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The concept of brain reserve capacity has emerged in stroke recovery research in recent years. Imaging-based biomarkers of brain health have helped to better understand outcome variability in clinical cohorts. Still, outcome inferences are far from being satisfactory, particularly in patients with severe initial deficits. Neurorehabilitation after stroke is a complex process, comprising adaption and learning processes, which, on their part, are critically influenced by motivational and reward-related cognitive processes. Amongst others, dopaminergic neurotransmission is a key contributor to these mechanisms. The question arises, whether the amount of structural reserve capacity in the dopaminergic system might inform about outcome variability after severe stroke. For this purpose, this study analysed imaging and clinical data of 42 severely impaired acute stroke patients. Brain volumetry was performed within the first 2 weeks after the event using the Computational Anatomy Toolbox CAT12, grey matter volume estimates were collected for seven key areas of the human dopaminergic system along the mesocortical, mesolimbic and nigrostriatal pathways. Ordinal logistic regression models related regional volumes to the functional outcome, operationalized by the modified Rankin Scale, obtained 3-6 months after stroke. Models were adjusted for age, lesion volume and initial impairment. The main finding was that larger volumes of the amygdala and the nucleus accumbens at baseline were positively associated with a more favourable outcome. These data suggest a link between the structural state of mesolimbic key areas contributing to motor learning, motivational and reward-related brain networks and potentially the success of neurorehabilitation. They might also provide novel evidence to reconsider dopaminergic interventions particularly in severely impaired stroke patients to enhance recovery after stroke., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Brain imaging and electrophysiology have significantly enhanced our current understanding of stroke-related changes in brain structure and function and their implications for recovery processes. In the motor domain, most studies have focused on key motor areas of the frontal lobe including the primary and secondary motor cortices. Time- and recovery-dependent alterations in regional anatomy, brain activity and inter-regional connectivity have been related to recovery. In contrast, the involvement of posterior parietal cortical areas in stroke recovery is poorly understood although these regions are similarly important for important aspects of motor functioning in the healthy brain. Just in recent years, the field has increasingly started to explore to what extent posterior parietal cortical areas might undergo equivalent changes in task-related activation, regional brain structure and inter-regional functional and structural connectivity after stroke. The aim of this scoping review is to give an update on available data covering these aspects and thereby providing novel insights into parieto-frontal interactions for systems neuroscience stroke recovery research in the upper limb motor domain., Competing Interests: The authors report no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Cortical thickness analyses have provided valuable insights into changes in cortical brain structure after stroke and their association with recovery. Across studies though, relationships between cortical structure and function show inconsistent results. Recent developments in diffusion-weighted imaging of the cortex have paved the way to uncover hidden aspects of stroke-related alterations in cortical microstructure, going beyond cortical thickness as a surrogate for cortical macrostructure. We re-analysed clinical and imaging data of 42 well-recovered chronic stroke patients from 2 independent cohorts (mean age 64 years, 4 left-handed, 71% male, 16 right-sided strokes) and 33 healthy controls of similar age and gender. Cortical fractional anisotropy and cortical thickness values were obtained for six key sensorimotor areas of the contralesional hemisphere. The regions included the primary motor cortex, dorsal and ventral premotor cortex, supplementary and pre-supplementary motor areas, and primary somatosensory cortex. Linear models were estimated for group comparisons between patients and controls and for correlations between cortical fractional anisotropy and cortical thickness and clinical scores. Compared with controls, stroke patients exhibited a reduction in fractional anisotropy in the contralesional ventral premotor cortex ( P = 0.005). Fractional anisotropy of the other regions and cortical thickness did not show a comparable group difference. Higher fractional anisotropy of the ventral premotor cortex, but not cortical thickness, was positively associated with residual grip force in the stroke patients. These data provide novel evidence that the contralesional ventral premotor cortex might constitute a key sensorimotor area particularly susceptible to stroke-related alterations in cortical microstructure as measured by diffusion MRI and they suggest a link between these changes and residual motor output after stroke., Competing Interests: The authors report no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Competing Interests: Conflict of interest P.F. is the founder and CEO of Pharmahungary Group, a group of R&D companies. The other authors have no conflict of interest to declare.

Background and Objectives: Care partners of hospitalized older adults report their caregiving needs are not being addressed. The Care Partner Hospital Assessment Tool (CHAT) is a feasible and appropriate tool for practitioners' use with care partners in the hospital setting. This article explores the face validity and acceptability of the CHAT among care partners of hospitalized older adults., Research Design and Methods: A qualitative descriptive study was used to identify common themes among care partners' responses from semistructured interviews. The CHAT was administered to care partners of older adults admitted to a medical-surgical unit in an academic medical center in Madison, WI, from October 2021 to January 2022. A semistructured, follow-up interview was completed by the same care partners after discharge. Interviews were transcribed and coded for themes to capture overall impressions of the CHAT. Care partners addressed the usefulness, comfort, content, and complexity of the CHAT., Results: Twelve care partners participated in the study. Care partners reported that the CHAT was easy to understand and complete, was judged to be useful to both the care partner and older adult, and helped identify care partner needs. Care partners suggested ways to improve the tool including administration, additional content areas to include, and modes of delivery., Discussion and Implications: The results establish the face validity of the CHAT and support the acceptability of the tool for use with care partners of hospitalized older adults., Competing Interests: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Imaging studies have evidenced that contralesional cortices are involved in recovery after motor stroke. Cortical thickness (CT) analysis has proven its potential to capture the changes of cortical anatomy, which have been related to recovery and treatment gains under therapy. An open question is whether CT obtained in the acute phase after stroke might inform correlational models to explain outcome variability. Data of 38 severely impaired (median NIH Stroke Scale 9, interquartile range: 6-13) acute stroke patients of 2 independent cohorts were reanalyzed. Structural imaging data were processed via the FreeSurfer pipeline to quantify regional CT of the contralesional hemisphere. Ordinal logistic regression models were fit to relate CT to modified Rankin Scale as an established measure of global disability after 3-6 months, adjusted for the initial deficit, lesion volume, and age. The data show that CT of contralesional cortices, such as the precentral gyrus, the superior frontal sulcus, and temporal and cingulate cortices, positively relates to the outcome after stroke. This work shows that the baseline cortical anatomy of selected contralesional cortices can explain the outcome variability after severe stroke, which further contributes to the concept of structural brain reserve with respect to contralesional cortices to promote recovery., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

