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Objective: To determine the long-term effectiveness of comprehensive support and counseling for spouse-caregivers and families in postponing or preventing nursing home placement of patients with Alzheimer disease (AD).Design: Randomized controlled intervention study.Setting: Outpatient research clinic in the New York City metropolitan area.Participants: Referred, volunteer sample of 206 spouse-caregivers of AD patients who enrolled in the study during a 3 1/2-year period. All patients were living at home at baseline and had at least 1 relative living in the area.Intervention: Caregivers in the treatment group were provided with 6 sessions of individual and family counseling within 4 months of enrollment in the study and were required to join support groups. In addition, counselors were available for further counseling at any time.Main Outcome Measure: Time from enrollment of caregivers in the study to placement of the AD patients in a nursing home.Results: Using Kaplan-Meier survival analysis, we estimated that the median time (weighted average of estimates for male and female caregivers) from baseline to nursing home placement of AD patients was 329 days longer in the treatment group than in the control group (z=2.29; P=.02). The relative risk (RR) from a Cox proportional hazard model of nursing home placement (intent-to-treat estimate) after adjusting for caregiver sex, patient age, and patient income was 0.65 (95% confidence interval [CI], 0.45 to 0.94; P=.02), indicating that caregivers were approximately two thirds as likely to place their spouses in nursing homes at any point in time if they were in the treatment group than if they were in the control group. Treatment had the greatest effect on risk of placement for patients who were mildly demented (RR, 0.18; 95% CI, 0.04 to 0.77) or moderately demented (RR, 0.38; 95% CI, 0.17 to 0.82).Conclusions: A program of counseling and support can substantially increase the time spouse-caregivers are able to care for AD patients at home, particularly during the early to middle stages of dementia when nursing home placement is generally least appropriate. [ABSTRACT FROM AUTHOR]

Although home-care of Alzheimer's disease (AD) patients is more cost-effective than institutionalization, there is limited knowledge concerning the causes and prevention of institutionalization. The goal of this project was to determine the circumstances related to institutionalization of AD patients and to determine if a family counseling program can reduce these precipitating factors. In Study 1, we surveyed 109 family members of institutionalized AD patients. Primary precipitating factors included difficulties with patient behavior, insufficient auxiliary help and respite, financial difficulties, and caregiver emotional and physical complaints. In Study 2 we evaluated the effectiveness of an enhanced counseling program which included specific intervention techniques to cope with precipitating factors. For 41 AD family members who were seriously contemplating institutionalization, the precipitating factors prior to counseling were similar to those found in Study 1. After six months of individual counseling, home visits, and participation in caregiver support groups, there was only one placement, and a consistent reduction in the precipitating factors. These preliminary results suggest that a specially designed counseling program may delay or forestall institutionalization. [ABSTRACT FROM AUTHOR]

Objectives: To assess the feasibility of scaling advanced care at home (ACAH) (otherwise known as hospital at home) within an integrated health care delivery system., Study Design: Retrospective cohort study of patients qualified for hospital-level care who were admitted to either ACAH or a traditional hospital., Methods: From April 29, 2020, to November 14, 2021, patients requiring hospital-level care received Kaiser Permanente at Home or traditional hospital care. In a subgroup of patients, we compared outcomes for Kaiser Permanente at Home vs traditional hospital care using regression models., Results: A total of 1005 patients were admitted to Kaiser Permanente at Home. Average daily census (ADC) was intentionally increased over time in stages, from 7.2 to 8.8, then to 12.7. The maximum daily census was 22, with a peak ADC of 16, representing 9% of the total hospital inpatient medicine service census. During this time, there were numeric decreases in Kaiser Permanente at Home escalation rates (17.5% to 10.8%), median length of stay (7.43 days to 5.46 days), and readmission rates (9.79% to 9.24%). A subgroup of Kaiser Permanente at Home patients contributed to the comparative analyses, which showed that patients admitted to Kaiser Permanente at Home were 64% less likely to experience delirium than patients admitted for traditional hospital care (OR, 0.36; 95% CI, 0.15-0.88; P = .026). Comparisons of quality metrics across stages of implementation (readmissions, escalations, length of stay) were inconclusive., Conclusion: In an integrated delivery system, ACAH care can be scaled and can create hospital capacity. However, our data were inconclusive regarding quality throughout scaling due to the small effective sample size, necessitating replication in a larger prospective study with adequate power/precision.

