RNA regulation of inflammatory responses in glia and its potential as a therapeutic target in central nervous system disorders.

A major hallmark of neuroinflammation is the activation of microglia and astrocytes with the induction of inflammatory mediators such as IL-1ß, TNF-α, iNOS, and IL-6. Neuroinflammation contributes to disease progression in a plethora of neurological disorders ranging from acute CNS trauma to chronic neurodegenerative disease. Posttranscriptional pathways of mRNA stability and translational efficiency are major drivers for the expression of these inflammatory mediators. A common element in this level of regulation centers around the adenine- and uridine-rich element (ARE) which is present in the 3' untranslated region (UTR) of the mRNAs encoding these inflammatory mediators. (ARE)-binding proteins (AUBPs) such as Human antigen R (HuR), Tristetraprolin (TTP) and KH- type splicing regulatory protein (KSRP) are key nodes for directing these posttranscriptional pathways and either promote (HuR) or suppress (TTP and KSRP) glial production of inflammatory mediators. This review will discuss basic concepts of ARE-mediated RNA regulation and its impact on glial-driven neuroinflammatory diseases. We will discuss strategies to target this novel level of gene regulation for therapeutic effect and review exciting preliminary studies that underscore its potential for treating neurological disorders.

The Trauma Dyad: The Role of Informal Caregivers for Older Adults After Traumatic Injury.

OBJECTIVE: To investigate the association between higher injury severity and increased informal caregiving received by injured older adults. SUMMARY OF BACKGROUND DATA: Injured older adults experience high rates of functional decline and disability after hospitalization. Little is known about the scope of caregiving received post-discharge, particularly from informal caregivers such as family. METHODS: We used the National Health and Aging Trends Study 2011 to 2018 linked to Medicare claims to identify adults ≥65 with hospital admission for traumatic injury and a National Health and Aging Trends Study interview within 12 months pre- and post-trauma. Injury severity was assessed using the injury severity score (ISS, low 0-9; moderate 10-15; severe 16-75). Patients reported the types and hours of formal and informal help received and any unmet care needs. Multi variable logistic regression models examined the association between ISS and increase in informal caregiving hours after discharge. RESULTS: We identified 430 trauma patients. Most were female (67.7%), non-Hispanic White (83.4%) and half were frail. The most common mechanism of injury was fall (80.8%) and median injury severity was low (ISS = 9). Those reporting receiving help with any activity increased post-trauma (49.0% to 72.4%, P < 0.01), and unmet needs nearly doubled (22.8% to 43.0%, P < 0.01). Patients had a median of 2 caregivers and most (75.6%) were informal, often family members. Median weekly hours of care received pre- versus post-injury increased from 8 to 14 (P < 0.01). ISS did not independently predict increase in caregiving hours; pre-trauma frailty predicted an increase in hours ≥8 per week. CONCLUSIONS: Injured older adults reported high baseline care needs which increased significantly after hospital discharge and were mostly met by informal caregivers. Injury was associated with increased need for assistance and unmet needs regardless of injury severity. These results can help set expectations for caregivers and facilitate post-acute care transitions.

Associations between peripheral inflammation and clinical phenotypes of bipolar depression in a lower-middle income country.

OBJECTIVE: There has been increased interest in repurposing anti-inflammatories for the treatment of bipolar depression. Evidence from high-income countries suggests that these agents may work best for specific depressive symptoms in a subset of patients with biochemical evidence of inflammation but data from lower-middle income countries (LMICs) is scarce. This secondary analysis explored the relationship between pretreatment inflammatory markers and specific depressive symptoms, clinical measures, and demographic variables in participants with bipolar depression in Pakistan. METHODS: The current study is a cross-sectional secondary analysis of a randomized controlled trial of two anti-inflammatory medications (minocycline and celecoxib) for bipolar depression (n = 266). A series of logistic and linear regression models were completed to assess the relationship between C-reactive protein (CRP) (CRP > or < 3 mg/L and log10CRP) and clinical and demographic features of interest and symptoms of depression. Baseline clinical trial data was used to extract clinical and demographic features and symptoms of depression were assessed using the 24-item Hamilton Depression Rating Scale. RESULTS: The prevalence of low-grade inflammation (CRP > 3 mg/L) in the sample was 70.9%. After adjusting for baseline body mass index, socioeconomic status, age, gender, symptoms related to anhedonia, fatigue, and motor retardation were most associated with low-grade inflammation. CONCLUSIONS: Bipolar disorder (BD) patients from LMICs may experience higher rates of peripheral inflammation than have been reported in Western populations with BD. Future trials of repurposed anti-inflammatory agents that enrich for participants with these symptom profiles may inform the development of personalized treatment for bipolar depression in LMICs.