The concept of brain reserve capacity positively influencing the process of recovery after stroke has been continuously developed in recent years. Global measures of brain health have been linked with a favourable outcome. Numerous studies have evidenced that the cerebellum is involved in recovery after stroke. However, it remains an open question whether characteristics of cerebellar anatomy, quantified directly after stroke, might have an impact on subsequent outcome after stroke. Thirty-nine first-ever ischaemic non-cerebellar stroke patients underwent MRI brain imaging early after stroke and longitudinal clinical follow-up. Structural images were used for volumetric analyses of distinct cerebellar regions. Ordinal logistic regression analyses were conducted to associate cerebellar volumes with functional outcome 3-6 months after stroke, operationalized by the modified Rankin Scale. Larger volumes of cerebellar lobules IV, VI, and VIIIB were positively correlated with favourable outcome, independent of the severity of initial impairment, age, and lesion volume ( P < 0.01). The total cerebellar volume did not exhibit a significant structure-outcome association. The present study reveals that pre-stroke anatomy of distinct cerebellar lobules involved in motor and cognitive functioning might be linked to outcome after acute non-cerebellar stroke, thereby promoting the emerging concepts of structural brain reserve for recovery processes after stroke., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objectives: There are disparities in the adherence to guideline-recommended therapies after coronary artery bypass graft (CABG). We therefore sought to evaluate the effect of guideline-adherent medical secondary prevention on 1-year outcome after CABG., Methods: Data were taken from the randomized 'Ticagrelor in CABG' trial. From April 2013 until April 2017, patients who underwent CABG were included. For the present analysis, we compared patients who were treated with optimal medical secondary prevention with those where 1 or more of the recommended medications were missing., Results: Follow-up data at 12 months were available in 1807 patients. About half (54%) of them were treated with optimal secondary prevention. All-cause mortality [0.5% vs 3.5%, hazard ratio (HR) 0.14 (0.05-0.37), P < 0.01], cardiovascular mortality [0.1% vs 1.7%, HR 0.06 (0.01-0.46), P = 0.007] and major adverse events [6.5% vs 11.5%, HR 0.54 (0.39-0.74), P < 0.01] were significantly lower in the group with optimal secondary prevention. The multivariable model for the primary end point based on binary concordance to guideline recommended therapy identified 3 independent factors: adherence to guideline recommended therapy [HR 0.55 (0.39-0.78), P < 0.001]; normal renal function [HR 0.99 (0.98-0.99), P = 0.040]; and off-pump surgery [HR 2.06 (1.02-4.18), P = 0.045]., Conclusions: Only every second patient receives optimal secondary prevention after CABG. Guideline adherent secondary prevention therapy is associated with lower mid-term mortality and less adverse cardiovascular events after 12 months., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Analyses of alterations of brain networks have gained an increasing interest in stroke rehabilitation research. Compared with functional networks derived from resting-state analyses, there is limited knowledge of how structural network topology might undergo changes after stroke and, more importantly, if structural network information obtained early after stroke could enhance recovery models to infer later outcomes. The present work re-analysed cross-sectional structural imaging data, obtained within the first 2 weeks, of 45 acute stroke patients (22 females, 24 right-sided strokes, age 68 ± 13 years). Whole-brain tractography was performed to reconstruct structural connectomes and graph-theoretical analyses were employed to quantify global network organization with a focus on parameters of network integration and modular processing. Graph measures were compared between stroke patients and 34 healthy controls (15 females, aged 69 ± 10 years) and they were integrated with four clinical scores of the late subacute stage, covering neurological symptom burden (National Institutes of Health Stroke Scale), global disability (modified Rankin Scale), activity-related disability (Barthel Index) and motor functions (Upper-Extremity Score of the Fugl-Meyer Assessment). The analyses were employed across the complete cohort and, based on clustering analysis, separately within subgroups stratified in mild to moderate ( n  = 21) and severe ( n  = 24) initial deficits. The main findings were (i) a significant reduction of network's global efficiency, specifically in patients with severe deficits compared with controls ( P  = 0.010) and (ii) a significant negative correlation of network efficiency with the extent of persistent functional deficits at follow-up after 3-6 months ( P  ≤ 0.032). Specifically, regression models revealed that this measure was capable to increase the explained variance in future deficits by 18% for the modified Rankin Scale, up to 24% for National Institutes of Health Stroke Scale, and 16% for Barthel Index when compared with models including the initial deficits and the lesion volume. Patients with mild to moderate deficits did not exhibit a similar impact of network efficiency on outcome inference. Clustering coefficient and modularity, measures of segregation and modular processing, did not exhibit comparable structure-outcome relationships, neither in severely nor in mildly affected patients. This study provides empirical evidence that structural network efficiency as a graph-theoretical marker of large-scale network topology, quantified early after stroke, relates to recovery. Notably, this contribution was only evident in severely but not mildly affected stroke patients. This suggests that the initial clinical deficit might shape the dependency of recovery on global network topology after stroke., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background and Objectives: The coronavirus disease 2019 (COVID-19) pandemic has negatively affected persons with existing chronic health conditions. The pandemic also has the potential to exacerbate the stresses of family caregiving. We compare family caregivers with noncaregivers on physical, psychosocial, and financial well-being outcomes during the pandemic and determine family caregivers most at risk for adverse outcomes., Research Design and Methods: We conducted a cross-sectional online survey of 576 family caregivers and 2,933 noncaregivers from April to May 2020 in Pittsburgh, PA region with a national supplement. Outcome measures included concurrent anxiety, depression, fatigue, sleep disturbance, social participation, and financial well-being and perceived changes due to COVID-19 (loneliness, financial well-being, food security). We also measured sociodemographic, caregiving contextual variables, and COVID-19-related caregiver stressors (COVID Caregiver Risk Index)., Results: Controlling for sociodemographics, family caregivers reported higher anxiety, depression, fatigue, sleep disturbance, lower social participation, lower financial well-being, increased food insecurity (all p < .01), and increased financial worries (p = .01). Caregivers who reported more COVID-19-related caregiver stressors and disruptions reported more adverse outcomes (all p < .01). In addition, caregivers who were female, younger, lower income, providing both personal/medical care, and providing care for cognitive/behavioral/emotional problems reported more adverse outcomes., Discussion and Implications: Challenges of caregiving are exacerbated by the COVID-19 pandemic. Family caregivers reported increased duties, burdens, and resulting adverse health, psychosocial, and financial outcomes. Results were generally consistent with caregiver stress-health process models. Family caregivers should receive increased support during this serious public health crisis., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Recent brain imaging has evidenced that parietofrontal networks show alterations after stroke which also relate to motor recovery processes. There is converging evidence for an upregulation of parietofrontal coupling between parietal brain regions and frontal motor cortices. The majority of studies though have included only moderately to mildly affected patients, particularly in the subacute or chronic stage. Whether these network alterations will also be present in severely affected patients and early after stroke and whether such information can improve correlative models to infer motor recovery remains unclear. In this prospective cohort study, 19 severely affected first-ever stroke patients (mean age 74 years, 12 females) were analysed which underwent resting-state functional MRI and clinical testing during the initial week after the event. Clinical evaluation of neurological and motor impairment as well as global disability was repeated after three and six months. Nineteen healthy participants of similar age and gender were also recruited. MRI data were used to calculate functional connectivity values between the ipsilesional primary motor cortex, the ventral premotor cortex, the supplementary motor area and the anterior and caudal intraparietal sulcus of the ipsilesional hemisphere. Linear regression models were estimated to compare parietofrontal functional connectivity between stroke patients and healthy controls and to relate them to motor recovery. The main finding was a significant increase in ipsilesional parietofrontal coupling between anterior intraparietal sulcus and the primary motor cortex in severely affected stroke patients ( P  <   0.003). This upregulation significantly contributed to correlative models explaining variability in subsequent neurological and global disability as quantified by National Institute of Health Stroke Scale and modified Rankin Scale, respectively. Patients with increased parietofrontal coupling in the acute stage showed higher levels of persistent deficits in the late subacute stage of recovery ( P  <   0.05). This study provides novel insights that parietofrontal networks of the ipsilesional hemisphere undergo neuroplastic alteration already very early after severe motor stroke. The association between early parietofrontal upregulation and future levels of persistent functional deficits and dependence from help in daily living might be useful in models to enhance clinical neurorehabilitative decision making., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

