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Abstract Background Adult day programs aim to facilitate aging in place by supporting the health and well-being of persons with dementia and providing respite to their caregivers. However, studies on the effects of day programs are inconclusive, and we especially lack insights into the context conditions and mechanisms of day programs that may produce different outcomes for different groups of persons with dementia and their caregivers. Our objective was to conduct a realist review, synthesizing research on day programs to develop program theories explaining how and why day programs do or do not produce positive or negative outcomes for different groups of persons with dementia, and caregivers. Methods We identified 14 literature reviews (including 329 references published between 1975 and 2021) on adult day programs. From this initial pool of studies, we will include those that focused on day program attendees with dementia or meaningful cognitive impairment, and/or their caregivers, and that report how day program contexts (C) and mechanisms (M) bring about outcomes (O) for attendees and caregivers. We will extract CMO statements (i.e., narratives that explain how and why day programs do or do not bring about certain outcomes for whom and under what circumstances). Using additional focused searches, citation mapping, citation tracking, and discussions with our researcher and expert team members, we will identify additional references. CMO statements will be synthesized, transformed into hypotheses, and linked and visualized to form program theories. Using focus groups and the James Lind Alliance Priority Setting Partnership method, we will discuss and prioritize our CMO statements and refine our program theories with 32 experts (older adults, caregivers, Alzheimer societies, caregiver organizations, day program staff and managers, and health system and policy decision makers). Discussion By identifying essential elements and processes of day programs and related knowledge gaps, this study will generate much-needed knowledge to leverage the full potential of day programs so they can provide appropriate care, preventing premature institutionalization, and unnecessary acute and primary care use. This will ultimately improve the quality of life of persons with dementia and their caregivers, alleviate caregiver burden, and reduce social costs. Systematic review registration PROSPERO CRD42024504030

Abstract Background Assisted living (AL) is an increasingly common residential setting for persons with dementia; yet concerns exist about sub-optimal care of this population in AL given its lower levels of staffing and services. Our objectives were to (i) examine associations between AL setting (dementia care vs. other), COVID-19 pandemic waves, and prevalent antipsychotic, antidepressant, anti-dementia, benzodiazepine, and anticonvulsant drug use among residents with dementia/cognitive impairment, and (ii) explore associations between resident and home characteristics and prevalent medication use. Methods We conducted a population-based, repeated cross-sectional study using linked clinical and health administrative databases for all publicly funded AL homes in Alberta, Canada, examined between January 2018 - December 2021. The quarterly proportion of residents dispensed a study medication was examined for each setting and period (pandemic vs. comparable historical [2018/2019 combined]) focusing on four pandemic waves (March-May 2020, September 2020-February 2021, March-May 2021, September-December 2021). Log-binomial GEE models estimated prevalence ratios (PR) for period (pandemic vs. historical periods), setting (dementia care vs. other) and period-setting interactions, adjusting for resident (age, sex) and home (COVID-19 cases, health region, ownership) characteristics. Results On March 1, 2020, there were 2,779 dementia care and 3,013 other AL residents (mean age 83, 69% female) with dementia/cognitive impairment. Antipsychotic use increased during waves 2–4 in both settings, but this was more pronounced in dementia care than other AL during waves 3 and 4 (e.g., adjusted [adj]PR 1.20, 95% CI 1.14–1.27 vs. adjPR 1.09, 95% CI 1.02–1.17, interaction p = 0.023, wave 3). Both settings showed a statistically significant but modest increase in antidepressant use and decrease in benzodiazepine use. For dementia care AL residents only, there was a statistically significant increase in gabapentinoid use during several waves (e.g., adjPR 1.32, 95% CI 1.10–1.59, wave 3). Other than a modest decrease in prevalent anti-dementia drug use for both settings in wave 2, no other significant pandemic effects were observed. Conclusions The persistence of the pandemic-associated increase in antipsychotic and antidepressant use in AL residents coupled with a greater increase in antipsychotic and gabapentinoid use for dementia care settings raises concerns about the attendant risks for residents with cognitive impairment.

A key issue in landscape management, whether public or private, is the mitigation of disturbance events that impact vegetation, ecosystem health, and thus ecosystem services (ESs). Although many studies have found significant tree mortality due to insect infestations, there is still insufficient understanding of how these infestations alter ESs and their associated economic values. Addressing this research gap can assist forest managers and decision-makers in refining and implementing adaptive management practices and policies, while enhancing the resilience of forests and their ESs. We investigated the impacts of bark beetle outbreaks on three ESs (timber provisioning, water retention, and carbon sequestration) in the Lake Tahoe region of Northern California and Northern Nevada. Using the landscape simulation model LANDIS-II, we examined differences between a business-as-usual management scenario and an enhanced management scenario with respect to the amount of aboveground tree biomass and ESs impacted by beetle outbreaks. Since insect infestation is also influenced by climate, each of the two management scenarios considered three different climate scenarios: a scenario with average historical climate (no climate change); a warmer, wetter scenario from the Model for Interdisciplinary Research on Climate (MIROC); and a hotter, drier scenario from the Centre National de Recherches Météorologiques (CNRM). Results show that a warmer and drier climate results in more beetle mortality than a wetter and cooler climate, resulting in greater negative impacts to ESs. The estimated loss of ES value is approximately $0.2 to $0.8 million USD per year. Enhanced management is more capable than business-as-usual practices to prevent beetle damages to trees and ESs.

