Contribution of vaccination to improved survival and health: modelling 50 years of the Expanded Programme on Immunization.

BACKGROUND: WHO, as requested by its member states, launched the Expanded Programme on Immunization (EPI) in 1974 to make life-saving vaccines available to all globally. To mark the 50-year anniversary of EPI, we sought to quantify the public health impact of vaccination globally since the programme's inception. METHODS: In this modelling study, we used a suite of mathematical and statistical models to estimate the global and regional public health impact of 50 years of vaccination against 14 pathogens in EPI. For the modelled pathogens, we considered coverage of all routine and supplementary vaccines delivered since 1974 and estimated the mortality and morbidity averted for each age cohort relative to a hypothetical scenario of no historical vaccination. We then used these modelled outcomes to estimate the contribution of vaccination to globally declining infant and child mortality rates over this period. FINDINGS: Since 1974, vaccination has averted 154 million deaths, including 146 million among children younger than 5 years of whom 101 million were infants younger than 1 year. For every death averted, 66 years of full health were gained on average, translating to 10·2 billion years of full health gained. We estimate that vaccination has accounted for 40% of the observed decline in global infant mortality, 52% in the African region. In 2024, a child younger than 10 years is 40% more likely to survive to their next birthday relative to a hypothetical scenario of no historical vaccination. Increased survival probability is observed even well into late adulthood. INTERPRETATION: Since 1974 substantial gains in childhood survival have occurred in every global region. We estimate that EPI has provided the single greatest contribution to improved infant survival over the past 50 years. In the context of strengthening primary health care, our results show that equitable universal access to immunisation remains crucial to sustain health gains and continue to save future lives from preventable infectious mortality. FUNDING: WHO.

MerCat2: a versatile k-mer counter and diversity estimator for database-independent property analysis obtained from omics data.

Motivation: MerCat2 ("Mer-Catenate2") is a versatile, parallel, scalable and modular property software package for robustly analyzing features in omics data. Using massively parallel sequencing raw reads, assembled contigs, and protein sequences from any platform as input, MerCat2 performs k-mer counting of any length k, resulting in feature abundance counts tables, quality control reports, protein feature metrics, and graphical representation (i.e. principal component analysis (PCA)). Results: MerCat2 allows for direct analysis of data properties in a database-independent manner that initializes all data, which other profilers and assembly-based methods cannot perform. MerCat2 represents an integrated tool to illuminate omics data within a sample for rapid cross-examination and comparisons. Availability and implementation: MerCat2 is written in Python and distributed under a BSD-3 license. The source code of MerCat2 is freely available at https://github.com/raw-lab/mercat2. MerCat2 is compatible with Python 3 on Mac OS X and Linux. MerCat2 can also be easily installed using bioconda: mamba create -n mercat2 -c conda-forge -c bioconda mercat2.

Vaccine coverage among children born to immigrant parents in Norway, 2000-2020.

BACKGROUND: The Norwegian Childhood Immunization Program maintains a high national coverage of 95-97% in the most recent years. Whether there are subgroups with lower uptake is less studied. This study examines pertussis and measles vaccination coverage among six immigrant groups in Norway. These vaccines are normally administered as part of different combination vaccines and their coverage rate indicate the national vaccination coverage against a range of additional infections. METHODS: Data from the Norwegian National Population Register were linked at individual level with vaccination data from the Norwegian Immunisation Registry. The final sample consisted of 53,052 children born during 2000-2018 in Norway to parents who were born in Iraq, Lithuania, Pakistan, Poland, Somalia, or Vietnam. Vaccination coverage was measured at 2-years of age. Multivariate linear regression was utilized to estimate the relationship between vaccinations status, year of birth, gender, mother's length of residency in Norway, and area of residence. RESULTS: At two years of age, the majority of the children were vaccinated. Coverage among the groups varied at, above, and below the national average for the two vaccines. For most of the years examined, children born by parents from Lithuania, Poland, and Somalia had lower coverage for the measles vaccine (range 81-84% in 2020) than the national level (97% in 2020). Children born by parents from the Eastern-European countries also had lower coverage than the national level for the pertussis vaccine (range 87-89% in 2020). DISCUSSION: This study illustrates how subgroups with lower vaccination coverage may exists within a well-established vaccination program with high national coverages. Differences in coverage were found for both vaccines, but the differences were more pronounced for the measles vaccine. The high vaccination coverage in Norway provides indirect protection through herd immunity for unvaccinated individuals, however, the lower vaccination coverage in some immigrant groups is a concern.

