Genetic Risk Factors in Isolated Dystonia Escape Genome-Wide Association Studies.

BACKGROUND: Despite considerable heritability, previous smaller genome-wide association studies (GWASs) have not identified any robust genetic risk factors for isolated dystonia. OBJECTIVE: The objective of this study was to perform a large-scale GWAS in a well-characterized, multicenter sample of >6000 individuals to identify genetic risk factors for isolated dystonia. METHODS: Array-based GWASs were performed on autosomes for 4303 dystonia participants and 2362 healthy control subjects of European ancestry with subgroup analysis based on age at onset, affected body regions, and a newly developed clinical score. Another 736 individuals were used for validation. RESULTS: This GWAS identified no common genome-wide significant loci that could be replicated despite sufficient power to detect meaningful effects. Power analyses imply that the effects of individual variants are likely very small. CONCLUSIONS: Moderate single-nucleotide polymorphism-based heritability indicates that common variants do not contribute to isolated dystonia in this cohort. Sequence-based GWASs (eg, by whole-genome sequencing) might help to better understand the genetic basis. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Delirium is more common and associated with worse outcomes in Parkinson's disease compared to older adult controls: results of two prospective longitudinal cohort studies.

BACKGROUND: Inpatient prevalence of Parkinson's disease (PD) delirium varies widely across the literature. Delirium in general older populations is associated with adverse outcomes, such as increased mortality, dementia, and institutionalisation. However, to date there are no comprehensive prospective studies in PD delirium. This study aimed to determine delirium prevalence in hospitalised PD participants and the association with adverse outcomes, compared to a control group of older adults without PD. METHODS: Participants were hospitalised inpatients from the 'Defining Delirium and its Impact in Parkinson's Disease' and the 'Delirium and Cognitive Impact in Dementia' studies comprising 121 PD participants and 199 older adult controls. Delirium was diagnosed prospectively using the Diagnostic and Statistical Manual of Mental Disorders 5th Edition criteria. Outcomes were determined by medical note reviews and/or home visits 12 months post hospital discharge. RESULTS: Delirium was identified in 66.9% of PD participants compared to 38.7% of controls (p < 0.001). In PD participants only, delirium was associated with a significantly higher risk of mortality (HR = 3.3 (95% confidence interval [CI] = 1.3-8.6), p = 0.014) and institutionalisation (OR = 10.7 (95% CI = 2.1-54.6), p = 0.004) 12 months post-discharge, compared to older adult controls. However, delirium was associated with an increased risk of developing dementia 12 months post-discharge in both PD participants (OR = 6.1 (95% CI = 1.3-29.5), p = 0.024) and in controls (OR = 13.4 (95% CI = 2.5-72.6), p = 0.003). CONCLUSION: Delirium is common in hospitalised PD patients, affecting two thirds of patients, and is associated with increased mortality, institutionalisation, and dementia. Further research is essential to understand how to accurately identify, prevent and manage delirium in people with PD who are in hospital.

Remote area nurses' experiences of workplace safety in very remote primary health clinics: A qualitative study.

AIM: To explore Remote Area Nurses' experiences of the implementation of workplace health and safety policies and risk mitigation strategies in Australian very remote primary health clinics. DESIGN: This qualitative study used online semi-structured interviews, with participants purposively sampled to maximize variation in work location and service type. Data were analysed using a reflexive thematic analysis approach. Coding was carried out inductively, with NVivo 12 aiding data management. SETTING: The interviews were conducted from 24 Februrary 2021 to 06 March 2021 with Remote Area Nurses from very remote primary health clinics in Australia. PARTICIPANTS: Fifteen Remote Area Nurses participated in the study. RESULTS: Thematic analysis revealed varied approaches to workplace safety among the different health services and regions. While the spread of 'never alone' policies in many clinics addressed one of the significant risks faced by Remote Area Nurses, gaps remained even for hazards specifically highlighted in existing work health and safety legislation. Meaningful collaboration with staff and the community, local orientation, preparation for the role and providing quality care were protective factors for staff safety. Understaffing, unsafe infrastructure and inadequate equipment were common concerns among Remote Area Nurses. CONCLUSION: Health services need to prioritize workplace safety and take a continuous quality improvement approach to its implementation. This will include ensuring safety strategies are appropriate for the local context, improving infrastructure maintenance, and establishing sustainable second responder systems such as a pool of drivers with local knowledge. IMPLICATIONS FOR THE PROFESSION: Poor personal safety contributes to burnout and high turnover of staff. Nurses' insights into the barriers and enablers of current workplace safety strategies will aid policymakers and employers in future improvements. REPORTING METHOD: COREQ reporting guidelines were followed. PIPE STATEMENT: A panel of six Remote Area Nurses collaborated in the development of this project.