Toll-like receptor (TLR) innate immunity signalling protects against pathogens, but excessive or prolonged signalling contributes to a range of inflammatory conditions. Structural information on the TLR cytoplasmic TIR (Toll/interleukin-1 receptor) domains and the downstream adaptor proteins can help us develop inhibitors targeting this pathway. The small molecule o-vanillin has previously been reported as an inhibitor of TLR2 signalling. To study its mechanism of action, we tested its binding to the TIR domain of the TLR adaptor MAL/TIRAP (MALTIR). We show that o-vanillin binds to MALTIR and inhibits its higher-order assembly in vitro. Using NMR approaches, we show that o-vanillin forms a covalent bond with lysine 210 of MAL. We confirm in mouse and human cells that o-vanillin inhibits TLR2 but not TLR4 signalling, independently of MAL, suggesting it may covalently modify TLR2 signalling complexes directly. Reactive aldehyde-containing small molecules such as o-vanillin may target multiple proteins in the cell.

Objectives Individual risk factors for dementia are well known, but the influence of co-occurring chronic conditions has not been considered. We identified clusters of chronic conditions using an unsupervised machine learning approach and examined associations with incident dementia. Approach Using linked population-based administrative databases, we followed all community-dwelling adults aged 40-54 years in Ontario, Canada from April 2002 until March 2019 for incident dementia. We estimated the prevalence of 29 chronic conditions using validated algorithms and/or diagnosis codes. We reduced dataset dimensionality using multiple correspondence analysis and a fuzzy c-means clustering algorithm identified the optimal number of clusters (between 3-6 tested). Associations between clusters and incident dementia were examined using a cause-specific hazard model adjusted for sociodemographic characteristics and accounting for the competing risk of death. Results We identified 82,359 eligible individuals (random 3% sample of total eligible individuals; mean age 46.5 years; 50.4% female). Regression analyses were based on 5 comorbidity clusters (fuzzy silhouette index:0.69). Compared to the low comorbidity cluster, persons in the cerebrovascular disease/metabolic (HRadj=3.06, 95%CI[2.42,3.86]) and neuro-related/mental health clusters (HRadj=2.51, 95%CI[2.05,3.07]) had the highest rates of incident dementia, followed by the cardiovascular risk factor cluster (HRadj=1.66,95%CI[1.32,2.09]). Persons in the cancer cluster did not have an increased incidence of dementia (HRadj=0.96,95%CI[0.77,1.20]). Conclusions We found significant associations between machine learning-derived clusters of chronic conditions and dementia. Implications Unsupervised machine learning approaches to identify clusters of chronic conditions may be a useful tool for considering the impact of multimorbidity on dementia risk.

BackgroundAdult day programs provide critical supports to older adults and their family or friend caregivers. High-quality care in the community for as long as possible and minimizing facility-based continuing care are key priorities of older adults, their caregivers, and health care systems. While most older adults in need of care live in the community, about 10% of newly admitted care home residents have relatively low care needs that could be met in the community with the right supports. However, research on the effects of day programs is inconsistent. The methodological quality of studies is poor, and we especially lack robust, longitudinal research. ObjectiveOur research objectives are to (1) compare patterns of day program use (including nonuse) by province (Alberta, British Columbia, and Manitoba) and time; (2) compare characteristics of older adults by day program use pattern (including nonuse), province, and time; and (3) assess effects of day programs on attendees, compared with a propensity score–matched cohort of older nonattendees in the community. MethodsIn this population-based retrospective cohort study, we will use clinical and health administrative data of older adults (65+ years of age) who received publicly funded continuing care in the community in the Canadian provinces of Alberta, British Columbia, and Manitoba between January 1, 2012, and December 31, 2024. We will compare patterns of day program use between provinces and assess changes over time. We will then compare characteristics of older adults (eg, age, sex, physical or cognitive disability, area-based deprivation indices, and caregiver availability or distress) by pattern of day program use or nonuse, province, and time. Finally, we will create a propensity score–matched comparison group of older adults in the community, who have not attended a day program. Using time-to-event models and general estimating equations, we will assess whether day program attendees compared with nonattendees enter care homes later; use emergency, acute, or primary care less frequently; experience less cognitive and physical decline; and have better mental health. ResultsThis will be a 3-year study (July 1, 2024, to June 30, 2027). We received ethics approvals from the relevant ethics boards. Starting on July 1, 2024, we will work with the 3 provincial health systems on data access and linkage, and we expect data analyses to start in early 2025. ConclusionsThis study will generate robust Canadian evidence on the question whether day programs have positive, negative, or no effects on various older adult and caregiver outcomes. This will be a prerequisite to improving the quality of care provided to older adults in day programs, ultimately improving the quality of life of older adults and their caregivers. Trial RegistrationClinicalTrials.gov NCT06440447; https://clinicaltrials.gov/study/NCT06440447 International Registered Report Identifier (IRRID)PRR1-10.2196/60896

