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Abstract Determining the genetic architecture of Alzheimer’s disease pathologies can enhance mechanistic understanding and inform precision medicine strategies. Here, we perform a genome-wide association study of cortical tau quantified by positron emission tomography in 3046 participants from 12 independent studies. The CYP1B1-RMDN2 locus is associated with tau deposition. The most significant signal is at rs2113389, explaining 4.3% of the variation in cortical tau, while APOE4 rs429358 accounts for 3.6%. rs2113389 is associated with higher tau and faster cognitive decline. Additive effects, but no interactions, are observed between rs2113389 and diagnosis, APOE4, and amyloid beta positivity. CYP1B1 expression is upregulated in AD. rs2113389 is associated with higher CYP1B1 expression and methylation levels. Mouse model studies provide additional functional evidence for a relationship between CYP1B1 and tau deposition but not amyloid beta. These results provide insight into the genetic basis of cerebral tau deposition and support novel pathways for therapeutic development in AD.

【Objective】WRKY transcription factor family plays an important role in plant growth, development and stress resistance. The biological functions of WRKY gene family members involved in abiotic stress of Benincasa hispida Cogn. (wax gourd) were explored.【Method】WRKY members of wax gourd were identified based on the genome database of wax gourd. The protein physicochemical properties, phylogeny, conserved motifs and cis-acting elements of the members of the BhWRKY gene family was systematically analyzed by bioinformatics method. And the expression of wax gourd WRKY was analyzed by qPCR.【Result】The results showed that there were 57 members in the BhWRKY gene family with amino acid numbers ranging from 126 to 650 and molecular weight ranging from 13.92 to 71.68 kD. The isoelectric point of protein ranged from 4.61 to 9.69. According to phylogenetic tree, the family was divided into 3 groups, and the second group was further divided into 5 subgroups. The number of WRKY exons of wax gourd ranged from 2 to 6. Chromosomal mapping analysis showed that 56 genes were located on 12 chromosomes, and one gene was not located on the chromosome. The conserved Motif 1 and Motif 3 were found in 56 genes, and the same group had similar conserved motif structure. Meanwhile, it was also found that the promoters of the BhWRKY genes all contained cis-responsive elements and hormone response elements related to stress response. WRKYs were specifically expressed in different tissues and fruit development stages of wax gourd. RT-PCR result showed that abiotic stress and hormone treatment could induce the expression of some BhWRKY genes.【Conclusion】A total of 57 WRKY genes of wax gourd are identified and members of the same subgroup have similar structures. There are differences in the expression of 57 WRKY genes in different tissues. Among them, BhWRKY2, BhWRKY5, BhWRKY39, BhWRKY11, BhWRKY31 and BhWRKY53 participate in different stress responses.

For patients with chronic spinal cord injury, the conventional treatment is rehabilitation and treatment of spinal cord injury complications such as urinary tract infection, pressure sores, osteoporosis, and deep vein thrombosis. Surgery is rarely performed on spinal cord injury in the chronic phase, and few treatments have been proven effective in chronic spinal cord injury patients. Development of effective therapies for chronic spinal cord injury patients is needed. We conducted a randomized controlled clinical trial in patients with chronic complete thoracic spinal cord injury to compare intensive rehabilitation (weight-bearing walking training) alone with surgical intervention plus intensive rehabilitation. This clinical trial was registered at ClinicalTrials.gov (NCT02663310). The goal of surgical intervention was spinal cord detethering, restoration of cerebrospinal fluid flow, and elimination of residual spinal cord compression. We found that surgical intervention plus weight-bearing walking training was associated with a higher incidence of American Spinal Injury Association Impairment Scale improvement, reduced spasticity, and more rapid bowel and bladder functional recovery than weight-bearing walking training alone. Overall, the surgical procedures and intensive rehabilitation were safe. American Spinal Injury Association Impairment Scale improvement was more common in T7–T11 injuries than in T2–T6 injuries. Surgery combined with rehabilitation appears to have a role in treatment of chronic spinal cord injury patients.

Summary: Amyloid-β (Aβ) and tau proteins accumulate within distinct neuronal systems in Alzheimer’s disease (AD). Although it is not clear why certain brain regions are more vulnerable to Aβ and tau pathologies than others, gene expression may play a role. We study the association between brain-wide gene expression profiles and regional vulnerability to Aβ (gene-to-Aβ associations) and tau (gene-to-tau associations) pathologies by leveraging two large independent AD cohorts. We identify AD susceptibility genes and gene modules in a gene co-expression network with expression profiles specifically related to regional vulnerability to Aβ and tau pathologies in AD. In addition, we identify distinct biochemical pathways associated with the gene-to-Aβ and the gene-to-tau associations. These findings may explain the discordance between regional Aβ and tau pathologies. Finally, we propose an analytic framework, linking the identified gene-to-pathology associations to cognitive dysfunction in AD at the individual level, suggesting potential clinical implication of the gene-to-pathology associations.

Introduction: Older adults with cognitive impairment (CI) are more likely to visit the emergency department (ED) than those without CI. They are also more likely to suffer poor outcomes after an ED visit. Family and friends who serve as care partners contribute significant time and resources to the care of these patients and may need particular attention to their emotional needs during and after the ED encounter. In this study, we examined the association between patient and care partner characteristics on care partner depression and anxiety at the time of the ED visit. Methods: Baseline data from 640 patient-care partner dyads who were enrolled in a two-site randomized controlled trial at New York University Lagone Health and Indiana University. The goal of the trial was to evaluate a tailored collabotative care management program to reduce readmissions of ED patients older than 75 years with CI and reduce care partner burden. Eligible patients were ED patients aged ≥75 years with CI as measured by the Mini-Cog or the proxy-reported Short Informant Questionnaire on Cognitive Decline in the Elderly and a planned dicharge home. Eligble care partners were self-identified or identified by the patient. We collected patient and care partner demographics, care partner-reported patient medical and psychiatric history, daily needs of the patient, and patient-care partner relationship. We used descriptive statistics and logistic regression to identify factors associated with symptoms of depression or anxiety in care partners, as assessed by Patient Health Questionnaire (PHQ-9) and General Anxiety Disorder (GAD-7) scores, respectively. Results: Depression and anxiety data were available on all 640 care partners. In total, 251 (39.2%) had depression as measured by a score of ≥5 on the PHQ-9 and 299 (46.7%) had anxiety based on a score ≥5 on the GAD-7. Patient functional impairment (OR 1.04, 95% CI 1.01, 1.07), behavioral and psychological symptoms (OR 1.08, 95% CI 1.04, 1.13) and care partner social support (OR 0.91, CI 0.88, 0.95) were significantly associated with care partner depression. Similarly, patient functional impairment (OR 1.04, 95% CI 1.01, 1.07), behavioral and psychological symptoms (OR 1.11, 95% CI 1.07, 1.16) and care partner social support (OR 0.94, CI 0.90, 0.97) were also significantly associated with care partner anxiety as was patient race (p=0.041). Conclusion: Care partners of older adults with CI who present to the ED demonstrate depression and anxiety, but discharge from the ED represents an opportunity to focus on integration of care partners into aftercare in a well-informed, supportive fashion.