Introduction: Incubation of drug-craving refers to a time-dependent increase in drug cue-elicited craving that occurs during protracted withdrawal. Historically, rat models of incubated cocaine craving employed extended-access (typically 6 h/day) intravenous drug self-administration (IV-SA) procedures, although incubated cocaine craving is reported to occur following shorter-access IV-SA paradigms. The notoriously low-throughput of extended-access IV-SA prompted us to determine whether two different short-access IV-SA procedures akin to those in the literature result in qualitatively similar changes in glutamate receptor expression and the activation of downstream signaling molecules within prefrontal cortex (PFC) subregions as those reported previously by our group under 6h-access conditions., Methods: For this, adult, male Sprague-Dawley rats were trained to intravenously self-administer cocaine for 2 h/day for 10 consecutive days (2-h model) or for 6 h on day 1 and 2 h/day for the remaining 9 days of training (Mixed model). A sham control group was also included that did not self-administer cocaine., Results: On withdrawal day 3 or 30, rats were subjected to a 2-h test of cue-reinforced responding in the absence of cocaine and a time-dependent increase in drug-seeking was observed under both IV-SA procedures. Immunoblotting of brain tissue collected immediately following the cue test session indicated elevated phospho-Akt1, phospho-CaMKII and Homer2a/b expression within the prelimbic subregion of the PFC of cocaine-incubated rats. However, we failed to detect incubation-related changes in Group 1 metabotropic glutamate receptor or ionotropic glutamate receptor subunit expression in either subregion., Discussion: These results highlight further a role for Akt1-related signaling within the prelimbic cortex in driving incubated cocaine craving, and provide novel evidence supporting a potential role also for CaMKII-dependent signaling through glutamate receptors in this behavioral phenomenon., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Huerta Sanchez, Sankaran, Li, Doan, Chiu, Shulman, Shab, Kippin and Szumlinski.)

The use of alternative promoters, splicing, and cleavage and polyadenylation (APA) generates mRNA isoforms that expand the diversity and complexity of the transcriptome. Here, we uncovered thousands of previously undescribed 5' uncapped and polyadenylated transcripts (5' UPTs). We show that these transcripts resist exonucleases due to a highly structured RNA and N6-methyladenosine modification at their 5' termini. 5' UPTs appear downstream of APA sites within their host genes and are induced upon APA activation. Strong enrichment in polysomal RNA fractions indicates 5' UPT translational potential. Indeed, APA promotes downstream translation initiation, non-canonical protein output, and consistent changes to peptide presentation at the cell surface. Lastly, we demonstrate the biological importance of 5' UPTs using Bcl2, a prominent anti-apoptotic gene whose entire coding sequence is a 5' UPT generated from 5' UTR-embedded APA sites. Thus, APA is not only accountable for terminating transcripts, but also for generating downstream uncapped RNAs with translation potential and biological impact., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Carriers of GBA1 gene variants have a significant risk of developing Parkinson’s disease (PD). A cohort study of GBA carriers between 40−75 years of age was initiated to study the presence of prodromal PD features. Participants underwent non-invasive tests to assess different domains of PD. Ninety-eight unrelated GBA carriers were enrolled (43 males) at a median age (range) of 51 (40−74) years; 71 carried the N370S variant (c.1226A > G) and 25 had a positive family history of PD. The Montreal Cognitive Assessment (MoCA) was the most frequently abnormal (23.7%, 95% CI 15.7−33.4%), followed by the ultrasound hyperechogenicity (22%, 95% CI 14−32%), Unified Parkinson’s Disease Rating Scale part III (UPDRS-III) (17.2%, 95% CI 10.2−26.4%), smell assessment (12.4%, 95% CI 6.6−20.6%) and abnormalities in sleep questionnaires (11%, 95% CI 5.7−19.4%). Significant correlations were found between tests from different domains. To define the risk for PD, we assessed the bottom 10th percentile of each prodromal test, defining this level as “abnormal”. Then we calculated the percentage of “abnormal” tests for each subject; the median (range) was 4.55 (0−43.5%). Twenty-two subjects had more than 15% “abnormal” tests. The limitations of the study included ascertainment bias of individuals with GBA-related PD in relatives, some incomplete data due to technical issues, and a lack of well-characterized normal value ranges in some tests. We plan to enroll additional participants and conduct longitudinal follow-up assessments to build a model for identifying individuals at risk for PD and investigate interventions aiming to delay the onset or perhaps to prevent full-blown PD.

