Nuclear instance segmentation and tracking for preimplantation mouse embryos.

For investigations into fate specification and morphogenesis in time-lapse images of preimplantation embryos, automated 3D instance segmentation and tracking of nuclei are invaluable. Low signal-to-noise ratio, high voxel anisotropy, high nuclear density, and variable nuclear shapes can limit the performance of segmentation methods, while tracking is complicated by cell divisions, low frame rates, and sample movements. Supervised machine learning approaches can radically improve segmentation accuracy and enable easier tracking, but they often require large amounts of annotated 3D data. Here we first report a novel mouse line expressing near-infrared nuclear reporter H2B-miRFP720. We then generate a dataset (termed BlastoSPIM) of 3D images of H2B-miRFP720-expressing embryos with ground truth for nuclear instances. Using BlastoSPIM, we benchmark seven convolutional neural networks and identify Stardist-3D as the most accurate instance segmentation method. With our BlastoSPIM-trained Stardist-3D models, we construct a complete pipeline for nuclear instance segmentation and lineage tracking from the 8-cell stage to the end of preimplantation development (>100 nuclei). Finally, we demonstrate BlastoSPIM's usefulness as pre-train data for related problems, both for a different imaging modality and for different model systems.

Pharmacogenomic insights in psychiatric care: uncovering novel actionability, allele-specific CYP2D6 copy number variation, and phenoconversion in 15,000 patients.

Pharmacogenomic testing has emerged as an aid in clinical decision making for psychiatric providers, but more data is needed regarding its utility in clinical practice and potential impact on patient care. In this cross-sectional study, we determined the real-world prevalence of pharmacogenomic actionability in patients receiving psychiatric care. Potential actionability was based on the prevalence of CYP2C19 and CYP2D6 phenotypes, including CYP2D6 allele-specific copy number variations (CNVs). Combined actionability additionally incorporated CYP2D6 phenoconversion and the novel CYP2C-TG haplotype in patients with available medication data. Across 15,000 patients receiving clinical pharmacogenomic testing, 65% had potentially actionable CYP2D6 and CYP2C19 phenotypes, and phenotype assignment was impacted by CYP2D6 allele-specific CNVs in 2% of all patients. Of 4114 patients with medication data, 42% had CYP2D6 phenoconversion from drug interactions and 20% carried a novel CYP2C haplotype potentially altering actionability. A total of 87% had some form of potential actionability from genetic findings and/or phenoconversion. Genetic variation detected via next-generation sequencing led to phenotype reassignment in 22% of individuals overall (2% in CYP2D6 and 20% in CYP2C19). Ultimately, pharmacogenomic testing using next-generation sequencing identified potential actionability in most patients receiving psychiatric care. Early pharmacogenomic testing may provide actionable insights to aid clinicians in drug prescribing to optimize psychiatric care.

Comparative effectiveness of perioperative physical activity in older adults with lung cancer and their family caregivers: design of a multicenter pragmatic randomized trial.

BACKGROUND: With a median age at diagnosis of 70, lung cancer remains a significant public health challenge for older Americans. Surgery is a key component in treating most patients with non-metastatic lung cancer. These patients experience postoperative pain, fatigue, loss of respiratory capacity, and decreased physical function. Data on quality of life (QOL) in older adults undergoing lung cancer surgery is limited, and few interventions are designed to target the needs of older adults and their family caregivers (FCGs). The primary aim of this comparative effectiveness trial is to determine whether telephone-based physical activity coaching before and after surgery will be more beneficial than physical activity self-monitoring alone for older adults and their FCGs. METHODS: In this multicenter comparative effectiveness trial, 382 older adults (≥ 65 years) with lung cancer and their FCGs will be recruited before surgery and randomized to either telephone-based physical activity coaching or physical activity self-monitoring alone. Participants allocated to the telephone-based coaching comparator will receive five telephone sessions with coaches (1 pre and 4 post surgery), an intervention resource manual, and a wristband pedometer. Participants in the self-monitoring only arm will receive American Society of Clinical Oncology (ASCO) physical activity information and wristband pedometers. All participants will be assessed at before surgery (baseline), at discharge, and at days 30, 60, and 180 post-discharge. The primary endpoint is the 6-minute walk test (6MWT) at 30 days post-discharge. Geriatric assessment, lower extremity function, self-reported physical function, self-efficacy, and QOL will also be assessed. DISCUSSION: The trial will determine whether this telephone-based physical activity coaching approach can enhance postoperative functional capacity and QOL outcomes for older adults with lung cancer and their FCGs. Trial results will provide critical findings to inform models of postoperative care for older adults with cancer and their FCGs. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06196008.