Abstract Background and Aims Given the growing utilization of critical care services by an aging population, development of population‐level risk models which predict intensive care unit (ICU) survivorship and mortality may offer advantages for researchers and health systems. Our objective was to develop a risk model for ICU survivorship and mortality among community dwelling older adults. Methods This was a population‐based cohort study of 48,127 patients who were 50 years and older with at least one primary care visit between January 1, 2017, and December 31, 2017. We used electronic health record (EHR) data to identify variables predictive of ICU survivorship. Results ICU admission and mortality within 2 years after index primary care visit date were used to divide patients into three groups of “alive without ICU admission”, “ICU survivors,” and “death.” Multinomial logistic regression was used to identify EHR predictive variables for the three patient outcomes. Cross‐validation by randomly splitting the data into derivation and validation data sets (60:40 split) was used to identify predictor variables and validate model performance using area under the receiver operating characteristics (AUC) curve. In our overall sample, 92.2% of patients were alive without ICU admission, 6.2% were admitted to the ICU at least once and survived, and 1.6% died. Greater deciles of age over 50 years, diagnoses of chronic obstructive pulmonary disorder or chronic heart failure, and laboratory abnormalities in alkaline phosphatase, hematocrit, and albumin contributed highest risk score weights for mortality. Risk scores derived from the model discriminated between patients that died versus remained alive without ICU admission (AUC = 0.858), and between ICU survivors versus alive without ICU admission (AUC = 0.765). Conclusion Our risk scores provide a feasible and scalable tool for researchers and health systems to identify patient cohorts at increased risk for ICU admission and survivorship. Further studies are needed to prospectively validate the risk scores in other patient populations.

Abstract Background Delirium is a highly prevalent and morbid syndrome in mechanically ventilated intensive care unit (ICU) patients. Music is a promising non-pharmacological intervention with beneficial effects on anxiety and stress, while its effects on delirium duration and severity are not well understood. Methods/design Our study is a two-arm, randomized parallel-group, clinical trial to evaluate the efficacy of music intervention compared to a silence-track attention control on delirium/coma duration in mechanically ventilated critically ill older adults. One hundred sixty mechanically ventilated adults 50 years of age or older will be randomized to one of two arms within 72 h of ICU admission: (1) 1-h music listening sessions twice daily through noise-canceling headphones, or (2) 1-h sessions of a silence track twice daily through noise-canceling headphones. Our primary aim is to compare delirium/coma-free days after randomization during the 7-day study intervention phase using the Confusion Assessment Method for the ICU (CAM ICU) and the Richmond Agitation Sedation Scale (RASS) for delirium and coma. Secondary outcomes include pain and anxiety evaluated twice daily during the intervention phase and throughout the duration of ICU stay using the Critical Care Pain Observation Tool (CPOT) and visual analog scale-anxiety (VAS-A). Enrolled participants will be followed after hospital discharge to further measure cognition as well as screening for depression and anxiety using the following telephone-based instruments: Indiana University Telephone-Based Assessment of Neuropsychological Status (IU TBANS), Patient Health Questionnaire-9 (PHQ-9), and Generalized Anxiety Disorder-7 (GAD-7). Discussion This randomized clinical trial will measure the efficacy of a music listening intervention for delirium and coma duration early in the intensive care unit among older adults. Trial registration. ClinicalTrials.gov. NCT04182334 .

Abstract Introduction The study examined Black and White prospective participants’ views of barriers to and facilitators of participation in Alzheimer's disease (AD) biomarker research. Methods In a mixed‐methods study, 399 community‐dwelling Black and White older adults (age ≥55) who had never participated in AD research completed a survey about their perceptions of AD biomarker research. Individuals from lower socioeconomic and education backgrounds and Black men were over‐sampled to address perspectives of traditionally under‐represented groups. A subset of participants (n = 29) completed qualitative interviews. Results Most participants expressed interest in biomarker research (overall 69%). However, Black participants were comparatively more hesitant than White participants (28.9% vs 15.1%), were more concerned about study risks (28.9% vs 15.1%), and perceived multiple barriers to participating in brain scans. These results persisted even after adjusting for trust and perceived knowledge of AD. Information was a primary barrier (when absent) and incentive (when provided) for AD biomarker research participation. Black older adults desired more information about AD (eg, risk, prevention), general research processes, and specific biomarker procedures. They also desired return of results to make informed decisions about their health, research‐sponsored community awareness events, and for researchers to mitigate the burden placed on participants in research (eg, transportation, basic needs). Conclusion Our findings increase representativeness in the literature by focusing on individuals with no history of AD research experience and those from traditionally underrepresented groups in research. Results suggest that the research community needs to improve information sharing and raising awareness, increase their presence in the communities of underrepresented groups, reduce incidental costs, and provide valuable personal health information to participants to increase interest. Specific recommendations for improving recruitment are addressed. Future studies will assess the implementation of evidence‐based, socioculturally sensitive recruitment strategies to increase enrollment of Black older adults into AD biomarker studies. HIGHLIGHTS Individuals from under‐represented groups are interested in Alzheimer's disease (AD) biomarker research. After adjusting for trust and AD knowledge, Black participants were still more hesitant. Information is a barrier (when absent) to and incentive (when given) for biomarker studies. Reducing burden (e.g., transportation) is essential for recruiting Black older adults.

Abstract Introduction Community advisory boards (CABs) and researcher partnerships present a promising opportunity to accelerate enrollment of underrepresented groups (URGs). We outline the framework for how the CAB and researchers at the Indiana Alzheimer's Disease Research Center (IADRC) partnered to accelerate URG participation in AD neuroimaging research. Methods CAB and the IADRC researchers partnered to increase the CAB's impact on URG study enrollment through community and research interactions. Community interactions included the CAB collaboratively building a network of URG focused community organizations and collaborating with those URG‐focused organizations to host IADRC outreach and recruitment events. Research interactions included direct impact (CAB members referring themselves or close contacts as participants) and strategic impact, mainly by the CAB working with researchers to develop and refine URG focused outreach and recruitment strategies for IADRC and affiliated studies to increase URG representation. We created a database infrastructure to measure how these interactions impacted URG study enrollment. Results Out of the 354 URG research referrals made to the IADRC between October 2019 and December 2022, 267 referrals were directly referred by the CAB (N = 36) or from community events in which CAB members organized and/or volunteered at (N = 231). Out of these 267 referrals, 34 were enrolled in IADRC and 2 were enrolled in Indiana University Longitudinal Early Onset AD Study (IU LEADS). Of note, both studies require the prospective participants to be willing to do MRI and PET scans. As of December 2022, 30 out of the 34 enrolled participants have received a consensus diagnosis; the majority were cognitively normal (64.7%), with the remainder having mild cognitive impairment (17.6%) or early‐stage AD (2.9%). Discussion The IADRC CAB‐researcher partnership had a measurable impact on the enrollment of African American/Black adults in AD neuroimaging studies. Future studies will need to test whether this conceptual model works for other sites and for other URGs.

ObjectiveIn critically ill adults with delirium, biomarkers of systemic inflammation, astrocyte activation, neuroprotection, and systemic inflammation measured at one week of critical illness may be associated with mortality.DesignProspective observational study.SettingIntensive care unit (ICU).Patients178 ICU patients with delirium, alive and remaining in ICU at one week.InterventionsNone.Measurements and main resultsBlood samples collected for a pair of previously published, negative, clinical trials were utilized. Samples were collected at study enrollment/ICU admission (Day 1 sample) and one week later (Day 8 sample), and analyzed for interleukins (IL)-6, 8, 10, Insulin-like Growth Factor (IGF), S100 Binding Protein (S100B), Tumor Necrosis Factor Alpha (TNF-A) and C-Reactive Protein (CRP). Delirium, delirium severity, and coma were assessed twice daily using Confusion Assessment Method for the Intensive Care Unit (CAM-ICU), CAM-ICU-7, and Richmond Agitation-Sedation Scale (RASS), respectively. Mortality was assessed until discharge using the electronic medical record. Logistic regression models adjusting for age, sex, severity of illness, comorbidities, sepsis, and randomization status, were used to assess the relationship among biomarkers and mortality. Higher IL-10 quartiles at day 8 were associated with increased odds of hospital mortality (IL-10: OR 2.00 95%CI: 1.1-3.65, p = 0.023). There was a significant interaction between day 1 and day 8 biomarker quartiles only for IL-6. Patients with IL-6 values in the first three quartiles on admission to the ICU that transitioned to higher IL-6 quartiles at day 8 had increased probability of hospital mortality.ConclusionIn this hypothesis-generating study, higher IL-6 and IL-10 quartiles at one week, and increase in IL-6 from day 1 to day 8 were associated with increased hospital mortality. Studies with larger sample sizes are needed to confirm the mechanisms for these observations.