Abstract Background Positron emission tomography–magnetic resonance (PET-MR) attenuation correction is challenging because the MR signal does not represent tissue density and conventional MR sequences cannot image bone. A novel zero echo time (ZTE) MR sequence has been previously developed which generates signal from cortical bone with images acquired in 65 s. This has been combined with a deep learning model to generate a synthetic computed tomography (sCT) for MR-only radiotherapy. This study aimed to evaluate this algorithm for PET-MR attenuation correction in the pelvis. Methods Ten patients being treated with ano-rectal radiotherapy received a $$^{18}$$ 18 F-FDG-PET-MR in the radiotherapy position. Attenuation maps were generated from ZTE-based sCT (sCTAC) and the standard vendor-supplied MRAC. The radiotherapy planning CT scan was rigidly registered and cropped to generate a gold standard attenuation map (CTAC). PET images were reconstructed using each attenuation map and compared for standard uptake value (SUV) measurement, automatic thresholded gross tumour volume (GTV) delineation and GTV metabolic parameter measurement. The last was assessed for clinical equivalence to CTAC using two one-sided paired t tests with a significance level corrected for multiple testing of $$p \le 0.05/7 = 0.007$$ p ≤ 0.05 / 7 = 0.007 . Equivalence margins of $$\pm 3.5\%$$ ± 3.5 % were used. Results Mean whole-image SUV differences were −0.02% (sCTAC) compared to −3.0% (MRAC), with larger differences in the bone regions (−0.5% to −16.3%). There was no difference in thresholded GTVs, with Dice similarity coefficients $$\ge 0.987$$ ≥ 0.987 . However, there were larger differences in GTV metabolic parameters. Mean differences to CTAC in $${\mathrm {SUV}}_{\max}$$ SUV max were $$1.0 \pm 0.8\%$$ 1.0 ± 0.8 % (± standard error, sCTAC) and $$-4.6 \pm 0.9\%$$ - 4.6 ± 0.9 % (MRAC), and $$1.0 \pm 0.7\%$$ 1.0 ± 0.7 % (sCTAC) and $$-4.3 \pm 0.8\%$$ - 4.3 ± 0.8 % (MRAC) in $${\mathrm {SUV}}_{\rm mean}$$ SUV mean . The sCTAC was statistically equivalent to CTAC within a $$\pm 3.5\%$$ ± 3.5 % equivalence margin for $${\mathrm {SUV}}_{\max}$$ SUV max and $${\mathrm {SUV}}_{\rm mean}$$ SUV mean ( $$p = 0.007$$ p = 0.007 and $$p = 0.002$$ p = 0.002 ), whereas the MRAC was not ( $$p = 0.88$$ p = 0.88 and $$p = 0.83$$ p = 0.83 ). Conclusion Attenuation correction using this radiotherapy ZTE-based sCT algorithm was substantially more accurate than current MRAC methods with only a 40 s increase in MR acquisition time. This did not impact tumour delineation but did significantly improve the accuracy of whole-image and tumour SUV measurements, which were clinically equivalent to CTAC. This suggests PET images reconstructed with sCTAC would enable accurate quantitative PET images to be acquired on a PET-MR scanner.

Abstract Background Involving collaborators and partners in research may increase relevance and uptake, while reducing health and social inequities. Collaborators and partners include people and groups interested in health research: health care providers, patients and caregivers, payers of health research, payers of health services, publishers, policymakers, researchers, product makers, program managers, and the public. Evidence syntheses inform decisions about health care services, treatments, and practice, which ultimately affect health outcomes. Our objectives are to: A. Identify, map, and synthesize qualitative and quantitative findings related to engagement in evidence syntheses B. Explore how engagement in evidence synthesis promotes health equity C. Develop equity-oriented guidance on methods for conducting, evaluating, and reporting engagement in evidence syntheses Methods Our diverse, international team will develop guidance for engagement with collaborators and partners throughout multiple sequential steps using an integrated knowledge translation approach: 1. Reviews. We will co-produce 1 scoping review, 3 systematic reviews and 1 evidence map focusing on (a) methods, (b) barriers and facilitators, (c) conflict of interest considerations, (d) impacts, and (e) equity considerations of engagement in evidence synthesis. 2. Methods study, interviews, and survey. We will contextualise the findings of step 1 by assessing a sample of evidence syntheses reporting on engagement with collaborators and partners and through conducting interviews with collaborators and partners who have been involved in producing evidence syntheses. We will use these findings to develop draft guidance checklists and will assess agreement with each item through an international survey. 3. Consensus. The guidance checklists will be co-produced and finalised at a consensus meeting with collaborators and partners. 4. Dissemination. We will develop a dissemination plan with our collaborators and partners and work collaboratively to improve adoption of our guidance by key organizations. Conclusion Our international team will develop guidance for collaborator and partner engagement in health care evidence syntheses. Incorporating partnership values and expectations may result in better uptake, potentially reducing health inequities.

