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Risk factors for poor cognition among older adults in low‐ and middle‐income countries
(Wiley, 2025-12-23) Vella, Ashleigh S.; Lin, Keshuo; Lipnicki, Darren M.; Stephan, Blossom C. M.; Thalamuthu, Anbupalam; Llibre‐Rodriguez, Juan J.; Guerchet, Maelenn; Preux, Pierre‐Marie; Shahar, Suzana; Ding, Ding; Turana, Yuda; Costa, Erico; Xiao, Shifu; Walker, Richard; Paddick, Stella‐Maria; Hendrie, Hugh C.; Gao, Sujuan; Krishna, Murali; Scazufca, Marcia; D'Orsi, Eleonora; Guerra, Ricardo Oliveira; Gureje, Oye; Mubangizi, Vincent; Sachdev, Perminder S.; Jiang, Jiyang; Psychiatry, School of Medicine
Background:
Research into an effective dementia treatment is ongoing. Therefore, identifying individuals at risk of declining cognition and dementia is fundamental for initiating modifiable risk factor interventions that can delay dementia onset. Research into modifiable risk factors has almost exclusively been from high‐income countries, despite 60% of individuals with dementia living in low‐ and middle‐income countries (LMICs). Addressing this research inequality, the current study examines cross‐sectional relationships between risk factors and cognitive performance in LMICs, with the aim of identifying modifiable risk factors particularly suitable for interventions in these regions.
Method:
Data were obtained from 15 members of the Cohort Studies of Memory in an International Consortium (COSMIC), representing 11 countries (Brazil, China, Colombia, Cuba, India, Indonesia, Malaysia, Nigeria, Republic of Congo, Tanzania, & Uganda) across 6 continents (participants: 53,136; Mage = 70.75, SDage = 7.87; 57% female). We investigated (after harmonisation) the following risk factors: age, APOE ε4, anxiety, body mass index (BMI), blood pressure, cardiovascular disease, cholesterol, depression, diabetes, education, excessive alcohol, hypertension, hearing loss, physical activity, sex, smoking status, and stroke history. Harmonised global cognition was the outcome. On the AD Workbench, we performed linear regressions for each risk factor within each study at baseline. Cross‐sectional results from all studies were pooled in a multivariate meta‐analysis, with a random intercept for Country and study. We investigated age, sex and education as risk factors, and included them as covariates when analysing other factors.
Result:
Older age (β=‐.231, p < .001), being male (β=.151, p < .001), less education (β=1.569, p < .001), history of angina (β=‐.099, p < .001), anxiety (β=‐.262, p < .001), depression (β=‐.203, p < .001), stroke (β=‐.375, p < .001), diabetes (β=‐.060, p = .002), excessive alcohol consumption (β=‐.190, p < .001), currently smoking (β=‐.097, p < .001), and less physical activity (β=.160, p < .001) were significantly associated with worse global cognition. Heterogeneity in the relationship between risk factors and cognition exists across countries, warranting further analyses for each LMIC.
Conclusion:
Findings suggest that risk factor interventions may help to reduce dementia in LMICs, though country level heterogeneity in the effects suggests that tailoring interventions to regions will be needed. Future research will explore how the factors we identified predict incidence of dementia in LMICs using Machine Learning models.
Generation of CRISPR-Cas9 Engineered OPTNE478G Human Embryo Stem Cell Line for Investigation into Mitophagy Defects
(2025-07-25) Tebbe, Maverick; Kathri, Saajid; Surma, Michelle; Das, Arupratan
Background: Optineurin (OPTN) is a mitophagy adaptor protein linking damaged, ubiquitinated mitochondria to autophagosomes for lysosomal degradation. The E50K and E478G OPTN mutations are associated with normal tension glaucoma and ALS, respectively. Currently, it is unknown whether the E50K mutation selectively affects retinal ganglion cells and the E478G mutation selectively affects motor neurons. Given OPTN’s role in mitophagy, investigating the mitophagy defects in human stem cell-differentiated (hRGCs) and induced motor neurons (iMNs) harboring these mutations provides an avenue to explore the cellular mechanisms of these diseases.