OBJECTIVES:. Critically ill patients with COVID-19 experience high rates of delirium and coma. Whether delirium occurs through novel mechanisms in COVID-19 is not known. We analyzed the relationship among biomarkers of inflammation (C-reactive protein [CRP]), hypercoagulability (d-dimer), and lung macrophage activation (ferritin), and the primary composite outcome of delirium/coma next day. We also measured associations between biomarkers and next day delirium and coma independently, and delirium severity. DESIGN:. Retrospective, observational cohort study. SETTING:. ICUs at two large, urban, academic referral hospitals. PATIENTS:. All consecutive adult patients admitted to the ICU from March 1, 2020, to June 7, 2020, with COVID-19 with clinical biomarkers and delirium assessments performed. INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. Daily concentrations of CRP, d-dimer, and ferritin were obtained. Coma (assessed by Richmond Agitation-Sedation Scale) and delirium (assessed by Confusion Assessment Method for the ICU/Confusion Assessment Method for the ICU-7) were measured bid. A cohort of 197 ICU patients with COVID-19 were included. Higher d-dimer (odds ratio [OR], 1.57; 95% CI, 1.17–2.12; p < 0.01) and ferritin quartiles (OR, 1.36; 95% CI, 1.02–1.81; p < 0.01) were associated with greater odds of the composite outcome of delirium/coma next day. d-dimer was associated with greater odds of next day delirium (OR, 1.49; 95% CI, 1.14–1.94; p < 0.01) and coma independently (OR, 1.52; 95% CI, 1.08–2.14; p = 0.017). Higher ferritin quartiles were associated with greater odds of next day delirium (OR, 1.33; 95% CI, 1.04–1.70; p = 0.026) and coma independently (OR, 1.59; 95% CI, 1.14–2.23; p < 0.01). Higher CRP quartiles were associated with coma (OR, 1.36; 95% CI, 1.03–1.79; p = 0.030) and delirium severity the next day (β = 0.30; se, 0.07; p ≤ 0.01). CONCLUSIONS:. Our hypothesis-generating study found d-dimer and ferritin were associated with delirium/coma the following day, as well as delirium and coma independently. CRP was associated with next day coma and delirium severity. Larger studies to validate these results are needed.

Objective:. To compare differences in baseline depression and anxiety screenings between older injured patients with pre-existing diagnoses and those without. Background:. Little is known about the prevalence and impact of psychiatric comorbidities on early postinjury depression and anxiety in nonneurologically injured older adults. Methods:. This was a retrospective post-hoc analysis of data from the Trauma Medical Home, a multicenter randomized controlled trial (R01AG052493-01A1) that explored the effect of a collaborative care model on postinjury recovery for older adults compared to usual care. Results:. Nearly half of the patients screened positive for at least mild depressive symptoms as measured by the Patient Health Questionnaire-9. Forty-one percent of the patients screened positive for at least mild anxiety symptoms as measured by the Generalized Anxiety Disorder Scale. Female patients with a history of concurrent anxiety and depression, greater injury severity scores, and higher Charlson scores were more likely to have mild anxiety at baseline assessment. Patients with a history of depression only, a prior history of depression and concurrent anxiety, and higher Charlson scores (greater medical comorbidity) had greater odds of at least mild depression at the time of hospital discharge after traumatic injury. Conclusions:. Anxiety and depression are prevalent in the older adult trauma population, and affect women disproportionately. A dual diagnosis of depression and anxiety is particularly morbid. Mental illness must be considered and addressed with the same importance as other medical diagnoses in patients with injuries.

In order to accurately evaluate the fracturing stimulation effect of horizontal wells in shale gas reservoirs, it is suggested to establish a model to predict the temperature distribution in the wellbore of horizontal well and an inversion model of DTS data by using MCMC algorithm, and optimize the production profile interpretation process. In this paper, the characteristics of temperature profile of fractured horizontal wells in shale gas reservoirs were analyzed and the main factors affecting the temperature profile were figured out. Finally, the newly established inversion model was applied to the production profile interpretation of one case well in a certain shale gas reservoir. And the following research results were obtained. First, the temperature profile of fractured horizontal wells is in the shape of irregular “saw tooth”, and each “saw tooth” corresponds to an effective hydraulic fracture with fluid inflow. Second, the longer the fracture is, the greater the wellbore temperature drop at the corresponding fracture location is, and the gas flow rate in the fracture is positively correlated with the temperature drop. Third, from the perspective of influence degree, the factors influencing the temperature profile of fractured horizontal wells in shale gas reservoirs are ranked from the strong to the weak as follows: fracture half-length, gas flow rate, permeability of stimulated area, wellbore diameter, fracture conductivity, horizontal inclination angle, and comprehensive thermal conductivity, among which, the first three are main controlling factors. Fourth, the MCMC inversion method is applied to invert the DST temperature data of the case well. The temperature profile predicted in the model is better accordant with the measured DTS profile, and the absolute error of the predicted temperature at different levels of effective hydraulic fractures is less than 0.02 °C. The interpreted gas flow rate of each fracturing stage is closer to the field measurement, and the deviation of the maximum gas flow rate of a single fracturing stage is only 180.35 m3/d. The absolute error between single-well gas production rate and gas production rate measured at the wellhead is less than 3 m3/d, which proves the reliability of this newly developed inversion model.

BackgroundOlder adults with cognitive impairment have more emergency department visits and 30-day readmissions and are more likely to die after visiting the emergency department than people without cognitive impairment. Emergency department providers frequently do not identify cognitive impairment. Use of cognitive screening tools, along with better understanding of root causes for emergency department visits, could equip health care teams with the knowledge needed to develop individually tailored care management strategies for post–emergency department care. By identifying and directly addressing patients’ and informal caregivers’ (or care partners’) psychosocial and health care needs, such strategies could reduce the need for repeat acute care. We have used the terms “caregiver” and “care partner” interchangeably. ObjectiveWe aimed to describe the protocol for a randomized controlled trial of a new care management intervention, the Program of Intensive Support in Emergency Departments for Care Partners of Cognitively Impaired Patients (POISED) trial, compared with usual care. We described the research design, intervention, outcome measures, data collection techniques, and analysis plans. MethodsEmergency department patients who were aged ≥75 years and screened positive for cognitive impairment via either the Mini-Cog or the proxy-reported Short Informant Questionnaire on Cognitive Decline in the Elderly, with a planned discharge to home, were recruited to participate with their identified informal (family or friend) caregiver in the 2-site POISED randomized controlled trial at New York University Langone Health and Indiana University. The intervention group received 6 months of care management from the POISED Care Team of registered nurses and specialty-trained paraprofessionals, who perform root cause analyses, administer standardized assessments, provide advice, recommend appropriate referrals, and, when applicable, implement dementia-specific comorbid condition protocols. The control group received care as recommended at emergency department discharge (usual care) and were given information about resources for further cognitive assessment. The primary outcome is repeat emergency department use; secondary outcomes include caregiver activation for patient health care management, caregiver depression, anxiety, and experience of social support as important predisposing and time-varying enabling and need characteristics. Data were collected from questionnaires and patients’ electronic health records. ResultsRecruitment was conducted between March 2018 and May 2021. Study findings will be published in peer-reviewed journals and presented to peer audiences, decision makers, stakeholders, and other interested persons. ConclusionsThe POISED intervention is a promising approach to tailoring care management based on root causes for emergency department admission of patients with cognitive impairment with the aim of reducing readmissions. This trial will provide insights for caregivers and emergency department and primary care providers on appropriate, personalized, and proactive treatment plans for older adults with cognitive impairment. The findings will be relevant to audiences concerned with quality of life for individuals with cognitive impairment and their caregivers. Trial RegistrationClinicalTrials.gov NCT03325608; https://clinicaltrials.gov/ct2/show/NCT03325608 International Registered Report Identifier (IRRID)DERR1-10.2196/36607

