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Introduction: In recent years, major progress has been made in understanding the human visual system because of new investigative techniques. These developments often contradict older concepts about visual function. Methods: A detailed literature search and interprofessional discussions. Results: Recent innovative neurological tests are described that are able to show much more accurately the visual pathways, the process of vision, and the close relationships among sensory modalities. These tests also reveal the remarkable neuroplasticity of the human brain and disorders of connectivity that frequently involve visual function. Discussion: How these recent neurological advances may benefit service providers is discussed. Implications for practitioners: It is important that from time to time new neurological and ophthalmic developments are summarized for professionals who are involved in the clinical management of individuals with visual disorders and how the newly acquired knowledge affects the diagnosis and intervention strategies. Visual rehabilitation must be based on up-to-date science, which continually changes and grows with research.

Abstract Aggression—and its role in human societal development—continues to be hotly debated within both the sciences and the humanities. Whatever the evolutionary origins and repercussions of interpersonal and intergroup conflict for the human story, cultures around the globe have invested significant time and effort into designing deadly hand-held weaponry. Here, we describe for the first time, how humans deliver a deadly strike using two iconic and widespread Aboriginal Australian weapons: the kodj and the leangle with parrying shield. We present the world’s first evaluation of striking biomechanics and human and weapon efficiency regarding this class of implement. Results demonstrate the leangle is far more effective at delivering devastating blows to the human body, while the kodj—a multi-functional tool—is more efficient for a human to manoeuvre and still capable of delivering severe blows that can cause death. Together, these data provide the beginnings of an in-depth understanding of how hand-held weaponry has impacted the human body throughout the deep past.

Abstract Neurocognitive aging researchers are increasingly focused on the locus coeruleus, a neuromodulatory brainstem structure that degrades with age. With this rapid growth, the field will benefit from consensus regarding which magnetic resonance imaging (MRI) metrics of locus coeruleus structure are most sensitive to age and cognition. To address this need, the current study acquired magnetization transfer- and diffusion-weighted MRI images in younger and older adults who also completed a free recall memory task. Results revealed significantly larger differences between younger and older adults for maximum than average magnetization transfer-weighted contrast (MTC), axial than mean or radial single-tensor diffusivity (DTI), and free than restricted multi-compartment diffusion (NODDI) metrics in the locus coeruleus; with maximum MTC being the best predictor of age group. Age effects for all imaging modalities interacted with sex, with larger age group differences in males than females for MTC and NODDI metrics. Age group differences also varied across locus coeruleus subdivision for DTI and NODDI metrics, and across locus coeruleus hemispheres for MTC. Within older adults, however, there were no significant effects of age on MTC or DTI metrics, only an interaction between age and sex for free diffusion. Finally, independent of age and sex, higher restricted diffusion in the locus coeruleus was significantly related to better (lower) recall variability, but not mean recall. Whereas MTC has been widely used in the literature, our comparison between the average and maximum MTC metrics, inclusion of DTI and NODDI metrics, and breakdowns by locus coeruleus subdivision and hemisphere make important and novel contributions to our understanding of the aging of locus coeruleus structure.

Abstract Perceptual grouping is impaired following mild traumatic brain injury (mTBI). This may affect visual size perception, a process influenced by perceptual grouping abilities. We conducted two experiments to evaluate visual size perception in people with self-reported history of mTBI, using two different size-contrast illusions: the Ebbinghaus Illusion (Experiment 1) and the Müller-Lyer illusion (Experiment 2). In Experiment 1, individuals with mTBI and healthy controls were asked to compare the size of two target circles that were either the same size or different sizes. The target circles appeared by themselves (no-context condition), or were surrounded by smaller or larger circles (context condition). Similar levels of accuracy were evident between the groups in the no-context condition. However, size judgements by mTBI participants were more accurate in the context condition, suggesting that they processed the target circles separately from the surrounding circles. In Experiment 2, individuals with mTBI and healthy controls judged the length of parallel lines that appeared with arrowheads (context condition) or without arrowheads (no context condition). Consistent with Experiment 1, size judgements by mTBI participants were more accurate than size judgements by control participants in the context condition. These findings suggest that mTBI influences size perception by impairing perceptual grouping of visual stimuli in near proximity.

Abstract Biological samples are often frozen and stored for years and/or thawed multiple times, thus assessing their stability on long-term storage and repeated freeze–thaw cycles is crucial. The study aims were to assess:—the long-term stability of two major enzymatic and non-enzymatic metabolites of arachidonic acid, i.e. urinary 11-dehydro-thromboxane-(Tx) B2, 8-iso-prostaglandin (PG)F2α, and creatinine in frozen urine samples;—the effect of multiple freeze–thaw cycles. Seven-hundred and three urine samples measured in previously-published studies, stored at −40 °C, and measured for a second time for 11-dehydro-TxB2 (n = 677) and/or 8-iso-PGF2α (n = 114) and/or creatinine (n = 610) were stable over 10 years and the 2 measurements were highly correlated (all rho = 0.99, P

BackgroundThe COVID-19 pandemic significantly transformed the landscape of work and collaboration, impacting design research methodologies and techniques. Co-design approaches have been both negatively and positively affected by the pandemic, prompting a need to investigate and understand the extent of these impacts, changes, and adaptations, specifically in the health sector. Despite the challenges that the pandemic imposed on conducting co-design and related projects, it also encouraged a re-evaluation of co-design practices, leading to innovative solutions and techniques. Designers and researchers have explored alternative ways to engage stakeholders and end users, leveraging digital workshops and participatory digital platforms. These adaptations have the potential to enhance inclusivity, allowing for a wider range of individuals to contribute their perspectives and insights through co-design and thus contribute to healthcare change. ObjectiveThis study aims to explore the impacts of the pandemic on co-design and related practices, focusing on co-design practices in healthcare that have been gained, adapted, or enhanced, with a specific focus on issues of equity, diversity, and inclusion. MethodsThe study uses a realist synthesis methodology to identify and analyze the effects of the pandemic on co-design approaches in health, drawing on a range of sources including first-person experiences, gray literature, and academic literature. A community of practice in co-design in health will be engaged to support this process. ResultsBy examining the experiences and insights of professionals, practitioners, and communities who were actively involved in co-design and have navigated the challenges and opportunities of the pandemic, we can gain a deeper understanding of the strategies, tools, and techniques that have facilitated effective co-design during the pandemic, contributing to building resilience and capacity in co-design in health beyond the pandemic. ConclusionsBy involving community partners, community of practice (research), and design practitioners, we expect closer proximity to practice with capacity building occurring through the realist process, thus enabling rapid adoption and refinement of new techniques or insights that emerge. Ultimately, this research will contribute to the advancement of co-design methodologies and inform the future of co-design in health. International Registered Report Identifier (IRRID)DERR1-10.2196/58318

Key Clinical Message We report a patient with nonimmune fetal hydrops and multiple pathologic fractures. RNA analysis revealed a novel PIEZO1 variant. This report is the first to elucidate PIEZO1's role as a critical regulator of bone mass and strength.