Once-daily oral small-molecule glucagon-like peptide-1 receptor agonist lotiglipron (PF-07081532) for type 2 diabetes and obesity: Two randomized, placebo-controlled, multiple-ascending-dose Phase 1 studies.

AIM: To investigate the effects of lotiglipron (PF-07081532), a once-daily, oral small-molecule glucagon-like peptide-1 receptor agonist, in participants with type 2 diabetes (T2D) and/or obesity. MATERIALS AND METHODS: Two Phase 1 randomized, double-blind, placebo-controlled, multiple-ascending-dose studies were conducted to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of lotiglipron. RESULTS: Across the studies, 74 participants with T2D were treated for 28 or 42 days, and 26 participants with obesity without diabetes were treated for 42 days, following randomization to placebo or lotiglipron (target doses 10-180 mg/day, with dose titration to higher target doses). Most adverse events were mild (89.6%), with nausea the most frequently reported in both studies. There were no clinically meaningful adverse trends noted in safety laboratory tests, vital signs, or electrocardiogram parameters. In participants with T2D, lotiglipron resulted in dose-dependent reductions in mean daily glucose. The 180-mg dose was associated with least squares mean decreases from baseline in glycated haemoglobin (-1.61% [90% confidence interval {CI} -2.08, -1.14] vs. -0.61% [-1.56, 0.34] for placebo) and body weight (-5.10 kg [90% CI -6.62, -3.58] vs. -2.06 kg [90% CI -4.47, 0.36] for placebo) after 42 days; a similar magnitude of weight loss was seen in participants with obesity. The observed pharmacokinetic profile supported once-daily dosing. CONCLUSIONS: The profile of once-daily lotiglipron with doses up to 180 mg, as observed in these two Phase 1 studies, indicated a safety and tolerability profile consistent with the mechanism of action, with dose-dependent reductions in glycaemic indices (T2D) and body weight (both populations) after multiple doses. CLINICALTRIALS: gov identifier: NCT04305587, NCT05158244.

Influence of egg density on larval development and adult body size of cat fleas (Ctenocephalides felis).

Fleas (Siphonaptera) are holometabolous insects with larval and adult stages that exhibit vastly different ecologies from each other. Adult fleas are parasitic and feed exclusively on the blood of a vertebrate host, whereas flea larvae do not live on hosts and consume dried faecal blood from adult fleas. Because flea larvae rely on adult flea faeces for food, excrement and eggs must fall in the same location; thus, larval density is likely high in these restricted habitats. However, the influence of larval density on the subsequent adult stage has not been examined. In the present study, we utilized egg density to investigate density-dependent effects on larval development and adult body size in the cat flea (Ctenocephalides felis Bouché) (Siphonaptera: Pulicidae). Specifically, eggs were collected to create three different larval densities (n = 50, 100 and 150 per 56.7 cm2), and hatched larvae from all groups were fed an excess amount of adult faecal pellets. Larval development was measured by recording the proportion of eggs that developed to the pupal stage and the proportion of eggs that reached adulthood (eclosion). The body size of eclosed adults was quantified for both sexes using head length and length of the total body. We found that the number of eggs had no effect on the proportion of larvae that pupated or the proportion of larvae that eclosed; however, higher egg densities resulted in larger body sizes for both sexes. Overall, these data yield significant insight into how the ecology of larval fleas impacts the biology of the resultant adults.

Prospective cohort study of rotational thromboelastometry in established biliary obstruction: dispelling the myth of auto-anticoagulation.