The lipid droplet protein DHRS3 is a regulator of melanoma cell state.

Lipid droplets are fat storage organelles composed of a protein envelope and lipid rich core. Regulation of this protein envelope underlies differential lipid droplet formation and function. In melanoma, lipid droplet formation has been linked to tumor progression and metastasis, but it is unknown whether lipid droplet proteins play a role. To address this, we performed proteomic analysis of the lipid droplet envelope in melanoma. We found that lipid droplet proteins were differentially enriched in distinct melanoma states; from melanocytic to undifferentiated. DHRS3, which converts all-trans-retinal to all-trans-retinol, is upregulated in the MITFLO/undifferentiated/neural crest-like melanoma cell state and reduced in the MITFHI/melanocytic state. Increased DHRS3 expression is sufficient to drive MITFHI/melanocytic cells to a more undifferentiated/invasive state. These changes are due to retinoic acid mediated regulation of melanocytic genes. Our data demonstrate that melanoma cell state can be regulated by expression of lipid droplet proteins which affect downstream retinoid signaling.

Estimating the Potential Public Health Value of BCG Revaccination.

An upcoming trial may provide further evidence that adolescent/adult-targeted BCG revaccination prevents sustained Mycobacterium tuberculosis infection, but its public health value depends on its impact on overall tuberculosis morbidity and mortality, which will remain unknown. Using previously calibrated models for India and South Africa, we simulated BCG revaccination assuming 45% prevention-of-infection efficacy, and we evaluated scenarios varying additional prevention-of-disease efficacy between +50% (reducing risk) and -50% (increasing risk). Given the assumed prevention-of-infection efficacy and range in prevention-of-disease efficacy, BCG revaccination may have a positive health impact and be cost-effective. This may be useful when considering future evaluations and implementation of adolescent/adult BCG revaccination.

The Full Value of Vaccine Assessments Concept-Current Opportunities and Recommendations.

For vaccine development and adoption decisions, the 'Full Value of Vaccine Assessment' (FVVA) framework has been proposed by the WHO to expand the range of evidence available to support the prioritization of candidate vaccines for investment and eventual uptake by low- and middle-income countries. Recent applications of the FVVA framework have already shown benefits. Building on the success of these applications, we see important new opportunities to maximize the future utility of FVVAs to country and global stakeholders and provide a proof-of-concept for analyses in other areas of disease control and prevention. These opportunities include the following: (1) FVVA producers should aim to create evidence that explicitly meets the needs of multiple key FVVA consumers, (2) the WHO and other key stakeholders should develop standardized methodologies for FVVAs, as well as guidance for how different stakeholders can explicitly reflect their values within the FVVA framework, and (3) the WHO should convene experts to further develop and prioritize the research agenda for outcomes and benefits relevant to the FVVA and elucidate methodological approaches and opportunities for standardization not only for less well-established benefits, but also for any relevant research gaps. We encourage FVVA stakeholders to engage with these opportunities.

DeGenPrime provides robust primer design and optimization unlocking the biosphere.

Motivation: Polymerase chain reaction (PCR) is the world's most important molecular diagnostic with applications ranging from medicine to ecology. PCR can fail because of poor primer design. The nearest-neighbor thermodynamic properties, picking conserved regions, and filtration via penalty of oligonucleotides form the basis for good primer design. Results: DeGenPrime is a console-based high-quality PCR primer design tool that can utilize MSA formats and degenerate bases expanding the target range for a single primer set. Our software utilizes thermodynamic properties, filtration metrics, penalty scoring, and conserved region finding of any proposed primer. It has degeneracy, repeated k-mers, relative GC content, and temperature range filters. Minimal penalty scoring is included according to secondary structure self-dimerization metrics, GC clamping, tri- and tetra-loop hairpins, and internal repetition. We compared PrimerDesign-M, DegePrime, ConsensusPrimer, and DeGenPrime on acceptable primer yield. PrimerDesign-M, DegePrime, and ConsensusPrimer provided 0%, 11%, and 17% yield, respectively, for the alternative iron nitrogenase (anfD) gene target. DeGenPrime successfully identified quality primers within the conserved regions of the T4-like phage major capsid protein (g23), conserved regions of molybdenum-based nitrogenase (nif), and its alternatives vanadium (vnf) and iron (anf) nitrogenase. DeGenPrime provides a universal and scalable primer design tool for the entire tree of life. Availability and implementation: DeGenPrime is written in C++ and distributed under a BSD-3-Clause license. The source code for DeGenPrime is freely available on www.github.com/raw-lab/degenprime.