Abstract Short-term intake of selective serotonin reuptake inhibitors (SSRIs) modulates threat-related amygdala responses in healthy individuals. However, how SSRI intake over a clinically relevant time period modulates threat-related amygdala responses is less clear. In a semi-randomised, double-blind, placebo-controlled study of 64 healthy individuals (SSRI n = 32, placebo n = 32), we examined the effect of 3–5 weeks of SSRI escitalopram (20 mg daily) on brain response to angry, fearful and neutral faces using BOLD fMRI. Data was analysed using a whole-brain region-wise approach extracting standardised effects (i.e., Cohen’s D). The study was conducted at the Copenhagen University Hospital. A priori, we hypothesised that SSRI would attenuate amygdala responses to angry and fearful faces but not to neutral ones. Whether SSRI modulates correlations between amygdala responses to emotional faces and negative mood states was also explored. Compared to placebo, 3–5 weeks of SSRI intake did not significantly affect the amygdala response to angry, fearful, or neutral faces (|Cohen’s D|

Abstract At the molecular level, triple-negative breast cancer (TNBC) is frequently categorized as PAM50 basal-like subtype, but despite the advances in molecular analyses, the clinical outcome for these subtypes is uncertain. Long non-coding RNAs (lncRNAs) are master regulators of genes involved in hallmarks of cancer, which makes them suitable biomarkers for breast cancer (BRCA) diagnosis and prognosis. Here, we evaluated the regulatory role of lncRNA SOX9-AS1 in these subtypes. Using the BRCA-TCGA cohort, we observed that SOX9-AS1 was significantly overexpressed in basal-like and TNBC in comparison with other BRCA subtypes. Survival analyzes showed that SOX9-AS1 overexpression was associated with a favorable prognosis in TNBC and basal-like patients. To study the functions of SOX9-AS1, we determined the expression levels in a panel of nine BRCA cell lines finding increased levels in MDA-MB-468 and HCC1187 TNBC. Using subcellular fractionation in these cell lines, we ascertained that SOX9-AS1 was located in the cytoplasmic compartment. In addition, we performed SOX9-AS1 gene silencing using two short-harping constructs, which were transfected in both cell models and performed a genome-wide RNA-seq analysis. Data showed that 351 lncRNAs and 740 mRNAs were differentially expressed in MDA-MB-468 while 56 lncRNAs and 100 mRNAs were modulated in HCC1187 cells (Log2FC 1.5, p.adj value

Lymphoid restricted membrane protein (LRMP) is a specific regulator of the hyperpolarization-activated cyclic nucleotide-sensitive isoform 4 (HCN4) channel. LRMP prevents cAMP-dependent potentiation of HCN4, but the interaction domains, mechanisms of action, and basis for isoform-specificity remain unknown. Here, we identify the domains of LRMP essential for this regulation, show that LRMP acts by disrupting the intramolecular signal transduction between cyclic nucleotide binding and gating, and demonstrate that multiple unique regions in HCN4 are required for LRMP isoform-specificity. Using patch clamp electrophysiology and Förster resonance energy transfer (FRET), we identified the initial 227 residues of LRMP and the N-terminus of HCN4 as necessary for LRMP to associate with HCN4. We found that the HCN4 N-terminus and HCN4-specific residues in the C-linker are necessary for regulation of HCN4 by LRMP. Finally, we demonstrated that LRMP-regulation can be conferred to HCN2 by addition of the HCN4 N-terminus along with mutation of five residues in the S5 region and C-linker to the cognate HCN4 residues. Taken together, these results suggest that LRMP inhibits HCN4 through an isoform-specific interaction involving the N-terminals of both proteins that prevents the transduction of cAMP binding into a change in channel gating, most likely via an HCN4-specific orientation of the N-terminus, C-linker, and S4-S5 linker.

Abstract The sound of a person’s voice is commonly used to identify the speaker. The sound of speech is also starting to be used to detect medical conditions, such as depression. It is not known whether the manifestations of depression in speech overlap with those used to identify the speaker. In this paper, we test the hypothesis that the representations of personal identity in speech, known as speaker embeddings, improve the detection of depression and estimation of depressive symptoms severity. We further examine whether changes in depression severity interfere with the recognition of speaker’s identity. We extract speaker embeddings from models pre-trained on a large sample of speakers from the general population without information on depression diagnosis. We test these speaker embeddings for severity estimation in independent datasets consisting of clinical interviews (DAIC-WOZ), spontaneous speech (VocalMind), and longitudinal data (VocalMind). We also use the severity estimates to predict presence of depression. Speaker embeddings, combined with established acoustic features (OpenSMILE), predicted severity with root mean square error (RMSE) values of 6.01 and 6.28 in DAIC-WOZ and VocalMind datasets, respectively, lower than acoustic features alone or speaker embeddings alone. When used to detect depression, speaker embeddings showed higher balanced accuracy (BAc) and surpassed previous state-of-the-art performance in depression detection from speech, with BAc values of 66% and 64% in DAIC-WOZ and VocalMind datasets, respectively. Results from a subset of participants with repeated speech samples show that the speaker identification is affected by changes in depression severity. These results suggest that depression overlaps with personal identity in the acoustic space. While speaker embeddings improve depression detection and severity estimation, deterioration or improvement in mood may interfere with speaker verification.

Objective Integrating a palliative approach to care into primary care is an emerging evidence-based practice. Despite the evidence, this type of care has not been widely adopted into primary care settings. The objective of this study was to examine the barriers to and facilitators of successful implementation of a palliative approach to care in primary care practices by applying an implementation science framework.Design This convergent mixed methods study analysed semistructured interviews and expression of interest forms to evaluate the implementation of a protocol, linked to implementation strategies, for a palliative approach to care called Early Palliation through Integrated Care (EPIC) in three primary care practices. This study assessed barriers to and facilitators of implementation of EPIC and was guided by the Consolidated Framework for Implementation Research (CFIR). A framework analysis approach was used during the study to determine the applicability of CFIR constructs and domains.Setting Primary care practices in Canada. Interviews were conducted between September 2020 and November 2021.Participants 10 individuals were interviewed, who were involved in implementing EPIC. Three individuals from each practice were reinterviewed to clarify emerging themes.Results Overall, there were implementation barriers at multiple levels that caused some practices to struggle. However, barriers were mitigated when practices had the following facilitators: (1) a high level of intra-practice collaboration, (2) established practices with organisational structures that enhanced communications, (3) effective leveraging of EPIC project supports to transition care, (4) perceptions that EPIC was an opportunity to make a long-term change in their approach to care as opposed to a limited term project and (5) strong practice champions.Conclusions Future implementation work should consider assessing facilitators identified in our results to better gauge primary care pre-implementation readiness. In addition, providing primary care practices with support to help offset the additional work of implementing innovations and networking opportunities where they can share strategies may improve implementation success.

Introduction Fifty per cent of patients with cancer require radiotherapy during their disease course, however, only 10%–40% of patients in low-income and middle-income countries (LMICs) have access to it. A shortfall in specialised workforce has been identified as the most significant barrier to expanding radiotherapy capacity. Artificial intelligence (AI)-based software has been developed to automate both the delineation of anatomical target structures and the definition of the position, size and shape of the radiation beams. Proposed advantages include improved treatment accuracy, as well as a reduction in the time (from weeks to minutes) and human resources needed to deliver radiotherapy.Methods ARCHERY is a non-randomised prospective study to evaluate the quality and economic impact of AI-based automated radiotherapy treatment planning for cervical, head and neck, and prostate cancers, which are endemic in LMICs, and for which radiotherapy is the primary curative treatment modality. The sample size of 990 patients (330 for each cancer type) has been calculated based on an estimated 95% treatment plan acceptability rate. Time and cost savings will be analysed as secondary outcome measures using the time-driven activity-based costing model. The 48-month study will take place in six public sector cancer hospitals in India (n=2), Jordan (n=1), Malaysia (n=1) and South Africa (n=2) to support implementation of the software in LMICs.Ethics and dissemination The study has received ethical approval from University College London (UCL) and each of the six study sites. If the study objectives are met, the AI-based software will be offered as a not-for-profit web service to public sector state hospitals in LMICs to support expansion of high quality radiotherapy capacity, improving access to and affordability of this key modality of cancer cure and control. Public and policy engagement plans will involve patients as key partners.