Abstract Background Understanding healthcare professionals' (HCPs) experiences of caring for women with false‐positive screening test results in the National Health Service Breast Screening Programme (NHSBSP) is important for reducing the impact of such results. Methods Interviews were undertaken with 12 HCPs from a single NHSBSP unit, including advanced radiographer practitioners, breast radiographers, breast radiologists, clinical nurse specialists (CNSs), and a radiology healthcare assistant. Data were analysed thematically using Template Analysis. Results Two themes were produced: (1) Gauging and navigating women's anxiety during screening assessment was an inevitable and necessary task for all participants. CNSs were perceived as particularly adept at this, while breast radiographers reported a lack of adequate formal training. (2) Controlling the delivery of information to women (including amount, type and timing of information). HCPs reported various communication strategies to facilitate women's information processing and retention during a distressing time. Conclusions Women's anxiety could be reduced through dedicated CNS support, but this should not replace support from other HCPs. Breast radiographers may benefit from more training to emotionally support recalled women. While HCPs emphasised taking a patient‐centred communication approach, the use of other strategies (e.g., standardised scripts) and the constraints of the ‘one‐stop shop’ model pose challenges to such an approach. Patient and Public Contribution During the study design, two Patient and Public Involvement members (women with false‐positive‐breast screening test results) were consulted to gain an understanding of patient perspectives and experiences of being recalled specifically in the NHSBSP. Their feedback informed the formulations of the research aim, objectives and the direction of the interview guide.

Abstract Group heteroscedasticity is commonly observed in pseudo-bulk single-cell RNA-seq datasets and its presence can hamper the detection of differentially expressed genes. Since most bulk RNA-seq methods assume equal group variances, we introduce two new approaches that account for heteroscedastic groups, namely voomByGroup and voomWithQualityWeights using a blocked design (voomQWB). Compared to current gold-standard methods that do not account for group heteroscedasticity, we show results from simulations and various experiments that demonstrate the superior performance of voomByGroup and voomQWB in terms of error control and power when group variances in pseudo-bulk single-cell RNA-seq data are unequal.

Abstract Background Intact cognitive function is crucial for healthy aging. Functional social support is thought to protect against cognitive decline. We conducted a systematic review to investigate the association between functional social support and cognitive function in middle- and older-aged adults. Methods Articles were obtained from PubMed, PsycINFO, Sociological Abstracts, CINAHL, and Scopus. Eligible articles considered any form of functional social support and cognitive outcome. We narratively synthesized extracted data by following the Synthesis Without Meta-Analysis (SWiM) guidelines and assessed risk of bias using the Newcastle–Ottawa Scale (NOS). Results Eighty-five articles with mostly low risk-of-bias were included in the review. In general, functional social support—particularly overall and emotional support—was associated with higher cognitive function in middle- and older-aged adults. However, these associations were not all statistically significant. Substantial heterogeneity existed in the types of exposures and outcomes evaluated in the articles, as well as in the specific tools used to measure exposures and outcomes. Conclusions Our review highlights the role of functional social support in the preservation of healthy cognition in aging populations. This finding underscores the importance of maintaining substantive social connections in middle and later life. Systematic review registration Rutter EC, Tyas SL, Maxwell CJ, Law J, O'Connell ME, Konnert CA, Oremus M. Association between functional social support and cognitive function in middle-aged and older adults: a protocol for a systematic review. BMJ Open;10(4):e037301. https://doi.org/10.1136/bmjopen-2020-037301

To help educators deliver their physiology laboratory courses remotely, we developed an inexpensive, customizable hardware kit along with freely available teaching resources. We based the course design on four principles that should allow students to conduct insightful experiments on different physiological systems. First, the experimental setup should not be constrained to laboratory environments. Second, students should be able to take this course without prior coding and electronics experience. Third, the hardware kit should be relatively inexpensive, and all other resources should be freely available. Fourth, all resources should be customizable for educators. The hardware kit consists of commercially available electronic components, with a microcontroller as its hub (Arduino friendly). All measurement systems can be assembled without soldering. The hardware kit is cost-effective (approximately the cost of a textbook) and can be customized depending upon instructional needs. All software is freely available, and we share all necessary codes in open-access online repositories for simple use and customizability. All lab manuals and additional video tutorials are also freely available online and customizable. In our particular course, we have weekly asynchronous physiology lectures and one synchronous laboratory session, where students can get help with their equipment. In this article, we only focus on the novel and open-source laboratory part of the course. The laboratory includes four units [data acquisition, ECG, electromyography (EMG), activity classification] and one final project. It is our intent that these resources will allow other educators to rapidly implement their own remote physiology laboratories or to extend our work into other pedagogical applications of wearable technology.

Insect toxins with tandem repeats of neurotoxin domains have been found with enhanced receptor avidity. Here, the authors describe a bivalent toxin from remipede venom that targets ryanodine receptors, a rare target for animal venoms.

Abstract Background Foot and ankle involvement is common in rheumatic and musculoskeletal diseases (RMDs). High-quality evidence is lacking to determine the effectiveness of treatments for these disorders. Heterogeneity in the outcomes used across clinical trials and observational studies hinders the ability to compare findings, and some outcomes are not always meaningful to patients and end-users. The Core set of Outcome Measures for FOot and ankle disorders in RheumaTic and musculoskeletal diseases (COMFORT) study aims to develop a core outcome set (COS) for use in all trials of interventions for foot and ankle disorders in RMDs. This protocol addresses core outcome domains (what to measure) only. Future work will focus on core outcome measurement instruments (how to measure). Methods COMFORT: Core Domain Set is a mixed-methods study involving the following: (i) identification of important outcome domains through literature reviews, qualitative interviews and focus groups with patients and (ii) prioritisation of domains through an online, modified Delphi consensus study and subsequent consensus meeting with representation from all stakeholder groups. Findings will be disseminated widely to enhance uptake. Conclusions This protocol details the development process and methodology to identify and prioritise domains for a COS in the novel area of foot and ankle disorders in RMDs. Future use of this standardised set of outcome domains, developed with all key stakeholders, will help address issues with outcome variability. This will facilitate comparing and combining study findings, thus improving the evidence base for treatments of these conditions. Future work will identify suitable outcome measurement instruments for each of the core domains. Trial registration This study is registered with the Core Outcome Measures in Effectiveness Trials (COMET) database, as of June 2022: https://www.comet-initiative.org/Studies/Details/2081

X-ray photoelectron spectroscopy probes the chemical environment in a molecule at a specific atomic site. Here the authors extend this concept with a site selective trigger to follow chemical bond changes as they occur on the femtosecond time scale.