The corticospinal tract is the most intensively investigated tract of the human motor system in stroke rehabilitative research. Diffusion-tensor-imaging gives insights into its microstructure, and transcranial magnetic stimulation assesses its excitability. Previous data on the interrelationship between both measures are contradictory. Correlative or predictive models which associate them with motor outcome are incomplete. Free water correction has been developed to enhance diffusion-tensor-imaging by eliminating partial volume with extracellular water, which could improve capturing stroke-related microstructural alterations, thereby also improving structure-function relationships in clinical cohorts. In the present cross-sectional study, data of 18 chronic stroke patients and 17 healthy controls, taken from a previous study on cortico-cerebellar motor tracts, were re-analysed: The data included diffusion-tensor-imaging data quantifying corticospinal tract microstructure with and without free water correction, transcranial magnetic stimulation data assessing recruitment curve properties of motor evoked potentials and detailed clinical data. Linear regression modelling was used to interrelate corticospinal tract microstructure, recruitment curves properties and clinical scores. The main finding of the present study was that free water correction substantially strengthens structure-function associations in stroke patients: Specifically, our data evidenced a significant association between fractional anisotropy of the ipsilesional corticospinal tract and its excitability ( P  = 0.001, adj. R 2  = 0.54), with free water correction explaining additional 20% in recruitment curve variability. For clinical scores, only free water correction leads to the reliable detection of significant correlations between ipsilesional corticospinal tract fractional anisotropy and residual grip ( P  = 0.001, adj. R 2  = 0.70) and pinch force ( P  < 0.001, adj. R 2  = 0.72). Finally, multimodal models can be improved by free water correction as well. This study evidences that corticospinal tract microstructure directly relates to its excitability in stroke patients. It also shows that unexplained variance in motor outcome is considerably reduced by free water correction arguing that it might serve as a powerful tool to improve existing models of structure-function associations and potentially also outcome prediction after stroke., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Alternative splicing (AS) and alternative polyadenylation (APA) generate diverse transcripts in mammalian genomes during development and differentiation. Epigenetic marks such as trimethylation of histone H3 lysine 36 (H3K36me3) and DNA methylation play a role in generating transcriptome diversity. Intragenic CpG islands (iCGIs) and their corresponding host genes exhibit dynamic epigenetic and gene expression patterns during development and between different tissues. We hypothesise that iCGI-associated H3K36me3, DNA methylation and transcription can influence host gene AS and/or APA. We investigate H3K36me3 and find that this histone mark is not a major regulator of AS or APA in our model system. Genomewide, we identify over 4000 host genes that harbour an iCGI in the mammalian genome, including both previously annotated and novel iCGI/host gene pairs. The transcriptional activity of these iCGIs is tissue- and developmental stage-specific and, for the first time, we demonstrate that the premature termination of host gene transcripts upstream of iCGIs is closely correlated with the level of iCGI transcription in a DNA-methylation independent manner. These studies suggest that iCGI transcription, rather than H3K36me3 or DNA methylation, interfere with host gene transcription and pre-mRNA processing genomewide and contributes to the spatiotemporal diversification of both the transcriptome and proteome., (© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Brain imaging has recently evidenced that the structural state of distinct reciprocal cortico-cerebellar fiber tracts, the dentato-thalamo-cortical tract (DTCT), and the cortico-ponto-cerebellar tract (CPCeT), significantly influences residual motor output in chronic stroke patients, independent from the level of damage to the corticospinal tract (CST). Whether such structural information might also directly relate to measures of cortical excitability is an open question. Eighteen chronic stroke patients with supratentorial ischemic lesions and 17 healthy controls underwent transcranial magnetic stimulation to assess recruitment curves of motor evoked potentials of both hemispheres. Diffusion-weighted imaging and probabilistic tractography were applied to reconstruct reciprocal cortico-cerebellar motor tracts between the primary motor cortex and the cerebellum. Tract-related microstructure was estimated by means of fractional anisotropy, and linear regression modeling was used to relate it to cortical excitability. The main finding was a significant association between cortical excitability and the structural integrity of the DTCT, the main cerebellar outflow tract, independent from the level of damage to the CST. A comparable relationship was neither detectable for the CPCeT nor for the healthy controls. This finding contributes to a mechanistic understanding of the putative supportive role of the cerebellum for residual motor output by facilitating cortical excitability after stroke., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

The time course of topological reorganization that occurs in the structural connectome after an ischaemic stroke is currently not well understood. We aimed to determine the evolution of structural brain networks in stroke patients with motor deficits and relate changes in their global topology to residual symptom burden and functional impairment. In this prospective cohort study, ischaemic stroke patients with supratentorial infarcts and motor symptoms were assessed longitudinally by advanced diffusion MRI and detailed clinical testing of upper extremity motor function at four time points from the acute to the chronic stage. For each time point, structural connectomes were reconstructed, and whole-hemisphere global network topology was quantified in terms of integration and segregation parameters. Using non-linear joint mixed-effects regression modelling, network evolution was related to lesion volume and clinical outcome. Thirty patients were included for analysis. Graph-theoretical analysis demonstrated that, over time, brain networks became less integrated and more segregated with decreasing global efficiency and increasing modularity. Changes occurred in both stroke and intact hemispheres and, in the latter, were positively associated with lesion volume. Greater change in topology was associated with larger residual symptom burden and greater motor impairment 1, 3 and 12 months after stroke. After ischaemic stroke, brain networks underwent characteristic changes in both ipsi- and contralesional hemispheres. Topological network changes reflect the severity of damage to the structural network and are associated with functional outcome beyond the impact of lesion volume., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Beyond disruption of neuronal pathways, focal stroke lesions induce structural disintegration of distant, yet connected brain regions via retrograde neuronal degeneration. Stroke lesions alter functional brain connectivity and topology in large-scale brain networks. These changes are associated with the degree of clinical impairment and recovery. In contrast, changes of large scale, structural brain networks after stroke are less well reported. We therefore aimed to analyse the impact of focal lesions on the structural connectome after stroke based on data from diffusion-weighted imaging and probabilistic fibre tracking. In total, 17 patients (mean age 64.5 ± 8.4 years) with upper limb motor deficits in the chronic stage after stroke and 21 healthy participants (mean age 64.9 ± 10.3 years) were included. Clinical deficits were evaluated by grip strength and the upper extremity Fugl-Meyer assessment. We calculated global and local graph theoretical measures to characterize topological changes in the structural connectome. Results from our analysis demonstrated significant alterations of network topology in both ipsi- and contralesional, primarily unaffected, hemispheres after stroke. Global efficiency was significantly lower in stroke connectomes as an indicator of overall reduced capacity for information transfer between distant brain areas. Furthermore, topology of structural connectomes was shifted toward a higher degree of segregation as indicated by significantly higher values of global clustering and modularity. On a level of local network parameters, these effects were most pronounced in a subnetwork of cortico-subcortical brain regions involved in motor control. Structural changes were not significantly associated with clinical measures. We propose that the observed network changes in our patients are best explained by the disruption of inter- and intrahemispheric, long white matter fibre tracts connecting distant brain regions. Our results add novel insights on topological changes of structural large-scale brain networks in the ipsi- and contralesional hemisphere after stroke., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background and Objectives: Older adults face significant long-term care and health care costs. But some of these costs can potentially be offset through family caregivers who may serve as substitutes for formal care or directly improve the care recipient's health and reduce health care utilization and expenditures. This article reviews the current literature to determine whether it is possible through existing work to compare the costs of care for individuals with versus without family caregivers and, if not, where the data, measurement, and other methodological challenges lie., Research Design and Methods: A mapping review of published works containing information on health care utilization and expenditures and caregiving was conducted. A narrative approach was used to review and identify methodological challenges in the literature., Results: Our review identified 47 articles that met our criteria and had information on caregiving and health care costs or utilization. Although findings were mixed, for the most part, having a family caregiver was associated with reduced health care utilization and a decreased risk of institutionalization however, the precise difference in health care expenditures for individuals with caregivers compared to those without was rarely examined, and findings were inconsistent across articles reviewed., Discussion and Implications: The number of family caregivers providing care to loved ones is expected to grow with the aging of the Baby Boomers. Various programs and policies have been proposed to support these caregivers, but they could be costly. These costs can potentially be offset if family caregivers reduce health care spending. More research is needed, however, to quantify the savings stemming from family caregiving., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Little is known about the impact of neighborhood context on family caregivers, or how environmental factors combine with individual-level caregiver risk factors to affect caregiver outcomes., Objectives: To combine Geographic Information System (GIS) and survey methods to examine the effects of caregiver residence in disadvantaged/underserved neighborhoods on caregiver outcomes., Research Design and Methods: Telephone surveys with 758 caregivers from the Pittsburgh Regional Caregiver Survey geocoded for classification into Environmental Justice Areas (EJAs) and Medically Underserved Areas (MUAs). We examine the impact of EJA/MUA caregiver residence on care recipient unmet needs for care, caregiver depression and burden, and positive aspects of caregiving, adjusting for sociodemographics, caregiving context, care recipient disability level, caregiving intensity, and additional risk factors., Results: There was spatial clustering of caregiver depression and burden outside of the disadvantaged/underserved areas, while positive aspects of caregiving were clustered within EJAs/MUAs. Approximately 36% of caregivers lived in EJAs/MUAs, and they differed, sociodemographically, on caregiver risk factors and caregiver outcomes. Multivariable models showed that caregivers residing in EJAs/MUAs were less likely to be depressed and reported more positive aspects of caregiving after adjusting for known individual-level risk factors. Residence in disadvantaged/underserved areas also modified the effects of several risk factors on caregiver outcomes., Discussion and Implications: Caregiver outcomes show interesting spatial patterns. Unexpectedly, caregivers living in these potentially challenging environments were less depressed and reported more gains from caregiving after adjusting for known risk factors. Results suggest that socioeconomic disadvantage does not necessarily translate into poor caregiver outcomes. Understanding the mechanism for these effects is important to designing effective caregiver interventions. The paper also demonstrates the value of using GIS methods to study caregiving.