BACKGROUND: Patients with obstructive jaundice are conventionally described as hypocoagulable due to vitamin K malabsorption. However, associated underlying malignancy and synthetic liver dysfunction are mediators of hypercoagulability. The actual effect of biliary obstruction on the coagulation profile is not well characterised. This study aimed to define the coagulation status of patients with established biliary obstruction using rotational thromboelastometry (ROTEM). METHODS: This prospective cohort study, conducted in an Australian metropolitan hospital, included patients with a total bilirubin level of >150 umol/L and biliary obstruction on imaging. The primary outcome was the coagulation profile assessed using ROTEM. RESULTS: 20 patients were included (median age 74.5 years), 15 were male and 17 had a malignant cause for biliary obstruction. The median bilirubin level was 209 umol/L (IQR: 175.0 umol/L - 255.8 umol/L). On ROTEM, all patients had normal or reduced clot formation times, and normal or increased maximum clot firmness. This confirmed all patients had a normal or hypercoagulable clotting profile, and none were auto-anticoagulated. Vitamin K administration before ROTEM did not vary the coagulation profile. DISCUSSION: Patients with established biliary obstruction and jaundice, predominantly due to malignancy, were normo or hypercoagulable. The belief that obstructive jaundice is associated with a hypocoagulable state should be questioned.

Depression and Anxiety in Long-Term Care Residents During the COVID-19 Pandemic: The Influence of Telehealth Availability, Cognitive Status, and Trauma History.

OBJECTIVES: The present study investigates the impact of disrupted mental health services during the COVID-19 pandemic on depression and anxiety symptoms in long-term care (LTC) residents. METHODS: The study examined clinical data from 5,645 residents who received at least two psychological services in a long-term care (LTC) or assisted living (AL) setting between March 2019 and March 2021. A series of multiple regressions were run to explore the effects of the COVID-19 shutdown on depression and anxiety symptoms while examining the effects of COVID-19-related facility closure and facility telehealth capabilities. Follow-up regression analyses explored the impact of cognitive impairment and positive trauma history on depression and anxiety symptoms. RESULTS: Post-COVID levels of anxiety and depression were higher for residents with higher levels of pre-COVID anxiety and depression. The interaction between facility closure and availability of telehealth services and trauma history predicted self-report anxiety symptoms. Clinician-observed anxiety symptoms were predicted by cognitive impairment. Residents with a history of trauma had an increase in self-reported anxiety symptoms. CONCLUSIONS: Telehealth appeared to mitigate anxiety during the pandemic for residents with higher pre-COVID anxiety. CLINICAL IMPLICATIONS: For those individuals with severe anxiety, results suggest the importance of ensuring that mental health services are available to mitigate symptoms via telehealth when infection control disrupts the usual delivery of treatment.

Associations of humor, morale, and unit cohesion on posttraumatic stress disorder symptoms.

Military personnel experience many stressors during deployments that can lead to symptoms of posttraumatic stress disorder (PTSD). However, not all military personnel who are exposed to deployment stressors develop PTSD symptoms. Recent research has explored factors that contribute to military personnel resilience, a multifaceted and multidetermined construct, as a means to mitigate and prevent PTSD symptoms. Much of this research has focused on the effects of individual-level factors (e.g., use of coping strategies like humor, the morale of individual unit members), with some research focusing on unit-level factors (e.g., the cohesiveness of a unit). However, there is little research exploring how these factors relate to each other in mitigating or reducing PTSD symptoms. In this study, we examined the association between deployment stressors, perceived unit cohesion, morale, humor, and PTSD symptoms in a sample of 20,901 active-duty military personnel using structural equation modeling. Results indicated that perceived unit cohesion, humor, and morale were positively associated with each other and negatively associated with PTSD symptoms over and above the effect of deployment stressors. These findings highlight the influence of resilience factors on PTSD symptoms beyond their substantial overlap and have implications for future research as well as the potential development of interventions for military personnel.

Brentuximab vedotin in combination with nivolumab in relapsed or refractory Hodgkin lymphoma: 3-year study results.

