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Abstract Riboswitches are structured RNA elements that regulate gene expression upon binding to small molecule ligands. Understanding the mechanisms by which small molecules impact riboswitch activity is key to developing potent, selective ligands for these and other RNA targets. We report the structure-informed design of chemically diverse synthetic ligands for PreQ1 riboswitches. Multiple X-ray co-crystal structures of synthetic ligands with the Thermoanaerobacter tengcongensis (Tte)-PreQ1 riboswitch confirm a common binding site with the cognate ligand, despite considerable chemical differences among the ligands. Structure probing assays demonstrate that one ligand causes conformational changes similar to PreQ1 in six structurally and mechanistically diverse PreQ1 riboswitch aptamers. Single-molecule force spectroscopy is used to demonstrate differential modes of riboswitch stabilization by the ligands. Binding of the natural ligand brings about the formation of a persistent, folded pseudoknot structure, whereas a synthetic ligand decreases the rate of unfolding through a kinetic mechanism. Single round transcription termination assays show the biochemical activity of the ligands, while a GFP reporter system reveals compound activity in regulating gene expression in live cells without toxicity. Taken together, this study reveals that diverse small molecules can impact gene expression in live cells by altering conformational changes in RNA structures through distinct mechanisms.

Abstract The current experiments searching for neutrinoless double- $$\beta $$ β ( $$0\nu \beta \beta $$ 0 ν β β ) decay also collect large statistics of Standard Model allowed two-neutrino double- $$\beta $$ β ( $$2\nu \beta \beta $$ 2 ν β β ) decay events. These can be used to search for Beyond Standard Model (BSM) physics via $$2\nu \beta \beta $$ 2 ν β β decay spectral distortions. 100Mo has a natural advantage due to its relatively short half-life, allowing higher $$2\nu \beta \beta $$ 2 ν β β decay statistics at equal exposures compared to the other isotopes. We demonstrate the potential of the dual read-out bolometric technique exploiting a 100Mo exposure of 1.47 kg $$\times $$ × years, acquired in the CUPID-Mo experiment at the Modane underground laboratory (France). We set limits on $$0\nu \beta \beta $$ 0 ν β β decays with the emission of one or more Majorons, on $$2\nu \beta \beta $$ 2 ν β β decay with Lorentz violation, and $$2\nu \beta \beta $$ 2 ν β β decay with a sterile neutrino emission. In this analysis, we investigate the systematic uncertainty induced by modeling the $$2\nu \beta \beta $$ 2 ν β β decay spectral shape parameterized through an improved model, an effect never considered before. This work motivates searches for BSM processes in the upcoming CUPID experiment, which will collect the largest amount of $$2\nu \beta \beta $$ 2 ν β β decay events among the next-generation experiments.

Abstract Si and its oxides have been extensively explored in theoretical research due to their technological importance. Simultaneously describing interatomic interactions within both Si and SiO2 without the use of ab initio methods is considered challenging, given the charge transfers involved. Herein, this challenge is overcome by developing a unified machine learning interatomic potentials describing the Si/SiO2/O system, based on the moment tensor potential (MTP) framework. This MTP is trained using a comprehensive database generated using density functional theory simulations, encompassing diverse crystal structures, point defects, extended defects, and disordered structure. Extensive testing of the MTP is performed, indicating it can describe static and dynamic features of very diverse Si, O, and SiO2 atomic structures with a degree of fidelity approaching that of DFT.

Abstract Aim Illicitly manufactured fentanyl and its analogs are the primary drivers of opioid overdose deaths in the United States (U.S.). People who use drugs may be exposed to fentanyl or its analogs intentionally or unintentionally. This study sought to identify strategies used by rural people who use drugs to reduce harms associated with unintentional fentanyl exposure. Methods This analysis focused on 349 semi-structured qualitative interviews across 10 states and 58 rural counties in the U.S conducted between 2018 and 2020. Interview guides were collaboratively standardized across sites and included questions about drug use history (including drugs currently used, frequency of use, mode of administration) and questions specific to fentanyl. Deductive coding was used to code all data, then inductive coding of overdose and fentanyl codes was conducted by an interdisciplinary writing team. Results Participants described being concerned that fentanyl had saturated the drug market, in both stimulant and opioid supplies. Participants utilized strategies including: (1) avoiding drugs that were perceived to contain fentanyl, (2) buying drugs from trusted sources, (3) using fentanyl test strips, 4) using small doses and non-injection routes, (5) using with other people, (6) tasting, smelling, and looking at drugs before use, and (7) carrying and using naloxone. Most people who used drugs used a combination of these strategies as there was an overwhelming fear of fatal overdose. Conclusion People who use drugs living in rural areas of the U.S. are aware that fentanyl is in their drug supply and use several strategies to prevent associated harms, including fatal overdose. Increasing access to harm reduction tools (e.g., fentanyl test strips, naloxone) and services (e.g., community drug checking, syringe services programs, overdose prevention centers) should be prioritized to address the polysubstance-involved overdose crisis. These efforts should target persons who use opioids and other drugs that may contain fentanyl.

Abstract Landslides sometimes creep for decades before undergoing runaway acceleration and catastrophic failure. Observing and monitoring the evolution of strain in time and space is crucial to understand landslide processes, including the transition from slow to fast movement. However, the limited spatial or temporal resolution of existing landslide monitoring instrumentation limits the study of these processes. We employ distributed acoustic sensing strain data below 1 Hertz frequency during a three-day rainfall at the Hollin Hill landslide and quantify strain-rate changes at meter and sub-minute scales. We observe near-surface strain onset at the head scarp, strain acceleration at a developing rupture zone, retrogression towards the scarp, and flow-lobe activity. These processes with displacements of less than 0.5 mm are undetected using other methods. However, the millimeter processes over three days agree with previously observed seasonal landslide patterns. Here, we show landslide processes occurring with nanostrain-rate sensitivity at spatiotemporal resolution previously not possible.