Aims: The antiplatelet treatment strategy providing optimal balance between thrombotic and bleeding risks in patients undergoing coronary artery bypass grafting (CABG) is unclear. We prospectively compared the efficacy of ticagrelor and aspirin after CABG., Methods and Results: We randomly assigned in double-blind fashion patients scheduled for CABG to either ticagrelor 90 mg twice daily or 100 mg aspirin (1:1) once daily. The primary outcome was the composite of cardiovascular death, myocardial infarction (MI), repeat revascularization, and stroke 12 months after CABG. The main safety endpoint was based on the Bleeding Academic Research Consortium classification, defined as BARC ≥4 for periprocedural and hospital stay-related bleedings and BARC ≥3 for post-discharge bleedings. The study was prematurely halted after recruitment of 1859 out of 3850 planned patients. Twelve months after CABG, the primary endpoint occurred in 86 out of 931 patients (9.7%) in the ticagrelor group and in 73 out of 928 patients (8.2%) in the aspirin group [hazard ratio 1.19; 95% confidence interval (CI) 0.87-1.62; P = 0.28]. All-cause mortality (ticagrelor 2.5% vs. aspirin 2.6%, hazard ratio 0.96, CI 0.53-1.72; P = 0.89), cardiovascular death (ticagrelor 1.2% vs. aspirin 1.4%, hazard ratio 0.85, CI 0.38-1.89; P = 0.68), MI (ticagrelor 2.1% vs. aspirin 3.4%, hazard ratio 0.63, CI 0.36-1.12, P = 0.12), and stroke (ticagrelor 3.1% vs. 2.6%, hazard ratio 1.21, CI 0.70-2.08; P = 0.49), showed no significant difference between the ticagrelor and aspirin group. The main safety endpoint was also not significantly different (ticagrelor 3.7% vs. aspirin 3.2%, hazard ratio 1.17, CI 0.71-1.92; P = 0.53)., Conclusion: In this prematurely terminated and thus underpowered randomized trial of ticagrelor vs. aspirin in patients after CABG no significant differences in major cardiovascular events or major bleeding could be demonstrated., Clinicaltrials.gov Identifier: NCT01755520., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Unexpected cardiac adverse effects are the leading causes of discontinuation of clinical trials and withdrawal of drugs from the market. Since the original observations in the mid-90s, it has been well established that cardiovascular risk factors and comorbidities (such as ageing, hyperlipidaemia, and diabetes) and their medications (e.g. nitrate tolerance, adenosine triphosphate-dependent potassium inhibitor antidiabetic drugs, statins, etc.) may interfere with cardiac ischaemic tolerance and endogenous cardioprotective signalling pathways. Indeed drugs may exert unwanted effects on the diseased and treated heart that is hidden in the healthy myocardium. Hidden cardiotoxic effects may be due to (i) drug-induced enhancement of deleterious signalling due to ischaemia/reperfusion injury and/or the presence of risk factors and/or (ii) inhibition of cardioprotective survival signalling pathways, both of which may lead to ischaemia-related cell death and/or pro-arrhythmic effects. This led to a novel concept of 'hidden cardiotoxicity', defined as cardiotoxity of a drug that manifests only in the diseased heart with e.g. ischaemia/reperfusion injury and/or in the presence of its major comorbidities. Little is known on the mechanism of hidden cardiotoxocity, moreover, hidden cardiotoxicity cannot be revealed by the routinely used non-clinical cardiac safety testing methods on healthy animals or tissues. Therefore, here, we emphasize the need for development of novel cardiac safety testing platform involving combined experimental models of cardiac diseases (especially myocardial ischaemia/reperfusion and ischaemic conditioning) in the presence and absence of major cardiovascular comorbidities and/or cotreatments., (© The Author(s) 2018. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: The serum troponin assay is the biochemical gold standard for detecting myocardial infarction (MI). A major diagnostic issue is that some believe troponin levels can rise with reversible injury, in the absence of radiologically detectable infarct., Hypothesis: Because cell death activates intracellular proteases, troponin released by irreversible infarct will be more proteolyzed than that released by milder processes. Our goal was to quantify proteolytic digestion of cardiac troponin I in patients with varying degrees of myocardial injury., Methods: Serum or plasma samples from 29 patients with cardiac troponin I elevations were analyzed for proteolytic degradation, using 3 different sandwich ELISAs designed to specifically detect the N-terminal, core, or C-terminal regions of cardiac troponin I., Results: As predicted, the degree of proteolytic digestion increased with increasing severity of injury, as estimated by the total troponin level, and this trend was more pronounced for C-terminal (vs N-terminal) degradation. The highest degree of proteolytic digestion was observed in patients with ST-elevation MI; the least, in type 2 MI (supply-demand ischemia rather than acute thrombus formation)., Conclusions: The proteolytic degradation pattern of cardiac troponin I may be a better indicator of clinically significant MI than total serum troponin level. Distinguishing between intact and degraded forms of troponin may be useful for (a) identifying those patients with clinically significant infarct in need of revascularization, (b) monitoring intracellular proteolysis as a possible target for therapeutic intervention, and (c) providing an impetus for standardizing the epitopes used in the troponin I assay., (© 2018 American Association for Clinical Chemistry.)

Background: Disabled older adults' needs for help with daily activities sometimes go unmet with potentially long-term negative consequences for health and well-being., Objectives: To examine the relationship between care recipient unmet needs and (1) concerns about being a burden; (2) perceptions of caregiver burden; and (3) and caregiver self-reports of burden in community-dwelling care recipient-caregiver dyads., Research Design and Methods: Telephone surveys with 196 linked caregiver - care recipient dyads from the 2017 Pittsburgh Regional Caregiver Survey . Of 376 caregivers who gave initial permission to contact the recipient (February-July), 262 caregivers were recontacted and gave permission to attempt a care recipient survey (September-October; n = 196 completed; 74.8% response rate). In addition to the burden measures, we controlled for several covariates, including disability level, receipt of paid help, and care recipient and caregiver sociodemographics., Results: Slightly more than one fourth (27.2%) of care recipients were "very concerned" about being a burden, and 43.6% were "somewhat concerned." Care recipient concerns about being a burden (exp( B ) = 1.71, 95% confidence interval [CI] exp( B ) [1.15, 2.54]); and caregiver self-reported burden (exp( B ) = 1.82, 95% CI exp( B ) [1.17, 2.85]) were independent predictors of more care recipient unmet needs. Recipient perceptions of caregiver burden were not independently predictive. Care recipients with higher disability levels, those without paid help, and those whose caregiver was not a spouse/child also reported more unmet needs. The impact of burden on unmet needs was stronger for instrumental activities of daily living/mobility needs than for activities of daily living needs., Discussion and Implications: Potential interventions to reduce unmet needs should take a dyadic approach, focusing on reducing both care recipient perceptions of being a burden and caregiver experienced burden.