Deepening our understanding: Collaboration through online peer-to-peer participatory action research with children.

Child-led research is growing globally, yet there are still limitations for children's leadership in all phases of research. This article, co-written with adult and child researchers, examines child-led research undertaken online with 9 children from Ontario and Quebec over a one-year period. The article explores the process of participating in and collaborating on an online peer-to-peer participatory action research project from the brainstorming stage to recruitment, design, data collection, analysis, and dissemination of knowledge. While much literature exists on older children and youth leading research, this research provides a unique contribution to the literature on the possibilities of creating space for children ages 11 to 14 to lead research. This article finds that the child researchers most valued: (1) Play and fun; (2) Engaging in new experiences; and (3) Learning. The article concludes that child-led research is feasible, and it can create better research and provide a transformative opportunity for child and adult researchers.

Examining workplace safety for remote area nurses in Australia: a cross-sectional descriptive study.

INTRODUCTION: Australia's remote health sector has chronic understaffing issues and serves an isolated, culturally diverse population with a high burden of disease. Workplace health and safety (WHS) impacts the wellbeing and sustainability of the remote health workforce. Additionally, poor WHS contributes to burnout, high turnover of staff and reduced quality of care. The issue of poor WHS in Australian very remote primary health clinics was highlighted by the murder of remote area nurse (RAN) Gayle Woodford in 2016. Following her death, a national call for change led by peak bodies and Gayle's family resulted in the development of many WHS recommendations and strategies for the remote health sector. However, it is unclear whether they have been implemented. The aim of this study is to identify which WHS recommendations have been implemented, from the perspective of RANs. METHODS: A cross-sectional online survey of 173 RANs was conducted during December 2020 and January 2021. The survey was open to all RANs who had worked in a very remote (MM 7 of the Modified Monash (MM) Model) primary health clinic in Australia more recently than January 2019. A convenience sampling approach was used. The survey tool was developed by the project team using a combination of validated tools and remote-specific workplace safety recommendations. Broad recommendations, such as having a safe clinic building, safe staff accommodation, local orientation, and 'never alone' policy, were broken down into specific safety criteria. These criteria were used to generate workplace safety scores to quantify how well each recommendation had been met, and clustered into the following domains: preparation of staff, safe work environment and safe work practices. Descriptive statistics were used and the safety scores between different states and territories were also compared. RESULTS: Overall, the average national workplace safety score was 53% (standard deviation (SD) 19.8%) of recommendations met in participants' most recent workplace, with median 38.5% (interquartile range (IQR) 15.4-61.5%) of staff preparation recommendations, median 59.4% (IQR 43.8-78.1%) of safe work environment recommendations, and median 50.0% (IQR 30.0-66.7%) of safe work practices recommendations met. Within domains, some recommendations had greater uptake than others, and the safety scores of different states/territories also varied. Significant variation was found between the Northern Territory (57.5%, SD 18.7%) and Queensland (41.7%, SD 16.7%) (p<0.01), and between South Australia (74.5%, IQR 35.9%) and Queensland (p<0.05). Last, many RANs were still expected to attend after-hours call-outs on their own, with only 64.1% (n=107/167) of participants reporting a 'never alone' policy or process in their workplace. CONCLUSION: The evidence from this study revealed that some recommended safety strategies had been implemented, but significant gaps remained around staff preparation, fatigue management and infrastructure safety. Ongoing poor WHS likely contributes to the persistently high turnover of RANs, negatively affecting the quality and continuity of health care in remote communities. Variation in safety scores between regions warns of a fragmentation of approaches to WHS within the remote health sector, despite the almost identical WHS legislation in different states/territories. These gaps highlight the need to establish and enforce a national minimum standard of workplace safety in the remote health sector.