Abstract Cytokine release syndrome (CRS) was associated with teclistamab treatment in the phase I/II MajesTEC‐1 study. Cytokines, especially interleukin (IL)‐6, are known suppressors of cytochrome P450 (CYP) enzymes' activity. A physiologically based pharmacokinetic model evaluated the impact of IL‐6 serum levels on exposure of substrates of various CYP enzymes (1A2, 2C9, 2C19, 3A4, 3A5). Two IL‐6 kinetics profiles were assessed, the mean IL‐6 profile with a maximum concentration (Cmax) of IL‐6 (21 pg/mL) and the IL‐6 profile of the patient presenting the highest IL‐6 Cmax (288 pg/mL) among patients receiving the recommended phase II dose of teclistamab in MajesTEC‐1. For the mean IL‐6 kinetics profile, teclistamab was predicted to result in a limited change in exposure of CYP substrates (area under the curve [AUC] mean ratio 0.87–1.20). For the maximum IL‐6 kinetics profile, the impact on omeprazole, simvastatin, midazolam, and cyclosporine exposure was weak to moderate (mean AUC ratios 1.90–2.23), and minimal for caffeine and s‐warfarin (mean AUC ratios 0.82–1.25). Maximum change in exposure for these substrates occurred 3–4 days after step‐up dosing in cycle 1. These results suggest that after cycle 1, drug interaction from IL‐6 effect has no meaningful impact on CYP activities, with minimal or moderate impact on CYP substrates. The highest risk of drug interaction is expected to occur during step‐up dosing up to 7 days after the first treatment dose (1.5 mg/kg subcutaneously) and during and after CRS.

BackgroundPeople with chronic diseases can benefit from wearable devices in managing their health and encouraging healthy lifestyle habits. Wearables such as activity trackers or blood glucose monitoring devices can lead to positive health impacts, including improved physical activity adherence or better management of type 2 diabetes. Few literature reviews have focused on the intersection of various chronic diseases, the wearable devices used, and the outcomes evaluated in intervention studies, particularly in the context of primary health care. ObjectiveThis study aims to identify and describe (1) the chronic diseases represented in intervention studies, (2) the types or combinations of wearables used, and (3) the health or health care outcomes assessed and measured. MethodsWe conducted a scoping review following the Joanna Briggs Institute guidelines, searching the MEDLINE and Web of Science databases for studies published between 2012 and 2022. Pairs of reviewers independently screened titles and abstracts, applied the selection criteria, and performed full-text screening. We included interventions using wearables that automatically collected and transmitted data to adult populations with at least one chronic disease. We excluded studies with participants with only a predisposition to develop a chronic disease, hospitalized patients, patients with acute diseases, patients with active cancer, and cancer survivors. We included randomized controlled trials and cohort, pretest-posttest, observational, mixed methods, and qualitative studies. ResultsAfter the removal of 1987 duplicates, we screened 4540 titles and abstracts. Of the remaining 304 articles after exclusions, we excluded 215 (70.7%) full texts and included 89 (29.3%). Of these 89 texts, 10 (11%) were related to the same interventions as those in the included studies, resulting in 79 studies being included. We structured the results according to chronic disease clusters: (1) diabetes, (2) heart failure, (3) other cardiovascular conditions, (4) hypertension, (5) multimorbidity and other combinations of chronic conditions, (6) chronic obstructive pulmonary disease, (7) chronic pain, (8) musculoskeletal conditions, and (9) asthma. Diabetes was the most frequent health condition (18/79, 23% of the studies), and wearable activity trackers were the most used (42/79, 53% of the studies). In the 79 included studies, 74 clinical, 73 behavioral, 36 patient technology experience, 28 health care system, and 25 holistic or biopsychosocial outcomes were reported. ConclusionsThis scoping review provides an overview of the wearable devices used in chronic disease self-management intervention studies, revealing disparities in both the range of chronic diseases studied and the variety of wearable devices used. These findings offer researchers valuable insights to further explore health care outcomes, validate the impact of concomitant device use, and expand their use to other chronic diseases. Trial RegistrationOpen Science Framework Registries (OSF) s4wfm; https://osf.io/s4wfm

Modern maple sugaring operations use vacuum tubing systems to enhance sap flow and maximize yield. The positioning of tapholes is a crucial aspect influencing tree health and sap yields, but is limited by dropline length. Inverting droplines to expand the tappable zone and reduce the risk of over-tapping has raised concerns about vacuum efficiency and microbial contamination.We examined over 2200 trees on multiple high-vacuum 5/16″ tubing systems at two sites over three seasons, tapping at various heights above and below the lateral line. Our analysis showed no significant decrease in sap yield or sugar concentration when tapping below the lateral line. Taps at extreme heights above the lateral line produced slightly more sap (estimated at 0.6 l of sap per tap for a good production season) and marginally sweeter sap (0.06 °Brix). However, differences in vacuum management had a more significant impact on yield. Additionally, there was no evidence of increased microbial activity or changes in sap pH due to relative tapping height.These findings demonstrate that tapping below the lateral line effectively doubles the tappable zone without significantly affecting sap yield or quality, promoting sustainable maple sugaring practices by ensuring long-term productivity without compromising sap yields or quality.