Background and Objectives: Family caregivers (CGs) are critical to the provision of long-term services and support for older adults. Numerous intervention programs to alleviate CG distress have been developed and evaluated yet few have been implemented in community settings. This paper describes and presents outcomes from Community REACH, a community implementation of the evidence-based Resources for Enhancing Alzheimer's Caregiver Health (REACH) II program., Research Design and Methods: Community REACH involved a partnership between REACH II investigators and United HomeCare Services (UHCS), a nonprofit home health organization that provides home health, personal care, companion, and respite services. The intervention program, an adapted version of an evidence-based program, was a 6-month multicomponent psychosocial intervention, which involved six individual face-to-face and six individual telephone sessions, and telephone support groups. One hundred and forty-six CGs who were primarily female (76%) and Latino, and providing care for an individual with Alzheimer's disease (AD) were enrolled. Program effectiveness was assessed by examining changes in perceived social support, burden, and depression, and CG self-efficacy., Results: At 6 months, CGs reported significant decreases in depression, burden, being and bothered by the care recipient's memory problems. There was also a significant decline in the number of CGs at risk for clinical depression. These improvements were maintained at 12 months and there was an increase in feelings of social support., Discussion and Implications: The findings indicate that evidence-based CG programs can be successfully implemented in community settings and benefit CGs of AD patients. A continued partnership between the program developers and community partners is key to implementation success.

Functional imaging studies have argued that interactions between cortical motor areas and the cerebellum are relevant for motor output and recovery processes after stroke. However, the impact of the underlying structural connections is poorly understood. To investigate this, diffusion-weighted brain imaging was conducted in 26 well-characterized chronic stroke patients (aged 63 ± 1.9 years, 18 males) with supratentorial ischemic lesions and 26 healthy participants. Probabilistic tractography was used to reconstruct reciprocal cortico-cerebellar tracts and to relate their microstructural integrity to residual motor functioning applying linear regression modeling. The main finding was a significant association between cortico-cerebellar structural connectivity and residual motor function, independent from the level of damage to the cortico-spinal tract. Specifically, white matter integrity of the cerebellar outflow tract, the dentato-thalamo-cortical tract, was positively related to both general motor output and fine motor skills. Additionally, the integrity of the descending cortico-ponto-cerebellar tract contributed to rather fine motor skills. A comparable structure-function relationship was not evident in the controls. The present study provides first tract-related structural data demonstrating a critical importance of distinct cortico-cerebellar connections for motor output after stroke., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Purpose of the Study: We report the results of a study designed to assess whether and how much informal caregivers are willing to pay for technologies designed to help monitor and support care recipients (CRs) in performing kitchen and personal care tasks., Design and Methods: We carried out a web survey of a national sample of adult caregivers (age 18-64) caring for an older adult (N = 512). Respondents completed a 25min online survey that included questions about their caregiving situation, current use of everyday technology, use of specific caregiving technologies, general attitudes toward technology, and questions about technologies designed to help them monitor and provide assistance for CRs' kitchen and self-care activities., Results: About 20% of caregivers were not willing to pay anything for kitchen and self-care technologies. Among those willing to pay something, the mean amount was approximately $50 per month for monitoring technologies and $70 per month for technologies that both monitored and provided some assistance. Younger caregivers, those caring for a person with Alzheimer's disease, and caregivers with more positive attitudes toward and experience with technology were willing to pay more. Most caregivers feel that the government or private insurance should help pay for these technologies., Implications: Caregivers are receptive and willing to pay for technologies that help them care for their CR, although the amount they are willing to pay is capped at around $70 per month. The combination of private pay and government subsidy may facilitate development and dissemination of caregiver technologies., (© The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose of This Study: To characterize illness perceptions among persons with mild cognitive impairment (PWMCI) and their family care partners, and to examine whether PWMCI's and their family care partners' illness perceptions were associated with their own, as well as the other member of the dyad's, emotional reactions to MCI., Design and Methods: This cross-sectional study of PWMCI and their family care partners (n = 60 dyads) used patient and relative versions of the Revised Illness Perception Questionnaire (IPQ-R) to assess metacognitive and emotional features of illness perception in MCI along 5 dimensions of perceived: seriousness of potential consequences, personal controllability, timeline, fluctuation (cycling) of symptoms, and illness coherence (clear vs. confusing)., Results: As compared to family members, PWMCI perceived MCI to be less potentially serious and to be more within their personal control, but dyads otherwise shared similar perceptions of MCI. Among PWMCI, perceived seriousness of the potential consequences of MCI was the only dimension to be significantly correlated with emotional distress. For family members, increased MCI-related emotional distress was significantly associated with perceptions of MCI as potentially serious, permanent, or confusing. A dyadic analysis using APIM showed that MCI-related emotional distress, in both PWMCI and family members, was linked to the PWMCI's perception of the seriousness of MCI., Implications: MCI-related education and support should be tailored for both the PWMCI and family member audiences, while acknowledging interdependence of illness perceptions within family units. Tailored information and support will be critical in managing MCI going forward, as illness perceptions are likely key factors on which individuals will plan for the future or base medical decisions., (© The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Despite improvements in modern cardiovascular therapy, the morbidity and mortality of ischaemic heart disease (IHD) and heart failure (HF) remain significant in Europe and worldwide. Patients with IHD may benefit from therapies that would accelerate natural processes of postnatal collateral vessel formation and/or muscle regeneration. Here, we discuss the use of cells in the context of heart repair, and the most relevant results and current limitations from clinical trials using cell-based therapies to treat IHD and HF. We identify and discuss promising potential new therapeutic strategies that include ex vivo cell-mediated gene therapy, the use of biomaterials and cell-free therapies aimed at increasing the success rates of therapy for IHD and HF. The overall aim of this Position Paper of the ESC Working Group Cellular Biology of the Heart is to provide recommendations on how to improve the therapeutic application of cell-based therapies for cardiac regeneration and repair., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Purpose of the Study: To examine whether compassionate love in both individuals with Alzheimer's disease (AD) and their spousal caregivers related to less caregiving burden, more positive caregiving appraisals, and less depressive symptoms for caregivers., Design and Methods: Fifty-eight individuals with AD and their spousal caregivers participated in interviews in which both partners reported their compassionate love for their partner, and caregivers self-reported burden, positive appraisals of caregiving, and depressive symptoms., Results: As hypothesized, both AD individuals' and caregivers' compassionate love were associated with less burden and more positive appraisals of caregiving. Also, care givers' compassionate love mediated the association between AD individuals' compassionate love and caregivers' burden as well as the association between AD individuals' compassionate love and caregivers' positive appraisals of caregiving. Finally, there was a marginally significant association between caregivers' compassionate love and less caregiver depressive symptoms., Implications: Results suggest that AD individuals' compassionate love is related to compassionate love in caregivers, which in turn relates to reduced burden but not significantly less depressive symptoms for caregivers. Assessing caregivers' and AD individuals' feelings of compassionate love may be useful in identifying caregivers who are resilient and those who are at a heightened risk for caregiving burden. Also, interventions that enhance both partners' compassionate love may benefit caregivers., (© The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: When examining older adults' health behaviors and psychological health, it is important to consider the social context., Purpose: The purpose of this study was to examine in older adult marriages whether each spouse's physical activity predicted changes in their own (actor effects) and their partner's (partner effects) depressive symptoms. Gender differences were also examined., Method: Each spouse within 1260 married couples (at baseline) in the Cardiovascular Health Study completed self-report measures at wave 1 (1989-1990), wave 3 (1992-1993), and wave 7 (1996-1997). Dyadic path analyses were performed., Results: Husbands' physical activity significantly predicted own decreased depressive symptoms (actor effect). For both spouses, own physical activity did not significantly predict the spouse's depressive symptoms (partner effects). However, husbands' physical activity and depressive symptoms predicted wives' physical activity and depressive symptoms (partner effects), respectively. Depressive symptoms did not predict physical activity., Conclusion: Findings suggest that husbands' physical activity is particularly influential for older married couples' psychological health.