The paramagnetism of a lanthanoid tag site-specifically installed on a protein provides a rich source of structural information accessible by nuclear magnetic resonance (NMR) and electron paramagnetic resonance (EPR) spectroscopy. Here we report a lanthanoid tag for selective reaction with cysteine or selenocysteine with formation of a (seleno)thioether bond and a short tether between the lanthanoid ion and the protein backbone. The tag is assembled on the protein in three steps, comprising (i) reaction with 4-fluoro-2,6-dicyanopyridine (FDCP); (ii) reaction of the cyano groups with α-cysteine, penicillamine or β-cysteine to complete the lanthanoid chelating moiety; and (iii) titration with a lanthanoid ion. FDCP reacts much faster with selenocysteine than cysteine, opening a route for selective tagging in the presence of solvent-exposed cysteine residues. Loaded with Tb3+ and Tm3+ ions, pseudocontact shifts were observed in protein NMR spectra, confirming that the tag delivers good immobilisation of the lanthanoid ion relative to the protein, which was also manifested in residual dipolar couplings. Completion of the tag with different 1,2-aminothiol compounds resulted in different magnetic susceptibility tensors. In addition, the tag proved suitable for measuring distance distributions in double electron–electron resonance experiments after titration with Gd3+ ions.

Abstract Background Family and friend caregivers play significant roles in advocating for and ensuring quality health and social care of residents in Assisted Living (AL) homes. However, little is known about how the COVID-19 pandemic and related visitor restrictions affected their health and mental well-being. We examined the prevalence and correlates of anxiety and depressive symptoms among caregivers of AL residents during the initial wave of COVID-19 in two Canadian provinces. Methods A cross-sectional web-based survey was conducted among family/friend caregivers of AL residents in Alberta and British Columbia (Oct 28, 2020—Mar 31, 2021) to collect data on their sociodemographic, health and caregiving characteristics, as well as concerns about residents’ health and social care before and during the first wave of the pandemic. A clinically significant anxiety disorder and depressive symptoms were assessed with the GAD-7 and CES-D10 instruments, respectively. Separate multivariable (modified) Poisson regression models identified caregiver correlates of each mental health condition. Results Among the 673 caregivers completing the survey (81% for Alberta residents), most were women (77%), white (90%) and aged ≥ 55 years (81%). Clinically significant anxiety and depression were present in 28.6% and 38.8% of caregivers respectively. Both personal stressors (comorbidity level, income reduction, low social support) and caregiving stressors exacerbated by the pandemic were independently associated with caregiver anxiety and depression. The latter included increased concern about the care recipients’ depression (adjusted risk ratio [adjRR] = 1.84, 95% confidence interval [CI] 1.19–2.85 for caregiver anxiety and adjRR = 1.75, 95% CI 1.26–2.44 for caregiver depressive symptoms) and reported intention to withdraw the resident from AL because of COVID-19 (adjRR = 1.24, 95%CI 0.95–1.63 for caregiver anxiety and adjRR = 1.37, 95%CI 1.13–1.67 for caregiver depressive symptoms). Conclusions Caregivers of residents in AL homes reported significant personal and caregiving-related stressors during the initial wave of COVID-19 that were independently associated with an increased likelihood of experiencing clinically significant anxiety and depressive symptoms. Healthcare providers and AL staff should be aware of the prevalence and varied correlates of caregivers’ mental health during public health crises so that appropriate screening and support may identified and implemented.

Abstract Atypical teratoid/rhabdoid tumors (AT/RT) are the most common malignant brain tumors of infancy and have a dismal 4-year event-free survival (EFS) of 37%. We have previously shown that mTOR activation contributes to AT/RT’s aggressive growth and poor survival. Targeting the mTOR pathway with the dual mTORC1/2 inhibitor TAK-228 slows tumor growth and extends survival in mice bearing orthotopic xenografts. However, responses are primarily cytostatic with limited durability. The aim of this study is to understand the impact of mTOR inhibitors on AT/RT signaling pathways and design a rational combination therapy to drive a more durable response to this promising therapy. We performed RNASeq, gene expression studies, and protein analyses to identify pathways disrupted by TAK-228. We find that TAK-228 decreases the expression of the transcription factor NRF2 and compromises AT/RT cellular defenses against oxidative stress and apoptosis. The BH3 mimetic, Obatoclax, is a potent inducer of oxidative stress and apoptosis in AT/RT. These complementary mechanisms of action drive extensive synergies between TAK-228 and Obatoclax slowing AT/RT cell growth and inducing apoptosis and cell death. Combination therapy activates the integrative stress response as determined by increased expression of phosphorylated EIF2α, ATF4, and CHOP, and disrupts the protective NOXA.MCL-1.BIM axis, forcing stressed cells to undergo apoptosis. Combination therapy is well tolerated in mice bearing orthotopic xenografts of AT/RT, slows tumor growth, and extends median overall survival. This novel combination therapy could be added to standard upfront therapies or used as a salvage therapy for relapsed disease to improve outcomes in AT/RT.