Purpose: We sought to determine the feasibility of delivering a Supportive Oncology Care at Home intervention among patients with pancreatic cancer., Methods: We prospectively enrolled patients with pancreatic cancer from a parent trial of neoadjuvant fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX). The intervention entailed (1) remote monitoring of patient-reported symptoms, vital signs, and body weight; (2) a hospital-at-home care model; and (3) structured communication with the oncology team. We defined the intervention as feasible if ≥ 60% of patients enrolled in the study and ≥ 60% completed the daily assessments within the first 2-weeks of enrollment. We determined rates of treatment delays, urgent clinic visits, emergency department visits, and hospitalizations among those who did (n = 20) and did not (n = 24) receive Supportive Oncology Care at Home from the parent trial., Results: From January 2019 to September 2020, we enrolled 80.8% (21/26) of potentially eligible patients. One patient became ineligible following consent because of moving out of state, resulting in 20 participants (median age = 67 years). In the first 2 weeks of enrollment, 65.0% of participants completed all daily assessments. Overall, patients reported 96.1% of daily symptoms, 96.1% of daily vital signs, and 92.5% of weekly body weights. Patients receiving the intervention had lower rates of treatment delays (55.0% v 75.0%), urgent clinic visits (10.0% v 25.0%), and emergency department visits/hospitalizations (45.0% v 62.5%) compared with those not receiving the intervention from the same parent trial., Conclusion: Findings demonstrate the feasibility and acceptability of a Supportive Oncology Care at Home intervention. Future work will investigate the efficacy of this intervention for decreasing health care use and improving patient outcomes., Competing Interests: Ryan D. NippThis author is an Associate Editor for JCO Oncology Practice. Journal policy recused the author from having any role in the peer review of this manuscript. Colin D. WeekesHonoraria: Celgene, Lilly, BayerConsulting or Advisory Role: Celgene, Merrimack, IpsenResearch Funding: Celgene, Genentech/Roche, AstraZeneca, Dicephera Pharmaceuticals Inc, Novartis, Actuate Therapeutics Eric J. RoelandConsulting or Advisory Role: Napo Pharmaceuticals, AIM Specialty Health, Helsinn Therapeutics, Byomass, Veloxis, PRA Health, Actimed Therapeutics, Takeda, MeterHealthExpert Testimony: Regents of the University of California Aparna R. ParikhStock and Other Ownership Interests: C2i genomicsConsulting or Advisory Role: Lilly, Natera, Checkmate Pharmaceuticals, Pfizer, Roche/Genentech, Inivata, Biofidelity, Guardant HealthResearch Funding: Plexxikon (Inst), Bristol Myers Squibb (Inst), Genentech (Inst), Guardant Health (Inst), Array BioPharma (Inst), Lilly (Inst), Novartis Pharmaceuticals UK Ltd (Inst), PureTech (Inst), PMV Pharma, Mirati Therapeutics (Inst), Daiichi Sankyo (Inst) Jennifer Y. WoHonoraria: PERResearch Funding: Genentech/Roche (Inst)Travel, Accommodations, Expenses: Lynx Group Melissa Hennessey SmithEmployment: Medically HomeStock and Other Ownership Interests: Medically HomeResearch Funding: Medically HomeTravel, Accommodations, Expenses: Medically Home Patricia M.C. BrownEmployment: Medically HomeStock and Other Ownership Interests: Medically Home Group IncConsulting or Advisory Role: AllscriiptsResearch Funding: Medically Home Group IncTravel, Accommodations, Expenses: Medically Home Group Eliza ShulmanEmployment: Medically HomeLeadership: Medically HomeStock and Other Ownership Interests: Medically Home Alec C. KimmelmanStock and Other Ownership Interests: Vescor Therapeutics, Rafael PharmaceuticalsConsulting or Advisory Role: Vescor Therapeutics, AbbVie, DecipheraPatents, Royalties, Other Intellectual Property: Inventor on patents pertaining to Kras-regulated metabolic pathways, redox control pathways in pancreatic cancer, targeting GOT1 as a therapeutic approach and the autophagic control of iron metabolism, and targeting alanine transport in pancreatic cancer David TingLeadership: PanTher TherapeuticsStock and Other Ownership Interests: PanTher Therapeutics, ROME Therapeutics, TellBioConsulting or Advisory Role: ROME Therapeutics, Millipore, Foundation Medicine, Pfizer, NanoString Technologies, Tekla Capital Management, Ikena OncologyResearch Funding: ACD Biotechne (Inst), PureTech (Inst), Ribon Therapeutics (Inst)Patents, Royalties, Other Intellectual Property: Patent licensed to Rome Therapeutics by my Institution (Inst); patent license to PanTher Therapeutics (Inst), patent license to TellBio Inc (Inst) Theodore S. HongStock and Other Ownership Interests: PanTher TherapeuticsConsulting or Advisory Role: Merck, Synthetic Biologics, Novocure, Syndax, Boston ScientificResearch Funding: Taiho Pharmaceutical (Inst), AstraZeneca (Inst), IntraOp (Inst), Tesaro (Inst), Bristol Myers Squibb (Inst), Ipsen (Inst) Joseph