Explore the vast range of titles available.

Background Cognitive impairment and dementia are frequently under-recognized. Health system strategies anchored in primary care are essential to address gaps in timely, comprehensive diagnosis. The goal of this paper is to describe the adaptation of a tablet-based brain health assessment (TabCAT-BHA) intervention and the study protocol to test its effectiveness in improving the detection of cognitive impairment, including dementia. Methods This mixed-methods, pragmatic, cluster randomized, hybrid effectiveness-implementation trial is being conducted in two 18-month waves with 26 Kaiser Permanente Southern California primary care clinics, with 13 serving as intervention clinics and 13 as usual care clinics. Patients 65 years and older with memory concerns ( n  ~ 180,000) receiving care at the 26 clinics will be included in the analyses. Primary care clinics are provided the following practice supports as part of the TabCAT-BHA intervention: brief education and training on neurocognitive disorders and study workflows; digital tools to assess cognitive function and support clinician decision making and documentation; and registered nurse support during the work-up and post-diagnosis periods for primary care providers, patients, and families. The intervention was adapted based on engagement with multiple levels of clinical and operational leaders in the healthcare system. Effectiveness outcomes include rates of cognitive impairment diagnosis in primary care and rates of completed standardized cognitive assessments and specialist referrals with incident diagnoses. Implementation outcomes include acceptability-appropriateness-feasibility, adoption, and fidelity. Results We identified seven themes organized by system-, provider-, and patient-level domains that were used to adapt the TabCAT-BHA intervention. Accordingly, changes were made to the provider education, diagnostic work-up, and post-diagnostic support. Results will be reported in fall of 2027. Conclusions Our engagement with multiple primary and specialty care clinical and operational leaders to adapt the TabCAT-BHA intervention to these primary care clinics has informed the protocol to evaluate the intervention’s effectiveness for improving the detection of cognitive impairment, including dementia, in an integrated healthcare system. Trial Registation Clinicaltrials.gov: NCT06090578 (registered 10/24/23).

Conventional plasmid DNA vectors play a significant role in gene therapy, but they also have considerable limitations: they can elicit adverse immune responses because of bacterial sequences they contain for maintenance and amplification in prokaryotes, their bioavailability is compromised because of their large molecular size, and they may be genotoxic. We constructed an in vivo platform to produce ministring DNA—mini linear covalently closed DNA vectors—that are devoid of unwanted bacterial sequences and encode only the gene(s) of interest and necessary eukaryotic expression elements. Transfection of rapidly and slowly dividing human cells with ministring DNA coding for enhanced green fluorescent protein resulted in significantly improved transfection, bioavailability, and cytoplasmic kinetics compared with parental plasmid precursors and isogenic circular covalently closed DNA counterparts. Ministring DNA that integrated into the genome of human cells caused chromosomal disruption and apoptotic death of possibly oncogenic vector integrants; thus, they may be safer than plasmid and circular DNA vectors.

Quetiapine is a Food and Drug Administration (FDA) approved second-generation antipsychotic. It is also commonly used at low dose for its sedative properties to treat insomnia in the older population. Quetiapine at standard doses has been associated with increased risk of cerebrovascular events, cognitive decline, and mortality in patients with dementia, especially within older adults. However, there are limited data describing its safety at lower doses, especially for the treatment of insomnia in older adults. This study aims to compare the safety of low-dose quetiapine versus trazodone or mirtazapine for insomnia in older adults in the USA. This was a retrospective cohort study that included patients aged 65 years or older who started low-dose quetiapine, trazodone, or mirtazapine for the treatment of insomnia from October 2018 to September 2021. The primary outcome was all-cause mortality and secondary outcomes included new incidences of stroke or transient ischemic attack, dementia, and falls with or without traumatic fractures. They were identified from electronic medical records using ICD-10-CM clinical diagnosis codes. Eligible patients were followed from the initiation of the drug until death, end of target drug exposure or escalation of dose, end of health plan membership, or 30 September 30 2022, whichever came first. Patients initiated mirtazapine or trazodone were matched to each patient who initiated quetiapine at a 4:1 ratio using propensity score matching method. We included 375 patients initiated on low-dose quetiapine, who were matched to 1500 patients started on trazodone and 1500 patients started on mirtazapine. Comparing patients who received quetiapine with trazodone, the quetiapine group had an increased risk of mortality (hazard ratio (HR) 3.1, 95% confidence interval (CI) 1.2-8.1; P < 0.05), dementia (HR 8.1, 95% CI 4.1-15.8; P < 0.05), and falls (HR 2.8, 95% CI 1.4-5.3; P < 0.05). When comparing quetiapine with mirtazapine, quetiapine group had an increased risk of dementia (HR 7.1, 95% CI 3.5-14.4; P < 0.05). No significant differences were detected in other outcomes. Caution should be taken in practice when using low-dose quetiapine for insomnia in older adults. It is associated with significantly higher rates of mortality, dementia, and falls when compared with trazodone and a higher dementia rate when compared with mirtazapine.