Feasibility of Transcatheter Closure of Large Secundum Atrial Septal Defect with Absent Superior or Inferior Rim.

Introduction: Surgical closure of a large secundum atrial septal defect (ASD) with an absent superior or inferior rim is the standard method of management, but transcatheter closure of such a defect is possible and feasible. Objectives: To evaluate the feasibility, effectiveness, and safety of transcatheter closure of large secundum ASD with an absent superior or inferior rim through implantation of a cheatham platinum (CP) stent at the entrance of the superior vena cava (SVC) or inferior vena cava (IVC) into the right atrium (RA) to create a suitable rim for subsequent complete closure of the defect using a septal occluder. Patients and Methods. This case series was carried out at Ibn Al-Bitar Center for Cardiac Surgery, Baghdad, Iraq from 2014 to 2019, five patients underwent such transcatheter approach for closure of large secundum ASD with the absent superior or inferior rim by implantation of CP stent at the entrance of vena cave into the RA. Result: The ages and weights of patients who were enrolled in this study ranged from 9-31 years (15.2 ± 9 years) and 31.5-62 kg (42.6 ± 12 kg). Three patients had absent superior rims, and the other two had absent inferior rims. The Q p /Q s was ranged from 1.9-3.2 (2.78 ± 0.29), and the mean pulmonary arterial pressure ranged from 22-29 mmHg (25.4 ± 3 mmHg). The defects with an absent superior rim were closed successfully by implantation of CP stents of 45, 45, and 39 mm to create a rim which supported the left atrial disc of 30, 38, and 32 mm atrial septal occluder (ASO), respectively, while large secundum ASD with an absent inferior rim could be effectively closed by implantation of two overlapping bare CP stents of 45 mm to create an IVC rim that supported 34 mm and 30 mm atrial septal occluder. Conclusion and recommendation. Transcatheter closure of large secundum ASD with absent superior or inferior rim is possible and effective by implantation of covered and bare CP stents at the entrance of SVC and IVC, respectively. Although these procedures are relatively difficult and challenging, especially in the closure of large defects associated with absent inferior rim, they carry a high risk of stent migration (8 zig, 45 mm), so we recommend using a CP-stent (10 zig, 60 mm).

Identification and expression of alternatively spliced novel isoforms of cancer associated MYD88 lacking death domain in mouse.

MYD88 is an adaptor protein known to involve in activation of NF-κB through IL-1 receptor and TLR stimulation. It consists of N-terminal death domain and C-terminal Toll/IL-R homology domain that mediates its interaction with IL-1R associated kinase and IL-1R/TLR, respectively. MYD88 contributes to various types of carcinogenesis due to its involvement in oncogene induced inflammation. In the present study, we have recognized two new alternatively spliced variants of MyD88 gene in mouse using bioinformatics tools and molecular biology techniques in combination. The newly identified non-coding exon (NE-1) from 5' upstream region alternatively splices with either exon E-2 or exon E-5 to produce two novel transcript variants MyD88N1 and MyD88N2 respectively. The transcript variant MyD88N1 was expressed in several tissues studied while the variant MyD88N2 was found to be expressed only in the brain. The analysis of the upstream region of novel exon by in silico approach revealed new promoter region PN, which possess potential signature sequences for diverse transcription factors, suggesting complex gene regulation. Studies of post translational modifications of conceptualized amino acid sequences of these isoforms revealed diversity in properties. Western blot analysis further confirmed the expression of protein isoform MYD88N1.

Identification of two novel isoforms of mouse NUR77 lacking N-terminal domains.