Objectives Aspirin could be offered for colorectal cancer prevention for the UK general population. To ensure the views of the general population are considered in future guidance, we explored public perceptions of aspirin for preventive therapy.Design We conducted an online survey to investigate aspirin use, and awareness of aspirin for cancer prevention among the UK general population. We conducted semistructured interviews with a subsample of survey respondents to explore participants’ acceptability towards aspirin for cancer preventive therapy. We analysed the interview data using reflexive thematic analysis and mapped the themes onto the Theoretical Domains Framework, and the Necessity and Concerns Framework.Setting Online survey and remote interviews.Participants We recruited 400 UK respondents aged 50–70 years through a market research company to the survey. We purposefully sampled, recruited and interviewed 20 survey respondents.Results In the survey, 19.0% (76/400) of respondents were aware that aspirin can be used to prevent cancer. Among those who had previously taken aspirin, 1.9% (4/216) had taken it for cancer prevention. The interviews generated three themes: (1) perceived necessity of aspirin; (2) concerns about side effects; and (3) preferred information sources. Participants with a personal or family history of cancer were more likely to perceive aspirin as necessary for cancer prevention. Concerns about taking aspirin at higher doses and its side effects, such as gastrointestinal bleeding, were common. Many described wanting guidance and advice on aspirin to be communicated from sources perceived as trustworthy, such as healthcare professionals.Conclusions Among the general population, those with a personal or family history of cancer may be more receptive towards taking aspirin for preventive therapy. Future policies and campaigns recommending aspirin may be of particular interest to these groups. Multiple considerations about the benefits and risks of aspirin highlight the need to support informed decisions on the medication.

OBJECTIVES/GOALS: The CDC estimates that Influenza infections account for an average of 420,000 hospitalizations and 34,700 deaths in the U.S. each year. This project explores the underlying mechanisms of the infectious process of Influenza A in human lung organoids by examining the differential transcriptomic expression compared to uninfected controls. METHODS/STUDY POPULATION: Lung organoids were cultured from differentiated human bronchial epithelial cells from lung transplant donors on an air-liquid interface until they were confirmed to contain both mucous producing and ciliated cells. Lung organoids are ideal models in translational science due to their structural and functional characteristics which closely mimic those of in vivo human epithelial tissue. Half the organoids were exposed to Influenza A pH1N1 for 72h; the other half served as uninfected controls. RNA was isolated from both groups and sequenced using the Oxford Nanopore MinION which generates full length reads. Reads were aligned to the human reference genome (GRCh38.p14) using Minimap2. RESULTS/ANTICIPATED RESULTS: The MinION sequenced an average of 3.24m reads per sample and a total of 13,128 genes were relevantly expressed (defined as greater than 1 read per million in at least half the samples). ANOVA with a 5% false discovery rate (Benjamini and Hochberg correction) revealed 5,417 differentially expressed genes between infected and control groups. Within this subset, we identified downregulation of mucociliary clearance, mitochondrial and ß-oxidation, peroxisome, and glutathione replenishment genes. We further identified upregulation in inflammatory markers, lactate dehydrogenase enzymes, and several s100 proteins. The downregulation of mitochondrial and β-oxidation markers and the upregulation of lactate dehydrogenase enzymes revealed a Warburg-like phenotype which has not previously been reported. DISCUSSION/SIGNIFICANCE: This study reveals a novel Warburg-like phenotype in Influenza A infection alongside downregulated mucociliary clearance and upregulated inflammatory processes. These findings improve our understanding of Influenza A infection and point to potential therapeutic targets to advance precision medicine approaches to treatment.

There are many pressing questions about how to deliver adult social care services. Where research evidence exists to address these questions, there is often limited use by social care commissioners, providers and the workforce. Sometimes this is attributed to the lack of perceived relevance and accessibility of the research itself, at other times it is considered to be a matter of individual and organizational capacity. As things stand, there is a gap between social care research and practice. Improving interaction between different stakeholders in the research process is a contemporary mechanism for promoting the production of research that is useful, usable and used. This paper describes one collaborative approach called Research Practice Partnerships (RPPs). These partnerships share the goal of benefit for all partners and are supported by a growing international evidence base. This paper summarizes some of the key literature from different countries and contexts where the approach has been tried. It highlights the main features of RPPs, introduces a project setting up three new partnerships in the care home sector in England and highlights aspects of the theory of change that will guide the evaluation of the partnerships. In doing so, the paper introduces a promising collaborative approach to a social care audience and considers whether RPPs have the potential to achieve meaningful and impactful research in social care contexts.

BackgroundThere is increasing evidence that co-design can lead to more engaging, acceptable, relevant, feasible, and even effective interventions. However, no guidance is provided on the specific designs and associated methods or methodologies involved in the process. We propose the development of the Preferred Components for Co-design in Research (PRECISE) guideline to enhance the consistency, transparency, and quality of reporting co-design studies used to develop complex health interventions. ObjectiveThe aim is to develop the first iteration of the PRECISE guideline. The purpose of the PRECISE guideline is to improve the consistency, transparency, and quality of reporting on studies that use co-design to develop complex health interventions. MethodsThe aim will be achieved by addressing the following objectives: to review and synthesize the literature on the models, theories, and frameworks used in the co-design of complex health interventions to identify their common elements (components, values or principles, associated methods and methodologies, and outcomes); and by using the results of the scoping review, prioritize the co-design components, values or principles, associated methods and methodologies, and outcomes to be included in the PRECISE guideline. ResultsThe project has been funded by the Canadian Institutes of Health Research. ConclusionsThe collective results of this project will lead to a ready-to-implement PRECISE guideline that outlines a minimum set of items to include when reporting the co-design of complex health interventions. The PRECISE guideline will improve the consistency, transparency, and quality of reports of studies. Additionally, it will include guidance on how to enact or enable the values or principles of co-design for meaningful and collaborative solutions (interventions). PRECISE might also be used by peer reviewers and editors to improve the review of manuscripts involving co-design. Ultimately, the PRECISE guideline will facilitate more efficient use of new results about complex health intervention development and bring better returns on research investments. International Registered Report Identifier (IRRID)PRR1-10.2196/50463

Objectives We investigated the feasibility and validity of establishing a nationwide e-cohort of individuals with a diagnosis of attention deficit hyperactivity disorder (ADHD) and/or autism spectrum disorder (ASD) for future longitudinal research.Design Individuals with a childhood diagnosis of ADHD/ASD as recorded on routinely available healthcare datasets were compared with matched controls and a sample of directly assessed individuals with ADHD.Setting This study used data from the Welsh Secure Anonymised Information Linkage Databank in Wales, UK. Routinely collected data from primary care, emergency department and hospital admissions were linked at person level.Participants All individuals in Wales, UK born between 1 January 1991 and 31 December 2000. Individuals with a recorded diagnosis of ADHD and/or ASD by age 18 years were identified using International Classification of Diseases, 10th Revision and National Health Service (NHS) READ codes and matched to 3 controls each and 154 individuals with ADHD recruited from an established research study.Outcome measures Recorded service use for anxiety and depression, alcohol and drug use and self-harm including emergency department use in young adulthood (age 16–25 years).Results 7726 individuals had a recorded diagnosis of ADHD (80% male) and 5001 of ASD (79% male); 1.4% and 0.9% of the population, respectively. Cox’s regression analyses showed ADHD was associated with increased risks of anxiety/depression (HR: 2.36, 95% CI: 2.20 to 2.53), self-harm (HR: 5.70, 95% CI: 5.07 to 6.40), alcohol (HR: 3.95, 95% CI: 3.42 to 4.56), drug use (HR: 5.88, 95% CI: 5.08 to 6.80) and emergency department service use (HR: 1.36, 95% CI: 1.31 to 1.41). Those with ASD were at increased risk of anxiety/depression (HR: 2.11, 95% CI: 1.91 to 2.34), self-harm (HR: 2.93, 95% CI: 2.45 to 3.50) and drug use (HR: 2.21, 95% CI: 1.66 to 2.95) but not alcohol use. The ADHD e-cohort were similar to the directly assessed cohort.Conclusions Our identification strategy demonstrated the feasibility of establishing a large e-cohort of those with ADHD/ASD with expected patterns of poorer early adult outcomes, demonstrating a valid method of identifying large samples for future longitudinal studies without selective attrition.