Interest in technology for older adults is driven by multiple converging trends: the rapid pace of technological development; the unprecedented growth of the aging population in the United States and worldwide; the increase in the number and survival of persons with disability; the growing and unsustainable costs of caring for the elderly people; and the increasing interest on the part of business, industry, and government agencies in addressing health care needs with technology. These trends have contributed to the strong conviction that technology can play an important role in enhancing quality of life and independence of older individuals with high levels of efficiency, potentially reducing individual and societal costs of caring for the elderly people. The purpose of this "Forum" position article is to integrate what we know about older adults and technology systems in order to provide direction to this vital enterprise. We define what we mean by technology for an aging population, provide a brief history of its development, introduce a taxonomy for characterizing current technology applications to older adults, summarize research in this area, describe existing development and evaluation processes, identify factors important for the acceptance of technology among older individuals, and recommend future directions for research in this area., (© The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Corticocortical interactions between the primary motor cortex, the ventral premotor cortex and posterior parietal motor areas, such as the anterior and caudal intraparietal sulcus, are relevant for skilled voluntary hand function. It remains unclear to what extent these brain regions and their interactions also contribute to basic motor functions after stroke. We hypothesized that white matter integrity of the underlying parietofrontal motor pathways between these brain regions might relate to residual motor function after stroke. Twenty-five chronic stroke patients were recruited (aged 64 ± 8.8 years, range 46-75, 17 males, one left-handed) and evaluated 34 months after stroke (range 12-169 months) by means of grip force, pinch force and the Fugl-Meyer assessment of the upper extremity. Based on these measures, motor function was estimated applying a factor analysis with principal component extraction. Using diffusion tensor imaging and probabilistic tractography we reconstructed probable intrahemispheric trajectories between the primary motor cortex, the ventral premotor cortex and the anterior and caudal intraparietal sulcus in each patient. White matter integrity was estimated for each individual tract by means of fractional anisotropy. Generalized linear modelling was used to relate tract-related fractional anisotropy to the motor function. We found that the white matter integrity of the fibre tracts connecting the ventral premotor cortex and the primary motor cortex (P < 0.001) and the anterior intraparietal sulcus and the ventral premotor cortex (P < 0.01) positively correlated with motor function. The other tracts investigated did not show a similar structure-behaviour association. Providing first structural connectivity data for parietofrontal connections in chronic stroke patients, the present results indicate that both the ventral premotor cortex and the posterior parietal cortex might play a relevant role in generating basic residual motor output after stroke., (© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The dentato-thalamo-cortical tract (DTCT) connects the lateral cerebellum with contralateral motor and nonmotor areas, such as the primary motor cortex (M1), the ventral premotor cortex (PMv), and the dorsolateral prefrontal cortex (DLPFC). As the acquisition of precisely timed finger movements requires the interplay between these brain regions, the structural integrity of the underlying connections might explain variance in behavior. Diffusion tensor imaging was used to 1) reconstruct the DTCT connecting the dentate nucleus with M1, PMv, and DLPFC and 2) examine to which extent their microstructural integrity (tract-related fractional anisotropy) relates to learning gains in a motor-sequence learning paradigm consisting of a synchronization and continuation part. Continuous DTCT were reconstructed from the dentate nucleus to all cortical target areas. We found that the microstructural integrity of the DTCT connecting the left dentate nucleus with the right DLPFC was associated with better early consolidation in rhythm continuation (R = -0.69, P = 0.02). The present data further advances the knowledge about a right-hemispheric timing network in the human brain with the DLPFC as an important node contributing to learning gains in precise movement timing., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

We evaluated whether a 76-locus polygenic risk score (PRS) and Breast Imaging Reporting and Data System (BI-RADS) breast density were independent risk factors within three studies (1643 case patients, 2397 control patients) using logistic regression models. We incorporated the PRS odds ratio (OR) into the Breast Cancer Surveillance Consortium (BCSC) risk-prediction model while accounting for its attributable risk and compared five-year absolute risk predictions between models using area under the curve (AUC) statistics. All statistical tests were two-sided. BI-RADS density and PRS were independent risk factors across all three studies (P interaction = .23). Relative to those with scattered fibroglandular densities and average PRS (2(nd) quartile), women with extreme density and highest quartile PRS had 2.7-fold (95% confidence interval [CI] = 1.74 to 4.12) increased risk, while those with low density and PRS had reduced risk (OR = 0.30, 95% CI = 0.18 to 0.51). PRS added independent information (P < .001) to the BCSC model and improved discriminatory accuracy from AUC = 0.66 to AUC = 0.69. Although the BCSC-PRS model was well calibrated in case-control data, independent cohort data are needed to test calibration in the general population., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: In addition to patient self-efficacy, spouse confidence in patient efficacy may also independently predict patient health outcomes. However, the potential influence of spouse confidence has received little research attention., Purpose: The current study examined the influence of patient and spouse efficacy beliefs for arthritis management on patient health., Methods: Patient health (i.e., arthritis severity, perceived health, depressive symptoms, lower extremity function), patient self-efficacy, and spouse confidence in patients' efficacy were assessed in a sample of knee osteoarthritis patients (N = 152) and their spouses at three time points across an 18-month period. Data were analyzed using structural equation models., Results: Consistent with predictions, spouse confidence in patient efficacy for arthritis management predicted improvements in patient depressive symptoms, perceived health, and lower extremity function over 6 months and in arthritis severity over 1 year., Conclusions: Our findings add to a growing literature that highlights the important role of spouse perceptions in patients' long-term health.

Purpose: We report the results of a study designed to assess whether and how much potential individual end users are willing to pay for Quality of Life Technologies (QoLTs) designed to enhance functioning and independence., Design and Methods: We carried out a web survey of a nationally representative sample of U.S. baby boomers (aged 45-64; N = 416) and older adults (aged 65 and greater, N = 114). Respondents were first instructed to assume that they needed help with kitchen activities/personal care and that technology was available to help with things like meal preparation/dressing, and then they were asked the most they would be willing to pay each month out of pocket for these technologies., Results: We modeled willingness to pay some (72% of respondents) versus none (28%), and the most people were willing to pay. Those willing to pay something were on average willing to pay a maximum of $40.30 and $45.00 per month for kitchen and personal care technology assistance, respectively. Respondents concerned about privacy or who were currently using assistive technology were less willing to pay. Respondents with higher incomes, who were Hispanic, or who perceived a higher likelihood of needing help in the future were more willing to pay., Implications: Consumers' willingness to pay out of pocket for technologies to improve their well-being and independence is limited. In order to be widely adopted, QoLTs will have to be highly cost effective so that third party payers such as Medicare and private insurance companies are willing to pay for them.