ObjectiveTo compare techniques for computing clustering and switching scores in terms of agreement, correlation, and empirical value as predictors of incident cognitive impairment (ICI).MethodsWe transcribed animal and letter F fluency recordings on 640 cases of ICI and matched controls from a national epidemiological study, amending each transcription with word timings. We then calculated clustering and switching scores, as well as scores indexing speed of responses, using techniques described in the literature. We evaluated agreement among the techniques with Cohen’s κ and calculated correlations among the scores. After fitting a base model with raw scores, repetitions, and intrusions, we fit a series of Bayesian logistic regression models adding either clustering and switching scores or speed scores, comparing the models in terms of several metrics. We partitioned the ICI cases into acute and progressive cases and repeated the regression analysis for each group.ResultsFor animal fluency, we found that models with speed scores derived using the slope difference algorithm achieved the best values of the Watanabe–Akaike Information Criterion (WAIC), but with good net reclassification improvement (NRI) only for the progressive group (8.2%). For letter fluency, different models excelled for prediction of acute and progressive cases. For acute cases, NRI was best for speed scores derived from a network model (3.4%), while for progressive cases, the best model used clustering and switching scores derived from the same network model (5.1%). Combining variables from the best animal and letter F models led to marginal improvements in model fit and NRI only for the all-cases and acute-cases analyses.ConclusionSpeed scores improve a base model for predicting progressive cognitive impairment from animal fluency. Letter fluency scores may provide complementary information.

African descent populations have a lower Alzheimer disease risk from ApoE ε4 compared to other populations. Ancestry analysis showed that the difference in risk between African and European populations lies in the ancestral genomic background surrounding the ApoE locus (local ancestry). Identifying the mechanism(s) of this protection could lead to greater insight into the etiology of Alzheimer disease and more personalized therapeutic intervention. Our objective is to follow up the local ancestry finding and identify the genetic variants that drive this risk difference and result in a lower risk for developing Alzheimer disease in African ancestry populations. We performed association analyses using a logistic regression model with the ApoE ε4 allele as an interaction term and adjusted for genome-wide ancestry, age, and sex. Discovery analysis included imputed SNP data of 1,850 Alzheimer disease and 4,331 cognitively intact African American individuals. We performed replication analyses on 63 whole genome sequenced Alzheimer disease and 648 cognitively intact Ibadan individuals. Additionally, we reproduced results using whole-genome sequencing of 273 Alzheimer disease and 275 cognitively intact admixed Puerto Rican individuals. A further comparison was done with SNP imputation from an additional 8,463 Alzheimer disease and 11,365 cognitively intact non-Hispanic White individuals. We identified a significant interaction between the ApoE ε4 allele and the SNP rs10423769_A allele, (β = -0.54,SE = 0.12,p-value = 7.50x10-6) in the discovery data set, and replicated this finding in Ibadan (β = -1.32,SE = 0.52,p-value = 1.15x10-2) and Puerto Rican (β = -1.27,SE = 0.64,p-value = 4.91x10-2) individuals. The non-Hispanic Whites analyses showed an interaction trending in the "protective" direction but failing to pass a 0.05 significance threshold (β = -1.51,SE = 0.84,p-value = 7.26x10-2). The presence of the rs10423769_A allele reduces the odds ratio for Alzheimer disease risk from 7.2 for ApoE ε4/ε4 carriers lacking the A allele to 2.1 for ApoE ε4/ε4 carriers with at least one A allele. This locus is located approximately 2 mB upstream of the ApoE locus, in a large cluster of pregnancy specific beta-1 glycoproteins on chromosome 19 and lies within a long noncoding RNA, ENSG00000282943. This study identified a new African-ancestry specific locus that reduces the risk effect of ApoE ε4 for developing Alzheimer disease. The mechanism of the interaction with ApoEε4 is not known but suggests a novel mechanism for reducing the risk for ε4 carriers opening the possibility for potential ancestry-specific therapeutic intervention.

Understanding the reorganization of neural circuits spared after spinal cord injury in the motor cortex and spinal cord would provide insights for developing therapeutics. Using optogenetic mapping, we demonstrated a transhemispheric recruitment of neural circuits in the contralateral cortical M1/M2 area to improve the impaired forelimb function after a cervical 5 right-sided hemisection in mice, a model mimicking the human Brown-Séquard syndrome. This cortical reorganization can be elicited by a selective cortical optogenetic neuromodulation paradigm. Areas of whisker, jaw, and neck, together with the rostral forelimb area, on the motor cortex ipsilateral to the lesion were engaged to control the ipsilesional forelimb in both stimulation and nonstimulation groups 8 weeks following injury. However, significant functional benefits were only seen in the stimulation group. Using anterograde tracing, we further revealed a robust sprouting of the intact corticospinal tract in the spinal cord of those animals receiving optogenetic stimulation. The intraspinal corticospinal axonal sprouting correlated with the forelimb functional recovery. Thus, specific neuromodulation of the cortical neural circuits induced massive neural reorganization both in the motor cortex and spinal cord, constructing an alternative motor pathway in restoring impaired forelimb function.

Although a large number of trials in the SCI field have been conducted, few proven gains have been realized for patients. In the present study, we determined the efficacy of a novel combination treatment involving surgical intervention and long-term weight-bearing walking training in spinal cord injury (SCI) subjects clinically diagnosed as complete or American Spinal Injury Association Impairment Scale (AIS) Class A (AIS-A). A total of 320 clinically complete SCI subjects (271 male and 49 female), aged 16–60 years, received early (≤ 7 days, n = 201) or delayed (8–30 days, n = 119) surgical interventions to reduce intraspinal or intramedullary pressure. Fifteen days post-surgery, all subjects received a weight-bearing walking training with the “Kunming Locomotion Training Program (KLTP)” for a duration of 6 months. The neurological deficit and recovery were assessed using the AIS scale and a 10-point Kunming Locomotor Scale (KLS). We found that surgical intervention significantly improved AIS scores measured at 15 days post-surgery as compared to the pre-surgery baseline scores. Significant improvement of AIS scores was detected at 3 and 6 months and the KLS further showed significant improvements between all pair-wise comparisons of time points of 15 days, 3 or 6 months indicating continued improvement in walking scores during the 6-month period. In conclusion, combining surgical intervention within 1 month post-injury and weight-bearing locomotor training promoted continued and statistically significant neurological recoveries in subjects with clinically complete SCI, which generally shows little clinical recovery within the first year after injury and most are permanently disabled. This study was approved by the Science and Research Committee of Kunming General Hospital of PLA and Kunming Tongren Hospital, China and registered at ClinicalTrials.gov (Identifier: NCT04034108) on July 26, 2019.