Nur77 is a member of nuclear receptor superfamily that acts as a transcription factor and regulates expression of multiple genes. Subcellular localization of Nur77 protein plays an important role in the survival and cell death. In this study, we have predicted and confirmed alternatively spliced two new transcripts of Nur77 gene in mouse. The newly identified transcripts have their alternatively spliced first exon located upstream of published 5'-UTR of the gene. Transcription factor binding sites in the possible promoter regions of these transcripts were also analyzed. Expression of novel transcript variants was found to be significantly lower than the already published transcript. New transcript variants encode for NUR77 protein isoforms which are significantly smaller in size due to lack of transactivation domain and a part of DNA binding domain. Western blot analysis using NUR77 specific antibody confirmed the existence of these smaller variants in mouse. Localization of these new isoforms was predicted to be majorly outside the nucleus. In silico analysis of the conceptually translated proteins was performed using different bioinformatics tools. The results obtained in this study offer further insight into novel area of research on extensively studied Nur77. © 2017 IUBMB Life, 69(2):106-114, 2017.

Unravelling the interaction of pirenzepine, a gastrointestinal disorder drug, with calf thymus DNA: An in vitro and molecular modelling study.

Pirenzepine is an anti-ulcer agent which belongs to the anti-cholinergic group of gastrointestinal disorder drugs and functions as an M1 receptor selective antagonist. Drug-DNA interaction studies are of great significance as it helps in the development of new therapeutic drugs. It provides a deeper understanding into the mechanism through which therapeutic drugs control gene expression. Interaction of pirenzepine with calf-thymus DNA (Ct-DNA) was determined via a series of biophysical techniques. UV-visible absorption and fluorescence spectroscopy confirmed the formation of pirenzepine-Ct-DNA complex. The values of binding constant from various experiments were calculated to be in the order of 103 M-1 which is consistent with the groove binding mode. Various spectrofluorimetric experiments like competitive displacement of well known dyes with drug, iodide quenching experiments and the effect of Ct-DNA denaturation in presence of drug confirmed the binding of pirenzepine to the groove of Ct-DNA. The binding mode was further established by viscometric, circular dichroic and molecular modelling studies. Thermodynamic parameters obtained from isothermal titration calorimetric studies suggest that the interaction of pirenzepine with Ct-DNA is enthalpically driven. The value of TΔS and ΔH calculated from calorimetric studies were found to be 4.3 kcal mol-1 and -2.54 kcal mol-1 respectively, indicating that pirenzepine-Ct-DNA complex is mainly stabilized by hydrophobic interaction and hydrogen bonding. The binding energy calculated was -7.5 kcal mol-1 from modelling studies which was approximately similar to that obtained by isothermal titration calorimetric studies. Moreover, the role of electrostatic interaction in the binding of pirenzepine to Ct-DNA cannot be precluded.

Identification of differentially expressed three novel transcript variants of mouse ARNT gene.

The aryl hydrocarbon receptor nuclear translocator (ARNT/HIF1-ß) is an obligatory transcriptional partner of the aryl hydrocarbon receptor (AHR) and hypoxia-inducible factor-1α (HIF-1α). It has a basic helix-loop-helix domain that belongs to period-ARNT-single-minded (PAS) protein family. PAS proteins act as heterodimeric transcription factors with ARNT being master dimerization partner. The ARNT-HIF-1α complex is an important transcriptional regulator of the hypoxic response of the tumor cells. Previous studies have reported two transcript variants of the gene produced by alternative splicing in mouse. One transcript variant contains all 22 exons while the other variant lacks exon-E5. In our study, using combinatorial approach comprising bioinformatics tools and molecular biology techniques involving RT-PCR, semi-nested PCR, sequencing and qPCR, we have identified three novel transcript variants of Arnt gene in mouse. All three new transcripts arise as a result of alternative splicing of newly identified exons with exon-E2, replacing reported exon-E1. These transcripts encode for three protein isofoms having different N-termini. The expression of these transcripts was found to be different in different tissues of adult mice. In silico analysis of the upstream region of the new exons revealed three distinct promoter regions designated as PA, PB and PC present upstream of newly identified exons. These promoters possess potential signature sequences for common as well as different transcription factors suggesting complex regulation of Arnt gene. In silico post translational studies of the conceptually translated amino acid sequences of these transcripts show similarity in some of the properties while differ in others. The diversity at N-termini of protein isoforms suggests the possibility of forming different complexes in different tissues and may also be important for unique interactions with partner molecules.