Implementing scalable and sustainable, evidence-informed diagnostic care pathways to improve earlier detection of cognitive impairment (CI) in primary care requires extensive engagement with front-line clinicians, physician and administrative leaders and careful coordination with intersecting specialties. In preparation for a pragmatic, cluster, randomized trial with 26 primary care clinics in an integrated health system, we conducted pre-implementation stakeholder engagement meetings to adapt core elements of practice support: 1) provider education and training; 2) digital tools to assess cognitive function (TabCAT-Brain Health Assessment) and support clinician decision making and documentation; and 3) registered nurse (RN) support during the work-up and post-diagnosis periods for primary care physicians (PCPs), patients, and families. We used thematic analysis of meeting transcripts to guide intervention adaptations. The overarching theme from these meetings was that PCPs want to provide the best brain health care possible within the constraints of their limited time and gaps in expertise. Patients with memory concerns complete the TabCAT-BHA with a nonclinical staff who provide results to RNs. For individuals found to have a high likelihood of CI, the RN assesses the patient's functional status and behavior with a care partner, reviews the medical record, and triangulates findings with cognitive test results to arrive at a preliminary classification of mild cognitive impairment (MCI) or dementia, and orders lab tests and imaging on behalf of the PCP. The RN then routes a summary to the patient's PCP with scripted guidance on disclosing a new diagnosis with the patient/family, or, for complex patients, pends a specialty referral for PCP approval. Once the PCP has disclosed the initial diagnosis of MCI or dementia, the RN then provides initial care planning and navigation with the patient/family. A total of 740 Tab-CAT BHAs have been completed since March 2024, with 80% of patients (54% Spanish speakers) having a classification of mild or major neurocognitive disorder. PCPs' reception of the program has been overwhelmingly positive, with 85% reporting that they are very to extremely likely to recommend the TabCAT-BHA care pathway to their peers. Practice supports must be tailored to local contexts to achieve high acceptability and sustainability.

While population norms for cognitive tests are well established, none exists for assessing daily function that could easily and quickly assist busy physicians in determining if patients have mild (mild cognitive impairment, MCI) or major (dementia) neurocognitive disorder. The purpose of this analysis is to describe test characteristics of a simple question directed at patients' family and friend care partners to assist primary care in distinguishing between MCI and dementia. Patients 65 and older with memory concerns were referred by their primary care physicians to the Brain Health Assessment (BHA) care pathway as part of a large pragmatic trial to test a practice bundle to improve earlier detection of cognitive impairment in primary care within an integrated healthcare system serving diverse patients (53% completed the assessment in Spanish). Registered nurses assisted physicians with the work-up for memory concerns by synthesizing information gathered from objective cognitive testing with the TabCAT-BHA, assessments of patients' function via their nominated care partners (instrumental and basic activities of daily living), and chart review to arrive at a preliminary classification of whether patients had MCI or dementia. Care partners were asked whether they \"would feel comfortable leaving (their) relative alone for 2 days without any help from others?\". We calculated standard test characteristics for this question with the nurses' preliminary staging. 440 care partners completed the functional assessment interview and provided a response to the question. Of 155 patients with a preliminary staging of dementia, 130 (84%) care partners endorsed not feeling comfortable leaving their relative alone compared to 36 (13%) of 285 care partners of patients with MCI. For patients with dementia, spouses were only slightly more likely (89%) to provide positive endorsement the question compared to adult children (85%). Overall, this question has high sensitivity (84%), specificity (87%), positive (78%) and negative (91%) predictive value for distinguishing dementia from MCI. Although care partners' social desirability is a consideration, a simple question could have high utility for busy primary care providers to not only feel confident to diagnose dementia but also, help facilitate care and safety planning for the patient.