The high-glucose tolerance of yeast is the main factor determining the efficiency of high-density alcohol fermentation. Zygosaccharomyces mellis LGL-1 isolated from honey could survive under 700 g/L high-glucose stress and its tolerant characteristics were identified in our previous study. This study was performed to explore and clarify the high-glucose tolerance mechanism of Z. mellis LGL-1. Comparative transcriptomic analysis was used to analyze the genes with differential expression in Z. mellis under high-glucose conditions of 300, 500 and 700 g/L. With 300 g/L samples as reference, there were 937 and 2380 differentially expressed genes (DEGs) in the 500 and 700 g/L samples, respectively. Meanwhile, there was 825 significant DEGs in the 700 g/L samples compared with that of the 500 g/L samples. The result revealed that transcriptional changes in multiple metabolic pathways occur in response to high-glucose stress. q-RT PCR analysis further confirmed that several stress response pathways, such as the high osmolarity glycerol mitogen-activated protein kinase (HOG-MAPK) signal transduction pathway, trehalose synthesis pathway and oxidative stress response are closely related to high-glucose tolerance in Z. mellis. This study clarifies mechanisms of Z. mellis in response to high-glucose osmotic stress, providing theoretical basis for the process control of high-density alcohol fermentation.

Abstract Background It is estimated that 55 million adults will be 65 years and older in the USA by 2020. These older adults are at increased risk for injury and their recovery is multi-faceted. A collaborative care model may improve psychological and functional outcomes of the non-neurologically impaired older trauma patient and reduce health care costs. Methods This is a randomized controlled trial of 430 patients aged 50 and older who have suffered a non-neurologic injury and are admitted to a level one trauma center in Indianapolis, IN, or Madison, WI. Participants will be assigned to either the Trauma Medical Home (TMH) intervention or usual care. The TMH intervention is a collaborative care model that includes validated protocols addressing the multi-faceted needs of this population, with the help of care coordination software and a mobile office concept. The primary outcome is self-reported physical recovery at 6- and 12-month follow-up. Secondary outcomes include self-reported psychological recovery, acute health care utilization, and cost-effectiveness of the intervention at 6 and 12 months. The TMH collaborative care model will be delivered by a registered nurse care coordinator. The assessments will be completed by trained blinded research assistants. Discussion The proposed study will evaluate a collaborative care model to help maximize psychological and functional recovery for non-neurologically injured older patients at four level one trauma centers in the Midwest. Trial registration Clinical Trials. NCT03108820 . Registered on 11 April 2017. Protocol Version 6: Study # 1612690852. April 12, 2019. Sponsor: Indiana University. Human subjects and IRB contact information: irb@iu.edu Prospectively registered in the WHO ICTRP on 4 June 2017.

Abstract Background Multiple national expert panels have identified early detection of Alzheimer’s disease and related dementias (ADRD) as a national priority. However, the United States Preventive Services Task Force (USPSTF) does not currently support screening for ADRD in primary care given that the risks and benefits are unknown. The USPSTF stresses the need for research examining the impact of ADRD screening on family caregiver outcomes. Methods The Caregiver Outcomes of Alzheimer’s Disease Screening (COADS) is a randomized controlled trial that will examine the potential benefits or harms of ADRD screening on family caregivers. It will also compare the effectiveness of two strategies for diagnostic evaluation and management after ADRD screening. COADS will enroll 1800 dyads who will be randomized into three groups (n = 600/group): the ‘Screening Only’ group will receive ADRD screening at baseline and disclosure of the screening results, with positive-screen participants receiving a list of local resources for diagnostic follow-up; the ‘Screening Plus’ group will receive ADRD screening at baseline coupled with disclosure of the screening results, with positive-screen participants referred to a dementia collaborative care program for diagnostic evaluation and potential care; and the control group will receive no screening. The COADS trial will measure the quality of life of the family member (the primary outcome) and family member mood, anxiety, preparedness and self-efficacy (the secondary outcomes) at baseline and at 6, 12, 18 and 24 months. Additionally, the trial will examine the congruence of depressive and anxiety symptoms between older adults and family members at 6, 12, 18 and 24 months and compare the effectiveness of two strategies for diagnostic evaluation and management after ADRD screening between the two groups randomized to screening (Screening Only versus Screening Plus). Discussion We hypothesize that caregivers in the screening arms will express higher levels of health-related quality of life, lower depressive and anxiety symptoms, and better preparation for caregiving with higher self-efficacy at 24 months. Results from this study will directly inform the National Plan to Address Alzheimer’s Disease, the USPSTF and other organizations regarding ADRD screening and early detection policies. Trial registration ClinicalTrials.gov, NCT03300180. Registered on 3 October.

Abstract Introduction Heart failure (HF) is a prevalent, serious chronic illness that affects 6.5 million adults in the United States. Among patients with HF, the prevalence of attention impairment is reported to range from 15% to 27%. Although attention is fundamental to human activities including HF self‐care, cognitive interventions for patients with HF that target improvement in attention are scarce. The COgnitive intervention to Restore attention using nature Environment (CORE) study aims to test the preliminary efficacy of the newly developed Nature‐VR, a virtual reality‐based cognitive intervention that is based on the restorative effects of nature. Nature‐VR development was guided by Attention Restoration Theory. The target outcomes are attention, HF self‐care, and health‐related quality of life (HRQoL). Our exploratory aims examine the associations between attention and several putative/established HF biomarkers (eg, oxygen saturation, brain‐derived neurotrophic factor, apolipoprotein E, dopamine receptor, and dopamine transporter genes) as well as the effect of Nature‐VR on cognitive performance in other domains (ie, global cognition, memory, visuospatial, executive function, and language), cardiac and neurological events, and mortality. Methods This single‐blinded, two‐group randomized‐controlled pilot study will enroll 74 participants with HF. The Nature‐VR intervention group will view three‐dimensional nature pictures using a virtual reality headset for 10 minutes per day, 5 days per week for 4 weeks (a total of 200 minutes). The active comparison group, Urban‐VR, will view three‐dimensional urban pictures using a virtual reality headset to match the Nature‐VR intervention in intervention dose and delivery mode, but not in content. After baseline interviews, four follow‐up interviews will be conducted to assess sustained effects of Nature‐VR at 4, 8, 26, and 52 weeks. Discussion The importance and novelty of this study consists of using a first‐of‐its kind, immersive virtual reality technology to target attention and in investigating the health outcomes of the Nature‐VR cognitive intervention among patients with HF.

Abstract Introduction Diffusion magnetic resonance imaging may allow for microscopic characterization of white matter degeneration in early stages of Alzheimer's disease. Methods Multishell Diffusion magnetic resonance imaging data were acquired from 100 participants (40 cognitively normal, 38 with subjective cognitive decline, and 22 with mild cognitive impairment [MCI]). White matter microscopic degeneration in 27 major tracts of interest was assessed using diffusion tensor imaging (DTI), neurite orientation dispersion and density imaging, and q‐space imaging. Results Lower DTI fractional anisotropy and higher radial diffusivity were observed in the cingulum, thalamic radiation, and forceps major of participants with MCI. These tracts of interest also had the highest predictive power to discriminate groups. Diffusion metrics were associated with cognitive performance, particularly Rey Auditory Verbal Learning Test immediate recall, with the highest association observed in participants with MCI. Discussion While DTI was the most sensitive, neurite orientation dispersion and density imaging and q‐space imaging complementarily characterized reduced axonal density accompanied with dispersed and less restricted white matter microstructures.