Background: Physical activity is critical for the management of knee osteoarthritis, and the spouse may play a role in encouraging or discouraging physical activity., Purpose: The purpose of this study was to examine four types of spousal influence-spouses' daily activity, autonomy support, pressure, and persuasion-on the daily physical activity of adults living with knee osteoarthritis., Methods: A total of 141 couples reported their daily experiences for 22 days using a handheld computer and wore an accelerometer to measure moderate activity and steps., Results: Spouses' autonomy support for patient physical activity, as well as their own level of activity, was concurrently associated with patients' greater daily moderate activity and steps. In addition, on days when male patients perceived that spouses exerted more pressure to be active, they spent less time in moderate activity., Conclusions: Couple-oriented interventions for knee osteoarthritis should target physical activity in both partners and spousal strategies for helping patients stay active.

Motivation: Molecular simulation has historically been a low-throughput technique, but faster computers and increasing amounts of genomic and structural data are changing this by enabling large-scale automated simulation of, for instance, many conformers or mutants of biomolecules with or without a range of ligands. At the same time, advances in performance and scaling now make it possible to model complex biomolecular interaction and function in a manner directly testable by experiment. These applications share a need for fast and efficient software that can be deployed on massive scale in clusters, web servers, distributed computing or cloud resources., Results: Here, we present a range of new simulation algorithms and features developed during the past 4 years, leading up to the GROMACS 4.5 software package. The software now automatically handles wide classes of biomolecules, such as proteins, nucleic acids and lipids, and comes with all commonly used force fields for these molecules built-in. GROMACS supports several implicit solvent models, as well as new free-energy algorithms, and the software now uses multithreading for efficient parallelization even on low-end systems, including windows-based workstations. Together with hand-tuned assembly kernels and state-of-the-art parallelization, this provides extremely high performance and cost efficiency for high-throughput as well as massively parallel simulations., Availability: GROMACS is an open source and free software available from http://www.gromacs.org., Supplementary Information: Supplementary data are available at Bioinformatics online.

Alternative polyadenylation increases transcriptome diversity by generating multiple transcript isoforms from a single gene. It is thought that this process can be subject to epigenetic regulation, but few specific examples of this have been reported. We previously showed that the Mcts2/H13 locus is subject to genomic imprinting and that alternative polyadenylation of H13 transcripts occurs in an allele-specific manner, regulated by epigenetic mechanisms. Here, we demonstrate that allele-specific polyadenylation occurs at another imprinted locus with similar features. Nap1l5 is a retrogene expressed from the paternally inherited allele, is situated within an intron of a 'host' gene Herc3, and overlaps a CpG island that is differentially methylated between the parental alleles. In mouse brain, internal Herc3 polyadenylation sites upstream of Nap1l5 are used on the paternally derived chromosome, from which Nap1l5 is expressed, whereas a downstream site is used more frequently on the maternally derived chromosome. Ablating DNA methylation on the maternal allele at the Nap1l5 promoter increases the use of an internal Herc3 polyadenylation site and alters exon splicing. These changes demonstrate the influence of epigenetic mechanisms in regulating Herc3 alternative mRNA processing. Internal Herc3 polyadenylation correlates with expression levels of Nap1l5, suggesting a possible role for transcriptional interference. Similar mechanisms may regulate alternative polyadenylation elsewhere in the genome.

Background: Competing theories of adaptation and wear-and-tear describe psychological distress patterns among family caregivers., Purpose: This study seeks to characterize psychological distress patterns in family caregivers and identify predictors., Methods: One hundred three caregivers of care recipients with primary malignant brain tumors were interviewed within 1, 4, 8, and 12 months post-diagnosis regarding psychological distress; care recipients were interviewed regarding clinical/functional characteristics. Group-based trajectory modeling identified longitudinal distress patterns, and weighted logistic/multinomial regression models identified predictors of distress trajectories., Results: Group-based trajectory modeling identified high-decreasing (51.1 % of caregivers) and consistently low (48.9 %) depressive symptom trajectories, high-decreasing (75.5 %) and low-decreasing (24.5 %) anxiety trajectories, and high (37.5 %), moderate (40.9 %), and low-decreasing (21.6 %) caregiver burden trajectories. High depressive symptoms were associated with high trajectories for both anxiety and burden, lower caregivers age, income, and social support, and lower care recipient functioning., Conclusions: Our data support the adaptation hypothesis; interventions should target those at risk for persistent distress.

Background: Methylated DNA immunoprecipitation (MeDIP) is a popular enrichment based method and can be combined with sequencing (termed MeDIP-seq) to interrogate the methylation status of cytosines across entire genomes. However, quality control and analysis of MeDIP-seq data have remained to be a challenge., Results: We report genome-wide DNA methylation profiles of wild type (wt) and mutant mouse cells, comprising 3 biological replicates of Thymine DNA glycosylase (Tdg) knockout (KO) embryonic stem cells (ESCs), in vitro differentiated neural precursor cells (NPCs) and embryonic fibroblasts (MEFs). The resulting 18 methylomes were analysed with MeDUSA (Methylated DNA Utility for Sequence Analysis), a novel MeDIP-seq computational analysis pipeline for the identification of differentially methylated regions (DMRs). The observed increase of hypermethylation in MEF promoter-associated CpG islands supports a previously proposed role for Tdg in the protection of regulatory regions from epigenetic silencing. Further analysis of genes and regions associated with the DMRs by gene ontology, pathway, and ChIP analyses revealed further insights into Tdg function, including an association of TDG with low-methylated distal regulatory regions., Conclusions: We demonstrate that MeDUSA is able to detect both large-scale changes between cells from different stages of differentiation and also small but significant changes between the methylomes of cells that only differ in the KO of a single gene. These changes were validated utilising publicly available datasets and confirm TDG's function in the protection of regulatory regions from epigenetic silencing.

Progressive multi-focal leucoencephalopathy and progressive multi-focal leucoencephalopathy-immune reconstitution inflammatory syndrome are caused by infection of the central nervous system with the JC polyoma virus. Both are complications of monoclonal antibody therapy in multiple sclerosis and other autoimmune diseases. Progressive multi-focal leucoencephalopathy-immune reconstitution inflammatory syndrome can obscure the diagnosis of progressive multi-focal leucoencephalopathy and lead to severe clinical disability and possibly death. Different from progressive multi-focal leucoencephalopathy, in which demyelination results from oligodendrocyte lysis by JC virus in the absence of an immune response, tissue destruction in progressive multi-focal leucoencephalopathy-immune reconstitution inflammatory syndrome is caused by a vigorous immune response within the brain. The cells and mediators that are involved in progressive multi-focal leucoencephalopathy-immune reconstitution inflammatory syndrome are as yet poorly understood. We examined two patients with multiple sclerosis, who developed progressive multi-focal leucoencephalopathy and later progressive multi-focal leucoencephalopathy-immune reconstitution inflammatory syndrome under natalizumab therapy. Due to initially negative JC viral deoxyribonucleic acid testing in the cerebrospinal fluid, a diagnostic brain biopsy was performed in one patient. Histopathology revealed brain inflammation characterized by a prominent T cell infiltrate (CD4(+)> CD8(+) T cells), but also B/plasma cells and monocytes. Despite very low JC viral load, both patients showed high intrathecal anti-JC virus antibodies. Brain-infiltrating CD4(+) T cells were studied regarding antigen specificity and function. CD4(+) T cells were highly specific for peptides from several JC virus proteins, particularly the major capsid protein VP1. T cell phenotyping revealed CD4(+) Th1 and bifunctional Th1-2 cells. The latter secrete large amounts of interferon-γ and interleukin-4 explaining the strong brain inflammation, presence of plasma cells and secretion of intrathecal anti-VP1 antibodies. The functional phenotype of brain-infiltrating JC virus-specific CD4(+) T cells was confirmed and extended by examining brain-derived JC virus-specific CD4(+) T cell clones. Our data provide novel insight into the pathogenesis of progressive multi-focal leucoencephalopathy-immune reconstitution inflammatory syndrome and indicate that JC virus-specific CD4(+) T cells play an important role in both eliminating JC virus from the brain, but also in causing the massive inflammation with often fatal outcome.

