Browsing by Subject "Diseases"
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Item Adverse events following administration of COVID-19 vaccines in Saudi Arabia(Springer Nature, 2022-11-15) Alqahtani, Saleh; Jokhdar, Hani; Al‑Tawfiq, Jaffar A.; Al‑Otaibi, Salah; Assiri, Abdullah; Almudarra, Sami; Alabdulkareem, Khaled; Haji, Alhan; Medicine, School of MedicinePrevious studies investigated the frequency of different adverse events of COVID-19 vaccines. However, this study compares these adverse events between the two main COVID-19 vaccines used in Saudi Arabia (Pfizer-BioNTech and Oxford-AstraZeneca) using telemedicine technology. A cross-sectional study was conducted among 958 individuals, 7 days after receiving either Pfizer-BioNTech or Oxford-AstraZeneca vaccines during June 2021. Immediate adverse events were reported by 1.04% and 2.09% for Pfizer-BioNTech and Oxford-AstraZeneca vaccines, respectively, with no serious events. Recipients of Pfizer-BioNTech vaccine had a higher percentage of local adverse events (24.8% versus 9.8% in AstraZeneca vaccine). The most common reported systemic adverse events in both vaccines respectively were general fatigue (23.1% and 25.1%), fever (18.5% and 27.2%), myalgia (20.6% and 20.3%), and headache (15.2% and 17.2%). No significant difference was recorded between both vaccines regarding overall systemic adverse events; however, they were more frequent following the first dose of AstraZeneca vaccine compared to Pfizer-BioNTech vaccine, while the reverse was observed for the second dose. Adverse events were more frequent in females and younger age groups for both vaccines. Most of systemic and local adverse events were mild in nature. Further cohort studies are recommended to investigate the long-term adverse events of COVID-19 vaccines.Item APOE genotype-specific methylation patterns are linked to Alzheimer disease pathology and estrogen response(Springer Nature, 2024-02-29) Panitch, Rebecca; Sahelijo, Nathan; Hu, Junming; Nho, Kwangsik; Bennett, David A.; Lunetta, Kathryn L.; Au, Rhoda; Stein, Thor D.; Farrer, Lindsay A.; Jun, Gyungah R.; Radiology and Imaging Sciences, School of MedicineThe joint effects of APOE genotype and DNA methylation on Alzheimer disease (AD) risk is relatively unknown. We conducted genome-wide methylation analyses using 2,021 samples in blood (91 AD cases, 329 mild cognitive impairment, 1,391 controls) and 697 samples in brain (417 AD cases, 280 controls). We identified differentially methylated levels in AD compared to controls in an APOE genotype-specific manner at 25 cytosine-phosphate-guanine (CpG) sites in brain and 36 CpG sites in blood. Additionally, we identified seven CpG sites in the APOE region containing TOMM40, APOE, and APOC1 genes with P < 5 × 10-8 between APOE ε4 carriers and non-carriers in brain or blood. In brain, the most significant CpG site hypomethylated in ε4 carriers compared to non-carriers was from the TOMM40 in the total sample, while most of the evidence was derived from AD cases. However, the CpG site was not significantly modulating expression of these three genes in brain. Three CpG sites from the APOE were hypermethylated in APOE ε4 carriers in brain or blood compared in ε4 non-carriers and nominally significant with APOE expression in brain. Three CpG sites from the APOC1 were hypermethylated in blood, which one of the 3 CpG sites significantly lowered APOC1 expression in blood using all subjects or ε4 non-carriers. Co-methylation network analysis in blood and brain detected eight methylation networks associated with AD and APOE ε4 status. Five of the eight networks included genes containing network CpGs that were significantly enriched for estradiol perturbation, where four of the five networks were enriched for the estrogen response pathway. Our findings provide further evidence of the role of APOE genotype on methylation levels associated with AD, especially linked to estrogen response pathway.Item Author Correction: A pyramidal deep learning pipeline for kidney whole-slide histology images classification(Springer Nature, 2021-11-02) Abdeltawab, Hisham; Khalifa, Fahmi; Ghazal, Mohammed; Cheng, Liang; Gondim, Dibson; El‑Baz, Ayman; Pathology and Laboratory Medicine, School of MedicineThis corrects the article "A pyramidal deep learning pipeline for kidney whole-slide histology images classification" in volume 11, 20189.Item Cilia-associated wound repair mediated by IFT88 in retinal pigment epithelium(Springer Nature, 2023-05-21) Ning, Ke; Bhuckory, Mohajeet B.; Lo, Chien‑Hui; Sendayen, Brent E.; Kowal, Tia J.; Chen, Ming; Bansal, Ruchi; Chang, Kun‑Che; Vollrath, Douglas; Berbari, Nicolas F.; Mahajan, Vinit B.; Hu, Yang; Sun, Yang; Biology, School of SciencePrimary cilia are conserved organelles that integrate extracellular cues into intracellular signals and are critical for diverse processes, including cellular development and repair responses. Deficits in ciliary function cause multisystemic human diseases known as ciliopathies. In the eye, atrophy of the retinal pigment epithelium (RPE) is a common feature of many ciliopathies. However, the roles of RPE cilia in vivo remain poorly understood. In this study, we first found that mouse RPE cells only transiently form primary cilia. We then examined the RPE in the mouse model of Bardet-Biedl Syndrome 4 (BBS4), a ciliopathy associated with retinal degeneration in humans, and found that ciliation in BBS4 mutant RPE cells is disrupted early during development. Next, using a laser-induced injury model in vivo, we found that primary cilia in RPE reassemble in response to laser