A zebrafish system for identifying genetic dependencies in melanocytes and melanoma.

The advent of large-scale sequencing in both development and disease has identified large numbers of candidate genes that may be linked to important phenotypes. Validating the function of these candidates in vivo is challenging, due to low efficiency and low throughput of most model systems. This is especially the case in skin cells such as melanocytes, where the background mutation rate is high. We have developed a rapid and scalable system for assessing the role of candidate genes in a melanocyte specific manner using zebrafish. We generated transgenic zebrafish in which Cas9 was knocked-in to the endogenous mitfa locus, a master transcription factor of the melanocyte lineage. By introducing single guide RNA expression cassettes into mitfaCas9 embryos, we were able to achieve highly efficient melanocyte-specific mutation of genes important for melanocyte patterning and survival. These animals can be used to screen for dominant or recessive pigment defects in both the F0 generation (3 days) and F1 generation (3 months). We also utilized the mitfaCas9 line to study the role of melanoma genetic dependencies such as SOX10, demonstrating that loss of SOX10 reduces melanoma initiation yet promotes tumor progression by a switch to a SOX9hi state. This SOX10 to SOX9 switch has previously been observed in human patients, indicating that our system can be used to rapidly uncover biological states with relevance to human disease. Our high efficiency genetic approach can be readily applied to other cell lineages, with relevance to both development and disease.

Quality assurance in surgical trials of arteriovenous grafts for haemodialysis: A systematic review, a narrative exploration and expert recommendations.

BACKGROUND: Introducing new procedures and challenging established paradigms requires well-designed randomised controlled trials (RCT). However, RCT in surgery present unique challenges with much of treatment tailored to the individual patient circumstances, refined by experience and limited by organisational factors. There has been considerable debate over the outcomes of arteriovenous grafts (AVG) compared to AVF, but any differences may reflect differing practice and potential variability. It is essential, therefore, when considering an RCT of a novel surgical procedure or device that quality assurance (QA) is defined for both the new approach and the comparator. The aim of this systematic review was to evaluate the QA standards performed in RCT of AVG using a multi-national, multi-disciplinary approach and propose an approach for future RCT. METHOD: The methods of this have been previously registered (PROSPERO: CRD420234284280) and published. In summary, a four-stage review was performed: identification of RCT of AVG, initial review, multidisciplinary appraisal of QA methods and reconciliation. QA measures were sought in four areas - generic, credentialing, standardisation and monitoring, with data abstracted by a multi-national, multi-speciality review body. RESULTS: QA in RCT involving AVG in all four domains is highly variable, often sub-optimally described and has not improved over the past three decades. Few RCT established or defined a pre-RCT level of experience, none documented a pre-trial education programme, or had minimal standards of peri-operative management, no study had a defined pre-trial monitoring programme, and none assessed technical performance. CONCLUSION: QA in RCT is a relatively new area that is expanding to ensure evidence is reliable and reproducible. This review demonstrates that QA has not previously been detailed, but can be measured in surgical RCT of vascular access, and that a four-domain approach can easily be implemented into future RCT.

Assessment of Postmastectomy Radiation Therapy Receipt by Age and Association With Outcomes in Women With Breast Cancer.

PURPOSE: Postmastectomy radiation therapy (PMRT) reduces locoregional recurrence (LRR) and improves overall survival (OS) in patients with breast cancer. Young age has been recognized as a risk factor for LRR. The primary objective of this study was to determine if recommendations for PMRT differed among patients younger than 50 years as compared to women aged 50 years or older. METHODS: We reviewed medical records of patients with breast cancer who underwent mastectomy with or without PMRT from 2010 through 2018. Univariable and multivariable models were used to estimate the association of age with PMRT. RESULTS: Of 2471 patients, 839 (34%) were <50 years; 1632 (66%) were ≥50 years. Patients <50 years had a higher percentage of grade 3 tumors, hormone receptor (HR) negative and/or Her-2/neu positive tumors, clinical stage T2/T3 tumors, and nodal involvement. Compared with patients ≥50 years, patients <50 years were more likely to undergo PMRT (OR 1.57; P = .001) and regional node irradiation (RNI) to the internal mammary nodes. Advanced clinical and pathologic stage, invasive tumor histology, the presence of lymphovascular invasion, and treatment with systemic chemotherapy were predictors of PMRT receipt for patients <50 years (P < .05). PMRT was associated with improved OS and recurrence free survival (RFS) among all patients (P < .01). CONCLUSION: Patients <50 years were more likely to undergo PMRT and to receive RNI to the internal mammary nodes but were also more likely to have other risk factors for recurrence that would warrant a PMRT recommendation. PMRT improved OS and RFS for all patients.

Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy.

In digenic inheritance, pathogenic variants in two genes must be inherited together to cause disease. Only very few examples of digenic inheritance have been described in the neuromuscular disease field. Here we show that predicted deleterious variants in SRPK3, encoding the X-linked serine/argenine protein kinase 3, lead to a progressive early onset skeletal muscle myopathy only when in combination with heterozygous variants in the TTN gene. The co-occurrence of predicted deleterious SRPK3/TTN variants was not seen among 76,702 healthy male individuals, and statistical modeling strongly supported digenic inheritance as the best-fitting model. Furthermore, double-mutant zebrafish (srpk3-/-; ttn.1+/-) replicated the myopathic phenotype and showed myofibrillar disorganization. Transcriptome data suggest that the interaction of srpk3 and ttn.1 in zebrafish occurs at a post-transcriptional level. We propose that digenic inheritance of deleterious changes impacting both the protein kinase SRPK3 and the giant muscle protein titin causes a skeletal myopathy and might serve as a model for other genetic diseases.

DNA damage remodels the MITF interactome to increase melanoma genomic instability.

Since genome instability can drive cancer initiation and progression, cells have evolved highly effective and ubiquitous DNA damage response (DDR) programs. However, some cells (for example, in skin) are normally exposed to high levels of DNA-damaging agents. Whether such high-risk cells possess lineage-specific mechanisms that tailor DNA repair to the tissue remains largely unknown. Using melanoma as a model, we show here that the microphthalmia-associated transcription factor MITF, a lineage addition oncogene that coordinates many aspects of melanocyte and melanoma biology, plays a nontranscriptional role in shaping the DDR. On exposure to DNA-damaging agents, MITF is phosphorylated at S325, and its interactome is dramatically remodeled; most transcription cofactors dissociate, and instead MITF interacts with the MRE11-RAD50-NBS1 (MRN) complex. Consequently, cells with high MITF levels accumulate stalled replication forks and display defects in homologous recombination-mediated repair associated with impaired MRN recruitment to DNA damage. In agreement with this, high MITF levels are associated with increased single-nucleotide and copy number variant burdens in melanoma. Significantly, the SUMOylation-defective MITF-E318K melanoma predisposition mutation recapitulates the effects of DNA-PKcs-phosphorylated MITF. Our data suggest that a nontranscriptional function of a lineage-restricted transcription factor contributes to a tissue-specialized modulation of the DDR that can impact cancer initiation.

Modelling the health and economic impacts ofM72/AS01E vaccination and BCG-revaccination: Estimates for South Africa.

BACKGROUND: Tuberculosis remains a major public health problem in South Africa, with an estimated 300,000 cases and 55,000 deaths in 2021. New tuberculosis vaccines could play an important role in reducing this burden. Phase IIb trials have suggested efficacy of the M72/AS01E vaccine candidate and BCG-revaccination. The potential population impact of these vaccines is unknown. METHODS: We used an age-stratified transmission model of tuberculosis, calibrated to epidemiological data from South Africa, to estimate the potential health and economic impact of M72/AS01E vaccination and BCG-revaccination. We simulated M72/AS01E vaccination scenarios over the period 2030-2050 and BCG-revaccination scenarios over the period 2025-2050. We explored a range of product characteristics and delivery strategies. We calculated reductions in tuberculosis cases and deaths and costs and cost-effectiveness from health-system and societal perspectives. FINDINGS: M72/AS01E vaccination may have a larger impact than BCG-revaccination, averting approximately 80% more cases and deaths by 2050. Both vaccines were found to be cost-effective or cost saving (compared to no new vaccine) across a range of vaccine characteristics and delivery strategies from both the health system and societal perspective. The impact of M72/AS01E is dependent on the assumed efficacy of the vaccine in uninfected individuals. Extending BCG-revaccination to HIV-infected individuals on ART increased health impact by approximately 15%, but increased health system costs by approximately 70%. INTERPRETATION: Our results show that M72/AS01E vaccination or BCG-revaccination could be cost-effective in South Africa. However, there is considerable uncertainty in the estimated impact and costs due to uncertainty in vaccine characteristics and the choice of delivery strategy. FUNDING: This work was funded by the Bill & Melinda Gates Foundation (INV-001754). This work used the Cirrus UK National Tier-2 HPC Service at EPCC (https://www.cirrus.ac.uk) funded by the University of Edinburgh and EPSRC (EP/P020267/1).