Importance:. Delirium severity has been associated with a higher risk of mortality and an increasing morbidity burden. Recently defined delirium severity trajectories were predictive of 30-day mortality in a critically ill patient population. No studies to date have examined associations between delirium severity trajectories and 2-year mortality and healthcare utilization outcomes. Objectives:. To examine the associations between recently defined delirium severity trajectories and 2-year healthcare utilization outcomes of emergency department visits, rehospitalizations, and mortality. Design, Setting, and Participants:. This is a secondary analysis using data from the randomized controlled clinical trial Pharmacological Management of Delirium in the Intensive Care Unit and Deprescribing in the Pharmacologic Management of Delirium trial conducted from 2009 to 2015. Patients who were greater than or equal to 18 years old, were in the ICU for greater than or equal to 24 hours, and had a positive delirium assessment (Confusion Assessment Method for the ICU) were included in the original trial. Participants were included in the secondary analysis if 2-year healthcare utilization and mortality data were available (n = 431). Main Outcomes and Measures:. Healthcare utilization data within 2 years of the initial discharge date were pulled from the Indiana Network for Patient Care. Data over a 2-year period on emergency department visits (days to first emergency department visit, number of emergency department visits), inpatient hospitalizations (days to first hospitalizations, number of hospitalizations), and mortality (time to death) were extracted. Univariate relationships, Cox proportional hazard models, and competing risk modeling were used to examine statistical relationships in SAS v9.4. Results:. The overall sample (n = 431) had a mean age of 60 (sd, 16), 56% were females, and 49% African-Americans. No significant associations were identified between delirium severity trajectories and time to event for emergency department visit, mortality, or rehospitalization within 2 years of the index hospital discharge. Conclusions and Relevance:. This secondary analysis did not identify a significant relationship between delirium severity trajectories and healthcare utilization or mortality within 2 years of hospital discharge.

Abstract Background Alzheimer’s disease and related dementias (ADRD) impact a woman’s life expectancy and her ability to participate in medical decision-making about breast cancer screening, necessitating the involvement of family caregivers. Making decisions about mammography screening for women with ADRD is stressful. There are no data that suggest that breast cancer screening helps women with ADRD live longer or better. Decision aids may improve the quality of decision-making about mammography for ADRD patients and may inform family caregivers about the risks, benefits, and need for decision-making around mammography screening. Methods/design The Decisions about Cancer Screening in Alzheimer’s Disease (DECAD) trial, a randomized controlled clinical trial, will enroll 426 dyads of older women with ADRD (≥75 years) and a family caregiver from clinics and primary-care practices in Indiana to test a novel, evidence-based decision aid. This decision aid includes information about the impact of ADRD on life expectancy, the benefit of mammograms, and the impact on the quality of life for older women with ADRD. Dyads will be randomized to receive the decision aid or active control information about home safety. This trial will examine the effect on the caregiver’s decisional conflict (primary outcome) and the caregiver’s decision-making self-efficacy (secondary outcome). A second follow-up at 15 months will include a brief, semi-structured interview with the caregiver regarding the patient’s experience with mammograms and decision-making about mammograms. At the same time, a review of the patient’s electronic medical record (EMR) will look at discussions about mammography with their primary-care physician and mammogram orders, receipt, results, and burden (e.g., additional diagnostic procedures due to false-positive results, identification of an abnormality on the screening exam but further work-up declined, and identification of a clinically unimportant cancer). A third follow-up at 24 months will extract EMR data on mammogram orders, occurrences, results, and the burden of mammograms. Discussion We hypothesize that caregivers who receive the decision aid will have lower levels of decisional conflict and higher levels of decision-making self-efficacy compared to the control group. We also hypothesize that the DECAD decision aid will reduce mammography use among older women with ADRD. Trial registration Clinical Trials Register, NCT03282097. Registered on 13 September 2017.

Progressive accumulation of tau neurofibrillary tangles in the brain is a defining pathologic feature of Alzheimer's disease (AD). Tau pathology exhibits a predictable spatiotemporal spreading pattern, but the underlying mechanisms of this spread are poorly understood. Although AD is conventionally considered a disease of the gray matter, it is also associated with pronounced and progressive deterioration of the white matter (WM). A link between abnormal tau and WM degeneration is suggested by findings from both animal and postmortem studies, but few studies demonstrated their interplay in vivo. Recent advances in diffusion magnetic resonance imaging and the availability of tau positron emission tomography (PET) have made it possible to evaluate the association of tau and WM degeneration (tau-WM) in vivo. In this study, we explored the spatial pattern of tau-WM associations across the whole brain to evaluate the hypothesis that tau deposition is associated with WM microstructural alterations not only in isolated tracts, but in continuous structural connections in a stereotypic pattern. Sixty-two participants, including 22 cognitively normal subjects, 22 individuals with subjective cognitive decline, and 18 with mild cognitive impairment were included in the study. WM characteristics were inferred by classic diffusion tensor imaging (DTI) and a complementary diffusion compartment model – neurite orientation dispersion and density imaging (NODDI) that provides a proxy for axonal density. A data-driven iterative searching (DDIS) approach, coupled with whole-brain graph theory analyses, was developed to continuously track tau-WM association patterns. Without applying prior knowledge of the tau spread, we observed a distinct spatial pattern that resembled the typical propagation of tau pathology in AD. Such association pattern was not observed between diffusion and amyloid-β PET signal. Tau-related WM degeneration is characterized by an increase in the mean diffusivity (with a dominant change in the radial direction) and a decrease in the intra-axonal volume fraction. These findings suggest that cortical tau deposition (as measured in tau PET) is associated with a lower axonal packing density and greater diffusion freedom. In conclusion, our in vivo findings using a data-driven method on cross-sectional data underline the important role of WM alterations in the AD pathological cascade with an association pattern similar to the postmortem Braak staging of AD. Future studies will focus on longitudinal analyses to provide in vivo evidence of tau pathology spreads along neuroanatomically connected brain areas.

Abstract Introduction Head injuries (HI) are a risk factor for dementia, but the underlying etiology is not fully known. Understanding whether tau might mediate this relationship is important. Methods Cognition and tau deposition were compared between 752 individuals with (impaired, n = 302) or without cognitive impairment (CN, n = 450) with amyloid and [18F]flortaucipir positron emission tomography, HI history information, and cognitive testing from the Alzheimer's Disease Neuroimaging Initiative and the Indiana Memory and Aging Study. Results Sixty‐three (38 CN, 25 impaired) reported a history of HI. Higher neuropsychiatric scores and poorer memory were observed in those with a history of HI. Tau was higher in individuals with a history of HI, especially those who experienced a loss of consciousness (LOC). Results were driven by impaired individuals, especially amyloid beta‐positive individuals with history of HI with LOC. Discussion These findings suggest biological changes, such as greater tau, are associated with HI in individuals with cognitive impairment. Small effect sizes were observed; thus, further studies should replicate and extend these results.

Abstract Background Delirium affects nearly 70% of older adults hospitalized in the intensive care unit (ICU), and many of those will be left with persistent cognitive impairment or dementia. There are no effective and scalable recovery models to remediate ICU-acquired cognitive impairment and its attendant elevated risk for dementia or Alzheimer disease (AD). The Improving Recovery and Outcomes Every Day after the ICU (IMPROVE) trial is an ongoing clinical trial which evaluates the efficacy of a combined physical exercise and cognitive training on cognitive function among ICU survivors 50 years and older who experienced delirium during an ICU stay. This article describes the study protocol for IMPROVE. Methods IMPROVE is a four-arm, randomized controlled trial. Subjects will be randomized to one of four arms: cognitive training and physical exercise; cognitive control and physical exercise; cognitive training and physical exercise control; and cognitive control and physical exercise control. Facilitators administer the physical exercise and exercise control interventions in individual and small group formats by using Internet-enabled videoconference. Cognitive training and control interventions are also facilitator led using Posit Science, Inc. online modules delivered in individual and small group format directly into the participants’ homes. Subjects complete cognitive assessment, mood questionnaires, physical performance batteries, and quality of life scales at baseline, 3, and 6 months. Blood samples will also be taken at baseline and 3 months to measure pro-inflammatory cytokines and acute-phase reactants; neurotrophic factors; and markers of glial dysfunction and astrocyte activation. Discussion This study is the first clinical trial to examine the efficacy of combined physical and cognitive exercise on cognitive function in older ICU survivors with delirium. The results will provide information about potential synergistic effects of a combined intervention on a range of outcomes and mechanisms of action. Trial registration ClinicalTrials.gov, NCT03095417. Registered on 23 March 2017. Last updated on 15 May 2017.