Summary: Background: In Huntington's disease (HD), a CAG repeat expansion mutation in the Huntingtin (HTT) gene drives a gain-of-function toxicity that disrupts mRNA processing. Although dysregulation of gene splicing has been shown in human HD post-mortem brain tissue, post-mortem analyses are likely confounded by cell type composition changes in late-stage HD, limiting the ability to identify dysregulation related to early pathogenesis. Methods: To investigate gene splicing changes in early HD, we performed alternative splicing analyses coupled with a proteogenomics approach to identify early CAG length-associated splicing changes in an established isogenic HD cell model. Findings: We report widespread neuronal differentiation stage- and CAG length-dependent splicing changes, and find an enrichment of RNA processing, neuronal function, and epigenetic modification-related genes with mutant HTT-associated splicing. When integrated with a proteomics dataset, we identified several of these differential splicing events at the protein level. By comparing with human post-mortem and mouse model data, we identified common patterns of altered splicing from embryonic stem cells through to post-mortem striatal tissue. Interpretation: We show that widespread splicing dysregulation in HD occurs in an early cell model of neuronal development. Importantly, we observe HD-associated splicing changes in our HD cell model that were also identified in human HD striatum and mouse model HD striatum, suggesting that splicing-associated pathogenesis possibly occurs early in neuronal development and persists to later stages of disease. Together, our results highlight splicing dysregulation in HD which may lead to disrupted neuronal function and neuropathology. Funding: This research is supported by the Lee Kong Chian School of Medicine, Nanyang Technological University Singapore Nanyang Assistant Professorship Start-Up Grant, the Singapore Ministry of Education under its Singapore Ministry of Education Academic Research Fund Tier 1 (RG23/22), the BC Children's Hospital Research Institute Investigator Grant Award (IGAP), and a Scholar Award from the Michael Smith Health Research BC.

Close friendships are important for mental health and cognition in late childhood. However, whether the more close friends the better, and the underlying neurobiological mechanisms are unknown. Using the Adolescent Brain Cognitive Developmental study, we identified nonlinear associations between the number of close friends, mental health, cognition, and brain structure. Although few close friends were associated with poor mental health, low cognitive functions, and small areas of the social brain (e.g., the orbitofrontal cortex, the anterior cingulate cortex, the anterior insula, and the temporoparietal junction), increasing the number of close friends beyond a level (around 5) was no longer associated with better mental health and larger cortical areas, and was even related to lower cognition. In children having no more than five close friends, the cortical areas related to the number of close friends revealed correlations with the density of μ-opioid receptors and the expression of OPRM1 and OPRK1 genes, and could partly mediate the association between the number of close friends, attention-deficit/hyperactivity disorder (ADHD) symptoms, and crystalized intelligence. Longitudinal analyses showed that both too few and too many close friends at baseline were associated with more ADHD symptoms and lower crystalized intelligence 2 y later. Additionally, we found that friendship network size was nonlinearly associated with well-being and academic performance in an independent social network dataset of middle-school students. These findings challenge the traditional idea of ‘the more, the better,’ and provide insights into potential brain and molecular mechanisms.

Background: Persistent symptoms after SARS CoV-2 infection such as fatigue, shortness of breath, and cognitive dysfunction that cannot be explained by an alternative diagnosis have been termed long COVID and present a significant emerging public health problem. Current approaches include rehabilitation and symptom management involving multiple health disciplines and as yet there are no pharmaceutical approaches other than routine symptom management. Manual lymph drainage (MLD) has been used to support recovery during pulmonary rehabilitation and reduce chronic inflammation including symptoms associated with long COVID. Case description and outcomes: Two adult females who had reported long-COVID symptoms more than 10 weeks after the resolution of the acute infection were treated with MLD by Remedial Therapists trained in the Dr Vodder method of MLD. Respiratory function (Peak Flow Meter) and blood oxygen levels (Oximeter) were recorded before and after a one-minute sit-to-stand test prior to the treatment. The Dyspnea-12 Questionnaire, the Revised Piper Fatigue Scale, and Likert scales were used to collect client-reported outcomes. Six 45-min treatments were applied weekly, with a follow-up review and treatment at three months. In both cases, all outcomes improved after the third treatment with further improvement noted at three months. Conclusions: MLD may offer a non-invasive, non-pharmaceutical approach to the resolution of long-COVID symptoms such as cough, breathlessness, and fatigue.

We investigated epidemiologic and molecular characteristics of healthcare-associated (HA) and community-associated (CA) Clostridioides difficile infection (CDI) among adult patients in Canadian Nosocomial Infection Surveillance Program hospitals during 2015–2019. The study encompassed 18,455 CDI cases, 13,735 (74.4%) HA and 4,720 (25.6%) CA. During 2015–2019, HA CDI rates decreased by 23.8%, whereas CA decreased by 18.8%. HA CDI was significantly associated with increased 30-day all-cause mortality as compared with CA CDI (p

Abstract Although seeking to develop a general and accurate binding free energy calculation method for protein–protein and protein–ligand interactions has been a continuous effort for decades, only limited successes have been obtained so far. Here, we report the development of a metadynamics-based procedure that calculates Dissociation Free Energy (DFE) and its application to 19 non-congeneric protein–protein complexes and hundreds of protein–ligand complexes covering eight targets. We achieved very high correlations in comparison to experimental binding free energies for these diverse sets of systems, demonstrating the generality and accuracy of the method. Since structures of most proteins are available owing to the recent success of prediction by artificial intelligence, a general free energy method such as DFE, combined with other methods, can make structure-based drug design a widely viable and reliable solution to develop both traditional small molecule drugs and biologic drugs as well as PROTACS.

Abstract Beige and brown fat consume glucose and lipids to produce heat, using uncoupling protein 1 (UCP1). It is thought that full activation of brown adipose tissue (BAT) may increase total daily energy expenditure by 20%. Humans normally have more beige and potentially beige-able fat than brown fat. Strategies to increase beige fat differentiation and activation may be useful for the treatment of obesity and diabetes. Mice were fed chow or high-fat diet (HFD) with or without the iron chelator deferasirox. Animals fed HFD + deferasirox were markedly lighter than their HFD controls with increased energy expenditure (12% increase over 24 h, p

Bacterial resistance or tolerance to antibiotics is costly to patients and healthcare providers. With the impact of antibiotic resistance forecast to grow, alternative antimicrobial approaches are needed to help treat patients with antibiotic refractory infections and reduce reliance upon existing antibiotics. There is renewed interest in bacteriophage (phage) therapy as a promising antimicrobial strategy. We therefore performed the first multi-specialty survey about phage therapy and the first such survey among clinicians in the United Kingdom. An anonymous 10-question survey of clinicians from medical and surgical specialties in two Scottish Health Boards was performed. The 90 respondents spanned 26 specialties and were predominantly consultants (73.3%). The respondents were concerned about antibiotic resistance in their clinical practice; 83 respondents estimated having seen 711 patients in the last 12 months whose infections were refractory to antibiotics (delaying or preventing resolution). Over half (58.8%) of the respondents had previously heard of phage therapy. Staphylococci, Pseudomonas and E. coli were identified as the highest cross-specialty priorities for the development of phage therapy. Together, 77 respondents estimated seeing 300 patients in the last 12 months for whom phage therapy may have been appropriate (an average of 3.9 patients per clinician). Most respondents (71.1%, n = 90) were already willing to consider using phage therapy in appropriate cases. Additional comments from the respondents affirmed the potential utility of phage therapy and highlighted a need for more information. The results of this survey demonstrate substantial demand for and willingness to use phage therapy in appropriate cases, both from individual clinicians and across specialties. Demand from a wide range of specialties illustrates the broad clinical utility of phage therapy and potential scope of impact. Widening access to phage therapy could deliver substantial clinical and financial benefits for patients and health authorities alike.