Background and purpose: Simultaneous Positron Emission Tomography – Magnetic Resonance (PET-MR) imaging can potentially improve radiotherapy by enabling more accurate tumour delineation and dose painting. The use of PET-MR imaging for radiotherapy planning requires a comprehensive Quality Assurance (QA) programme to be developed. This study aimed to develop the QA tests required and assess their repeatability and stability. Materials and methods: QA tests were developed for: MR image quality, MR geometric accuracy, electromechanical accuracy, PET-MR alignment accuracy, Diffusion Weighted (DW)-MR Apparent Diffusion Coefficient (ADC) accuracy and PET Standard Uptake Value (SUV) accuracy. Each test used a dedicated phantom and was analysed automatically or semi-automatically, with in–house software. Repeatability was evaluated by three same-day measurements with independent phantom positions. Stability was assessed through 12 monthly measurements. Results: The repeatability Standard Deviations (SDs) of distortion for the MR geometric accuracy test were ⩽0.7mm. The repeatability SDs in ADC difference from reference were ⩽3% for the DW-MR accuracy test. The PET SUV difference from reference repeatability SD was 0.3%. The stability SDs agreed within 0.6mm, 1 percentage point and 1.4 percentage points of the repeatability SDs for the geometric, ADC and SUV accuracy tests respectively. There were no monthly trends apparent. These results were representative of the other tests. Conclusions: QA Tests for radiotherapy planning PET-MR have been developed. The tests appeared repeatable and stable over a 12-month period. The developed QA tests could form the basis of a QA programme that enables high-quality, robust PET-MR imaging for radiotherapy planning.

Abstract Our legs act as our primary contact with the surrounding environment, generating external forces that enable agile motion. To be agile, the nervous system has to control both the magnitude of the force that the feet apply to the ground and the point of application of this force. The purpose of this study was to characterize the performance of the healthy human neuromechanical system in controlling the force-magnitude and position of an externally applied force. To accomplish this, we built an apparatus that immobilized participants but allowed them to exert variable but controlled external forces with a single leg onto a ground embedded force plate. We provided real-time visual feedback of either the leg force-magnitude or force-position that participants were exerting against the force platform and instructed participants to best match their real-time signal to prescribed target step functions. We tested target step functions of a range of sizes and quantified the responsiveness and accuracy of the control. For the control of force-magnitude and for intermediate step sizes of 0.45 bodyweights, we found a bandwidth of 1.8 ± 0.5 Hz, a steady-state error of 2.6 ± 0.9%, and a steady-state variability of 2.7 ± 0.9%. We found similar control performance in terms of responsiveness and accuracy across step sizes and between force-magnitude and position control. Increases in responsiveness correlated with reductions in other measures of control performance, such as a greater magnitude of overshooting. We modelled the observed control performance and found that a second-order model was a good predictor of external leg force control. We discuss how benchmarking force control performance in young healthy humans aids in understanding differences in agility between humans, between humans and other animals, and between humans and engineered systems.

Presented herein are the first verifiable records of Neodilatilabrum Dekkers, 2008 in Australia. The two examples of Neodilatilabrum robustum (Sowerby, 1875) come from Point Cartwright and Dingo Beach, Queensland. These specimens represent an anomaly, being morphologically similar to a localized South China Sea population. The possible modalities to explain its presence at this locality are discussed. This discovery reaffirms the importance of proactive engagement between citizen scientists and institutional workers to enable a greater understanding of regional species richness.

Background and aim: The natural history of ductal carcinoma in situ (DCIS) is poorly understood. The aim of this cohort study was to determine the outcomes of women who had no surgery for screen-detected DCIS in the 6 months following diagnosis. Methods: English breast screening databases were retrospectively searched for women diagnosed with DCIS without invasive cancer at screening and who had no record of surgery within 6 months of diagnosis. These were cross-referenced with cancer registry data. Details of the potentially eligible women were sent to the relevant breast screening units for verification and for completion of data forms detailing clinical, radiological and pathological findings, non-surgical treatment and subsequent clinical course. Results: Data for 311 eligible women (median age 62 years) were available. 60 women developed invasive cancer, 56 ipsilateral and 4 contralateral. Ipsilateral invasion risk increased approximately linearly with time for at least 10 years. The 10-year cumulative risk of ipsilateral invasion was 9% (95% CI 4–21%), 39% (24–58%) and 36% (24–50%) for low, intermediate and high grade DCIS respectively and was higher in younger women, in those with larger DCIS lesions and in those with microinvasion. Most invasive cancers that developed were grade 2 or 3. Conclusion: The findings suggest that active surveillance may be a reasonable alternative to surgery in patients with low grade DCIS but that women with intermediate or high grade disease should continue to be offered surgery. This highlights the importance of reproducible grading of DCIS to ensure patients receive appropriate treatment.