The effects of joint hypermobility on pain and functional biomechanics in adolescents with juvenile fibromyalgia: secondary baseline analysis from a pilot randomized controlled trial.

BACKGROUND: Joint hypermobility is a common clinical finding amongst hereditary connective tissue disorders that is observed in pediatric rheumatological settings, and often associated with chronic pain. Joint hypermobility may also contribute to deficits in physical functioning and physical activity, but previous findings have been inconsistent. It is possible that physical activity impairment in joint hypermobility may be due to chronic aberrant movement patterns subsequent to increased joint laxity. METHOD: As part of a larger randomized pilot trial of juvenile onset fibromyalgia (JFM), a secondary analysis was conducted to explore whether adolescents with JFM and joint hypermobility differed from non-joint hypermobility peers in terms of pain, daily functioning, and biomechanics (i.e., kinetics and kinematics) during a moderately vigorous functional task. RESULTS: From the larger sample of adolescents with JFM (N = 36), 13 adolescents (36.1%) met criteria for joint hypermobility and 23 did not have joint hypermobility. Those with joint hypermobility exhibited poorer overall functioning (Md = 20, Q1,Q3 [5.8, 7.6] vs. Md = 29, Q1,Q3 [5.1, 7.6]) but there were no differences in pain (Md = 6.9, Q1,Q3 [22, 33], vs. Md = 6.45, Q1,Q3 [15, 29.5]). Inspection of time-series plots suggests those with joint hypermobility exhibited decreased hip flexion and frontal plane hip moment (e.g., resistance to dynamic valgus) during the landing phase (early stance) and greater hip and knee transverse plane moments during the propulsion phase (late stance) of the drop vertical jump task (DVJ). No other differences in lower extremity biomechanics were observed between study groups. CONCLUSIONS: In this exploratory study, there were small but notable differences in biomechanics between patients with JFM who also had joint hypermobility versus those without joint hypermobility during a landing and jumping task (e.g., DVJ). These differences may indicate decreased joint stiffness during landing, associated with increased joint laxity and decreased joint stability, which may put them at greater risk for injury. Further study with a larger sample size is warranted to examine whether these biomechanical differences in patients with JFM and joint hypermobility affect their response to typical physical therapy or exercise recommendations.

Examining the associations between physical activity, self-esteem, perceived stress, and internalizing symptoms among older adolescents.

INTRODUCTION: In older adolescence, stress has been found to be prevalent. It has been seen that higher physical activity (PA) relates to lower stress levels, which, in turn, relates to fewer anxiety and depressive symptoms (internalizing symptoms). However, how these associations function is not fully understood. PA is strongly associated with greater self-esteem in adolescents. As greater self-esteem is thought to aid better coping with stress and has been seen as beneficial for mental health in adolescents, PA may be associated with lower stress and better mental health through self-esteem and more adaptive stress appraisals. Therefore, the aim of the study was to examine the relationships between PA, self-esteem, stress, and mental health. METHODS: A cross-sectional design was employed, and path analysis was implemented. PA, self-esteem, stress appraisals, distress tolerance, perceived stress, anxiety, and depression were assessed using online questionnaires from 244 adolescent participants from the United Kingdom (aged 15-19, M = 16.75 [SD = 0.82], 145 female). RESULTS: Path analysis revealed that PA was associated with lower perceived stress through increased self-esteem, adaptive appraisals, and higher distress tolerance (total standardized indirect effect; p = .007 (-0.25 to -0.11). Moreover, lower perceived stress was associated with lower anxiety (standardized direct effect; p < .001 [2.65-4.0] and depressive symptoms (standardized direct effect; p < .001 [0.33-0.63]). CONCLUSIONS: Findings suggest that higher PA could be effective in improving mental health among older adolescents, due to its association with perceived stress through higher self-esteem and more adaptive appraisals of stress.

Pain and QOL in Pediatric Sickle Cell Disease: Buffering by Resilience Processes.