Redox cycling of endogenous copper by ferulic acid leads to cellular DNA breakage and consequent cell death: A putative cancer chemotherapy mechanism.

Ferulic acid (FA) is a plant polyphenol showing diverse therapeutic effects against cancer, diabetes, cardiovascular and neurodegenerative diseases. FA is a known antioxidant at lower concentrations, however at higher concentrations or in the presence of metal ions such as copper, it may act as a pro-oxidant. It has been reported that copper levels are significantly raised in different malignancies. Cancer cells are under increased oxidative stress as compared to normal cells. Certain therapeutic substances like polyphenols can further increase this oxidative stress and kill cancer cells without affecting the proliferation of normal cells. Through various in vitro experiments we have shown that the pro-oxidant properties of FA are enhanced in the presence of copper. Comet assay demonstrated the ability of FA to cause oxidative DNA breakage in human peripheral lymphocytes which was ameliorated by specific copper-chelating agent such as neocuproine and scavengers of ROS. This suggested the mobilization of endogenous copper in ROS generation and consequent DNA damage. These results were further validated through cytotoxicity experiments involving different cell lines. Thus, we conclude that such a pro-oxidant mechanism involving endogenous copper better explains the anticancer activities of FA. This would be an alternate non-enzymatic, and copper-mediated pathway for the cytotoxic activities of FA where it can selectively target cancer cells with elevated levels of copper and ROS.

Redox cycling of Cu(II) by 6-mercaptopurine leads to ROS generation and DNA breakage: possible mechanism of anticancer activity.

6-Mercaptopurine (6MP) is a well-known purine antimetabolite used to treat childhood acute lymphoblastic leukemia and other diseases. Cancer cells as compared to normal cells are under increased oxidative stress and show high copper level. These differences between cancer cells and normal cells can be targeted to develop effective cancer therapy. Pro-oxidant property of 6MP in the presence of metal ions is not well documented. Redox cycling of Cu(II) to Cu(I) was found to be efficiently mediated by 6MP. We have performed a series of in vitro experiments to demonstrate the pro-oxidant property of 6MP in the presence of Cu(II). Studies on human lymphocytes confirmed the DNA damaging ability of 6MP in the presence of Cu(II). Since 6MP possesses DNA damaging ability by producing reactive oxygen species (ROS) in the presence of Cu(II), it may also possess apoptosis-inducing activity by involving endogenous copper ions. Essentially, this would be an alternative and copper-dependent pathway for anticancer activity of 6MP.

Studying non-covalent drug-DNA interactions.

Drug-DNA interactions have been extensively studied in the recent past. Various techniques have been employed to decipher these interactions. DNA is a major target for a wide range of drugs that may specifically or non-specifically interact with DNA and affect its functions. Interaction between small molecules and DNA are of two types, covalent interactions and non-covalent interactions. Three major modes of non-covalent interactions are electrostatic interactions, groove binding and intercalative binding. This review primarily focuses on discussing various techniques used to study non-covalent interactions that occur between drugs and DNA. Additionally, we report several techniques that may be employed to analyse the binding mode of a drug with DNA. These techniques provide data that are reliable and simple to interpret.

Deciphering the interactions between chlorambucil and calf thymus DNA: a multi-spectroscopic and molecular docking study.

Non-covalent interactions of chlorambucil with calf thymus DNA was investigated using multi-spectroscopic techniques and molecular docking study. Binding constant calculated was found to be 1.54×10(4)M(-1) at 290K, significantly lower than various known intercalators. Quenching process was found to be static as evident by biomolecular quenching constant. Thermodynamic parameters revealed the involvement of hydrophobic interactions and hydrogen bonds in the binding. Chlorambucil was found to interact via external binding mode and follow groove binding as it replaces Hoechst (a typical groove binder) from the groove of DNA but does not replace intercalating dyes including ethidium bromide and acridine orange from the DNA helix. These results were further supported by KI quenching experiments, DNA melting studies, CD spectroscopy and molecular docking.

Ibuprofen causes photocleavage through ROS generation and intercalates with DNA: a combined biophysical and molecular docking approach.