This phase 1-2 study evaluated brentuximab vedotin (BV) combined with nivolumab (Nivo) as first salvage therapy in patients with relapsed/refractory (r/r) classical Hodgkin lymphoma (cHL). In parts 1 and 2, patients received staggered dosing of BV and Nivo in cycle 1, followed by same-day dosing in cycles 2 to 4. In part 3, both study drugs were dosed, same day, for all 4 cycles. At end of study treatment, patients could undergo autologous stem cell transplantation (ASCT) per investigator discretion. The objective response rate (ORR; N = 91) was 85%, with 67% achieving a complete response (CR). At a median follow-up of 34.3 months, the estimated progression-free survival (PFS) rate at 3 years was 77% (95% confidence interval [CI], 65% to 86%) and 91% (95% CI, 79% to 96%) for patients undergoing ASCT directly after study treatment. Overall survival at 3 years was 93% (95% CI, 85% to 97%). The most common adverse events (AEs) prior to ASCT were nausea (52%) and infusion-related reactions (43%), all grade 1 or 2. A total of 16 patients (18%) had immune-related AEs that required systemic corticosteroid treatment. Peripheral blood immune signatures were consistent with an activated T-cell response. Median gene expression of CD30 in tumors was higher in patients who responded compared with those who did not. Longer-term follow-up of BV and Nivo as a first salvage regimen shows durable efficacy and impressive PFS, especially in patients who proceeded directly to transplant, without additional toxicity concerns. This trial was registered at www.clinicaltrials.gov as #NCT02572167.

The emergence, implementation, and future growth of pharmacogenomics in psychiatry: a narrative review.

Psychotropic medication efficacy and tolerability are critical treatment issues faced by individuals with psychiatric disorders and their healthcare providers. For some people, it can take months to years of a trial-and-error process to identify a medication with the ideal efficacy and tolerability profile. Current strategies (e.g. clinical practice guidelines, treatment algorithms) for addressing this issue can be useful at the population level, but often fall short at the individual level. This is, in part, attributed to interindividual variation in genes that are involved in pharmacokinetic (i.e. absorption, distribution, metabolism, elimination) and pharmacodynamic (e.g. receptors, signaling pathways) processes that in large part, determine whether a medication will be efficacious or tolerable. A precision prescribing strategy know as pharmacogenomics (PGx) assesses these genomic variations, and uses it to inform selection and dosing of certain psychotropic medications. In this review, we describe the path that led to the emergence of PGx in psychiatry, the current evidence base and implementation status of PGx in the psychiatric clinic, and finally, the future growth potential of precision psychiatry via the convergence of the PGx-guided strategy with emerging technologies and approaches (i.e. pharmacoepigenomics, pharmacomicrobiomics, pharmacotranscriptomics, pharmacoproteomics, pharmacometabolomics) to personalize treatment of psychiatric disorders.

Racial Health Disparities Research in Cardiothoracic Surgery Under-represented in Major Meetings.

INTRODUCTION: Black/African Americans and Latinos face significant health disparities and systemic inequities. Heart and lung disease are leading factors affecting morbidity and mortality in these groups. Given this disparity, we sought to determine how often this topic is presented at the most relevant United States annual cardiothoracic surgery meetings. METHODS: Specialty-specific annual meeting abstract books were queried between 2015 and 2021. We included the Society of Thoracic Surgeons, American Association for Thoracic Surgery, Western Thoracic Surgical Association, and the Southern Thoracic Surgical Association. Scientific abstract titles and content were searched for the following keywords and phrases: "racial health disparities," "race," "racism," "racial bias," "institutional racism," and "health disparities". If an abstract included a keyword or phrase, it was counted as a racial health disparity abstract. We calculated the proportion of racial health disparity abstracts and abstracts published as manuscripts in the meeting-associated journals. RESULTS: A total of 3664 abstracts were presented between 2015 and 2021. Of those, 0.90% (33/3664) abstracts presented contained at least one of the keywords or phrases. Of these abstracts, the percentage that went on to publication represented 0.38% (14/3664) of the total number of abstracts presented. CONCLUSIONS: Abstracts on racial health disparities in cardiothoracic surgery represent a very small fraction of total meeting peer-reviewed content. There is a significant gap in research to identify and develop best practice strategies to address these disparities and mitigate structural racism within the care of underserved patients with cardiothoracic diseases.

Challenges and opportunities faced by nurse scientists in integrating data and technology in research to promote health equity.

Advances in technologies including omics, apps, imaging, sensors, and big data are increasingly being integrated into research by nurse scientists, but the impact on improving health equity is still unclear. In this article, nursing research faculty from one institution discuss challenges and opportunities experienced when integrating various technologies into their research aimed at promoting health equity. Using exemplars from faculty experiences, a three-pronged approach to keeping patients and communities and the goal of health equity central in research while incorporating advancing technologies is described. This approach includes establishing long-term engagement with populations underrepresented in research, adopting strategies to increase diversity in study participant recruitment, and training and collaboration among a diverse workforce of educators, clinicians, and researchers. Training nurse scientists in integrating data and technology for advancing the science on health equity will shift the culture of how we understand, collaborate, and grow with the communities in which we train and practice as nurse scientists.