Young Age as a Predictor of Chemotherapy Recommendation and Treatment in Breast Cancer: A National Cancer Database Study.

INTRODUCTION: Breast cancer, although the second most common malignancy in women in the United States, is rare in patients under the age of 40 y. However, this young patient population has high recurrence and mortality rates, with chemotherapy frequently used as adjuvant treatment. We aimed to determine whether age is an independent predictor of chemotherapy recommendation and subsequent treatment and the relationship to Oncotype Dx (ODX) recurrence score (RS). METHODS: The National Cancer Database was retrospectively reviewed from 2010-2016 to identify women with early-stage (pT1-pT3, pN0-pN1mic, M0), hormone receptor positive, human epidermal growth factor receptor 2 negative breast cancer who underwent ODX RS testing. RESULTS: Of 95,382 patients who met the inclusion criteria, risk groups using the traditional ODX RS cutoffs were 59% low, 33% intermediate, and 8% high. Using Trial Assigning Individualized Options for Treatment RS cutoffs, risk groups were 23% low, 62% intermediate, and 15% high. Chemotherapy recommendation decreased as age at diagnosis increased (P < 0.001). Increasing age was associated with decreased odds of chemotherapy recommendation in univariate models both continuously (odds ratio: 0.98, 95% confidence interval 0.97-0.98; P < 0.001) and categorically by decade (P < 0.001). Age by decade remained an independent prognosticator of chemotherapy recommendation (P < 0.001), adjusted for risk groups. CONCLUSIONS: Chemotherapy recommendation and treatment differs by age among patients with early-stage hormone receptor positive breast cancer who undergo ODX testing. While molecular profiling has been shown to accurately predict the benefit of chemotherapy, younger age at diagnosis is a risk factor for discordant use of ODX RS for treatment strategies in breast cancer; with patients aged 18-39 disproportionately affected.

Using an expanded algorithm to estimate prevalence of amyotrophic lateral sclerosis in U.S. and UK.

BACKGROUND: There is an increasing need to better understand the burden of amyotrophic lateral sclerosis (ALS) using real-world data (RWD). However, identifying ALS cases using RWD presents several challenges due to the rarity of ALS and the differences in database coding systems. METHODS: MarketScan claims, and the UK Clinical Practice Research Datalink (CPRD) databases were searched for diagnosis codes of ALS or MND, the only drugs approved for treating ALS (riluzole and edaravone) and clinical visits with 12-month enrolment prior to 1 January 2011. The main algorithm required ≥ 1 ALS diagnosis code together with prescriptions or clinical visits. We expanded the existing algorithm to identify unspecific (possible) ALS group that had codes for motor neuron disease (MND) and the ALS drugs. The study period was from 1 January 2011 until 31 December 2020. RESULTS: We identified 16,246 patients with ≥ 1 ALS code in Marketscan (denominator n = 85,279,619), yet only 184 were found in the UK CPRD (denominator n = 21,318,589). Using the main algorithm 9,433 ALS patients were included in MarketScan, with a prevalence ranged between 4.5 per 100,000 in 2019 and 6.2 in 2015. In MarketScan, 3,658 (4.3 per 100,000) had ≥ 1 MND code and the ALS drug codes (possible cases). In CPRD, 47.9% of 2,785 patients with ≥ 1 MND code had a prescription for riluzole (6.3 per 100,000), regarded as possible ALS cases. CONCLUSIONS: The expanded algorithm enabled the identification of a large population with ALS, or possible ALS, and the estimation of ALS prevalence in MarketScan and CPRD.

Incidence and Time Course of Symptomatic Thromboembolic Outcomes After Lower Extremity Arthroscopic Surgery, Ankle Fracture Surgery, and Achilles Tendon Repair.