OBJECTIVE: Sickle cell disease (SCD) is a group of inherited blood disorders. The central feature of this chronic condition is pain. Several identified risk factors exacerbate the impact of pain on quality of life (QOL) in SCD; however, there are relatively fewer investigations of strengths-based resilience variables that might buffer the influence of pain on living with SCD. The purpose of this study was to examine strength-based resilience processes in youth with SCD and their parents. Grounded in an ecological resilience-risk model, we evaluated whether adolescent and parent protective factors (pain acceptance, mindfulness, and psychological flexibility) moderated the relation between adolescent-reported pain burden and QOL. METHODS: Ninety-three 12- to 18-year-old adolescents with SCD and their parents participated. Adolescents completed assessments of pain characteristics, pain acceptance, mindfulness, and QOL. Parents completed instruments measuring demographic and disease variables and parent psychological flexibility. RESULTS: Pain variables were associated with protective factors in predicted directions. Adolescent acceptance and mindfulness were positively correlated with QOL. Parent psychological flexibility and adolescent QOL were not related. After controlling for demographic, pain, and disease variables, moderation analyses indicated that adolescent pain acceptance buffered the relation between SCD pain burden and QOL. Moderation analyses were not significant for adolescent mindfulness or parent psychological flexibility. CONCLUSIONS: Results suggest that strengths-based factors may play an important role for adolescents' QOL within the context of SCD pain. Interventions that enhance teenagers' ability to accept pain might be particularly useful to improve QOL in adolescents living with SCD pain.

Clinical and Demographic Characteristics of Upper Limb Dystonia.

BACKGROUND: Knowledge of characteristics in upper limb dystonia remains limited, derived primarily from small, single-site studies. OBJECTIVE: The objective of this study was to characterize demographic and clinical characteristics of upper limb dystonia from the Dystonia Coalition data set, a large, international, multicenter resource. METHODS: We evaluated clinical and demographic characteristics of 367 participants with upper limb dystonia from onset, comparing across subcategories of focal (with and without dystonia spread) versus nonfocal onset. RESULTS: Focal onset occurred in 80%; 67% remained focal without spread. Task specificity was most frequent in this subgroup, most often writer's cramp and affecting the dominant limb (83%). Focal onset with spread was more frequent in young onset (<21 years). Focal onset occurred equally in women and men; nonfocal onset affected women disproportionately. CONCLUSIONS: Upper limb dystonia distribution, focality, and task specificity relate to onset age and likelihood of regional spread. Observations may inform clinical counseling and design, execution, and interpretation of future studies. © 2020 International Parkinson and Movement Disorder Society.

Re-drawing the Maps for Endemic Mycoses.

Endemic mycoses such as histoplasmosis, coccidioidomycosis, blastomycosis, paracoccidioidomycosis, and talaromycosis are well-known causes of focal and systemic disease within specific geographic areas of known endemicity. However, over the past few decades, there have been increasingly frequent reports of infections due to endemic fungi in areas previously thought to be "non-endemic." There are numerous potential reasons for this shift such as increased use of immune suppressive medications, improved diagnostic tests, increased disease recognition, and global factors such as migration, increased travel, and climate change. Regardless of the causes, it has become evident that our previous understanding of endemic regions for these fungal diseases needs to evolve. The epidemiology of the newly described Emergomyces is incomplete; our understanding of it continues to evolve. This review will focus on the evidence underlying the established areas of endemicity for these mycoses as well as new data and reports from medical literature that support the re-thinking these geographic boundaries. Updating the endemic fungi maps would inform clinical practice and global surveillance of these diseases.

Union Transitions and Fertility Within First Premarital Cohabitations in Canada: Diverging Patterns by Education?

Cohabitation has become increasingly accepted and normalized as part of the family system in Canada and has become the most common way to form a first union. The changing role of cohabitation in the family system is often understood as being driven by the ideational changes associated with the second demographic transition, but increasing international evidence indicates that this explanation is incomplete. Using nationally representative retrospective data from Canadians born between 1940 and 1979 from the 2011 General Social Survey, this study examines transitions out of first premarital cohabitation and fertility within these unions as two measures of the changing role of cohabitation. Across birth cohorts, Canadians are increasingly likely to use cohabitation as an alternative to marriage and less likely to use cohabitation as a short-lived prelude to marriage. These overall trends support the second demographic transition perspective. However, this study also finds that Canadians without a bachelor's degree are far more likely to experience a birth within cohabitation and that their likelihood of transitioning to marriage has declined steeply across birth cohorts. This educational gradient in childbearing in cohabitation and the increasing educational differences in union transitions over time provide support for the diverging destinies thesis in Canada.