Mitochondria contain multiple copies of their own 16.6 kb circular genome. To explore the impact of mitochondrial DNA (mtDNA) damage on mitochondrial (mt) function and viability of AML cells, we screened a panel of DNA damaging chemotherapeutic agents to identify drugs that could damage mtDNA. We identified bleomycin as an agent that damaged mtDNA in AML cells at concentrations that induced cell death. Bleomycin also induced mtDNA damage in primary AML samples. Consistent with the observed mtDNA damage, bleomycin reduced mt mass and basal oxygen consumption in AML cells. We also demonstrated that the observed mtDNA damage was functionally important for bleomycin-induced cell death. Finally, bleomycin delayed tumor growth in xenograft mouse models of AML and anti-leukemic concentrations of the drug induced mtDNA damage in AML cells preferentially over normal lung tissue. Taken together, mtDNA-targeted therapy may be an effective strategy to target AML cells and bleomycin could be useful in the treatment of this disease.

Background and Objective Quetiapine is a Food and Drug Administration (FDA) approved second-generation antipsychotic. It is also commonly used at low dose for its sedative properties to treat insomnia in the older population. Quetiapine at standard doses has been associated with increased risk of cerebrovascular events, cognitive decline, and mortality in patients with dementia, especially within older adults. However, there are limited data describing its safety at lower doses, especially for the treatment of insomnia in older adults. This study aims to compare the safety of low-dose quetiapine versus trazodone or mirtazapine for insomnia in older adults in the USA. Methods This was a retrospective cohort study that included patients aged 65 years or older who started low-dose quetiapine, trazodone, or mirtazapine for the treatment of insomnia from October 2018 to September 2021. The primary outcome was all-cause mortality and secondary outcomes included new incidences of stroke or transient ischemic attack, dementia, and falls with or without traumatic fractures. They were identified from electronic medical records using ICD-10-CM clinical diagnosis codes. Eligible patients were followed from the initiation of the drug until death, end of target drug exposure or escalation of dose, end of health plan membership, or 30 September 30 2022, whichever came first. Patients initiated mirtazapine or trazodone were matched to each patient who initiated quetiapine at a 4:1 ratio using propensity score matching method. Results We included 375 patients initiated on low-dose quetiapine, who were matched to 1500 patients started on trazodone and 1500 patients started on mirtazapine. Comparing patients who received quetiapine with trazodone, the quetiapine group had an increased risk of mortality (hazard ratio (HR) 3.1, 95% confidence interval (CI) 1.2–8.1; P  < 0.05), dementia (HR 8.1, 95% CI 4.1–15.8; P  < 0.05), and falls (HR 2.8, 95% CI 1.4–5.3; P  < 0.05). When comparing quetiapine with mirtazapine, quetiapine group had an increased risk of dementia (HR 7.1, 95% CI 3.5–14.4; P  < 0.05). No significant differences were detected in other outcomes. Conclusions Caution should be taken in practice when using low-dose quetiapine for insomnia in older adults. It is associated with significantly higher rates of mortality, dementia, and falls when compared with trazodone and a higher dementia rate when compared with mirtazapine.

Background and Objective Quetiapine is a Food and Drug Administration (FDA) approved second-generation antipsychotic. It is also commonly used at low dose for its sedative properties to treat insomnia in the older population. Quetiapine at standard doses has been associated with increased risk of cerebrovascular events, cognitive decline, and mortality in patients with dementia, especially within older adults. However, there are limited data describing its safety at lower doses, especially for the treatment of insomnia in older adults. This study aims to compare the safety of low-dose quetiapine versus trazodone or mirtazapine for insomnia in older adults in the USA. Methods This was a retrospective cohort study that included patients aged 65 years or older who started low-dose quetiapine, trazodone, or mirtazapine for the treatment of insomnia from October 2018 to September 2021. The primary outcome was allcause mortality and secondary outcomes included new incidences of stroke or transient ischemic attack, dementia, and falls With or without traumatic fractures. They were identified from electronic medical records using ICD-10-CM clinical diagnosis codes. Eligible patients were followed from the initiation of the drug until death, end of target drug exposure or escalation of dose, end of health plan membership, or 30 September 30 2022, whichever came first. Patients initiated mirtazapine or trazodone were matched to each patient who initiated quetiapine at a 4:1 ratio using propensity score matching method. Results We included 375 patients initiated on low-dose quetiapine, who were matched to 1500 patients started on trazodone and 1500 patients started on mirtazapine. Comparing patients who received quetiapine with trazodone, the quetiapine group had an increased risk of mortality (hazard ratio (HR) 3.1, 95% confidence interval (CI) 1.2-8.1; P<0.05), dementia (HR 8.1, 95% CI 4.1-15.8; P<0.05), and falls (HR 2.8, 95% CI 1.4-5.3; P<0.05). When comparing quetiapine with mirtazapine, quetiapine group had an increased risk of dementia (HR 7.1, 95% CI 3.5-14.4; Р < 0.05). No significant differences were detected in other outcomes. Conclusions Caution should be taken in practice when using low-dose quetiapine for insomnia in older adults. It is associated with significantly higher rates of mortality, dementia, and falls when compared with trazodone and a higher dementia rate when compared with mirtazapine.