Metabolic power (net energy consumed while walking per unit time) is, on average, two-to-three times greater in children with cerebral palsy (CP) than their typically developing peers, contributing to greater physical fatigue, lower levels of physical activity and greater risk of cardiovascular disease. The goal of this study was to identify the causal effects of clinical factors that may contribute to high metabolic power demand in children with CP. We included children who 1) visited Gillette Children's Specialty Healthcare for a quantitative gait assessment after the year 2000, 2) were formally diagnosed with CP, 3) were classified as level I-III under the Gross Motor Function Classification System and 4) were 18 years old or younger. We created a structural causal model that specified the assumed relationships of a child's gait pattern (i.e., gait deviation index, GDI) and common impairments (i.e., dynamic and selective motor control, strength, and spasticity) with metabolic power. We estimated causal effects using Bayesian additive regression trees, adjusting for factors identified by the causal model. There were 2157 children who met our criteria. We found that a child's gait pattern, as summarized by the GDI, affected metabolic power approximately twice as much as the next largest contributor. Selective motor control, dynamic motor control, and spasticity had the next largest effects. Among the factors we considered, strength had the smallest effect on metabolic power. Our results suggest that children with CP may benefit more from treatments that improve their gait pattern and motor control than treatments that improve spasticity or strength.

Objective: This study explores the choices and constraints affecting timing of parenthood among those who became parents in their mid-thirties and early forties and how their fertility decisions were both affected by and negotiated within the interplay of different temporal frameworks. Background: Recent decades have seen a trend towards postponement of parenthood in many countries. Explanations for this delay include structural factors, changing social norms and the influence of the social meanings of age. The study assesses the influence of these factors on perceptions of the ‘right’ time to become parents. Method: The study draws on qualitative interviews with 23 women and men who participated in the third British National Survey of Sexual Attitudes and Lifestyles (Natsal-3) survey and had a first child when they were aged between 33 and 46. Results: Prerequisites for parenthood were seen as financial security, a suitable home and a steady relationship. Educational attainment and the achievement of personal and lifestyle goals affected the age at which parenthood was considered as were individual circumstances. Age was less influential than life stage as a criterion for readiness although, for women, chronological age was a decisive factor. Conclusions: Choice in shaping personal biographies was greater among participants than it would have been for previous generations but its consequences acted to constrain options regarding the timing of parenthood. Time taken to fulfil personal and professional ambitions, changing social norms regarding the appropriate age for parenthood as well as individual and structural factors resulted in less predictable life trajectories.

Purpose The introduction of breast screening in the UK led to an increase in the detection of non-invasive breast neoplasia, predominantly ductal carcinoma in situ (DCIS), a non-obligatory precursor of invasive breast cancer. The Sloane Project, a UK prospective cohort study of screen-detected non-invasive breast neoplasia, commenced in 2003 to evaluate the radiological assessment, surgical management, pathology, adjuvant therapy and outcomes for non-invasive breast neoplasia. Long-term follow-up and accurate data collection are essential to examine the clinical impact. Here, we describe the establishment, development and analytical processes for this large UK cohort study.Participants Women diagnosed with non-invasive breast neoplasia via the UK National Health Service Breast Screening Programme (NHSBSP) from 01 April 2003 are eligible, with a minimum age of 46 years. Diagnostic, therapeutic and follow-up data collected via proformas, complement date and cause of death from national data sources. Accrual for patients with DCIS ceased in 2012 but is ongoing for patients with epithelial atypia/in situ neoplasia, while follow-up for all continues long term.Findings to date To date, patients within the Sloane cohort comprise one-third of those diagnosed with DCIS within the NHSBSP and are representative of UK practice. DCIS has a variable outcome and confirms the need for longer-term follow-up for screen-detected DCIS. However, the radiology and pathology features of DCIS can be used to inform patient management. We demonstrate validation of follow-up information collected from national datasets against traditional, manual methods.Future plans Conclusions derived from the Sloane Project are generalisable to women in the UK with screen-detected DCIS. The follow-up methodology may be extended to other UK cohort studies and routine clinical follow-up. Data from English patients entered into the Sloane Project are available on request to researchers under data sharing agreement. Annual follow-up data collection will continue for a minimum of 20 years.

Elaborate behaviours are produced by tightly controlled flexor-extensor motor neuron activation patterns. Motor neurons are regulated by a network of interneurons within the spinal cord, but the computational processes involved in motor control are not fully understood. The neuroanatomical arrangement of motor and premotor neurons into topographic patterns related to their controlled muscles is thought to facilitate how information is processed by spinal circuits. Rabies retrograde monosynaptic tracing has been used to label premotor interneurons innervating specific motor neuron pools, with previous studies reporting topographic mediolateral positional biases in flexor and extensor premotor interneurons. To more precisely define how premotor interneurons contacting specific motor pools are organized, we used multiple complementary viral-tracing approaches in mice to minimize systematic biases associated with each method. Contrary to expectations, we found that premotor interneurons contacting motor pools controlling flexion and extension of the ankle are highly intermingled rather than segregated into specific domains like motor neurons. Thus, premotor spinal neurons controlling different muscles process motor instructions in the absence of clear spatial patterns among the flexor-extensor circuit components.