Purpose: assess psychometric properties of scales developed to assess experience and perception of physical, psychological, and existential suffering in older individuals., Design and Methods: scales were administered to 3 populations of older persons and/or their family caregivers: individuals with Alzheimer's disease (AD) and their family caregivers (N = 105 dyads), married couples in whom 1 partner had osteoarthritis (N = 53 dyads), and African American and Hispanic caregivers of care recipients with AD (N = 121). Care recipients rated their own suffering, whereas caregivers provided ratings of perceived suffering of their respective care recipients. In addition, quality of life, health, and functional status data were collected from all respondents via structured in-person interviews., Results: three scales showed high levels of internal consistency, test-retest reliability, and convergent and discriminant validity. The scales were able to discriminate differences in suffering as a function of type of disease, demonstrated high intra-person correlations and moderately high inter-person correlations and exhibited predicted patterns of association between each type of suffering and indicators of quality of life, health status, and caregiver outcomes of depression and burden., Implications: suffering is an important but understudied domain. This article provides valuable tools for assessing the experience and perception of suffering in humans.

Purpose: to examine racial differences in (a) the prevalence of financial exploitation and psychological mistreatment since turning 60 and in the past 6 months and (b) the experience-perpetrator, frequency, and degree of upset-of psychological mistreatment in the past 6 months., Design and Methods: random digit dial telephone recruitment and population-based survey (telephone and in-person) of 903 adults aged 60 years and older in Allegheny County (Pittsburgh), Pennsylvania (693 non-African American and 210 African American). Covariates included sex, age, education, marital status, household composition, cognitive function, instrumental activities of daily living/activities of daily living difficulties, and depression symptoms., Results: prevalence rates were significantly higher for African Americans than for non-African Americans for financial exploitation since turning 60 (23.0% vs. 8.4%) and in the past 6 months (12.9% vs. 2.4%) and for psychological mistreatment since turning 60 (24.4% vs. 13.2%) and in the past 6 months (16.1% vs. 7.2%). These differences remained once all covariates were controlled in logistic regression models. There were also racial differences in the experience of psychological mistreatment in the past 6 months. Risk for clinical depression was also a consistent predictor of financial exploitation and psychological mistreatment., Implications: although the results will need to be replicated in national surveys, the study suggests that racial differences in elder mistreatment are a potentially serious issue deserving of continued attention from researchers, health providers, and social service professionals.

Background: Evidence continues to build for the impact of the marital relationship on health as well as the negative impact of illness on the partner. Targeting both patient and partner may enhance the efficacy of psychosocial or behavioral interventions for chronic illness., Purpose: The purpose of this report is to present a cross-disease review of the characteristics and findings of studies evaluating couple-oriented interventions for chronic physical illness., Methods: We conducted a qualitative review of 33 studies and meta-analyses for a subset of 25 studies., Results: Identified studies focused on cancer, arthritis, cardiovascular disease, chronic pain, HIV, and Type 2 diabetes. Couple interventions had significant effects on patient depressive symptoms (d = 0.18, p < 0.01, k = 20), marital functioning (d = 0.17, p < 0.01, k = 18), and pain (d = 0.19, p < 0.01, k = 14) and were more efficacious than either patient psychosocial intervention or usual care., Conclusions: Couple-oriented interventions have small effects that may be strengthened by targeting partners' influence on patient health behaviors and focusing on couples with high illness-related conflict, low partner support, or low overall marital quality. Directions for future research include assessment of outcomes for both patient and partner, comparison of couple interventions to evidence-based patient interventions, and evaluation of mechanisms of change.

Background: Traditional prognostic factors for survival and treatment response of patients with breast cancer do not fully account for observed survival variation. We used available genotype data from a previously conducted two-stage, breast cancer susceptibility genome-wide association study (ie, Studies of Epidemiology and Risk factors in Cancer Heredity [SEARCH]) to investigate associations between variation in germline DNA and overall survival., Methods: We evaluated possible associations between overall survival after a breast cancer diagnosis and 10 621 germline single-nucleotide polymorphisms (SNPs) from up to 3761 patients with invasive breast cancer (including 647 deaths and 26 978 person-years at risk) that were genotyped previously in the SEARCH study with high-density oligonucleotide microarrays (ie, hypothesis-generating set). Associations with all-cause mortality were assessed for each SNP by use of Cox regression analysis, generating a per rare allele hazard ratio (HR). To validate putative associations, we used patient genotype information that had been obtained with 5' nuclease assay or mass spectrometry and overall survival information for up to 14 096 patients with invasive breast cancer (including 2303 deaths and 70 019 person-years at risk) from 15 international case-control studies (ie, validation set). Fixed-effects meta-analysis was used to generate an overall effect estimate in the validation dataset and in combined SEARCH and validation datasets. All statistical tests were two-sided., Results: In the hypothesis-generating dataset, SNP rs4778137 (C>G) of the OCA2 gene at 15q13.1 was statistically significantly associated with overall survival among patients with estrogen receptor-negative tumors, with the rare G allele being associated with increased overall survival (HR of death per rare allele carried = 0.56, 95% confidence interval [CI] = 0.41 to 0.75, P = 9.2 x 10(-5)). This association was also observed in the validation dataset (HR of death per rare allele carried = 0.88, 95% CI = 0.78 to 0.99, P = .03) and in the combined dataset (HR of death per rare allele carried = 0.82, 95% CI = 0.73 to 0.92, P = 5 x 10(-4))., Conclusion: The rare G allele of the OCA2 polymorphism, rs4778137, may be associated with improved overall survival among patients with estrogen receptor-negative breast cancer.

Background: Nonmelanoma skin cancer (NMSC) and malignant melanoma (CMM) are among the most common malignancies in the white population. The major risk factor for those malignancies is ultraviolet radiation (UV) causing directly DNA damage and promoting the development of skin cancer. It is suggested that the exposure to UV during childhood elevates an individual's lifetime risk of developing skin cancer more than exposure in adulthood. Since an increasing number of children spend the time of the most intense UV in a day-care centre, it seems an excellent place for establishing primary skin cancer prevention. Important targets are staff members and parents of the day-care centre, since sun protection of children depends directly on their knowledge and their attitude towards sun protection practices., Objectives: To establish a feasible certification program for sun protection in a German child day-care centre, for a better sun protection of the children and the reduction of skin cancer incidence in the long term., Methods: Initially sun protection practices of the centre at baseline were assessed. A written sun protection policy was developed in consultation with all members of the day-care centre as basis for certification. It was followed by training sessions for staff members (n=12) and parents (n=46). After a fixed period of time the final assessment of the child day-care centre was conducted and the centre then was certified for improved sun protection practices and better protection of the children. The primary assessed outcomes were the gain in knowledge of staff members and parents after the training sessions, the number of children wearing a hat when playing outside, the use of sunscreen and the percentage of shaded areas on the playground., Results: Sun protection was an issue more discussed during the time of intervention than before. Staff members (n=12) and parents (n=27) had a significant gain in knowledge (staff members: P=0.002; parents: P=0.001) concerning sun related issues. The number of children wearing a hat increased from 13.2% to 73%. The sunscreen use increased, 58.8% of staff members reported a more regular application of sunscreen to the children. There was a higher percentage of shaded area on the playground (70-80% before intervention, 90% after intervention). The intervention failed in keeping the children inside during the most intense UV and in educating the staff members to be a convincing example of sun protection by wearing appropriate clothes., Conclusions: The intervention showed that the introduction of a simple certification program including a written sun protection policy and training sessions for staff members and parents helps to improve children's sun protection. We suggest that a certificate for adequate sun protection acts as a motivating factor. It seems important to refresh sun protection practices each year by repeating training sessions and reviewing the sun protection policy.