Implementing scalable and sustainable, evidence‐informed diagnostic care pathways to improve earlier detection of cognitive impairment (CI) in primary care requires extensive engagement with front‐line clinicians, physician and administrative leaders and careful coordination with intersecting specialties. In preparation for a pragmatic, cluster, randomized trial with 26 primary care clinics in an integrated health system, we conducted pre‐implementation stakeholder engagement meetings to adapt core elements of practice support: 1) provider education and training; 2) digital tools to assess cognitive function (TabCAT‐Brain Health Assessment) and support clinician decision making and documentation; and 3) registered nurse (RN) support during the work‐up and post‐diagnosis periods for primary care physicians (PCPs), patients, and families. We used thematic analysis of meeting transcripts to guide intervention adaptations. The overarching theme from these meetings was that PCPs want to provide the best brain health care possible within the constraints of their limited time and gaps in expertise. Patients with memory concerns complete the TabCAT‐BHA with a nonclinical staff who provide results to RNs. For individuals found to have a high likelihood of CI, the RN assesses the patient's functional status and behavior with a care partner, reviews the medical record, and triangulates findings with cognitive test results to arrive at a preliminary classification of mild cognitive impairment (MCI) or dementia, and orders lab tests and imaging on behalf of the PCP. The RN then routes a summary to the patient's PCP with scripted guidance on disclosing a new diagnosis with the patient/family, or, for complex patients, pends a specialty referral for PCP approval. Once the PCP has disclosed the initial diagnosis of MCI or dementia, the RN then provides initial care planning and navigation with the patient/family. A total of 740 Tab‐CAT BHAs have been completed since March 2024, with 80% of patients (54% Spanish speakers) having a classification of mild or major neurocognitive disorder. PCPs’ reception of the program has been overwhelmingly positive, with 85% reporting that they are very to extremely likely to recommend the TabCAT‐BHA care pathway to their peers. Practice supports must be tailored to local contexts to achieve high acceptability and sustainability.

Background While population norms for cognitive tests are well established, none exists for assessing daily function that could easily and quickly assist busy physicians in determining if patients have mild (mild cognitive impairment, MCI) or major (dementia) neurocognitive disorder. The purpose of this analysis is to describe test characteristics of a simple question directed at patients’ family and friend care partners to assist primary care in distinguishing between MCI and dementia. Methods Patients 65 and older with memory concerns were referred by their primary care physicians to the Brain Health Assessment (BHA) care pathway as part of a large pragmatic trial to test a practice bundle to improve earlier detection of cognitive impairment in primary care within an integrated healthcare system serving diverse patients (53% completed the assessment in Spanish). Registered nurses assisted physicians with the work‐up for memory concerns by synthesizing information gathered from objective cognitive testing with the TabCAT‐BHA, assessments of patients’ function via their nominated care partners (instrumental and basic activities of daily living), and chart review to arrive at a preliminary classification of whether patients had MCI or dementia. Care partners were asked whether they “would feel comfortable leaving (their) relative alone for 2 days without any help from others?”. We calculated standard test characteristics for this question with the nurses’ preliminary staging. Results 440 care partners completed the functional assessment interview and provided a response to the question. Of 155 patients with a preliminary staging of dementia, 130 (84%) care partners endorsed not feeling comfortable leaving their relative alone compared to 36 (13%) of 285 care partners of patients with MCI. For patients with dementia, spouses were only slightly more likely (89%) to provide positive endorsement the question compared to adult children (85%). Overall, this question has high sensitivity (84%), specificity (87%), positive (78%) and negative (91%) predictive value for distinguishing dementia from MCI. Conclusions Although care partners’ social desirability is a consideration, a simple question could have high utility for busy primary care providers to not only feel confident to diagnose dementia but also, help facilitate care and safety planning for the patient.