Objective: The objective of the current pilot study was to investigate the feasibility and acceptability of a videoconference-based cognitive behavioral (CBT) intervention for caregivers of individuals living with mild cognitive impairment or early Alzheimer's disease. The intervention included psychoeducation on emotions, strategies for management of unhelpful emotions and thoughts, behavioral activation, breathing and relaxation, strategies for communication and information on external resources. Methods: This study used a cross-sectional design with two groups of four caregivers who received an 8-week CBT-based intervention via videoconference. Measures of feasibility and acceptability were collected post-intervention as well as suggestions for improvements. Results: Eight female caregivers were enrolled in the intervention, one participant opted out at the seventh session. Of those who completed the program, all participants reported that it was very easy to participate using the online modality. All participants felt that the intervention was at least partly adapted to their experience and needs as a caregiver. Five out of seven participants (71%) indicated that they felt better and would recommend the intervention to another caregiver. Conclusion: The current study demonstrated that it is feasible and acceptable to use a videoconference CBT-based group intervention with MCI or mild AD female caregivers. Innovation: This is the first videoconference-based cognitive behavioral intervention for caregivers of individuals living with MCI or mild AD.

Although most offenders who have committed a sex crime will not reoffend, an excessive amount of attention has been paid to the process that leads a minority to commit a new offense. What are the protective factors that contribute to the absence of recidivism among most of these sex offenders? This scoping review provides an overview of the current state of the literature on desistance among sex offenders as well as a list of the empirically tested protective factors that contribute to it. Peer-reviewed articles and grey literature were retrieved through database searches and reference harvesting following the elaboration of an internal grid composed of approximately 20 keywords and specific inclusion criteria. Articles were included if the majority of each study’s sample had committed a sex offense, factors explaining desistance from sexual offending were explicitly addressed, and all participants in the various studies were still considered desistors at the time of our search. From a database of 6,556 articles published between 1985 and 2022, 26 studies were retained, and more than 150 different protective factors were identified and grouped into 32 distinct subcategories. Our analysis revealed that the selected studies conceptualize desistance differently and that this choice not only affects the protective factors identified but could also influence ideas about how to intervene with sex offenders.

Degenerative cervical myelopathy (DCM) is the leading cause of spinal cord dysfunction in adults, representing substantial morbidity and significant financial and resource burdens. Typically, patients with progressive DCM will eventually receive surgical treatment. Nonetheless, despite advancements in pharmacotherapeutics, evidence for pharmacological therapy remains limited. Health professionals from various fields would find interest in pharmacological agents that could benefit patients with mild DCM or enhance surgical outcomes. This review aims to consolidate all clinical and experimental evidence on the pharmacological treatment of DCM. We conducted a comprehensive narrative review that presents all pharmacological agents that have been investigated for DCM treatment in both humans and animal models. Riluzole exhibits effectiveness solely in rat models, but not in treating mild DCM in humans. Cerebrolysin emerges as a potential neuroprotective agent for myelopathy in animals but had contradictory results in clinical trials. Limaprost alfadex demonstrates motor function improvement in animal models and exhibits promising outcomes in a small clinical trial. Glucocorticoids not only fail to provide clinical benefits but may also lead to adverse events. Cilostazol, anti-Fas ligand antibody, and Jingshu Keli display promise in animal studies, while erythropoietin, granulocyte colony-stimulating factor and limaprost alfadex exhibit potential in both animal and human research. Existing evidence mainly rests on weak clinical data and animal experimentation. Current pharmacological efforts target ion channels, stem cell differentiation, inflammatory, vascular, and apoptotic pathways. The inherent nature and pathogenesis of DCM offer substantial prospects for developing neurodegenerative or neuroprotective therapies capable of altering disease progression, potentially delaying surgical intervention, and optimizing outcomes for those undergoing surgical decompression.

Epithelial ovarian cancer (EOC) has not significantly benefited from advances in immunotherapy, mainly because of the lack of well-defined actionable antigen targets. Using proteogenomic analyses of primary EOC tumors, we previously identified 91 aberrantly expressed tumor-specific antigens (TSAs) originating from unmutated genomic sequences. Most of these TSAs derive from non-exonic regions, and their expression results from cancer-specific epigenetic changes. The present study aimed to evaluate the immunogenicity of 48 TSAs selected according to two criteria: presentation by highly prevalent HLA allotypes and expression in a significant fraction of EOC tumors. Using targeted mass spectrometry analyses, we found that pulsing with synthetic TSA peptides leads to a high-level presentation on dendritic cells. TSA abundance correlated with the predicted binding affinity to the HLA allotype. We stimulated naïve CD8 T cells from healthy blood donors with TSA-pulsed dendritic cells and assessed their expansion with two assays: MHC-peptide tetramer staining and TCR Vβ CDR3 sequencing. We report that these TSAs can expand sizeable populations of CD8 T cells and, therefore, represent attractive targets for EOC immunotherapy.