Abstract Background Patients admitted to intensive care units (ICU) with acute respiratory failure (ARF) face chronic complications that can impede return to normal daily function. A mobile, collaborative critical care model may enhance the recovery of ARF survivors. Methods The Mobile Critical Care Recovery Program (m-CCRP) study is a two arm, randomized clinical trial. We will randomize 620 patients admitted to the ICU with acute respiratory failure requiring mechanical ventilation in a 1:1 ratio to one of two arms (310 patients per arm) – m-CCRP intervention versus attention control. Those in the intervention group will meet with a care coordinator after hospital discharge in predetermined intervals to aid in the recovery process. Baseline assessments and personalized goal setting will be used to develop an individualized care plan for each patient after discussion with an interdisciplinary team. The attention control arm will receive printed material and telephone reminders emphasizing mobility and management of chronic conditions. Duration of the intervention and follow-up is 12 months post-randomization. Our primary aim is to assess the efficacy of m-CCRP in improving the quality of life of ARF survivors at 12 months. Secondary aims of the study are to evaluate the efficacy of m-CCRP in improving function (cognitive, physical, and psychological) of ARF survivors and to determine the efficacy of m-CCRP in reducing acute healthcare utilization. Discussion The proposed randomized controlled trial will evaluate the efficacy of a collaborative critical care recovery program in accomplishing the Institute of Healthcare Improvement’s triple aims of better health, better care, at lower cost. We have developed a collaborative critical care model to promote ARF survivors’ recovery from the physical, psychological, and cognitive impacts of critical illness. In contrast to a single disease focus and clinic-based access, m-CCRP represents a comprehensive, accessible, mobile, ahead of the curve intervention, focused on the multiple aspects of the unique recovery needs of ARF survivors. Trial registration NCT03053245, clinicaltrials.gov, registered February 1, 2017.

Abstract Introduction Type 2 diabetes mellitus (T2DM) is a risk factor for Alzheimer's disease. Cerebrospinal fluid (CSF) amyloid β (Aβ) 1‐42 is an important Alzheimer's disease biomarker. However, it is inconclusive on how T2DM is related to CSF Aβ1‐42. Methods Participants with T2DM were selected from the Alzheimer's Disease Neuroimaging Initiative by searching keywords from the medical history database. A two‐way analysis of covariance model was used to analyze how T2DM associates with CSF Aβ1‐42 or cerebral cortical Aβ. Results CSF Aβ1‐42 was higher in the T2DM group than the nondiabetic group. The inverse relation between CSF Aβ1‐42 and cerebral cortical Aβ was independent of T2DM status. Participants with T2DM had a lower cerebral cortical Aβ in anterior cingulate, precuneus, and temporal lobe than controls. Discussion T2DM is positively associated with CSF Aβ1‐42 but negatively with cerebral cortical Aβ. The decreased cerebral cortical Aβ associated with T2DM is preferentially located in certain brain regions.

The changes in histone acetylation mediated by histone deacetylases (HDAC) play a crucial role in plant development and response to environmental changes. Mammalian HDACs are regulated by post-translational modifications (PTM), such as phosphorylation, acetylation, ubiquitination and small ubiquitin-like modifier (SUMO) modification (SUMOylation), which affect enzymatic activity and transcriptional repression. Whether PTMs of plant HDACs alter their functions are largely unknown. In this study, we demonstrated that the Arabidopsis SUMO E3 ligase SAP AND MIZ1 DOMAIN-CONTAINING LIGASE1 (SIZ1) interacts with HISTONE DEACETYLASE 6 (HDA6) both in vitro and in vivo. Biochemical analyses indicated that HDA6 is not modified by SUMO1. Overexpression of HDA6 in siz1-3 background results in a decreased level of histone H3 acetylation, indicating that the activity of HDA6 is increased in siz1-3 plants. Chromatin immunoprecipitation (ChIP) assays showed that SIZ1 represses HDA6 binding to its target genes FLOWERING LOCUS C (FLC) and MADS AFFECTING FLOWERING 4 (MAF4), resulting in the upregulation of FLC and MAF4 by increasing the level of histone H3 acetylation. Together, these findings indicate that the Arabidopsis SUMO E3 ligase SIZ1 interacts with HDA6 and negatively regulates HDA6 function.

Background: Imaging techniques used to measure hippocampal atrophy are key to understanding the clinical progression of Alzheimer's disease (AD). Various semi-automated hippocampal segmentation techniques are available and require human expert input to learn how to accurately segment new data. Our goal was to compare 1) the performance of our automated hippocampal segmentation technique relative to manual segmentations, and 2) the performance of our automated technique when provided with a training set from two different raters. We also explored the ability of hippocampal volumes obtained using manual and automated hippocampal segmentations to predict conversion from MCI to AD. Methods: We analyzed 161 1.5 T T1-weighted brain magnetic resonance images (MRI) from the ADCS Donepezil/Vitamin E clinical study. All subjects carried a diagnosis of mild cognitive impairment (MCI). Three different segmentation outputs (one produced by manual tracing and two produced by a semi-automated algorithm trained with training sets developed by two raters) were compared using single measure intraclass correlation statistics (smICC). The radial distance method was used to assess each segmentation technique's ability to detect hippocampal atrophy in 3D. We then compared how well each segmentation method detected baseline hippocampal differences between MCI subjects who remained stable (MCInc) and those who converted to AD (MCIc) during the trial. Our statistical maps were corrected for multiple comparisons using permutation-based statistics with a threshold of p

As part of chromatin-remodeling complexes (CRCs), sucrose nonfermenting 2 (Snf2) family proteins alter chromatin structure and nucleosome position by utilizing the energy of ATP, which allows other regulatory proteins to access DNA. Plant genomes encode a large number of Snf2 proteins, and some of them have been shown to be the key regulators at different developmental stages in Arabidopsis. Yet, little is known about the functions of Snf2 proteins in tomato (Solanum lycopersicum). In this study, 45 Snf2s were identified by the homologous search using representative sequences from yeast (S. cerevisiae), fruit fly (D. melanogaster), and Arabidopsis (A. thaliana) against the tomato genome annotation dataset. Tomato Snf2 proteins (also named SlCHRs) could be clustered into 6 groups and distributed on 11 chromosomes. All SlCHRs contained a helicase-C domain with about 80 amino acid residues and a SNF2-N domain with more variable amino acid residues. In addition, other conserved motifs were also identified in SlCHRs by using the MEME program. Expression profile analysis indicated that tomato Snf2 family genes displayed a wide range of expressions in different tissues and some of them were regulated by the environmental stimuli such as salicylic acid, abscisic acid, salt, and cold. Taken together, these results provide insights into the functions of SlCHRs in tomato.