BackgroundCognitive flexibility (CF) enables individuals to readily shift from one concept or mode of practice/thoughts to another in response to changes in the environment and feedback, making CF vital to optimise success in obtaining goals. However, how CF relates to other executive functions (e.g., working memory, response inhibition), mental abilities (e.g., creativity, literacy, numeracy, intelligence, structure learning), and social factors (e.g., multilingualism, tolerance of uncertainty, perceived social support, social decision-making) is less well understood. The current study aims to (1) establish the construct validity of CF in relation to other executive function skills and intelligence, and (2) elucidate specific relationships between CF, structure learning, creativity, career decision making and planning, and other life skills.MethodsThis study will recruit up to 400 healthy Singaporean young adults (age 18-30) to complete a wide range of cognitive tasks and social questionnaires/tasks. The richness of the task/questionnaire battery and within-participant administration enables us to use computational modelling and structural equation modelling to examine connections between the latent constructs of interest.Significance and impactThe current study is the first systematic investigation into the construct validity of CF and its interrelationship with other important cognitive skills such as learning and creativity, within an Asian context. The study will further explore the concept of CF as a non-unitary construct, a novel theoretical proposition in the field. The inclusion of a structure learning paradigm is intended to inform future development of a novel intervention paradigm to enhance CF. Finally, the results of the study will be useful for informing classroom pedagogy and the design of lifelong learning policies and curricula, as part of the wider remit of the Cambridge-NTU Centre for Lifelong Learning and Individualised Cognition (CLIC).

Patients with Parkinson's disease undergo a loss of melanized neurons in substantia nigra pars compacta and locus coeruleus. Very few studies have assessed substantia nigra pars compacta and locus coeruleus pathology in Parkinson's disease simultaneously with magnetic resonance imaging (MRI). Neuromelanin-sensitive MRI measures of substantia nigra pars compacta and locus coeruleus volume based on explicit magnetization transfer contrast have been shown to have high scan-rescan reproducibility in controls, but no study has replicated detection of Parkinson's disease-associated volume loss in substantia nigra pars compacta and locus coeruleus in multiple cohorts with the same methodology. Two separate cohorts of Parkinson's disease patients and controls were recruited from the Emory Movement Disorders Clinic and scanned on two different MRI scanners. In cohort 1, imaging data from 19 controls and 22 Parkinson's disease patients were acquired with a Siemens Trio 3 Tesla scanner using a 2D gradient echo sequence with magnetization transfer preparation pulse. Cohort 2 consisted of 33 controls and 39 Parkinson's disease patients who were scanned on a Siemens Prisma 3 Tesla scanner with a similar imaging protocol. Locus coeruleus and substantia nigra pars compacta volumes were segmented in both cohorts. Substantia nigra pars compacta volume (Cohort 1: p = 0.0148; Cohort 2: p = 0.0011) and locus coeruleus volume (Cohort 1: p = 0.0412; Cohort 2: p = 0.0056) were significantly reduced in the Parkinson's disease group as compared to controls in both cohorts. This imaging approach robustly detects Parkinson's disease effects on these structures, indicating that it is a promising marker for neurodegenerative neuromelanin loss.

Introduction Individuals living with and beyond cancer from rural and remote areas lack accessibility to supportive cancer care resources compared with those in urban areas. Exercise is an evidence-based intervention that is a safe and effective supportive cancer care resource, improving physical fitness and function, well-being and quality of life. Thus, it is imperative that exercise oncology programs are accessible for all individuals living with cancer, regardless of geographical location. To improve accessibility to exercise oncology programs, we have designed the EXercise for Cancer to Enhance Living Well (EXCEL) study.Methods and analysis EXCEL is a hybrid effectiveness-implementation study. Exercise-based oncology knowledge from clinical exercise physiologists supports healthcare professionals and community-based qualified exercise professionals, facilitating exercise oncology education, referrals and programming. Recruitment began in September 2020 and will continue for 5 years with the goal to enroll ~1500 individuals from rural and remote areas. All tumour groups are eligible, and participants must be 18 years or older. Participants take part in a 12-week multimodal progressive exercise intervention currently being delivered online. The reach, effectiveness, adoption, implementation, and maintenance (RE-AIM) framework is used to determine the impact of EXCEL at participant and institutional levels. Physical activity, functional fitness and patient-reported outcomes are assessed at baseline and 12-week time points of the EXCEL exercise intervention.Ethics and dissemination The study was approved by the Health Research Ethics Board of Alberta. Our team will disseminate EXCEL information through quarterly newsletters to stakeholders, including participants, qualified exercise professionals, healthcare professionals and community networks. Ongoing outreach includes community presentations (eg, support groups, fitness companies) that provide study updates and exercise resources. Our team will publish manuscripts and present at conferences on EXCEL’s ongoing implementation efforts across the 5-year study.Trial registration number NCT04478851.

The current standards for health technology cost-effectiveness assessment rest on the creation of lifetime assumption-driven modeled simulations for imaginary pricing and consequent patient access recommendations. A recent BMJ paper reports a detailed assessment of 8,192 cost-effectiveness analyses, concluding that industry-sponsored modeled claims were more likely to publish incremental cost-effectiveness ratios (ICERs) below a USD 50,000 threshold than non-industry sponsored studies, supporting the claim that the product was cost-effective. This is unsurprising; indeed, the opposite can occur with a modeled claim deliberately resulting in ICER is excess of USD 50,000. This methodology is well entrenched with the recently published Consolidated Health Economic Evaluation Reporting Standards (CHEERS) 2022 guidance for creating imaginary cost-effectiveness modeled claims ensuring the opportunity for deliberately manipulated cost-effectiveness claims. This overlooks limitations imposed by fundamental measurement, rendering assumption-driven simulations redundant analytical exercises. Manipulation of ICERs and claims for cost-effectiveness are mathematically impossible; including cost-utility thresholds, because the preference or utilities supporting creation of quality-of-life years (QALYs) are ordinal scores. Nevertheless, with the promotion of CHEERS 2022, the belief in imaginary modeled value claims is both facilitated and reinforced. With CHEERS 2022, there is a concerted effort, largely in self-interest, to perpetuate the current belief system. This is a self-defeating strategy. Rather than admitting to the deficiencies of assumption-driven simulated imaginary claims, leaders are maintaining that health system decision makers can ignore standards of normal science and fundamental measurement in value claims for pharmaceutical products. This disregard of standards that are commonplace in the sciences and mainstream social sciences perpetuates the opportunity for self-serving modeled claims; where models are a marketing vehicle leading to sponsored systematic bias in formulary submissions. This supports the need for a NEW START paradigm for health technology assessment, focusing on evaluable single-attribute value claims, meeting the required standards for normal science and fundamental measurement.