Adding Value by Working with Sponsored Projects.

This case study describes how librarians at Rudolph Matas Library of the Health Sciences at Tulane University have partnered and worked with several departments that fall under the Vice President of Research. Examples include detailed literature searches, cooperative purchasing, and clinical trial registration. Some upcoming activities and opportunities for collaboration will also be discussed. Finally, the authors will share some valuable lessons learned through the process of collaboration with the research infrastructure of the university.

Spectral Shearing of Quantum Light Pulses by Electro-Optic Phase Modulation.

Frequency conversion of nonclassical light enables robust encoding of quantum information based upon spectral multiplexing that is particularly well-suited to integrated-optics platforms. Here we present an intrinsically deterministic linear-optics approach to spectral shearing of quantum light pulses and show it preserves the wave-packet coherence and quantum nature of light. The technique is based upon an electro-optic Doppler shift to implement frequency shear of heralded single-photon wave packets by ±200 GHz, which can be scaled to an arbitrary shift. These results demonstrate a reconfigurable method to controlling the spectral-temporal mode structure of quantum light that could achieve unitary operation.

Healthy Grandparenthood: How Long Is It, and How Has It Changed?

Healthy grandparenthood represents the period of overlap during which grandparents and grandchildren can build relationships, and grandparents can make intergenerational transfers to younger kin. The health of grandparents has important implications for upward and downward intergenerational transfers within kinship networks in aging societies. Although the length of grandparenthood is determined by fertility and mortality patterns, the amount of time spent as a healthy grandparent is also affected by morbidity. In this study, we estimate the length of healthy grandparenthood for the first time. Using U.S. and Canadian data, we examine changes in the length of healthy grandparenthood during years when grandparenthood was postponed, health improved, and mortality declined. We also examine variation in healthy grandparenthood by education and race/ethnicity within the United States. Our findings show that the period of healthy grandparenthood is becoming longer because of improvements in health and mortality, which more than offset delays in grandparenthood. Important variation exists within the United States by race/ethnicity and education, which has important implications for family relationships and transfers.

Clinical and demographic characteristics related to onset site and spread of cervical dystonia.

BACKGROUND: Clinical characteristics of isolated idiopathic cervical dystonia such as onset site and spread to and from additional body regions have been addressed in single-site studies with limited data and incomplete or variable dissociation of focal and segmental subtypes. The objectives of this study were to characterize the clinical characteristics and demographics of isolated idiopathic cervical dystonia in the largest standardized multicenter cohort. METHODS: The Dystonia Coalition, through a consortium of 37 recruiting sites in North America, Europe, and Australia, recruited 1477 participants with focal (60.7%) or segmental (39.3%) cervical dystonia on examination. Clinical and demographic characteristics were evaluated in terms of the body region of dystonia onset and spread. RESULTS: Site of dystonia onset was: (1) focal neck only (78.5%), (2) focal onset elsewhere with later segmental spread to neck (13.3%), and (3) segmental onset with initial neck involvement (8.2%). Frequency of spread from focal cervical to segmental dystonia (22.8%) was consistent with prior reports, but frequency of segmental onset with initial neck involvement was substantially higher than the 3% previously reported. Cervical dystonia with focal neck onset, more than other subtypes, was associated with spread and tremor of any type. Sensory tricks were less frequent in cervical dystonia with segmental components, and segmental cervical onset occurred at an older age. CONCLUSIONS: Subgroups had modest but significant differences in the clinical characteristics that may represent different clinical entities or pathophysiologic subtypes. These findings are critical for design and implementation of studies to describe, treat, or modify disease progression in idiopathic isolated cervical dystonia. © 2016 International Parkinson and Movement Disorder Society.

High-Resolution Analysis by Whole-Genome Sequencing of an International Lineage (Sequence Type 111) of Pseudomonas aeruginosa Associated with Metallo-Carbapenemases in the United Kingdom.