Abstract Background As part of the debate about screening for dementia, it is critical to understand why patients agree or disagree to diagnostic assessment after a positive screening test. We used the Perceptions Regarding Investigational Screening for Memory in Primary Care (PRISM‐PC) questionnaire to measure the characteristics of patients who screened positive for dementia but refused further diagnostic assessment. Methods Survey of patients ≥65 years old without a diagnosis of dementia attending primary care clinics in Indianapolis, IN, in 2008 and 2009. Results Five hundred and fifty‐four individuals completed the PRISM‐PC and 63 screened positive. Of those, 21 (33%) accepted and 42 (67%) refused diagnostic assessment. In adjusted models, having larger stigma domain scores and living alone were significantly associated with increased odds of refusing the diagnostic assessment. Conclusion Despite screening positive, many patients refused a diagnostic assessment. Living alone and the perceived stigmas of dementia are associated with the refusal of diagnostic assessment for dementia.

The identification of metal ion binding sites is important for protein function annotation and the design of new drug molecules. This study presents an effective method of analyzing and identifying the binding residues of metal ions based solely on sequence information. Ten metal ions were extracted from the BioLip database: Zn2+, Cu2+, Fe2+, Fe3+, Ca2+, Mg2+, Mn2+, Na+, K+ and Co2+. The analysis showed that Zn2+, Cu2+, Fe2+, Fe3+, and Co2+ were sensitive to the conservation of amino acids at binding sites, and promising results can be achieved using the Position Weight Scoring Matrix algorithm, with an accuracy of over 79.9% and a Matthews correlation coefficient of over 0.6. The binding sites of other metals can also be accurately identified using the Support Vector Machine algorithm with multifeature parameters as input. In addition, we found that Ca2+ was insensitive to hydrophobicity and hydrophilicity information and Mn2+ was insensitive to polarization charge information. An online server was constructed based on the framework of the proposed method and is freely available at http://60.31.198.140:8081/metal/HomePage/HomePage.html.

Eukaryotic genes are packed into a dynamic but stable nucleoprotein structure called chromatin. Chromatin-remodeling and modifying complexes generate a dynamic chromatin environment that ensures appropriate DNA processing and metabolism in various processes such as gene expression, as well as DNA replication, repair, and recombination. The INO80 and SWR1 chromatin remodeling complexes (INO80-c and SWR1-c) are ATP-dependent complexes that modulate the incorporation of the histone variant H2A.Z into nucleosomes, which is a critical step in eukaryotic gene regulation. Although SWR1-c has been identified in plants, plant INO80-c has not been successfully isolated and characterized. In this review, we will focus on the functions of the SWR1-c and putative INO80-c (SWR1/INO80-c) multi-subunits and multifunctional complexes in Arabidopsis thaliana. We will describe the subunit compositions of the SWR1/INO80-c and the recent findings from the standpoint of each subunit and discuss their involvement in regulating development and environmental responses in Arabidopsis.

ObjectiveHigher selenium level has been hypothesized to have the potential to reduce the risk of cardiovascular diseases including dyslipidemia. However, results from previous studies are inconsistent. This study aims to determine the association between selenium level and dyslipidemia in elderly Chinese with relatively low selenium status.MethodsA cross-sectional study of 1859 participants aged 65 or older from four rural counties in China was conducted. Serum total cholesterol (TC), triglycerides (TG), high density lipoprotein-cholesterol (HDLC) and low-density lipoprotein-cholesterol (LDLC), nail selenium concentration and APOE genotype were measured in all subjects. The four types of dyslipidemia were defined as >5.17 mmol/L for High-TC, >1.69 mmol/L for High-TG, >3.36 mmol/L for High-LDLC, and ResultsMean nail selenium concentration was 0.465 μg/gin this sample. Rates for High-TC, High-LDLC, High-TG, Low-HDLC were 18.13%, 13.23%, 12.21% and 32.76% respectively. Results from logistic models indicated that higher selenium levels were significantly associated with higher risk of High-TC, High-LDLC and lower risk of Low-HDLC adjusting for covariates (p < 0.0001). Compared with the lowest selenium quartile group, participants in selenium quartile groups 2, 3 and 4 had significantly higher rates of High-TC, High-LDLC, High-TG, and lower rate of Low-HDLC adjusting for covariates. No significant association was observed between selenium level and the risk of High-TG. APOEε4 carriers had higher rates of High-TC and High-LDLC. There was no interaction between selenium level and APOE with the rates of dyslipidemia.ConclusionsOur results suggest long-term selenium exposure level may be associated with the risk of dyslipidemia in elderly population. Future studies are needed to examine the underlying mechanism of the association.

Objective. To understand older primary care patients’ perceptions of the risks and benefits of dementia screening and to measure the association between attitudes and screening behaviors. Methods. Eligible patients completed the Perceptions Regarding Investigational Screening for Memory in Primary Care (PRISM-PC) questionnaire and then were asked to undergo dementia screening by a telephone screening instrument. Results. Higher scores on the PRISM-PC questionnaire items that measure attitudes about benefits of screening were associated with decreased odds of refusing screening. Participants who refused screening had significantly lower PRISM-PC questionnaire scores on the items that measure perceived benefits compared to those who agreed to screening. Participants who refused screening were less likely to agree on screening for other conditions, such as depression and cancer. Participants who know someone with Alzheimer’s disease (AD) were less likely to refuse screening. Discussion. Patients’ attitudes about the benefits of dementia screening are associated with their acceptance of dementia screening.

Objective: Most previous studies investigated the associations between intake of individual nutrients and risk of disease, which failed to consider the potential interactions and correlations between various nutrients contained in food. Although dietary quality scores provide a comprehensive evaluation of the entire diet, it remains elusive whether they are associated with the risk of pancreatic cancer. Methods: Dietary intake data collected with the Dietary Questionnaire (DQX) and Diet History Questionnaire (DHQ) were used to calculate HEI-2015 and DQI-R scores for participants in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. A high score indicates an increased intake of adequacy components and a decreased intake of moderation components. This study included 252 cases of pancreatic cancer documented from 58,477 persons during a median follow-up of 12.2years in the DQX cohort and 372 cases of pancreatic cancer ascertained from 101,721 persons during a median follow-up of 8.9years in the DHQ cohort. Cox proportional hazards regression analysis was performed to calculate hazard ratios (HR) and 95% confidence intervals (CI) for the associations between the two dietary quality scores and pancreatic cancer risk. Results: After adjustment for confounders, HEI-2015 and DQI-R scores were not significantly associated with pancreatic cancer risk. However, a significantly lower risk was observed for overweight persons with a higher HEI-2015 score in the DQX cohort (HR [95% CI] comparing the highest with lowest tertile: 0.52 [0.32, 0.85], p for trend = 0.009) and those with higher scores of some individual components. Conclusion: Collectively, overall dietary quality is not associated with an altered risk of pancreatic cancer in this US population. [ABSTRACT FROM AUTHOR]

Background: Incidence of cognitive impairment and its consequences have not been fully examined in heart failure (HF). Objective: The aim of this study was to examine associations of HF with cognitive decline, frequencies and risks of, and time-to-develop mild cognitive impairment (MCI) or dementia during 15-year follow-up. Methods: For this retrospective cohort study, data were retrieved from the National Alzheimer's Coordinating Center. Cognitive decline was assessed using the UniformData Set neuropsychological battery. Development of MCI and dementia was assessed using clinically diagnosed cognitive status. Results: Compared with participants without HF (n = 12 904), participants with HF (n = 256) had more decline in attention, executive function, and memory while controlling for covariates including apolipoprotein E4. Participants with HF developed MCI or dementia more frequently (44.9%vs 34.4%), developed dementia faster from normal cognition, and had a lower risk of dementia from MCI after controlling for covariates (hazard ratio, 0.71) than participants without HF. Conclusions: Heart failure was associated with accelerated cognitive decline. [ABSTRACT FROM AUTHOR]