Climate change will increase disturbance pressures on forested ecosystems worldwide. In many areas, longer, hotter summers will lead to more wildfire and more insect activity which will substantially increase overall forest mortality. Forest treatments reduce tree density and fuel loads, which in turn reduces fire and insect severity, but implementation has been limited compared to the area needing treatment. Ensuring that forests remain near their reference conditions will require a significant increase in the pace and scale of forest management. In order to assess what pace and scale may be required for a landscape at risk, we simulated forest and disturbance dynamics for the central Sierra Nevada, USA. Our modeling framework included forest growth and succession, wildfire, insect mortality and locally relevant management actions. Our simulations accounted for climate change (five unique global change models on a business-as-usual emissions pathway) and a wide range of plausible forest management scenarios (six total, ranging from less than 1% of area receiving management treatments per year to 6% per year). The climate projections we considered all led to an increasing climatic water deficit, which in turn led to widespread insect caused mortality across the landscape. The level of insect mortality limited the amount of carbon stored and sequestered while leading to significant composition changes, however, only one climate change projection resulted in increased fire over contemporary conditions. While increased pace and scale of treatments led to offsets in fire related tree mortality, managing toward historic reference conditions was not sufficient to reduce insect-caused forest mortality. As such, new management intensities and other adaptation actions may be necessary to maintain forest resilience under an uncertain future climate.

William J. Maxwell, editor of James Baldwin: The FBI File (2017), interviews Bill V. Mullen on his 2019 biography, James Baldwin: Living in Fire, along the way touching on both Baldwin’s early internationalism and his relevance to the current wave of racial discord and interracial possibility in the United States.

Abstract Background Investigations of transparency, reproducibility and replicability in science have been directed largely at individual studies. It is just as critical to explore these issues in syntheses of studies, such as systematic reviews, given their influence on decision-making and future research. We aim to explore various aspects relating to the transparency, reproducibility and replicability of several components of systematic reviews with meta-analysis of the effects of health, social, behavioural and educational interventions. Methods The REPRISE (REProducibility and Replicability In Syntheses of Evidence) project consists of four studies. We will evaluate the completeness of reporting and sharing of review data, analytic code and other materials in a random sample of 300 systematic reviews of interventions published in 2020 (Study 1). We will survey authors of systematic reviews to explore their views on sharing review data, analytic code and other materials and their understanding of and opinions about replication of systematic reviews (Study 2). We will then evaluate the extent of variation in results when we (a) independently reproduce meta-analyses using the same computational steps and analytic code (if available) as used in the original review (Study 3), and (b) crowdsource teams of systematic reviewers to independently replicate a subset of methods (searches for studies, selection of studies for inclusion, collection of outcome data, and synthesis of results) in a sample of the original reviews; 30 reviews will be replicated by 1 team each and 2 reviews will be replicated by 15 teams (Study 4). Discussion The REPRISE project takes a systematic approach to determine how reliable systematic reviews of interventions are. We anticipate that results of the REPRISE project will inform strategies to improve the conduct and reporting of future systematic reviews.

Introduction Obesity and overweight are strong potentially modifiable risk factors for postmenopausal breast and endometrial cancer. Bariatric surgery can achieve considerable weight loss and risk reduction of weight-related cancer but is unlikely to be a feasible cancer prevention strategy. Total diet replacement (TDR) can also lead to significant weight reduction. This study aims to examine the cellular and molecular changes in breast and endometrial tissue in high-risk women following TDR-induced weight loss, as well as longer-term adherence to a 12-month TDR weight loss intervention.Methods and analysis PROBE-TDR (PRevention Of Breast and Endometrial cancer using Total Diet Replacement) is a prospective, non-blinded, randomised controlled trial of 47 women at increased risk of breast and/or endometrial cancer. Randomisation is 2:1 to either an immediate 12-month TDR weight loss programme (n=31) or delayed dietary intervention (control) (n=16). The TDR programme includes an initial 12-week period of TDR (850 kcal/day) followed by a 40-week food-based diet, based on the nutritional principles of a Mediterranean diet, as either continued weight loss (~1500 kcal/day) or weight loss maintenance (~2000 kcal/day). Menstrual phase-matched biopsies of the breast and endometrium will be assessed at baseline and at the end of the 12-week TDR in the immediate diet group, compared with women randomised to the control group following their usual diet. The trial will also assess longer-term adherence and weight loss success across the 12-month programme in both the immediate and control groups.Ethics and dissemination Approval for this study has been obtained from the Health Research Authority and Health and Care Research Wales (approval 20/NW/0095). Results will be published in peer-reviewed journals, presented at conferences and shared with trial participants.Trial registration number International Standard Randomised Controlled Trial Number Registry (ISRCTN15358157).

Abstract Background In principle, risk-stratification as a routine part of the NHS Breast Screening Programme (NHSBSP) should produce a better balance of benefits and harms. The main benefit is the offer of NICE-approved more frequent screening and/ or chemoprevention for women who are at increased risk, but are unaware of this. We have developed BC-Predict, to be offered to women when invited to NHSBSP which collects information on risk factors (self-reported information on family history and hormone-related factors via questionnaire; mammographic density; and in a sub-sample, Single Nucleotide Polymorphisms). BC-Predict produces risk feedback letters, inviting women at high risk (≥8% 10-year) or moderate risk (≥5 to