Whole-genome sequencing (WGS) was carried out on 87 isolates of sequence type 111 (ST-111) of Pseudomonas aeruginosa collected between 2005 and 2014 from 65 patients and 12 environmental isolates from 24 hospital laboratories across the United Kingdom on an Illumina HiSeq instrument. Most isolates (73) carried VIM-2, but others carried IMP-1 or IMP-13 (5) or NDM-1 (1); one isolate had VIM-2 and IMP-18, and 7 carried no metallo-beta-lactamase (MBL) gene. Single nucleotide polymorphism analysis divided the isolates into distinct clusters; the NDM-1 isolate was an outlier, and the IMP isolates and 6/7 MBL-negative isolates clustered separately from the main set of 73 VIM-2 isolates. Within the VIM-2 set, there were at least 3 distinct clusters, including a tightly clustered set of isolates from 3 hospital laboratories consistent with an outbreak from a single introduction that was quickly brought under control and a much broader set dominated by isolates from a long-running outbreak in a London hospital likely seeded from an environmental source, requiring different control measures; isolates from 7 other hospital laboratories in London and southeast England were also included. Bayesian evolutionary analysis indicated that all the isolates shared a common ancestor dating back ∼50 years (1960s), with the main VIM-2 set separating approximately 20 to 30 years ago. Accessory gene profiling revealed blocks of genes associated with particular clusters, with some having high similarity (≥95%) to bacteriophage genes. WGS of widely found international lineages such as ST-111 provides the necessary resolution to inform epidemiological investigations and intervention policies.

Dominance of international 'high-risk clones' among metallo-ß-lactamase-producing Pseudomonas aeruginosa in the UK.

OBJECTIVES: Carbapenem-resistant isolates of Pseudomonas aeruginosa producing metallo-ß-lactamases (MBLs) are increasingly reported worldwide and often belong to particular 'high-risk clones'. This study aimed to characterize a comprehensive collection of MBL-producing P. aeruginosa isolates referred to the UK national reference laboratory from multiple UK laboratories over a 10 year period. METHODS: Isolates were referred to the UK national reference laboratory between 2003 and 2012 for investigation of resistance mechanisms and/or outbreaks. MBL genes were detected by PCR. Typing was carried out by nine-locus variable-number tandem repeat (VNTR) analysis and MLST. RESULTS: MBL-producing P. aeruginosa isolates were referred from 267 source patients and 89 UK laboratories. The most common isolation sites were urine (24%), respiratory (18%), wounds (17%) and blood (13%). VIM-type MBLs predominated (91% of all MBLs found), but a few IMP- and NDM-type enzymes were also identified. Diverse VNTR types were seen, but 86% of isolates belonged to six major complexes. MLST of representative isolates from each complex showed that they corresponded to STs 111, 233, 235, 357, 654 and 773, respectively. Isolates belonging to these complexes were received from between 9 and 25 UK referring laboratories each. CONCLUSIONS: The incidence of MBL-producing P. aeruginosa is increasing in the UK. The majority of these isolates belong to several 'high-risk clones', which have been previously reported internationally as host clones of MBLs.

Genetic environment of metallo-ß-lactamase genes in Pseudomonas aeruginosa isolates from the UK.

OBJECTIVES: We sought to characterize the genetic environment of blaVIM and blaIMP genes in Pseudomonas aeruginosa isolates from the UK; these included members of six previously described prevalent complexes, A-F, which correspond to international 'high-risk clones', along with diverse strains. METHODS: Metallo-ß-lactamase (MBL)-encoding class 1 integrons were amplified by PCR from 218 P. aeruginosa isolates producing VIM-type (n = 196) or IMP-type (n = 22) enzymes, referred from UK hospital laboratories between 2003 and 2012. The variable regions of selected integrons were sequenced using a primer walking method. RESULTS: One-hundred-and-nineteen isolates had an MBL-encoding integron with the 3' conserved sequence (3'CS), 65 had Tn5090-like 3' regions and 17 had the sul1 gene, but lacked the qacEΔ1 gene; the 3' region could not be amplified using any primer combinations for the remaining 17 isolates. Six integron profiles were each seen in more than five isolates. Predominant integron types were seen amongst isolates belonging to STs 111, 233, 654/964 and 773 (complexes A, C, D and F, respectively), whereas diverse integron profiles were seen in isolates belonging to ST235 (complex B) and ST357 (complex E). CONCLUSIONS: In UK P. aeruginosa isolates, MBL genes occur in diverse class 1 integron structures, though commonly with 3' regions containing the classical 3'CS or Tn5090-like regions. Four of the six main clonal complexes, referred from multiple laboratories, carried a predominant integron type, whereas the remaining two had more diverse types.

