in observational studies. However, the results of such studies are susceptible to biases owing to weak instruments, as well as the confounding effects of population stratification and horizontal pleiotropy. Here, we show that family data can be leveraged to design MR tests that are provably robust to confounding from population stratification, assortative mating, and dynastic effects. We show in simulations that our approach, MR-Twin, is robust to confounding from population stratification and is not affected by weak instrument bias, whereas standard MR methods yield inflated false positive rates. We then conduct an exploratory analysis of MR-Twin and other MR methods applied to 121 trait pairs in the UK Biobank data set. Our results suggest that confounding from population stratification can lead to false positives for existing MR methods, whereas MR-Twin is immune to this type of confounding, and that MR-Twin can help assess whether traditional approaches may be inflated owing to confounding from population stratification.

Introduction Home-based, virtually-supported care models may represent the most efficient and scalable approach to delivering prehabilitation services. However, virtual approaches to prehabilitation are understudied. This manuscript describes the protocol for an internal pilot randomised controlled trial of a virtually-delivered, multimodal prehabilitation intervention.Methods and analysis We will conduct a pragmatic, individual patient, internal pilot randomised controlled trial of home-based, virtually supported, multimodal prehabilitation compared with standard perioperative care in adults undergoing elective, inpatient thoracic, abdominal, pelvic and vascular surgery at five Canadian hospitals. Participants will be partially blinded; clinicians and outcome assessors will be fully blinded. The intervention consists of 3–12 weeks of a home-based, multimodal (exercise, nutrition and psychosocial support) prehabilitation programme supported through an online platform. The primary feasibility outcomes and their progression targets are (1) monthly recruitment of>6 participants at each centre, (2) intervention adherence of>75%, (3) retention of>90% of participants at the patient-reported primary outcome point of 30-days after surgery and (4) elicitation of patient, clinician and researcher-identified barriers to our pragmatic trial. A sample size of 144 participants will be adequate to estimate recruitment, adherence and retention rates with acceptable precision. All participants will be followed to either death or up to 1 year. As an internal pilot, if no substantive changes to the trial or intervention design are required, pilot participant outcome data will migrate, unanalysed by allocation, to the future full-scale trial.Ethics and dissemination Ethical approval has been granted by Clinical Trials Ontario (Project ID: 4479) and our ethics review board (Protocol Approval #20230399–01T). Results will be disseminated through presentations at scientific conferences, peer-reviewed publications, partner organisations and engagement of social and traditional media.Trial registration number ClinicalTrials.gov identifier NCT06042491. Protocol, V.1.2, dated 6 June 2024.

Purpose: Fertility issues are of great concern for young women undergoing treatment for breast cancer (BC). Fertility preservation (FP) protocols using controlled ovarian stimulation (COS) with letrozole have been widely used with overall good results. However, letrozole cannot be used in every country in this context. This study aimed to assess the efficacy of tamoxifen for COS in women with early BC undergoing FP. Methods: This multicentric prospective study included patients aged 18–40, diagnosed with stage I, II and III invasive BC, undergoing tamoxifen-COS before adjuvant or neoadjuvant chemotherapy (NAC). The primary endpoint was the efficacy of tamoxifen-COS protocol evaluated by the number of oocytes collected and vitrified. Secondary endpoints included the time interval before chemotherapy, breast cancer (BC) recurrence rates, and reproductive outcomes. Results: Ninety-five patients were included between 2014 and 2017, aged 31.5 ± 4 years on average. 37.9 % received NAC and 62.1 % received adjuvant chemotherapy. FP procedure was successful in 89.5 % of the cycles. The mean number of collected and vitrified oocytes was 12.8 ± 7.9 and 9.8 ± 6.2, respectively. The mean duration of COS was 10.4 ± 1.9 days. Median time before chemotherapy initiation was 3.6 weeks (IQR 3.1; 4.1) for women receiving NAC. Five-year relapse-free and overall survival rates were in-line with those expected in this population. Twenty-one women had spontaneous full-term pregnancies, while 5 underwent IVF cycles with frozen-thawed oocytes, without pregnancy. Conclusion: Tamoxifen-COS protocols appear to be feasible before adjuvant or NAC treatment in young BC patients and efficient in terms of oocyte yield.