Abstract Adolescence is a key period for neurocognitive maturation where deviation from normal developmental trajectories may be tied to adverse mental health outcomes. Cognitive disruptions have been noted in populations at risk for psychosis and are known to accompany periods of sleep deprivation. This study aims to assess the role of cognition as a mediator between sleep disruptions and psychosis risk. A cohort of 3801 high school students (51% female, mean age = 12.8, SD = 0.45 years) was recruited from 31 Montreal high schools. Measures of sleep, psychotic-like experiences, inhibition, working memory, perceptual reasoning, and delayed recall were collected from participants on a yearly basis over the five years of their high school education. A multi-level model mediation analysis was performed controlling for sex and time squared. Response inhibition was shown to be associated with, and to mediate (B = −0.005, SD = 0.003, p = 0.005*) the relationship between sleep disruptions (B = −0.011, SD = 0.004, p

Madalina Patron,1,2,* Mattias Neset,1,2,* Mariia Mielkozorova,2,* Daniel G Bisson,1,3,* Marie Vigouroux,4 Juan Pablo Cata,5,6 Pablo M Ingelmo,4,7,8 Jean A Ouellet,1,3 Lisbet Haglund,1,3,* Svetlana V Komarova1,2,* 1Shriners Hospital for Children, Montreal, Canada; 2Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montreal, Canada; 3Orthopaedic Research Laboratory, Department of Surgery, McGill University, Montreal, Canada; 4Edwards Family Interdisciplinary Center for Complex Pain, Montreal Children’s Hospital, Montreal, QC, Canada; 5Department of Anesthesia and Perioperative Medicine, The University of Texas – MD Anderson Cancer Center, Houston, TX, USA; 6Anesthesiology and Surgical Oncology Research Group, Houston, TX, USA; 7Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada; 8Research Institute, McGill University Health Center, Montreal, Canada*These authors contributed equally to this workCorrespondence: Svetlana V Komarova, Shriners Hospital for Children, 1003 Decarie Boulevard, Montreal, Quebec, H4A 0A9, Canada, Tel +1 514 282-7153, Email svetlana.komarova@mcgill.caPurpose: Pain is an understudied physiological effect of spaceflight. Changes in inflammatory and tissue degradation markers are often associated with painful conditions. Our aim was to evaluate the changes in markers associated with tissue deterioration after a short-term spaceflight.Patients and Methods: Plasma levels of markers for systemic inflammation and tissue degeneration markers were assessed in two astronauts before and within 24 h after the 17-day Axiom Space AX-1 mission.Results: After the spaceflight, C-reactive protein (CRP) was reduced in both astronauts, while INFγ, GM-CSF, TNFα, BDNF, and all measured interleukins were consistently increased. Chemokines demonstrated variable changes, with consistent positive changes in CCL3, 4, 8, 22 and CXCL8, 9, 10, and consistent negative change in CCL8. Markers associated with tissue degradation and bone turnover demonstrated consistent increases in MMP1, MMP13, NTX and OPG, and consistent decreases in MMP3 and MMP9.Conclusion: Spaceflight induced changes in the markers of systemic inflammation, tissue deterioration, and bone resorption in two astronauts after a short, 17-day, which were often consistent with those observed in painful conditions on Earth. However, some differences, such as a consistent decrease in CRP, were noted. All records for the effect of space travel on human health are critical for improving our understanding of the effect of this unique environment on humans.Keywords: spaceflight, astronaut, cytokine, interleukin, chemokine, bone turnover

The CUPID-Mo experiment, located at the Laboratoire Souterrain de Modane (France), was a demonstrator experiment for CUPID. It consisted of an array of 20Li2Mo100O4 (LMO) calorimeters, each equipped with a Ge light detector for particle identification. In this work, we present the result of a search for two-neutrino and neutrinoless double-β decays of Mo100 to the first 0+ and 2+ excited states of Ru100 using the full CUPID-Mo exposure (2.71kgyr of LMO). We measure the half-life of 2νββ decay to the 01+ state as T1/22ν→01+=(7.5±0.8(stat.)-0.3+0.4(syst.))×1020yr. The bolometric technique enables measurement of the electron energies as well as the γ rays from nuclear deexcitation and this allows us to set new limits on the two-neutrino decay to the 21+ state of T1/22ν→21+>4.4×1021yr(90% c.i.) and on the neutrinoless modes of T1/20ν→21+>2.1×1023yr(90% c.i.), T1/20ν→01+>1.2×1023yr(90% c.i.). Information on the electrons' spectral shape is obtained, which allows us to make the first comparison of the single and higher state dominance 2νββ decay models for the 01+ excited state of Ru100.

CUPID-Mo, located in the Laboratoire Souterrain de Modane (France), was a demonstrator for the next generation 0 νββ decay experiment, CUPID. It consisted of an array of 20 enriched Li 2100 MoO 4 bolometers and 20 Ge light detectors and has demonstrated that the technology of scintillating bolometers with particle identification capabilities is mature. Furthermore, CUPID-Mo can inform and validate the background prediction for CUPID. In this paper, we present a detailed model of the CUPID-Mo backgrounds. This model is able to describe well the features of the experimental data and enables studies of the 2 νββ decay and other processes with high precision. We also measure the radio-purity of the Li 2100 MoO 4 crystals which are found to be sufficient for the CUPID goals. Finally, we also obtain a background index in the region of interest of 3.7 -0.8+0.9 (stat) -0.7+1.5 (syst) ×10-3 counts/ Δ EFWHM/ mol iso/ year , the lowest in a bolometric 0 νββ decay experiment.

In this contribution we present the achievements of the CUORE experiment so far. It is the first tonne-scale bolometric detector and it is in stable data taking since 2018. We reached to collect about 1800 kg×yr of exposure of which more than 1 ton×year have been analysed. The CUORE detector is meant to search for the neutrinoless double β decay (0νββ) of the 130Te isotope. This is a beyond Standard Model process which could establish the nature of the neutrino to be Dirac or a Majorana particle. It is an alternative mode of the two-neutrinos double β decay, a rare decay which have been precisely measured by CUORE in the 130Te. We found no evidence of the 0νββ and we set a Bayesian lower limit of 2.2 ×1025yr on its half-life. The expertise achieved by CUORE set a milestone for any future bolometric detector, including CUPID, which is the planned next generation experiment searching for 0νββ with scintillating bolometers.