Objectives In December 2020, Derbyshire County Council in England introduced ‘walk-in’ asymptomatic community COVID-19 testing sites. Our study aimed to explore people’s views of the newly established COVID-19 community testing (CT) sites among those who attended and those who did not attend them, alongside gathering individuals’ experiences of attending a CT site to complete a lateral flow test.Setting This qualitative research study comprised of one-to-one interviews with those attending a COVID-19 CT sites in Derbyshire and those from the surrounding area who did not attend.Participants A combination of purposive and convenience sampling was used to recruit those who had (n=18) and those who had not attended (n=15) a walk-in asymptomatic CT site.Results Employers played a key role in raising awareness of the testing sites, with most attending CT at the request of their workplace. The experience of attending a CT site was overwhelmingly positive and those who got tested spoke about the reassurance a negative result offered, knowing they were not passing on the virus when going about their daily lives. However, there was a perception that awareness of CT sites was low across the county and some confusion about who was eligible to attend and under what circumstances. Individuals linked this to low level of advertising they had seen, in addition to a lack of clarity in the information provided.Conclusions People’s experience of attending a ‘walk-in’ asymptomatic CT site in Derbyshire was generally very positive; however, ensuring clear communication for future testing programmes is essential to maximise their uptake.

Abstract Managing age-related decrease of cognitive function is an important public health challenge, especially in the context of the global aging of the population. Over the last years several Cognitive Mobile Games (CMG) have been developed to train and challenge the brain. However, currently the level of evidence supporting the benefits of using CMG in real-life use is limited in older adults, especially at a late age. In this study we analyzed game scores and the processing speed obtained over the course of 100 sessions in 12,000 subjects aged 60 to over 80 years. Users who trained with the games improved regardless of age in terms of scores and processing speed throughout the 100 sessions, suggesting that old and very old adults can improve their cognitive performance using CMG in real-life use.

Background STAMPEDE has previously reported that radiotherapy (RT) to the prostate improved overall survival (OS) for patients with newly diagnosed prostate cancer with low metastatic burden, but not those with high-burden disease. In this final analysis, we report long-term findings on the primary outcome measure of OS and on the secondary outcome measures of symptomatic local events, RT toxicity events, and quality of life (QoL). Methods and findings Patients were randomised at secondary care sites in the United Kingdom and Switzerland between January 2013 and September 2016, with 1:1 stratified allocation: 1,029 to standard of care (SOC) and 1,032 to SOC+RT. No masking of the treatment allocation was employed. A total of 1,939 had metastatic burden classifiable, with 42% low burden and 58% high burden, balanced by treatment allocation. Intention-to-treat (ITT) analyses used Cox regression and flexible parametric models (FPMs), adjusted for stratification factors age, nodal involvement, the World Health Organization (WHO) performance status, regular aspirin or nonsteroidal anti-inflammatory drug (NSAID) use, and planned docetaxel use. QoL in the first 2 years on trial was assessed using prospectively collected patient responses to QLQ-30 questionnaire. Patients were followed for a median of 61.3 months. Prostate RT improved OS in patients with low, but not high, metastatic burden (respectively: 202 deaths in SOC versus 156 in SOC+RT, hazard ratio (HR) = 0·64, 95% CI 0.52, 0.79, p < 0.001; 375 SOC versus 386 SOC+RT, HR = 1.11, 95% CI 0.96, 1.28, p = 0·164; interaction p < 0.001). No evidence of difference in time to symptomatic local events was found. There was no evidence of difference in Global QoL or QLQ-30 Summary Score. Long-term urinary toxicity of grade 3 or worse was reported for 10 SOC and 10 SOC+RT; long-term bowel toxicity of grade 3 or worse was reported for 15 and 11, respectively. Conclusions Prostate RT improves OS, without detriment in QoL, in men with low-burden, newly diagnosed, metastatic prostate cancer, indicating that it should be recommended as a SOC. Trial registration ClinicalTrials.gov NCT00268476, ISRCTN.com ISRCTN78818544. Chris C Parker and colleagues report long-term findings on overall survival and local complications in men with metastatic prostate cancer treated with radiotherapy. Author summary Why was this study done? Prostate cancer is the most common cancer in males. Radiotherapy (RT) to the prostate is widely used as a radical treatment for nonmetastatic prostate cancer. A comparison was added to the STAMPEDE protocol to assess whether RT to the prostate would also be helpful for males with metastatic prostate cancer. A benefit in survival was targeted. The trial previously reported a clinically relevant, statistically significant overall survival (OS) benefit for patients with a low metastatic burden but not for men with a high metastatic burden. This long-term analysis assesses survival with substantially longer follow-up and more events and looked also at complications of local disease. What did the researchers do and find? A randomised controlled trial of adding RT to the prostate to standard of care (SOC) was incorporated into the STAMPEDE protocol. More than 2,000 patients joined the comparison between 2013 and 2016. The data set was frozen in 2021 and analysed using standard methods. There was a clear improvement in survival with prostate RT in the low metastatic burden group. There was no improvement in survival with prostate RT in the high metastatic burden group. Symptomatic local progression and the need for later local intervention were improved with RT in the low metastatic burden group. In the low metastatic burden group, the improvement with RT was similar whether the RT was given with a daily schedule (over 4.5 weeks) or a weekly schedule (over 6 weeks). The adverse effects of RT were manageable without any impact on long-term quality of life (QoL). What do these findings mean? Prostate RT is a relatively cheap, widely accessible, and well-tolerated treatment. Prostate RT is indicated in patients with newly diagnosed prostate cancer with a low metastatic burden. RT to the prostate is not routinely indicated for patients with a high metastatic burden.

Abstract Acute respiratory failure (ARF) requiring mechanical ventilation, a complicating factor in sepsis and other disorders, is associated with high morbidity and mortality. Despite its severity and prevalence, treatment options are limited. In light of accumulating evidence that mitochondrial abnormalities are common in ARF, here we applied broad spectrum quantitative and semiquantitative metabolomic analyses of serum from ARF patients to detect bioenergetic dysfunction and determine its association with survival. Plasma samples from surviving and non-surviving patients (N = 15/group) were taken at day 1 and day 3 after admission to the medical intensive care unit and, in survivors, at hospital discharge. Significant differences between survivors and non-survivors (ANOVA, 5% FDR) include bioenergetically relevant intermediates of redox cofactors nicotinamide adenine dinucleotide (NAD) and NAD phosphate (NADP), increased acyl-carnitines, bile acids, and decreased acyl-glycerophosphocholines. Many metabolites associated with poor outcomes are substrates of NAD(P)-dependent enzymatic processes, while alterations in NAD cofactors rely on bioavailability of dietary B-vitamins thiamine, riboflavin and pyridoxine. Changes in the efficiency of the nicotinamide-derived cofactors’ biosynthetic pathways also associate with alterations in glutathione-dependent drug metabolism characterized by substantial differences observed in the acetaminophen metabolome. Based on these findings, a four-feature model developed with semi-quantitative and quantitative metabolomic results predicted patient outcomes with high accuracy (AUROC = 0.91). Collectively, this metabolomic endotype points to a close association between mitochondrial and bioenergetic dysfunction and mortality in human ARF, thus pointing to new pharmacologic targets to reduce mortality in this condition.

Abstract Ice marginal lakes are a dynamic component of terrestrial meltwater storage at the margin of the Greenland Ice Sheet. Despite their significance to the sea level budget, local flood hazards and bigeochemical fluxes, there is a lack of Greenland-wide research into ice marginal lakes. Here, a detailed multi-sensor inventory of Greenland’s ice marginal lakes is presented based on three well-established detection methods to form a unified remote sensing approach. The inventory consists of 3347 ( $$\pm 8$$ ± 8 %) ice marginal lakes ( $$>0.05\,{{\text{ km }}^{2}}$$ > 0.05 km 2 ) detected for the year 2017. The greatest proportion of lakes lie around Greenland’s ice caps and mountain glaciers, and the southwest margin of the ice sheet. Through comparison to previous studies, a $$\sim 75$$ ∼ 75 % increase in lake frequency is evident over the west margin of the ice sheet since 1985. This suggests it is becoming increasingly important to include ice marginal lakes in future sea level projections, where these lakes will form a dynamic storage of meltwater that can influence outlet glacier dynamics. Comparison to existing global glacial lake inventories demonstrate that up to 56% of ice marginal lakes could be unaccounted for in global estimates of ice marginal lake change, likely due to the reliance on a single lake detection method.