Methods: This project generated a OPTN-E478G human embryonic stem cell (hESC) line through CRISPR-Cas9 gene editing. gRNA oligomers were annealed and cloned via transformation of DH5ɑ cells. Following sequencing, the gRNA-Cas9-GFP plasmid and donor plasmid with E478G insert were transfected into H7-WT-hESCs. The CRISPR-Cas9 system cut and repaired the double stranded break by homology-directed repair introducing the E478G mutation. GFP-positive colonies were isolated, expanded, and screened by PCR and restriction enzyme digestion. Western blot analysis of E50K and E478G mutants for hRGCs and iMNs were performed following introduction of the mitochondrial uncoupler CCCP, inducing mitophagy.
Results: Insertion of the gRNA into the Cas9-GFP plasmid was confirmed by sequencing. The hESCs were successfully transfected with the E478G plasmid as confirmed by restriction enzyme digestion of SapI and BspHI. Isolation of this stem cell population is ongoing and will be screened with restriction enzymes prior to sequencing. Western blots of NBR1 showed increased levels in WT-hRGCs and iMNs (E50K and E50K corrected), but not in E50K-hRGCs, indicating impaired mitophagy.
Conclusions: Our study reveals distinct mitophagy defects seen in the OPTN mutations E50K and E478G for the RGCs and iMNs. This project lays the groundwork for further studies, including live cell imaging, OPTN activation, and LC3b lipidation, to further define the implications of these mutations on mitophagy
Association Between Anxiety, Depression, and Opioid Use Disorder in Adult Surgical Patients: A Real-World Data Study
(2025-07-25) Bowman, Zachary; Cook, Nolan; Quach, Tommy; Jordan, Kevin; Roscoe, Michael
Background/Objective:
The opioid crisis remains a central issue in public health. Prior research has explored how postoperative opioid prescribing contributes to the development of opioid use disorder (OUD). Pre-existing psychiatric conditions may influence postoperative misuse of opioid medications, but existing research on this association is limited in scope and generalizability. This study aimed to evaluate whether a diagnosis of depression and/or anxiety is associated with increased odds of OUD among adult patients undergoing common opioid-prescribing surgical procedures.
Methods:
In this retrospective case-control study, we used de-identified Electronic Health Record data from the IU School of Medicine-Evansville RWEdataLab (CRC/Sidus Insights) Psychiatric database. Adult patients aged 18-70 who underwent a common opioid-prescribing surgical procedure were identified using CPT codes. Psychiatric and OUD diagnoses were identified using ICD-10 codes. Patients were grouped based on the presence or absence of an OUD diagnosis. Odds ratios were calculated to assess the association between OUD and prior diagnosis of anxiety, depression, or both.
Results:
Among 18,440 patients who underwent a qualifying surgery, 653 were diagnosed with OUD. Of these, 288 had depression, 280 had anxiety, and 223 had both diagnoses, indicating substantial overlap between conditions. Patients with depression (OR: 1.91; 95% CI: 1.63-2.23), anxiety (OR: 1.26; 95% CI: 1.08–1.48), and both conditions (OR: 3.84; 95% CI: 3.24–4.54) had significantly higher odds of OUD compared to surgical patients with other psychiatric diagnoses.
Conclusion and Clinical Implications:
These findings suggest that adult surgical patients with a history of anxiety and/or depression have increased odds of developing OUD. This underscores the clinical importance of individualized pain management and enhanced perioperative support for patients with psychiatric comorbidities. Future research should explore these associations in broader and more diverse populations and evaluate interventions that integrate mental health screening into preoperative planning.