Abstract INTRODUCTION In a 5‐year follow‐up study, we investigated the enduring effects of cognitive training on older adults with mild cognitive impairment (MCI). METHODS A randomized controlled single‐blind trial involved 145 older adults with MCI, assigned to cognitive training (MEMO+), an active control psychosocial intervention, or a no‐contact condition. Five‐year effects were measured on immediate and delayed memory recall, the Montreal Cognitive Assessment screening test (MoCA), self‐reported strategy use, and daily living difficulties. RESULTS At follow‐up, participants who received cognitive training showed a smaller decline in delayed memory and maintained MoCA scores, contrasting with greater declines in the control groups. Cognitive training participants outperformed controls in both delayed memory and MoCA scores at the 5‐year time point. No significant group differences were observed in self‐reported strategy use or difficulties in daily living. DISCUSSION Cognitive training provides long‐term benefits by mitigating memory decline and slowing clinical symptom progression in older adults with MCI. Highlights Cognitive training reduced the 5‐year memory decline of persons with MCI. Cognitive training also reduced decline on the Montreal Cognitive Assessment (MoCA). No intervention effect was found on strategy use or activities of daily living.

Introduction Healthcare gentrification is the process in which the distribution of healthcare resources within a neighbourhood affects residents' access to healthcare services. To understand the complexity of healthcare access and to consider the socio-structural dimensions affecting equity in access to care, we aim to explore how healthcare gentrification has been described in the scientific literature and to document the reported relations between gentrification and healthcare access.Methods and analysis We will conduct a scoping review from data published from inception to September 2024 based on the methodology developed by Arksey and O'Malley (2005) and improved by Levac et al (2010). We will search the following databases: MEDLINE (OVID), Embase (embase.com), CINAHL Plus with Full Text (EBSCO), Web of Science and Geobase (Engineering Village). The review will be conducted from February 2024 to September 2024. The search strategy will be elaborated in conjunction with a professional librarian. Screening of titles and abstracts and full-text screening will be done in duplicates. A third reviewer will arbitrate discrepancies during the screening process. We will present our results narratively.Ethics and dissemination This scoping review does not require ethical approval since it will be collected from publicly available documents. The results of this scoping review will also be presented as a scientific article, scientific conferences, research webinars also in social media, workshops and conferences organised by healthcare organisations or academic institutions or on any appropriate platform.

ABSTRACT: The aim of the current study was to investigate the potential of in ovo-fed amino acids (AA) to reduce the effects of heat stress on finishing broiler chickens. To achieve this, a total of 1,400 fertile hatching eggs were randomly distributed into 5 groups (n = 280/group) and injected with one of the following in ovo treatments on embryonic day 18: 52 µL of sterile diluent/egg (CTRL), CTRL + 1.0 mg of L-Leucine (T1), CTRL + 0.45 mg of leucine + 1.15 mg of methionine (T2), CTRL + 3.0 mg of methionine + 2.0 mg of cysteine (T3), and CTRL + 0.40 mg of leucine + 1.60 mg of methionine + 1.60 mg of cysteine (T4). After hatch, chicks were allocated according to a complete randomized block design comprising 2 thermal conditions: thermoneutral (24°C, 45% RH) and heat stress (34°C, 55–60% RH) with 5 pens/group/condition. The cyclical heat stress regimen (10 h/d) was then applied from d 29 to d 34. Compared to the CTRL group, T3 and T4 exhibited a higher BW during the starter phase (P < 0.001). T4 also had a lower feed conversion ratio (FCR) than CTRL during this same phase (P = 0.03). During the grower phase, males of all treatment groups consistently exhibited higher BW compared to the CTRL group, which was not observed among female birds (PSex × TRT = 0.005). During the finisher phase, the in ovo treatment effect on performance was not significant. However, heat-stressed birds from treatment group T3 and T4 exhibited lower facial temperatures (Pday × TRT < 0.001) as well as lower plasma (Pcondition x TRT = 0.039) and liver (Pcondition x TRT < 0.001) malonaldehyde concentrations compared to the CTRL group. In conclusion, in ovo-fed AA have the potential to modulate the effects of heat stress on finishing broiler chickens by limiting its detrimental consequences, including increased body temperature and oxidative damage.