Abstract Background There is a need to develop innovative solutions to enhance safe and green physical environments, which optimise health, wellbeing and community participation among older adults. To develop solutions that meet the needs of a diverse ageing population, an interdisciplinary approach is needed. Our aim was to identify the needs of older people in relation to ageing well in the environment by bringing together knowledge from different perspectives using Patient and Public Involvement. Methods An international consortium (Retrofit living For ageing well through Understanding and Redesign of Built environments consortium: ReFURB) was established in April 2018, including ten core members, to (i) explore cutting-edge solutions to safe living for ageing populations and (ii) develop innovative approaches to everyday physical environments, which bring about health benefits. We used a co-design, interdisciplinary framework involving older adults, carers, physiotherapists, geriatricians, engineers, human movement experts, geographers and psychologists from the UK and Australia. This engaged people in a 1 day workshop that comprised a series of presentations from international speakers on urban design, social connectedness, hazards and injury prevention, and the physical environment. Small group discussions (facilitated by consortium members) followed presentations to consider the opportunities, challenges and barriers encountered with ageing, which included the use of creative engagement activities (LEGO® Serious Play, mind maps, poster gallery walk), to help participants share personal stories and reflect on the issues raised. Thematic coding was used to synthesise the outputs of the small group work. Results Five themes were identified across the workshops: access and transport; involvement of the whole community; restoration rather than redesign; assistive and digital technology; and intergenerational approaches. These dimensions related to the physical, social and nature-based qualities of everyday environments, as they pertain to ageing well. Conclusions Co-design was a valuable tool that helped understand the perceptions of participants and essential to develop effective interventions and solutions. Participants highlighted several issues affecting people as they age and key environmental considerations to promote wellbeing, activity, and participation. The consortium identified gaps in the existing evidence base and are now planning activities to further develop research ideas in collaboration with our co-design participants.

Abstract Background The province of Ontario, Canada, has instituted indefinite school closures (SC) as well as other social distancing measures to mitigate the impact of the novel coronavirus disease 2019 (COVID-19) pandemic. We sought to evaluate the effect of SC on reducing attack rate and the need for critical care during COVID-19 outbreaks, while considering scenarios with concurrent implementation of self-isolation (SI) of symptomatic cases. Methods We developed an age-structured agent-based simulation model and parameterized it with the demographics of Ontario stratified by age and the latest estimates of COVID-19 epidemiologic characteristics. Disease transmission was simulated within and between different age groups by considering inter- and intra-group contact patterns. The effect of SC of varying durations on the overall attack rate, magnitude and peak time of the outbreak, and requirement for intensive care unit (ICU) admission in the population was estimated. Secondly, the effect of concurrent community-based voluntary SI of symptomatic COVID-19 cases was assessed. Results SC reduced attack rates in the range of 7.2–12.7% when the duration of SC increased from 3 to 16 weeks, when contacts among school children were restricted by 60–80%, and in the absence of SI by mildly symptomatic persons. Depending on the scenario, the overall reduction in ICU admissions attributed to SC throughout the outbreak ranged from 3.3 to 6.7%. When SI of mildly symptomatic persons was included and practiced by 20%, the reduction of attack rate and ICU admissions exceeded 6.3% and 9.1% (on average), respectively, in the corresponding scenarios. Conclusion Our results indicate that SC may have limited impact on reducing the burden of COVID-19 without measures to interrupt the chain of transmission during both pre-symptomatic and symptomatic stages. While highlighting the importance of SI, our findings indicate the need for better understanding of the epidemiologic characteristics of emerging diseases on the effectiveness of social distancing measures.

Abstract Background The Canadian Inherited Metabolic Diseases Research Network (CIMDRN) is a pan-Canadian practice-based research network of 14 Hereditary Metabolic Disease Treatment Centres and over 50 investigators. CIMDRN aims to develop evidence to improve health outcomes for children with inherited metabolic diseases (IMD). We describe the development of our clinical data collection platform, discuss our data quality management plan, and present the findings to date from our data quality assessment, highlighting key lessons that can serve as a resource for future clinical research initiatives relating to rare diseases. Methods At participating centres, children born from 2006 to 2015 who were diagnosed with one of 31 targeted IMD were eligible to participate in CIMDRN’s clinical research stream. For all participants, we collected a minimum data set that includes information about demographics and diagnosis. For children with five prioritized IMD, we collected longitudinal data including interventions, clinical outcomes, and indicators of disease management. The data quality management plan included: design of user-friendly and intuitive clinical data collection forms; validation measures at point of data entry, designed to minimize data entry errors; regular communications with each CIMDRN site; and routine review of aggregate data. Results As of June 2019, CIMDRN has enrolled 798 participants of whom 764 (96%) have complete minimum data set information. Results from our data quality assessment revealed that potential data quality issues were related to interpretation of definitions of some variables, participants who transferred care across institutions, and the organization of information within the patient charts (e.g., neuropsychological test results). Little information was missing regarding disease ascertainment and diagnosis (e.g., ascertainment method – 0% missing). Discussion Using several data quality management strategies, we have established a comprehensive clinical database that provides information about care and outcomes for Canadian children affected by IMD. We describe quality issues and lessons for consideration in future clinical research initiatives for rare diseases, including accurately accommodating different clinic workflows and balancing comprehensiveness of data collection with available resources. Integrating data collection within clinical care, leveraging electronic medical records, and implementing core outcome sets will be essential for achieving sustainability.

Emergency vaccination programs often are needed to control outbreaks of meningococcal disease caused by Neisseria meningitidis serogroup B (MenB) on college campuses. Such campaigns expend multiple campus and public health resources. We conducted a randomized, controlled, multicenter, observer-blinded trial comparing immunogenicity and tolerability of an accelerated vaccine schedule of 0 and 21 days to a longer interval of 0 and 60 days for 4-component MenB vaccine (MenB-4C) in students 17–25 years of age. At day 21 after the first MenB-4C dose, we observed protective human serum bactericidal titers >4 to MenB strains 5/99, H44/76, and NZ 98/254 in 98%–100% of participants. Geometric mean titers increased >22-fold over baseline. At day 180, >95% of participants sustained protective titers regardless of their vaccine schedule. The most common adverse event was injection site pain. An accelerated MenB-4C immunization schedule could be considered for rapid control of campus outbreaks.

One of the more unfortunate features of health technology assessment is the tenacity with which leaders in the field and organizations such as the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) and the Institute for Clinical and Economic Review (ICER) cling to an evaluation framework that fails to meet the standards of normal science. Believers subscribe to a meme that is clearly non-science (metaphysics and pseudoscience) and one that should have been discarded over 30 years ago. Certainly, subscribing to an impossible belief is not unusual; indeed it may make the belief that much stronger. Yet the meme is non-sustainable; it is also pointless as the economic evaluation claims are non-evaluable. There is no acknowledgement of the standards of normal science or the limitations imposed by the axioms of fundamental measurement. The purpose of this commentary is to make the case that the recent release of the Consolidated Health Economic Evaluation Reporting Standards 2022 (CHEERS 22) checklist is misleading; CHEERS 22 fails to address the manifest deficiencies in the approach to economic evaluations endorsed by ISPOR and ICER. Instead, it continues to promote economic evaluations in healthcare that invent evidence and non-empirically evaluable value claims. Given the widespread publicity that has accompanied the release of CHEERS 22, the purpose of this commentary is to detail the deficiencies in CHEERS 22 and propose an alternative framework for economic evaluation in health care to meet the information needs of formulary committees. This means abandoning the standards for economic evaluations that have dominated health technology assessment for 30 years, notably the key role assigned to the mathematically impossible quality adjusted life year (QALY). The proposed new start recommends single attribute evaluable value claims that meet ratio or interval measurement standards and are supported by evaluation protocols.