Ibuprofen is an important nonsteroidal anti-inflammatory drug endowed with various pharmacological and biological activities. In the present study, the photochemical properties of ibuprofen were evaluated by assaying the generation of various reactive oxygen species (ROS) such as superoxide, singlet oxygen and the hydroxyl radical. ROS generated by ibuprofen in the presence of white light causes DNA strand scission as observed by plasmid nicking assay. Ibuprofen induced ROS generation is also capable of causing DNA degradation in lymphocytes as observed by photocomet assay. ROS generation properties of ibuprofen were further strengthened by the formation of carbonyl groups in BSA and TBARS in linoleic acid as observed by carbonyl assay and lipid peroxidation assay respectively. We have also investigated the mode of interaction of ibuprofen with calf thymus DNA through a series of in vitro experiments. UV-visible spectroscopy established the formation of a complex between ibuprofen and Ct DNA. The steady state fluorescence experiments at different temperatures revealed a binding constant of ∼10(4) L mol(-1), which is indicative of intercalative binding between ibuprofen and the DNA helix. Analysis of the various thermodynamic parameters ΔG, ΔH and ΔS calculated at different temperatures indicated that the hydrogen bonds played a major role in the interaction. The intercalative binding mode is further confirmed by competitive displacement assays, urea denaturation, iodide quenching, viscosity measurements and CD analysis. In silico molecular docking revealed the binding of ibuprofen within the GC base pairs of DNA, confirming the intercalative binding mode.

Investigating the plasma-liver-brain axis of omega-3 fatty acid metabolism in mouse knock-in for the human apolipoprotein E epsilon 4 allele.

The metabolism of docosahexaenoic acid (DHA), an omega-3 fatty acid, is different in carriers of APOE4, the main genetic risk factor for late-onset Alzheimer's disease. The brain relies on the plasma DHA pool for its need, but the plasma-liver-brain axis in relation to cognition remains obscure. We hypothesized that this relationship is compromised in APOE4 mice considering the differences in fatty acid metabolism between APOE3 and APOE4 mice. Male and female APOE3 and APOE4 mice were fed either a diet enriched with DHA (0.7 g DHA/100 g diet) or a control diet for 8 months. There was a significant genotype × diet interaction for DHA concentration in the liver and adipose tissue. In the cortex, a genotype effect was found where APOE4 mice had a higher concentration of DHA than APOE3 mice fed the control diet. There was a significant genotype × diet interaction for the liver and hippocampal arachidonic acid (AA). APOE4 mice had 20-30% lower plasma DHA and AA concentrations than APOE3 mice, independent of diet. Plasma and liver DHA levels were significantly correlated in APOE3 and APOE4 mice. In APOE4 mice, there was a significant correlation between plasma, adipose tissues, cortex DHA and the Barnes maze and/or with a better recognition index. Moreover, higher AA levels in the liver and the hippocampus of APOE4 mice were correlated with lower cognitive performance. Our results suggest that there is a plasma-liver-brain axis of DHA that is modified in APOE4 mice. Moreover, our data support that APOE4 mice rely more on plasma DHA than APOE3 mice, especially in cognitive performance. Any disturbance in plasma DHA metabolism might have a greater impact on cognition in APOE4 carriers.

Decoupling of mRNA and Protein Expression in Aging Brains Reveals the Age-Dependent Adaptation of Specific Gene Subsets.

During aging, changes in gene expression are associated with a decline in physical and cognitive abilities. Here, we investigate the connection between changes in mRNA and protein expression in the brain by comparing the transcriptome and proteome of the mouse cortex during aging. Our transcriptomic analysis revealed that aging mainly triggers gene activation in the cortex. We showed that an increase in mRNA expression correlates with protein expression, specifically in the anterior cingulate cortex, where we also observed an increase in cortical thickness during aging. Genes exhibiting an aging-dependent increase of mRNA and protein levels are involved in sensory perception and immune functions. Our proteomic analysis also identified changes in protein abundance in the aging cortex and highlighted a subset of proteins that were differentially enriched but exhibited stable mRNA levels during aging, implying the contribution of aging-related post- transcriptional and post-translational mechanisms. These specific genes were associated with general biological processes such as translation, ribosome assembly and protein degradation, and also important brain functions related to neuroplasticity. By decoupling mRNA and protein expression, we have thus characterized distinct subsets of genes that differentially adjust to cellular aging in the cerebral cortex.