Summary: Background: Research in healthy young adults shows that characteristic patterns of brain activity define individual “brain-fingerprints” that are unique to each person. However, variability in these brain-fingerprints increases in individuals with neurological conditions, challenging the clinical relevance and potential impact of the approach. Our study shows that brain-fingerprints derived from neurophysiological brain activity are associated with pathophysiological and clinical traits of individual patients with Parkinson’s disease (PD). Methods: We created brain-fingerprints from task-free brain activity recorded through magnetoencephalography in 79 PD patients and compared them with those from two independent samples of age-matched healthy controls (N = 424 total). We decomposed brain activity into arrhythmic and rhythmic components, defining distinct brain-fingerprints for each type from recording durations of up to 4 min and as short as 30 s. Findings: The arrhythmic spectral components of cortical activity in patients with Parkinson’s disease are more variable over short periods, challenging the definition of a reliable brain-fingerprint. However, by isolating the rhythmic components of cortical activity, we derived brain-fingerprints that distinguished between patients and healthy controls with about 90% accuracy. The most prominent cortical features of the resulting Parkinson’s brain-fingerprint are mapped to polyrhythmic activity in unimodal sensorimotor regions. Leveraging these features, we also demonstrate that Parkinson’s symptom laterality can be decoded directly from cortical neurophysiological activity. Furthermore, our study reveals that the cortical topography of the Parkinson’s brain-fingerprint aligns with that of neurotransmitter systems affected by the disease’s pathophysiology. Interpretation: The increased moment-to-moment variability of arrhythmic brain-fingerprints challenges patient differentiation and explains previously published results. We outline patient-specific rhythmic brain signaling features that provide insights into both the neurophysiological signature and symptom laterality of Parkinson’s disease. Thus, the proposed definition of a rhythmic brain-fingerprint of Parkinson’s disease may contribute to novel, refined approaches to patient stratification. Symmetrically, we discuss how rhythmic brain-fingerprints may contribute to the improved identification and testing of therapeutic neurostimulation targets. Funding: Data collection and sharing for this project was provided by the Quebec Parkinson Network (QPN), the Pre-symptomatic Evaluation of Novel or Experimental Treatments for Alzheimer’s Disease (PREVENT-AD; release 6.0) program, the Cambridge Centre for Aging Neuroscience (Cam-CAN), and the Open MEG Archives (OMEGA). The QPN is funded by a grant from Fonds de Recherche du Québec - Santé (FRQS). PREVENT-AD was launched in 2011 as a $13.5 million, 7-year public-private partnership using funds provided by McGill University, the FRQS, an unrestricted research grant from Pfizer Canada, the Levesque Foundation, the Douglas Hospital Research Centre and Foundation, the Government of Canada, and the Canada Fund for Innovation. The Brainstorm project is supported by funding to SB from the NIH (R01-EB026299-05). Further funding to SB for this study included a Discovery grant from the Natural Sciences and Engineering Research Council of Canada of Canada (436355-13), and the CIHR Canada research Chair in Neural Dynamics of Brain Systems (CRC-2017-00311).

The QCD axion is a leading dark matter candidate that emerges as part of the solution to the strong CP problem in the Standard Model. The coupling of the axion to photons is the most common experimental probe, but much parameter space remains unexplored. The coupling of the QCD axion to the Standard Model scales linearly with the axion mass; therefore, the highly motivated region 0.4-120 neV, corresponding to a GUT-scale axion, is particularly difficult to reach. This paper presents the design requirements for a definitive search for GUT-scale axions and reviews the technological advances needed to enable this program.

The Cryogenic Underground Observatory for Rare Events (CUORE) is the first cryogenic experiment searching for 0 νββ decay that has been able to reach the one-tonne mass scale. The detector, located at the Laboratori Nazionali del Gran Sasso (LNGS) in Italy, consists of an array of 988 TeO 2 crystals arranged in a compact cylindrical structure of 19 towers. CUORE began its first physics data run in 2017 at a base temperature of about 10 mK and in April 2021 released its 3 rd result of the search for 0 νββ, corresponding to a tonne-year of TeO 2 exposure. This is the largest amount of data ever acquired with a solid state detector and the most sensitive measurement of 0 νββ decay in 130Te ever conducted. We present the current status of CUORE search for 0 νββ with the updated statistics of one tonne-yr. We finally give an update of the CUORE background model and the measurement of the 130Te 2 νββ decay half-life and decay to excited states of 130Xe , studies performed using an exposure of 300.7 kg yr.

The CUORE experiment is a ton-scale array of TeO 2 cryogenic bolometers located at the underground Laboratori Nazionali del Gran Sasso of Istituto Nazionale di Fisica Nucleare (INFN), in Italy. The CUORE detector consists of 988 crystals operated as source and detector at a base temperature of ∼ 10 mK. Such cryogenic temperature is reached and maintained by means of a custom built cryogen-free dilution cryostat, designed with the aim of minimizing the vibrational noise and the environmental radioactivity. The primary goal of CUORE is the search for neutrinoless double beta decay of 130Te , but thanks to its large target mass and ultra-low background it is suitable for the study of other rare processes as well, such as the neutrinoless double beta decay of 128Te. This tellurium isotope is an attractive candidate for the search of this process, due to its high natural isotopic abundance of 31.75%. The transition energy at (866.7 ± 0.7) keV lies in a highly populated region of the energy spectrum, dominated by the contribution of the two-neutrino double beta decay of 130Te. As the first ton-scale infrastructure operating cryogenic TeO 2 bolometers in stable conditions, CUORE is able to achieve a factor > 10 higher sensitivity to the neutrinoless double beta decay of this isotope with respect to past direct experiments.

The Cryogenic Underground Observatory for Rare Events (CUORE) at Laboratori Nazionali del Gran Sasso of INFN in Italy is an experiment searching for neutrinoless double beta (0νββ) decay. Its main goal is to investigate this decay in ^{130}Te, but its ton-scale mass and low background make CUORE sensitive to other rare processes as well. In this Letter, we present our first results on the search for 0νββ decay of ^{128}Te, the Te isotope with the second highest natural isotopic abundance. We find no evidence for this decay, and using a Bayesian analysis we set a lower limit on the ^{128}Te 0νββ decay half-life of T_{1/2}>3.6×10^{24}  yr (90% CI). This represents the most stringent limit on the half-life of this isotope, improving by over a factor of 30 the previous direct search results, and exceeding those from geochemical experiments for the first time.