Palaeolithic stone plaquettes are a type of mobiliary art featuring engravings and recovered primarily from Magdalenian sites, where they can number from single finds to several thousand examples. Where context is available, they demonstrate complex traces of use, including surface refreshing, heating, and fragmentation. However, for plaquettes with limited or no archaeological context, research tends to gravitate toward their engraved surfaces. This paper focuses on 50 limestone plaquettes excavated by Peccadeau de l’Isle from Montastruc, a Magdalenian rockshelter site in southern France with limited archaeological context; a feature common to many art bearing sites excavated across the 19th and early 20th Centuries. Plaquette use at Montastruc was explored via a programme of microscopy, 3D modelling, colour enhancement using DStretch©, virtual reality (VR) modelling, and experimental archaeology, the latter focusing on limestone heating related to different functional and non-functional uses. While the limited archaeological context available ensures the results remain only indicative, the data generated suggests plaquettes from Montastruc were likely positioned in proximity to hearths during low ambient light conditions. The interaction of engraved stone and roving fire light made engraved forms appear dynamic and alive, suggesting this may have been important in their use. Human neurology is particularly attuned to interpreting shifting light and shadow as movement and identifying visually familiar forms in such varying light conditions through mechanisms such as pareidolic experience. This interpretation encourages a consideration of the possible conceptual connections between art made and experienced in similar circumstances, such as parietal art in dark cave environments. The toolset used to investigate the Montastruc assemblage may have application to other collections of plaquettes, particularly those with limited associated context.

Background Respiratory syncytial virus (RSV) can cause severe disease in adults with cardiopulmonary conditions, such as congestive heart failure (CHF). We quantified the rate of RSV-associated hospitalization in adults by CHF status using population-based surveillance in the United States. Methods Population-based surveillance for RSV (RSV-NET) was performed in 35 counties in seven sites during two respiratory seasons (2015–2017) from October 1–April 30. Adults (≥18 years) admitted to a hospital within the surveillance catchment area with laboratory-confirmed RSV identified by clinician-directed testing were included. Presence of underlying CHF was determined by medical chart abstraction. We calculated overall and age-stratified (Results 2042 hospitalized RSV cases with CHF status recorded were identified. Most (60.2%, n = 1230) were ≥65 years, and 28.3% (n = 577) had CHF. The adjusted RSV hospitalization rate was 26.7 (95% CI: 22.2, 31.8) per 10,000 population in adults with CHF versus 3.3 (95% CI: 3.3, 3.3) per 10,000 in adults without CHF (RR: 8.1, 95% CI: 6.8, 9.7; RD: 23.4, 95% CI: 18.9, 28.5). Adults with CHF had higher rates of RSV-associated hospitalization in both age groups (Conclusions Adults with CHF had 8 times the rate of RSV-associated hospitalization compared with adults without CHF. Identifying high-risk populations for RSV infection can inform future RSV vaccination policies and recommendations.

Background Haiti has been experiencing a resurgence of diphtheria since December 2014. Little is known about the factors contributing to the spread and persistence of the disease in the country. Geographic information systems (GIS) and spatial analysis were used to characterize the epidemiology of diphtheria in Haiti between December 2014 and June 2021. Methods Data for the study were collected from official and open-source databases. Choropleth maps were developed to understand spatial trends of diphtheria incidence in Haiti at the commune level, the third administrative division of the country. Spatial autocorrelation was assessed using the global Moran’s I. Local indicators of spatial association (LISA) were employed to detect areas with spatial dependence. Ordinary least squares (OLS) and geographically weighted regression (GWR) models were built to identify factors associated with diphtheria incidence. The performance and fit of the models were compared using the adjusted r-squared (R2) and the corrected Akaike information criterion (AICc). Results From December 2014 to June 2021, the average annual incidence of confirmed diphtheria was 0.39 cases per 100,000 (range of annual incidence = 0.04–0.74 per 100,000). During the study period, diphtheria incidence presented weak but significant spatial autocorrelation (I = 0.18, pConclusion This study demonstrates that GIS and spatial analysis can support the investigation of epidemiological patterns. Furthermore, it shows that diphtheria incidence exhibited spatial variability in Haiti. The disease hotspots and potential risk factors identified in this analysis could provide a basis for future public health interventions aimed at preventing and controlling diphtheria transmission.

Retouched lithic tools result from the functional modification of their edges following knapping operations. The study of the later stages of the reduction sequence is fundamental to understanding the techno-functional features of any toolkit. In Australia, a gap exists in the study of the chaîne opératoire of lithic tools shaped or re-shaped through percussion retouching. In our previous works (Martellotta EF., 2021, Martellotta EF., 2022), we have presented evidence for the use of hardwood boomerangs for retouching purposes in Australian Aboriginal communities. Through a detailed experimental protocol, the present study demonstrates how boomerangs can function as retouchers. We found that the use-wear generated on the boomerang's surface during retouch activity is comparable to retouch-induced impact traces observed on Palaeolithic bone retouchers, as well as to experimental bone retouchers generated in our replication experiments. Finally, we explore the role that microscopic lithic chips embedded in the retouchers' surface play in the formation process of retouching marks. Our results address the need for a deeper investigation of percussion retouching techniques in Australian contexts, opening the possibility that uncommon objects-such as boomerangs-could be used for this task. This concept also highlights the broader topic of the highly diverse multipurpose application of many Indigenous tools throughout Australia. At the same time, the study reveals a deep functional connection between osseous and wooden objects-a topic rarely investigated in archaeological contexts.

Abstract Background and Aims In the United States, respiratory infections due to respiratory syncytial virus (RSV) cause an estimated 57 000 hospitalizations annually among children aged

Background: Volunteer programs that support older persons can assist them in accessing healthcare in an efficient and effective manner. Community-based initiatives that train volunteers to support patients with advancing illness is an important advance for public health. As part of implementing an effective community-based volunteer-based program, volunteers need to be sufficiently trained. Online training could be an effective and safe way to provide education for volunteers in both initial training and/or continuing education throughout their involvement as a volunteer.Method: We conducted an integrative review that synthesized literature on online training programs for volunteers who support older adults. The review included both a search of existing research literature in six databases, and an online search of online training programs currently being delivered in Canada. The purpose of this review was to examine the feasibility and acceptability of community-based organizations adopting an online training format for their volunteers.Results: The database search identified 13,626 records, these went through abstract and full text screen resulting in a final 15 records. This was supplemented by 2 records identified from hand searching the references, for a total of 17 articles. In addition to identifying Volunteers Roles and Responsibilities; Elements of Training; and Evaluation of Feasibility and Acceptability; a thematic analysis of the 17 records identified the categories: (1) Feasibility Promoting Factors; (2) Barriers to Feasibility; (3) Acceptability Promoting Factors; and (4) Barriers to Acceptability. Six programs were also identified in the online search of online training programs. These programs informed our understanding of delivery of existing online volunteer training programs.Discussion: Findings suggested that feasibility and acceptability of online training were promoted by (a) topic relevant training for volunteers; (b) high engagement of volunteers to prevent attrition; (c) mentorship or leadership component. Challenges to online training included a high workload; time elapsed between training and its application; and client attitude toward volunteers. Future research on online volunteer training should consider how online delivery can be most effectively paced to support volunteers in completing training and the technical skills needed to complete the training and whether teaching these skills can be integrated into programs.