Impact of Comorbid Dementia on Patterns of Hospice Use.

Background: The evidence base for understanding hospice use among persons with dementia is almost exclusively based on individuals with a primary terminal diagnosis of dementia. Little is known about whether comorbid dementia influences hospice use patterns. Objective: To estimate the prevalence of comorbid dementia among hospice enrollees and its association with hospice use patterns. Design: Pooled cross-sectional analysis of the nationally representative Health and Retirement Study (HRS) linked to Medicare claims. Subjects: Fee-for-service Medicare beneficiaries in the United States who enrolled with hospice and died between 2004 and 2016. Measurements: Dementia was assessed using a validated survey-based algorithm. Hospice use patterns were enrollment less than or equal to three days, enrollment greater than six months, hospice disenrollment, and hospice disenrollment after six months. Results: Of 3123 decedents, 465 (14.9%) had a primary hospice diagnosis of dementia and 943 (30.2%) had comorbid dementia and died of another illness. In fully adjusted models, comorbid dementia was associated with increased odds of hospice enrollment greater than six months (adjusted odds ratio [AOR] = 1.52, 95% confidence interval [CI]: 1.11-2.09) and hospice disenrollment following six months of hospice (AOR = 2.55, 95% CI: 1.43-4.553). Having a primary diagnosis of dementia was associated with increased odds of hospice enrollment greater than six months (AOR = 2.62, 95% CI: 1.86-3.68), hospice disenrollment (AOR = 1.82, 95% CI: 1.32-2.51), and hospice disenrollment following six months of hospice (AOR = 4.31, 95% CI: 2.37-7.82). Conclusion: Approximately 45% of the hospice population has primary or comorbid dementia and are at increased risk for long hospice enrollment periods and hospice disenrollment. Consideration of the high prevalence of comorbid dementia should be inherent in hospice staff training, quality metrics, and Medicare Hospice Benefit policies.

Cost-Effectiveness of a Culturally Adapted Manual-Assisted Brief Psychological Intervention for Self-Harm in Pakistan: A Secondary Analysis of the Culturally Adapted Manual-Assisted Brief Psychological Randomized Controlled Trial.

OBJECTIVES: Self-harm is a serious public health problem. A culturally adapted manual-assisted problem-solving training (C-MAP) intervention improved and sustained a reduction in suicidal ideation, hopelessness, and depression compared with treatment as usual (TAU) alone. Here, we evaluate its cost-effectiveness. METHODS: Patients admitted after an episode of self-harm were randomized individually to either C-MAP plus TAU or TAU alone in Karachi. Improvement in health-related quality-adjusted life-years (QALYs) was measured using the EQ-5D with 3 levels instrument at baseline, 3 months, and 6 months after randomization. The primary economic outcome was health service cost per QALY gained as the incremental cost-effectiveness ratio, based on 2019 US$ and a 6-month time horizon. Nonparametric bootstrapping was used to assess uncertainties and sensitivity analysis to examine the impact of hospitalization costs. RESULTS: A total of 108 and 113 participants were enrolled among the intervention and standard arms, respectively. The intervention resulted in 0.04 (95% confidence interval [CI] 0.00-0.08) more QALYs 6 months after enrolment. The mean cost per participant in the intervention arm was $1001 (95% CI 968-1031), resulting in an incremental cost of the intervention of $640 (95% CI 595-679). The incremental cost-effectiveness ratio for the C-MAP intervention versus TAU was $16 254 (95% CI 7116-99 057) per QALY gained. The probability that C-MAP is cost-effective was between 66% and 83% for cost-effective thresholds between $20 000 and $30 000. Cost-effectiveness results remained robust to sensitivity analyses. CONCLUSIONS: C-MAP may be a valuable self-harm intervention. Further studies with longer follow-up and larger sample sizes are needed to draw reliable conclusions.

Prospective assessment of dementia on transitions in homeboundness using multistate Markov models.