BACKGROUND: The incidence and time course of acute venous thromboembolism (VTE) after ambulatory surgery for lower extremity orthopaedic conditions is not well-defined. HYPOTHESIS: The purpose of this study was to analyze the incidence, the time course, and risk factors associated with clinically diagnosed acute deep vein thrombosis or pulmonary embolism within 3 months of surgery in patients undergoing specific operations for lower extremity injuries. METHODS: Patients undergoing arthroscopic procedures of the knee, ankle fracture surgery, Achilles tendon repair, and ankle arthroscopy from January 1, 2005, to December 31, 2010, were identified in the California Ambulatory Surgery database with linkage to hospital discharge data, emergency department data, and a death registry. Outcomes were acute VTE and death within 90 days. Time courses were compared using Kaplan-Meier analysis, and risk factors were analyzed using proportional hazard modeling. RESULTS: Analysis of data from 468,699 surgeries showed that the cumulative incidence of acute VTE was significantly higher after Achilles tendon repair (0.72%, P < 0.001) than ankle fracture surgery (0.33%), knee arthroscopy procedures (range, 0.29% to 0.41%), or ankle arthroscopy (0.24%). The time course of diagnosis of VTE was similar for all arthroscopic procedures (median postoperative day for diagnosis = 9 to 10; 80% by 22 to 36 days), whereas for Achilles tendon surgery, the time course was protracted (median postoperative day for diagnosis = 29 days; 80% by 51 days). Ninety-day mortality was low (<0.06%) after all procedures except ankle fracture (0.12%). Predictors of pulmonary embolism included age older than 60 years (HR, 3.1; 95% CI; 2.0 to 4.8, versus younger than 30 years), Achilles tendon repair (HR, 3.8; 95% CI; 2.8 to 5.3), and ankle fracture surgery (Hazard Ratio [HR], 2.1; 95% Confidence Interval [CI]; 1.5 to 2.8); Asian/Pacific Islander (HR, 0.3; 95% CI; 0.1 to 0.6) and Hispanic patients (HR, 0.5; 95% CI; 0.4 to 0.7) had significantly lower risk. DISCUSSION: The incidence and time course of onset of acute VTE after lower extremity orthopaedic surgeries varies significantly depending on the surgical procedure. These findings have implications regarding the use and duration of pharmacologic thromboprophylaxis.

Disparate Dementia Risk Factors Are Associated with Cognitive Impairment and Rates of Decline in African Americans.

OBJECTIVE: This study was undertaken to evaluate the frequency of modifiable dementia risk factors and their association with cognitive impairment and rate of decline in diverse participants engaged in studies of memory and aging. METHODS: Modifiable dementia risk factors and their associations with cognitive impairment and cognitive decline were determined in community-dwelling African American (AA; n = 261) and non-Hispanic White (nHW; n = 193) participants who completed ≥2 visits at the Mayo Clinic Alzheimer Disease Research Center in Jacksonville, Florida. Risk factors and their associations with cognitive impairment (global Clinical Dementia Rating [CDR] ≥ 0.5) and rates of decline (CDR Sum of Boxes) in impaired participants were compared in AA and nHW participants, controlling for demographics, APOE ɛ4 status, and Area Deprivation Index. RESULTS: Hypertension, hypercholesterolemia, obesity, and diabetes were overrepresented in AA participants, but were not associated with cognitive impairment. Depression was associated with increased odds of cognitive impairment in AA (odds ratio [OR] = 4.30, 95% confidence interval [CI] = 2.13-8.67) and nHW participants (OR = 2.79, 95% CI = 1.21-6.44) but uniquely associated with faster decline in AA participants (ß = 1.71, 95% CI = 0.69-2.73, p = 0.001). Fewer AA participants reported antidepressant use (9/49, 18%) than nHW counterparts (57/78, 73%, p < 0.001). Vitamin B12 deficiency was also associated with an increased rate of cognitive decline in AA participants (ß = 2.65, 95% CI = 0.38-4.91, p = 0.023). INTERPRETATION: Modifiable dementia risk factors are common in AA and nHW participants, representing important risk mitigation targets. Depression was associated with dementia in AA and nHW participants, and with accelerated declines in cognitive function in AA participants. Optimizing depression screening and treatment may improve cognitive trajectories and outcomes in AA participants. ANN NEUROL 2024;95:518-529.