Restrictive Practices and the 'Need' for Positive Behaviour Support (PBS): A Critical Discourse Examination of Disability Policy Beliefs.

BACKGROUND: Few studies have considered policies which underpin the promotion of positive behaviour support (PBS). The present study examined policy beliefs about PBS and their relationship to restrictive practices. METHODS: Discourse network analysis (a combination of critical discourse analysis and social network analysis) was used. RESULTS: A total of 11 policies were examined from which 38 belief statements were coded. One cluster was identified which promoted 13 dominant beliefs. Dominant discourses related to law, safety and the environment were evident. A conceptual representation of the shared PBS beliefs demonstrated contradictions in PBS policy. CONCLUSIONS: There is evidence that PBS policies have become informal rules for using restrictive practices, not reducing them. They are also acting as surrogates to debate conflicts between political, personal and bureaucratic interests. Three recommendations for improved PBS policy are provided.

Addressing isolation, loneliness and mental health during COVID: A university training partnership with senior living communities.

Older adults living in congregate housing have been uniquely impacted by the COVID-19 pandemic. The sudden interruption of routine activities, social isolation, and support adversely affected the wellbeing of residents in retirement facilities around the country and world. The stress of social isolation was fueled by the interruption of routine activities and support that in turn, adversely affected the wellbeing, mood, and cognition of many residents. Therefore, university clinical programs in psychology and counseling can address the needs of community older residents by preparing student clinicians to work with the aging population and to engage in telehealth models of outreach and interventions. This manuscript outlines a model of partnership between long-term care assisted living organizations and clinical training programs at a west coast university to meet community and educational needs of older residents.

Genome-wide Significance Thresholds for Admixture Mapping Studies.

Admixture mapping studies have become more common in recent years, due in part to technological advances and growing international efforts to increase the diversity of genetic studies. However, many open questions remain about appropriate implementation of admixture mapping studies, including how best to control for multiple testing, particularly in the presence of population structure. In this study, we develop a theoretical framework to characterize the correlation of local ancestry and admixture mapping test statistics in admixed populations with contributions from any number of ancestral populations and arbitrary population structure. Based on this framework, we develop an analytical approach for obtaining genome-wide significance thresholds for admixture mapping studies. We validate our approach via analysis of simulated traits with real genotype data for 8,064 unrelated African American and 3,425 Hispanic/Latina women from the Women's Health Initiative SNP Health Association Resource (WHI SHARe). In an application to these WHI SHARe data, our approach yields genome-wide significant p value thresholds of 2.1 × 10-5 and 4.5 × 10-6 for admixture mapping studies in the African American and Hispanic/Latina cohorts, respectively. Compared to other commonly used multiple testing correction procedures, our method is fast, easy to implement (using our publicly available R package), and controls the family-wise error rate even in structured populations. Importantly, we note that the appropriate admixture mapping significance threshold depends on the number of ancestral populations, generations since admixture, and population structure of the sample; as a result, significance thresholds are not, in general, transferable across studies.

Can the Risk Analysis Index for Frailty Predict Morbidity and Mortality in Patients Undergoing High-risk Surgery?