BACKGROUND: One in 20 older adults in the United States is homebound and rarely/never leaves home. Although being homebound decreases the quality of the lived experience of individuals with serious illnesses, little is known about the frequency or likelihood of transitions in or out of homebound status. The objective of this study was to characterize the probability of transitions to and from homebound status among older adults and examine the relationship between dementia status and homebound transitions. METHODS: Using 2011-2018 data from the National Health and Aging Trends Study (NHATS), a nationally representative longitudinal study of aging in the United States, we identified 6375 community-dwelling Medicare beneficiaries. Homebound status (independent, semi-homebound (leaving home but with difficulty or help), homebound (rarely or never leaving home), nursing home resident, dead) was assessed annually via self-report. Transition probabilities across states were assessed using a multistate Markov model. RESULTS: Less than half of homebound individuals remain homebound (probability = 41.5% [95% CI: 39.2%, 43.5%]) after 1 year. One out of four dies (24% [22.3%, 26.0%]) and there is a low probability (3.2% [2.5%, 4.1%]) of transition to a nursing home. Dementia status was associated with increased risk of progression from independence to homebound status (HR: 1.83 [1.01, 3.34]). Dementia was consistently associated with increased probabilities of transitions to death including a two-fold increased hazards of progression from homebound to death (HR: 2.18 [1.69, 2.81]). Homebound individuals with dementia have a 34.2% [25.8%, 48.1%] probability of death in 5 years, compared with 17.4% [13.7%, 24.3%] among those without dementia. DISCUSSION: Dementia is associated with greater risk of transitioning across homebound states. There is a greater need to support home-based care for patients with dementia, especially as the ongoing COVID pandemic has raised concerns about the need to invest in alternative models to nursing home care.

APOE and Alzheimer's Disease: From Lipid Transport to Physiopathology and Therapeutics.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by extracellular amyloid ß (Aß) and intraneuronal tau protein aggregations. One risk factor for developing AD is the APOE gene coding for the apolipoprotein E protein (apoE). Humans have three versions of APOE gene: ε2, ε3, and ε4 allele. Carrying the ε4 allele is an AD risk factor while carrying the ε2 allele is protective. ApoE is a component of lipoprotein particles in the plasma at the periphery, as well as in the cerebrospinal fluid (CSF) and in the interstitial fluid (ISF) of brain parenchyma in the central nervous system (CNS). ApoE is a major lipid transporter that plays a pivotal role in the development, maintenance, and repair of the CNS, and that regulates multiple important signaling pathways. This review will focus on the critical role of apoE in AD pathogenesis and some of the currently apoE-based therapeutics developed in the treatment of AD.

A national profile of kinlessness at the end of life among older adults: Findings from the Health and Retirement Study.

BACKGROUND/OBJECTIVES: The majority of end-of-life (EOL) caregiving is provided by unpaid family members. An increasing number of older adults are kinless (without close family/partnerships) and may have insufficient caregiver support to remain at home at the EOL. We therefore determined what proportion of older adults are kinless at the EOL and assessed the association of kinlessness with EOL care. DESIGN: Retrospective analysis of Health and Retirement Study decedents, 2002-2015. SETTING: US population-based sample. PARTICIPANTS: Decedents age 51+ who died within 1 year of interview (n = 3844) and subset who are community-dwelling at last interview. MEASUREMENTS: Kinlessness was defined as lacking a spouse/partner and children. Primary outcome measure was location of death. Secondary outcome measures included contextual EOL measures such as symptom burden and caregiver support. RESULTS: A total of 7.4% of decedents were kinless at the EOL. Kinless decedents were more likely to be female, nonwhite, enrolled in Medicaid, living alone, or living in a nursing home prior to death. Although community-dwelling kinless decedents received fewer hours of caregiving per week at the EOL (34.7 vs. 56.2, p < 0.05) and were more likely to die in nursing homes (18.1% vs. 10.3%, p < 0.05) than those with kin, they did not have higher EOL symptom burden or treatment intensity (e.g., intensive care unit use). In multinomial logistic analysis controlling for demographic and illness characteristics, kinless decedents living in the community before death had a twofold increased risk of dying in the nursing home (odds ratio [OR] = 2.02 [95% confidence interval (CI) = 1.09-3.72]) and a trend toward increased risk of hospital death (OR = 1.60 [95% CI = 0.96-2.69]) versus home setting. CONCLUSIONS: Kinless individuals are more likely to die in nursing homes, even if they are living in the community in their last year of life. Expanded long-term care services and policies are needed to enable all older adults regardless of their family support systems to receive high-quality EOL care.