Improved Breast Cancer Detection with Artificial Intelligence in a Real-World Digital Breast Tomosynthesis Screening Program
(Elsevier, 2025-12-01) Nepute, Joshua A; Peratikos, Meridith; Toledano, Alicia Y; Salvas, John P; Delks, Haley; Shisler, Julie L; Hoffmeister, Jeffrey W; Madden, Colleen M
OBJECTIVE: The purpose of this study is to compare radiologists' breast cancer screening performance before and after the implementation of an artificial intelligence (AI) detection system for digital breast tomosynthesis (DBT).
MATERIALS AND METHODS: This retrospective study included 4 radiologists reading DBT screening mammograms across 3 clinical sites during 2 distinct time periods. The pre-AI time period from September 1, 2018 to August 31, 2019 included 10,322 standard DBT interpretations with a computer-aided detection system. The post-AI from January 1 to March 18, 2020 and May 4 to December 31, 2020 included 6,407 DBT interpretations with concurrent use of a deep learning AI support system. Endpoints included cancer detection rate (CDR), abnormal interpretation rate (AIR), and positive predictive values for cancer among screenings with abnormal interpretation (PPV1) and biopsies performed (PPV3). Estimates and 95% confidence intervals (CIs) for each radiologist were calculated for each time point and the difference across time periods.
RESULTS: The CDR per 1000 exams increased from 3.7 without AI to 6.1 with AI (difference 2.4, P = .008, 95% CI: 0.6, 4.2). The AIR was 8.2% without AI and 6.5% with AI (difference -1.7, P < .001, 95% CI: -2.5, -0.8). The PPV1 increased from 4.2% to 8.8% with AI implementation (difference 4.6, P < .001, 95% CI: 3.0, 6.3) and PPV3 increased from 32.3% to 56.5% with AI support (difference 24.2, P = .033, 95% CI: 2.0, 46.4).
CONCLUSION: Real-world interpretation of DBT after implementation of an AI detection system resulted in increased CDR, reduced AIR, and significantly increased PPV1 and PPV3.
Cytotoxic CD8+ T cells recognize and kill Plasmodium vivax–infected reticulocytes
(Springer Nature, 2018-09-01) Junqueira, Caroline; Barbosa, Camila RR; Costa, Pedro AC; Teixeira-Carvalho, Andréa; Castro, Guilherme; Sen Santara, Sumit; Barbosa, Rafael P; Dotiwala, Farokh; Pereira, Dhelio B; Antonelli, Lis R; Lieberman, Judy; Gazzinelli, Ricardo T
Plasmodium vivax causes approximately 100 million clinical malaria cases yearly1,2. The basis of protective immunity is poorly understood and thought to be mediated by antibodies3,4. Cytotoxic CD8+ T cells protect against other intracellular parasites by detecting parasite peptides presented by human leukocyte antigen class I on host cells. Cytotoxic CD8+ T cells kill parasite-infected mammalian cells and intracellular parasites by releasing their cytotoxic granules5,6. Perforin delivers the antimicrobial peptide granulysin and death-inducing granzymes into the host cell, and granulysin then delivers granzymes into the parasite. Cytotoxic CD8+ T cells were thought to have no role against Plasmodium spp. blood stages because red blood cells generally do not express human leukocyte antigen class I7. However, P. vivax infects reticulocytes that retain the protein translation machinery. Here we show that P. vivax–infected reticulocytes express human leukocyte antigen class I. Infected patient circulating CD8+ T cells highly express cytotoxic proteins and recognize and form immunological synapses with P. vivax–infected reticulocytes in a human leukocyte antigen–dependent manner, releasing their cytotoxic granules to kill both host cell and intracellular parasite, preventing reinvasion. P. vivax–infected reticulocytes and parasite killing is perforin independent, but depends on granulysin, which generally efficiently forms pores only in microbial membranes8. We find that P. vivax depletes cholesterol from the P. vivax–infected reticulocyte cell membrane, rendering it granulysin-susceptible. This unexpected T cell defense might be mobilized to improve P. vivax vaccine efficacy.