APOE ε4 positivity predicts centrality of episodic memory nodes in patients with mild cognitive impairment: A cohort-based, graph theory-informed study of cognitive networks.

As network neuroscience can capture the systemic impact of APOE variability at a neuroimaging level, this study investigated the network-based cognitive endophenotypes of ε4-carriers and non-carriers across the continuum between normal ageing and Alzheimer's dementia (AD). We hypothesised that the impact of APOE-ε4 on cognitive functioning can be reliably captured by the measurement of graph-theory centrality. Cognitive networks were calculated in 8118 controls, 3482 MCI patients and 4573 AD patients, recruited in the National Alzheimer's Coordinating Center (NACC) database. Nodal centrality was selected as the neurofunctional readout of interest. ε4-carrier-vs.-non-carrier differences were tested in two independent NACC sub-cohorts assessed with either Version 1 or Version 2 of the Uniform Data Set neuropsychological battery. A significant APOE-dependent effect emerged from the analysis of the Logical-Memory nodes in MCI patients in both sub-cohorts. While non-carriers showed equal centrality in immediate and delayed recall, the latter was significantly less central among carriers (v1: bootstrapped confidence interval 0.107-0.667, p < 0.001; v2: bootstrapped confidence interval 0.018-0.432, p < 0.001). This indicates that, in carriers, delayed recall was, overall, significantly more weakly correlated with the other cognitive scores. These findings were replicated in the sub-groups of sole amnestic-MCI patients (n = 2971), were independent of differences in network communities, clinical severity or other demographic factors. No effects were found in the other two diagnostic groups. APOE-ε4 influences nodal properties of cognitive networks when patients are clinically classified as MCI. This highlights the importance of characterising the impact of risk factors on the wider cognitive network via network-neuroscience methodologies.

Effect of Age at Time of Irradiation, Sex, Genetic Diversity, and Granulopoietic Cytokine Radiomitigation on Lifespan and Lymphoma Development in Murine H-ARS Survivors.

Acute, high-dose radiation exposure results in life-threatening acute radiation syndrome (ARS) and debilitating delayed effects of acute radiation exposure (DEARE). The DEARE are a set of chronic multi-organ illnesses that can result in early death due to malignancy and other diseases. Animal models have proven essential in understanding the natural history of ARS and DEARE and licensure of medical countermeasures (MCM) according to the FDA Animal Rule. Our lab has developed models of hematopoietic (H)-ARS and DEARE in inbred C57BL/6J and Jackson Diversity Outbred (JDO) mice of both sexes and various ages and have used these models to identify mechanisms of radiation damage and effective MCMs. Herein, aggregate data from studies conducted over decades in our lab, consisting of 3,250 total-body lethally irradiated C57BL/6J young adult mice and 1,188 H-ARS survivors from these studies, along with smaller datasets in C57BL/6J pediatric and geriatric mice and JDO mice, were examined for lifespan and development of thymic lymphoma in survivors up to 3 years of age. Lifespan was found to be significantly shortened in H-ARS survivors compared to age-matched nonirradiated controls in all four models. Males and females exhibited similar lifespans except in the young adult C57BL/6J model where males survived longer than females after 16 months of age. The incidence of thymic lymphoma was increased in H-ARS survivors from the young adult and pediatric C57BL/6J models. Consistent with our findings in H-ARS, geriatric mice appeared more radioresistant than other models, with a lifespan and thymic lymphoma incidence more similar to nonirradiated controls than other models. Increased levels of multiple pro-inflammatory cytokines in DEARE bone marrow and serum correlated with shortened lifespan and malignancy, consistent with other animal models and human data. Of interest, G-CSF levels in bone marrow and serum 8-11 months after irradiation were significantly increased in females. Importantly, treatment with granulopoietic cytokine MCM for radiomitigation of H-ARS did not influence the long-term survival rate or incidence of thymic lymphoma in any model. Taken together, these findings indicate that the lifespan of H-ARS survivors was significantly decreased regardless of age at time of exposure or genetic diversity, and was unaffected by earlier treatment with granulopoietic cytokines for radiomitigation of H-ARS.