The Cryogenic Underground Observatory for Rare Events (CUORE) is the most sensitive experiment searching for neutrinoless double-beta decay (0νββ) in 130Te. CUORE uses a cryogenic array of 988 TeO2 calorimeters operated at ∼10 mK with a total mass of 741 kg. To further increase the sensitivity, the detector response must be well understood. Here, we present a non-linear thermal model for the CUORE experiment on a detector-by-detector basis. We have examined both equilibrium and dynamic electro-thermal models of detectors by numerically fitting non-linear differential equations to the detector data of a subset of CUORE channels which are well characterized and representative of all channels. We demonstrate that the hot-electron effect and electric-field dependence of resistance in NTD-Ge thermistors alone are inadequate to describe our detectors' energy-dependent pulse shapes. We introduce an empirical second-order correction factor in the exponential temperature dependence of the thermistor, which produces excellent agreement with energy-dependent pulse shape data up to 6 MeV. We also present a noise analysis using the fitted thermal parameters and show that the intrinsic thermal noise is negligible compared to the observed noise for our detectors.

We report the results of a search for MeV-scale astrophysical neutrinos in KamLAND presented as an excess in the number of coincident neutrino interactions associated with the publicly available high-energy neutrino datasets from the IceCube Neutrino Observatory. We find no statistically significant excess in the number of observed low-energy electron antineutrinos in KamLAND, given a coincidence time window of ±500 s, ±1,000 s, ±3,600 s, and ±10,000 s around each of the IceCube neutrinos. We use this observation to present limits from 1.8 MeV to 100 MeV on the electron antineutrino fluence, assuming a mono-energetic flux. We then compare the results to several astrophysical measurements performed by IceCube and place a limit at the 90% confidence level on the electron antineutrino isotropic thermal luminosity from the TXS 0506+056 blazar.

Abstract Malignancy grading of prostate cancer (PCa) is fundamental for risk stratification, patient counseling, and treatment decision-making. Deep learning has shown potential to improve the expert consensus for tumor grading, which relies on the Gleason score/grade grouping. However, the core problem of interobserver variability for the Gleason grading system remains unresolved. We developed a novel grading system for PCa and utilized artificial intelligence (AI) and multi-institutional international datasets from 2647 PCa patients treated with radical prostatectomy with a long follow-up of ≥10 years for biochemical recurrence and cancer-specific death. Through survival analyses, we evaluated the novel grading system and showed that AI could develop a tumor grading system with four risk groups independent from and superior to the current five grade groups. Moreover, AI could develop a scoring system that reflects the risk of castration resistant PCa in men who have experienced biochemical recurrence. Thus, AI has the potential to develop an effective grading system for PCa interpretable by human experts.

Abstract Background Patient-reported outcome and experience measures (PROMs and PREMs, respectively) are evidence-based, standardized questionnaires that can be used to capture patients’ perspectives of their health and health care. While substantial investments have been made in the implementation of PROMs and PREMs, their use remains fragmented and limited in many settings. Analysis of multi-level barriers and enablers to the implementation of PROMs and PREMs has been hampered by the lack of use of state-of-the-art implementation science frameworks. This umbrella review aims to consolidate available evidence from existing quantitative, qualitative, and mixed-methods systematic and scoping reviews covering factors that influence the implementation of PROMs and PREMs in healthcare settings. Methods An umbrella review of systematic and scoping reviews will be conducted following the guidelines of the Joanna Briggs Institute (JBI). Qualitative, quantitative, and mixed methods reviews of studies focusing on the implementation of PROMs and/or PREMs in all healthcare settings will be considered for inclusion. Eight bibliographical databases will be searched. All review steps will be conducted by two reviewers independently. Included reviews will be appraised and data will be extracted in four steps: (1) assessing the methodological quality of reviews using the JBI Critical Appraisal Checklist; (2) extracting data from included reviews; (3) theory-based coding of barriers and enablers using the Consolidated Framework for Implementation Research (CFIR) 2.0; and (4) identifying the barriers and enablers best supported by reviews using the Grading of Recommendations Assessment, Development and Evaluation-Confidence in the Evidence from Reviews of Qualitative research (GRADE-CERQual) approach. Findings will be presented in diagrammatic and tabular forms in a manner that aligns with the objective and scope of this umbrella review, along with a narrative summary. Discussion This umbrella review of quantitative, qualitative, and mixed-methods systematic and scoping reviews will inform policymakers, researchers, managers, and clinicians regarding which factors hamper or enable the adoption and sustained use of PROMs and PREMs in healthcare settings, and the level of confidence in the evidence supporting these factors. Findings will orient the selection and adaptation of implementation strategies tailored to the factors identified. Systematic review registration PROSPERO CRD42023421845.

Playful approaches are recommended to enhance wheelchair skills training with young people. Inclusive dance allows participants to discover motor skills and improve social participation. Integrating wheelchair skills training into dance has not been evaluated. This study aimed to explore participants’ experiences in dance while integrating wheelchair skills, and the influence of dance on wheelchair skills and wheelchair use confidence in young people. A convergent mixed-methods design was used during a one-week dance camp. Data collection combined observations, two focus groups (with young dancers who used manual wheelchairs and with professional dancers without disabilities), and evaluation of wheelchair skills and confidence. Data analyses included deductive thematic analysis guided by the Quality Parasport Participation Framework, merged with pre–post comparisons in wheelchair skills and confidence. Three young female dancers were 11, 12 and 15 years of age and three professional female dancers were 22, 27 and 27 years of age. Emergent themes included skill mastery, belongingness, and supportive environments. There were improvements in wheelchair skills and confidence (16.7%, 19.4%, 16.7%; 0.8%, 11.4%, 4.5%, respectively). Participants described overall positive experiences with the dance camp and perceived enhanced skills and confidence. This study advances knowledge about innovative approaches to integrate wheelchair skills training for young people. Future larger-scale controlled studies are needed to determine efficacy.