Introduction: Eye-tracking offers a distinctive opportunity to assess nurses’ clinical decision-making in simulation. Although its feasibility has been established in various scenarios, most studies have focused on a single participant, typically a physician in a leadership role. The application of eye-tracking in the challenging context of in-hospital cardiac arrest (IHCA) simulations, where nurses juggle diverse roles and undertake physical tasks such as chest compressions, has yet to be explored.Objectives: This study aimed to assess the feasibility and acceptability of eye-tracking with nurses’ during IHCA simulations. Additionally, the study aimed to describe eye-tracking metrics based on different resuscitation roles and to explore the relationship between eye-tracking metrics to pinpoint the most informative metrics for the design of future studies.Methods: In this single-group observational study, 56 newly hired nurses wore eye-tracking glasses during IHCA simulations. The primary feasibility criterion was the proportion of usable eye-tracking data. Secondary criteria included recruitment rate, calibration time, and glasses acceptability. The relationship among eye-tracking metrics was investigated through correlation analyses.Results: Calibration of the devices was rapid, and 85.7% of the data was usable. The glasses were comfortable, non-distracting, and did not impede nurses’ vision or performance. Data were mapped for five areas of interest: the patient’s head and chest, cardiac monitor, teammates, and resuscitation cart. Eye-tracking metrics exhibited variations based on resuscitation roles. Fixation count, fixation duration, and time to first fixation appeared to be the most informative metrics in IHCA simulation.Discussion and conclusion: These findings demonstrate the feasibility and acceptability of analyzing nurses’ eye-tracking data during IHCA simulations using a role-based approach. Future research should explore correlations with additional attention measures to enhance our understanding of nurse decision-making during cardiac arrest and improve educational strategies and outcomes.

The transcription factor receptor‐interacting protein 140 (RIP140) regulates intestinal homeostasis and tumorigenesis through Wnt signaling. In this study, we investigated its effect on the Notch/HES1 signaling pathway. In colorectal cancer (CRC) cell lines, RIP140 positively regulated HES1 gene expression at the transcriptional level via a recombining binding protein suppressor of hairless (RBPJ)/neurogenic locus notch homolog protein 1 (NICD)‐mediated mechanism. In support of these in vitro data, RIP140 and HES1 expression significantly correlated in mouse intestine and in a cohort of CRC samples, thus supporting the positive regulation of HES1 gene expression by RIP140. Interestingly, when the Notch pathway is fully activated, RIP140 exerted a strong inhibition of HES1 gene transcription controlled by the level of HES1 itself. Moreover, RIP140 directly interacts with HES1 and reversed its mitogenic activity in human CRC cells. In line with this observation, HES1 levels were associated with a better patient survival only when tumors expressed high levels of RIP140. Our data identify RIP140 as a key regulator of the Notch/HES1 signaling pathway, with a dual effect on HES1 gene expression at the transcriptional level and a strong impact on colon cancer cell proliferation.

ABSTRACT: Net energy for lactation (NEL) and metabolizable protein (MP) are the 2 main nutritional forces that drive synthesis of milk components. This study investigated mammary-gland metabolism in dairy cows in response to variations in the supply of NEL and MP. Four Holstein dairy cows were randomly assigned to a 4 × 4 Latin square design, in which each experimental period consisted of 14 d of dietary treatment. The diets provided 2 levels of NEL (low energy, 25.0 Mcal/d vs. high energy, 32.5 Mcal/d) and 2 levels of MP (low protein, 1,266 g/d vs. high protein, 2,254 g/d of protein digestible in the intestine) in a 2 × 2 factorial arrangement. Performance and dry matter intake (DMI) were measured during the last 5 d of each period, and the mammary net balance was measured on d 13 by collecting 6 sets of blood samples from the left carotid artery and left mammary vein. Mammary plasma flow was measured according to the Fick principle for Phe and Tyr. The mammary net balance of carbon equaled the uptake of nutrients expressed as carbon minus the output of lactose, fatty acids (FA) synthesized in the mammary gland, AA of milk protein, and glycerol-3P from triglyceride on d 13. Milk, lactose, fat, and protein yields increased when NEL and MP supplies increased. However, increasing the NEL supply increased FA synthesis more than increasing the protein supply did. In addition, FA secretion increased more than lactose secretion when the NEL supply increased. Increasing the NEL supply increased the left half-udder uptake of all major energy-yielding nutrients by increasing mammary plasma flow. However, nutrient uptake increased more than milk output did, which in turn increased carbon dioxide output. This increase in nutrient oxidation by the mammary gland decreased the mammary efficiency of nutrients utilization when the NEL supply increased. Increasing MP supply tended to increase glucose uptake through mammary clearance and increased mammary AA uptake with no change in mammary plasma flow. In addition, the protein supply did not change the mammary uptake of acetate or β-hydroxybutyrate. The increase in milk-component secretions in response to either NEL or MP supplies occurred through different metabolic adaptations (increase in mammary plasma flow vs. clearances, respectively). These results suggest that the nutrient use by the mammary gland is highly flexible, which helps in maintaining milk and milk-component yields even with limiting nutrient supplies.