OBJECTIVE: To determine the effectiveness of the revised Risk Analysis Index (RAI-rev), administrative Risk Analysis Index (RAI-A), cancer-corrected Risk Analysis Index [RAI-rev (cancer-corrected)], and 5-variable modified Frailty Index for predicting 30-day morbidity and mortality in patients undergoing high-risk surgery. BACKGROUND: There are several frailty composite measures, but none have been evaluated for predicting morbidity and mortality in patients undergoing high-risk surgery. METHODS: Using the National Surgical Quality Improvement Program database, we performed a retrospective study of patients who underwentcolectomy/proctectomy, coronary artery bypass graft (CABG), pancreaticoduodenectomy, lung resection, or esophagectomy from 2006 to 2017. RAI-rev, RAI-A, RAI-rev (cancer corrected), and 5-variable modified Frailty Index scores were calculated. Pearson's chi-square tests and C-statistics were used to assess the predictive accuracy of each score's logistic regression model. RESULTS: In the cohort of 283,545 patients, there were 178,311 (63%) colectomy/proctectomy, 38,167 (14%) pancreaticoduodenectomy, 40,328 (14%) lung resection, 16,127 (6%) CABG, and 10,602 (3%) esophagectomy cases. The RAI-rev was a fair predictor of mortality in the total cohort (C-statistic, 0.71, 95% CI 0.70-0.71, P < 0.001) and for patients who underwent colectomy/proctectomy (C-statistic 0.73, 95% CI 0.72-0.74, P < 0.001) and CABG (C-statistic 0.70, 95% CI 0.68-0.73, P < 0.001), but a poor predictor of mortality in all other operation cohorts. The RAI-A was a fair predictor of mortality for colectomy/proctectomy patients (C-statistic 0.74, 95% CI 0.73- 0.74, P < 0.001). All indices were poor predictors of morbidity. The RAI-rev (cancer corrected) did not improve the accuracy of morbidity and mortality prediction. CONCLUSION: The presently studied frailty indices are ineffective predictors of 30-day morbidity and mortality for patients undergoing high-risk operations.

Pharmacogenomics of Clozapine-induced agranulocytosis: a systematic review and meta-analysis.

Although clozapine is the most effective pharmacotherapy for treatment-resistant schizophrenia, it is under-utilized, and initiation is often delayed. One reason is the occurrence of a potentially fatal adverse reaction, clozapine-induced agranulocytosis (CIA). Identifying genetic variations contributing to CIA would help predict patient risk of developing CIA and personalize treatment. Here, we (1) review existing pharmacogenomic studies of CIA, and (2) conduct meta-analyses to identify targets for clinical implementation. A systematic literature search identified studies that included individuals receiving clozapine who developed CIA and controls who did not. Results showed that individuals carrying the HLA-DRB1*04:02 allele had nearly sixfold (95% CI 2.20-15.80, pcorrected = 0.03) higher odds of CIA with a negative predictive value of 99.3%. Previously unreplicated alleles, TNFb5, HLA-B*59:01, TNFb4, and TNFd3 showed significant associations with CIA after multiple-testing corrections. Our findings suggest that a predictive HLA-DRB1*04:02-based pharmacogenomic test may be promising for clinical implementation but requires further investigation.

NCCN Guidelines® Insights: Lung Cancer Screening, Version 1.2022.

The NCCN Guidelines for Lung Cancer Screening recommend criteria for selecting individuals for screening and provide recommendations for evaluation and follow-up of lung nodules found during initial and subsequent screening. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for Lung Cancer Screening.

BDNF Val66Met Moderates the Effects of Hypertension on Executive Functioning in Older Adults Diagnosed With aMCI.

OBJECTIVE: To investigate whether the BDNF Val66Met polymorphism influences the associations of hypertension, executive functioning and processing speed in older adults diagnosed with amnestic Mild Cognitive Impairment (aMCI). DESIGN: Secondary data analysis using moderation modeling. SETTING: Veterans Affairs Hospital, Palo Alto, CA. PARTICIPANTS: Sample included 108 community-dwelling volunteers (mean age 71.3 ± 9.2 years) diagnosed with aMCI. MEASUREMENTS: Cognitive performance was evaluated from multiple baseline assessments (Trail Making Test; Stroop Color-Word Test; Symbol Digit Modality Test) and grouped into standardized composite scores representing executive function and processing speed domains. BDNF genotypes were determined from whole blood samples. Hypertension was assessed from resting blood pressures or by self-report. RESULTS: Controlling for age, BDNF Val66Met moderated the effects of hypertension on executive functioning, but added no significant variance to processing speed scores. Specifically, hypertensive carriers of the BDNF Met allele performed significantly below the sample mean on tasks of executive functioning, and evidenced significantly lower scores when compared to Val-Val homozygotes and normotensive participants. CONCLUSIONS: Results posit that the executive functioning of non-demented older adults may be susceptible to interactions between BDNF genotype and hypertension, and Val-Val homozygotes and normotensive older adults may be more resilient to these effects of cognitive change. Further research is needed to understand the underlying processes and to implement strategies that target modifiable risk factors and promote cognitive resilience.