ABSTRACT: Heat stress (HS) impedes cattle behavior and performance and is an animal comfort and welfare issue. The objective of this study was to characterize the time budget and circadian rhythm of lying behavior in dairy cows during HS and to assess the effect of dietary supplementation of vitamin D3 and Ca. Twelve multiparous Holstein cows (42.2 ± 5.6 kg milk/d; 83 ± 27 d in milk) housed in tiestalls were used in a split-plot design with the concentration of dietary vitamin E and Se as main plots (LESe: 11.1 IU/kg and 0.55 mg/kg, and HESe: 223 IU/kg and 1.8 mg/kg, respectively). Within each plot cows were randomly assigned to (1) HS with low concentrations of vitamin D3 and Ca (HS, 1,012 IU/kg and 0.73%, respectively), (2) HS with high concentrations of vitamin D3 and Ca (HS+D3/Ca; 3,764 IU/kg and 0.97%, respectively), or (3) thermoneutral pair-fed (TNPF) with low concentrations of vitamin D3 and Ca (1,012 IU/kg and 0.73%, respectively) in a Latin square design with 14-d periods and 7-d washouts. Lying behavior was measured with HOBO Loggers in 15-min intervals. Overall, cows in HS spent less time lying per day relative to TNPF from d 7 to 14. Daily lying time was positively correlated with milk yield, energy-corrected milk yield, and feed efficiency, and was negatively correlated with rectal temperature, respiratory rate, fecal calprotectin, tumor necrosis factor-α, and C-reactive protein. A treatment by time interaction was observed for lying behavior: the time spent lying was lesser for cows in HS than in TNPF in the early morning (0000–0600 h) and in the night (1800–2400 h). The circadian rhythm of lying behavior was characterized by fitting a cosine function of time into linear mixed model. Daily rhythmicity of lying was detected for cows in TNPF and HS+D3/Ca, whereas only a tendency in HS cows was observed. Cows in TNPF had the highest mesor (the average level of diurnal fluctuations; 34.2 min/h) and amplitude (the distance between the peak and mesor; 17.9 min/h). Both the mesor and amplitude were higher in HS+D3/Ca relative to HS (26.6 vs. 25.2 min/h and 3.91 min/h vs. 2.18 min/h, respectively). The acrophase (time of the peak) of lying time in TNPF, HS, and HS+D3/Ca were 0028, 0152, and 0054 h, respectively. Lastly, a continuous increase in daily lying time in TNPF was observed during the first 4 d of the experimental period in which DMI was gradually restricted, suggesting that intake restrictions may shift feeding behavior and introduce biases in the behavior of animals. In conclusion, lying behavior was compromised in dairy cows under HS, characterizing reduced daily lying time and disrupted circadian rhythms, and the compromised lying behavior can be partially restored by supplementation of vitamin D3 and Ca. Further research may be required for a more suitable model to study behavior of cows under HS.

Forest Day de Larrañaga,1,2 Alexandre Joubert,3 Isabelle Drouin,3 Isabelle Ouellet,3 Pei Zhi Li,1 Bryan A Ross,1– 3 Carolyn J Baglole,1,2 Jean Bourbeau1– 3 1Research Institute of McGill University Health Centre, Montreal, Quebec, Canada; 2Department of Medicine, Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada; 3COPD Clinic, McGill University Health Centre, Montreal, Quebec, CanadaCorrespondence: Jean Bourbeau, Respiratory Epidemiology and Clinical Research Unit, Research Institute of the McGill University Health Centre, 5252 De Maisonneuve, room 3D.62, Montreal, QC, H4A 3S5, Canada, Email jean.bourbeau@mcgill.caIntroduction: We describe the use of anti-IL-5 monoclonal antibodies from a COPD clinic, a source other than traditional clinical trials. The objectives were to characterize the patient subgroup prescribed anti-IL-5 monoclonal antibodies and to report potential benefits.Methods: This is a retrospective case series study of 17 patients treated in a COPD subspecialty clinic. All patients had a diagnosis of COPD (post-bronchodilator FEV1/FVC < 0.7) and had been prescribed an anti-IL-5 biologic for at least 8 months. Acute exacerbations of COPD (AECOPDs) were collected as reported in electronic medical records.Results: All patients (17) enrolled were treated with biologics for ≥ 8 months, and 13 (76%) for ≥ 1 year. Patients were characterized by severe disease traits, FEV1 < 50% predicted, recurrent exacerbations (3.5 moderate-to-severe AECOPDs in the year before treatment), high peripheral blood eosinophil counts (≥ 250 cells/μL in the previous year), all on inhaled triple therapy, and only 1 patient with a diagnosis of asthma prior to smoking. There was a statistically significant decrease in the exacerbation rate compared with baseline after 8 and 12 months of anti-IL-5 treatment, respectively, yielding the equivalent of a 2– 3x reduction in exacerbation rate. Absolute FEV1 decreased, and the decline in FEV1 % of predicted reached statistical significance (p< 0.05); CAT score improved (p< 0.05).Discussion: This real-world evidence data aligns with existing studies suggesting the potential benefit of anti-IL-5 treatment for specific patients with COPD and therefore advocates for further investigation of RCTs on the use of anti-IL-5 biologics for well-characterized patients with COPD.Keywords: COPD, biologics, anti-IL5 therapy, blood eosinophil count, RWE, RWD