A. GreerResearch Funding: NCCN/AstraZeneca (Inst), Gaido Health/BCG Digital Ventures (Inst), Blue Note Therapeutics (Inst)Patents, Royalties, Other Intellectual Property: Royalties from Springer Publishing Company for the edited book, The Massachusetts General Hospital Handbook of Behavioral Medicine. David P. RyanStock and Other Ownership Interests: MPM Capital, Acworth Pharmaceuticals, Thrive Earlier Detection Corp, Exact SciencesHonoraria: UpToDate, Research to PracticeConsulting or Advisory Role: MPM Capital, Oncorus, Gritstone Bio, Maverick Therapeutics, TCR2 Therapeutics, Twentyeight-Seven Therapeutics, Innocrin PharmaResearch Funding: Stand up to Cancer (Inst)Patents, Royalties, Other Intellectual Property: McGraw Hill Chapter Royalties, Johns Hopkins University PressExpert Testimony: Boehringer IngelheimOther Relationship: TCR2 Therapeutics Areej El-JawahriConsulting or Advisory Role: AIM Specialty Health, Novartis, GlaxoSmithKline, IncyteNo other potential conflicts of interest were reported.

Objective: Children with medical complexity (CMC) are hypothesized to have unique housing and accessibility needs due to their medical fragility and medical technology dependency; however, research on prevalence and types of housing need in CMC is limited. The objective was to describe housing need in families of CMC, and to compare housing need across CMC, children with one chronic condition (Type 1 diabetes; CT1D) and healthy children (HC)., Methods: This cross-sectional descriptive study assessed housing suitability, adequacy, affordability, stress, stability, and accessibility using survey methodology. Participants were caregivers of CMC, CT1D and HC at a tertiary-care pediatric hospital. The association of housing need outcomes across groups was analyzed using logistic and ordinal logistic regression models, adjusting for income, educational attainment, employment status, community type, immigration status, child age, and number of people in household., Results: Four hundred ninety caregivers participated. Caregivers of CMC reported increased risk of housing-related safety concerns (aOR 3.1 [1.3-7.5]), using a common area as a sleeping area (5.6 [2.0-16.8]), reducing spending (4.6 [2.3-9.5]) or borrowing money to afford rent (2.9 [1.2-6.7]), experiencing housing stress (3.3 [1.8-6.0]), and moving or considering moving to access health/community services (15.0 [6.4-37.6]) compared to HC., Conclusions: CMC were more likely to experience multiple indicators of housing need compared to CT1D and HC even after adjusting for sociodemographic factors, suggesting an association between complexity of child health conditions and housing need. Further research and practise should consider screening for and supporting housing need in CMC., (Copyright © 2021 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Hearing loss is one of the top contributors to years lived with disability and is a risk factor for dementia. Molecular evidence on the cellular origins of hearing loss in humans is growing. Here, we performed a genome-wide association meta-analysis of clinically diagnosed and self-reported hearing impairment on 723,266 individuals and identified 48 significant loci, 10 of which are novel. A large proportion of associations comprised missense variants, half of which lie within known familial hearing loss loci. We used single-cell RNA-sequencing data from mouse cochlea and brain and mapped common-variant genomic results to spindle, root, and basal cells from the stria vascularis, a structure in the cochlea necessary for normal hearing. Our findings indicate the importance of the stria vascularis in the mechanism of hearing impairment, providing future paths for developing targets for therapeutic intervention in hearing loss., Competing Interests: Declaration of interests The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. C.R.C. is supported by the UK National Institute for Health Research (NIHR) Biomedical Research Center but the views expressed herein are his own and do not represent those of NIHR nor the UK Department of Health and Social Care. Y.Z. and V.M.L. are co-founders and shareholders of PersoMedix AB. In addition, V.M.L. is CEO and shareholder of HepaPredict AB and discloses support by the Robert Bosch Foundation, Merck KGaA, and Eli Lilly and Company. J.H.L. is co-founder and share-holder of Oscellaria AB. H.L. receives support from a consulting contract between Data Tecnica International and the National Institute on Aging (NIA), National Institutes of Health (NIH). M.A.N. received a competitive contract awarded to Data Tecnica International LLC by the National Institutes of Health to support open science research, and he also currently serves on the scientific advisory board for Clover Therapeutics and is an advisor to Neuron23 Inc as a data science fellow. P.F.S. is consultant and shareholder of Neumora., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)