Abstract Cannabis sativa L., previously concealed by prohibition, is now a versatile and promising plant, thanks to recent legalization, opening doors for medical research and industry growth. However, years of prohibition have left the Cannabis research community lagging behind in understanding Cannabis genetics and trait inheritance compared to other major crops. To address this gap, we conducted a comprehensive genome-wide association study (GWAS) of nine key agronomic and morphological traits, using a panel of 176 drug-type Cannabis accessions from the Canadian legal market. Utilizing high-density genotyping-by-sequencing (HD-GBS), we successfully generated dense genotyping data in Cannabis, resulting in a catalog of 800 K genetic variants, of which 282 K common variants were retained for GWAS analysis. Through GWAS analysis, we identified 18 markers significantly associated with agronomic and morphological traits. Several identified markers exert a substantial phenotypic impact, guided us to putative candidate genes that reside in high linkage-disequilibrium (LD) with the markers. These findings lay a solid foundation for an innovative cannabis research, leveraging genetic markers to inform breeding programs aimed at meeting diverse needs in the industry.

Background: The major drivers of carbon dioxide (CO2eq) emissions of external beam radiation therapy (EBRT) are not well known and limit our ability to initiate mitigation strategies. Material and methods: We describe the carbon footprint of four typical centers. We explore direct EBRT associated factors such as the impact of fractionation and use of MRI-LINAC, as well as indirect factors (e.g. patient rides). Treatment strategy related CO2eq emissions are included in a health technology assessment analysis that takes into account CO2eq emissions. Results: A typical EBRT treatment emits from 185 kgCO2eq to 2066 kgCO2eq. CO2eq emissions are mostly driven by (i) accelerator acquisition and maintenance (37.8 %), (ii) patients and workers rides (32.7 %), (iii) drugs and medical devices (7.3 %), (iv) direct energy consumption (6.1 %), and (v) building and bunker construction (5.6 %) with a substantial heterogeneity among centers. Hypofractionation has a strong impact to mitigate emissions. MRI-LINAC is associated with a substantial increase in CO2eq emissions per fraction and requires ultra hypofractionation in 5 fractions to achieve a similar carbon footprint compared to 20 fractions treatment schemes. The expected limited small increase in toxicities due to hypofractionation (when existing) are in the same range as avoided detrimental effects to future people’s health thanks to CO2eq mitigation. Conclusion: Carbon footprint of EBRT is not neglectable and could be mitigated. When safely feasible, hypofractionation is one of the main factors to decrease this impact. Taking into account CO2eq emissions has a substantial impact on the health technology assessment of EBRT, favoring hypofractionated regimens.

Abstract This study assesses the reliability and limitations of the Geostationary Lightning Mapper (GLM) in detecting continuing currents by comparing observations from ground‐based high‐speed cameras with GLM‐16 data. Our findings show that the GLM's one‐group detection efficiency (DE_1) is 53%, while the more stringent five‐consecutive‐group detection efficiency (DE_5) is 10%. Optical signals detected by the GLM predominantly occur during the early stages of continuing currents. Additionally, there is a notable disparity in detection efficiencies between positive and negative continuing currents, with positive continuing currents being detected more frequently. The application of the logistic regression model developed by Fairman and Bitzer (2022) further illustrates the limitations in continuing current identification. The study underscores the challenges of relying solely on satellite data to monitor and analyze continuing currents, emphasizing the need for advancements in detection technologies and methodologies to reliably detect continuing current at a large spatial scale.

La discapacidad en los pueblos indígenas es un tema que ha despertado un creciente interés en diversos estudios en Latinoamérica en los últimos años. Sin embargo, la forma de acercarse teóricamente a este campo no es unívoca. Este artículo pretende poner en discusión las distintas formas de aproximarse a la comprensión de la discapacidad en los pueblos indígenas, y así proponer que este vínculo puede darse de distintas maneras, de acuerdo con el posicionamiento epistemológico que sostenga la relación entre las culturas. Se reconoce, además, que estos enfoques tienen consecuencias tanto en la academia como en los territorios. Esta reflexión desarrollará siete formas de aproximación que sugieren un camino no necesariamente lineal, pero sí progresivo hacia la interculturalidad crítica como enfoque investigativo y activista en el campo de la discapacidad en los pueblos indígenas.