injury during RPE wound healing and then rapidly disassemble after the repair is completed. Finally, we demonstrated that RPE-specific depletion of primary cilia in a conditional mouse model of cilia loss promoted wound healing and enhanced cell proliferation. In summary, our data suggest that RPE cilia contribute to both retinal development and repair and provide insights into potential therapeutic targets for more common RPE degenerative diseases.Item Circulating HMGB1 is elevated in veterans with Gulf War Illness and triggers the persistent pro-inflammatory microglia phenotype in male C57Bl/6J mice(Springer Nature, 2021-07-12) Garza-Lombó, Carla; Thang, Morrent; Greve, Hendrik J.; Mumaw, Christen L.; Messenger, Evan J.; Ahmed, Chandrama; Quinn, Emily; Sullivan, Kimberly; Block, Michelle L.; Pharmacology and Toxicology, School of MedicineGulf War Illness (GWI) is a chronic, multi-symptom peripheral and CNS condition with persistent microglial dysregulation, but the mechanisms driving the continuous neuroimmune pathology are poorly understood. The alarmin HMGB1 is an autocrine and paracrine pro-inflammatory signal, but the role of circulating HMGB1 in persistent neuroinflammation and GWI remains largely unknown. Using the LPS model of the persistent microglial pro-inflammatory response, male C57Bl/6J mice injected with LPS (5 mg/kg IP) exhibited persistent changes in microglia morphology and elevated pro-inflammatory markers in the hippocampus, cortex, and midbrain 7 days after LPS injection, while the peripheral immune response had resolved. Ex vivo serum analysis revealed an augmented pro-inflammatory response to LPS when microglia cells were cultured with the 7-day LPS serum, indicating the presence of bioactive circulating factors that prime the microglial pro-inflammatory response. Elevated circulating HMGB1 levels were identified in the mouse serum 7 days after LPS administration and in the serum of veterans with GWI. Tail vein injection of rHMGB1 in male C57Bl/6 J mice elevated TNFα mRNA levels in the liver, hippocampus, and cortex, demonstrating HMGB1-induced peripheral and CNS effects. Microglia isolated at 7 days after LPS injection revealed a unique transcriptional profile of 17 genes when compared to the acute 3 H LPS response, 6 of which were also upregulated in the midbrain by rHMGB1, highlighting a distinct signature of the persistent pro-inflammatory microglia phenotype. These findings indicate that circulating HMGB1 is elevated in GWI, regulates the microglial neuroimmune response, and drives chronic neuroinflammation that persists long after the initial instigating peripheral stimulus.Item Cryo-EM structures of amyloid-β and tau filaments in Down syndrome(Springer Nature, 2024) Fernandez, Anllely; Hoq, Md Rejaul; Hallinan, Grace I.; Li, Daoyi; Bharath, Sakshibeedu R.; Vago, Frank S.; Zhang, Xiaoqi; Ozcan, Kadir A.; Newell, Kathy L.; Garringer, Holly J.; Jiang, Wen; Ghetti, Bernardino; Vidal, Ruben; Pathology and Laboratory Medicine, School of MedicineAdult individuals with Down syndrome (DS) develop Alzheimer disease (AD). Whether there is a difference between AD in DS and AD regarding the structure of amyloid-β (Aβ) and tau filaments is unknown. Here we report the structure of Aβ and tau filaments from two DS brains. We found two Aβ40 filaments (types IIIa and IIIb) that differ from those previously reported in sporadic AD and two types of Aβ42 filaments (I and II) identical to those found in sporadic and familial AD. Tau filaments (paired helical filaments and straight filaments) were identical to those in AD, supporting the notion of a common mechanism through which amyloids trigger aggregation of tau. This knowledge is important for understanding AD in DS and assessing whether adults with DS could be included in AD clinical trials.Item Delirium severity does not differ between medical and surgical intensive care units after adjusting for medication use(Springer Nature, 2022-08-24) Ortiz, Damaris; Lindroth, Heidi L.; Braly, Tyler; Perkins, Anthony J.; Mohanty, Sanjay; Meagher, Ashley D.; Khan, Sikandar H.; Boustani, Malaz A.; Khan, Babar A.; Surgery, School of MedicineSevere delirium is associated with an increased risk of mortality, institutionalization, and length of stay. Few studies have examined differences in delirium severity between different populations of critically ill patients. The objective of the study was to compare delirium severity and the presence of the four core features between adults in the surgical intensive care unit (SICU) and medical intensive care unit (MICU) while controlling for variables known to be associated with delirium. This is a secondary analysis of two parallel randomized multi-center trials conducted from March 2009 to January 2015 at 3 Indianapolis hospitals. A total of 474 adults with delirium were included in the analysis. Subjects were randomized in a 1:1 ratio in random blocks of 4 by a computer program. Patients were randomized to either haloperidol prescribing or de-prescribing regimen vs usual care. Delirium severity was assessed daily or twice-daily using the CAM-ICU-7 beginning after 24 h of ICU admission and until discharge from the hospital, death, or 30 days after enrollment. Secondary outcomes included hospital length of stay, hospital and 30-day mortality, and delirium-related adverse events. These outcomes were compared between SICU and MICU settings for this secondary analysis. Out of 474 patients, 237 were randomized to intervention. At study enrollment, the overall cohort had a mean age of 59 (SD 16) years old, was 54% female, 44% African-American, and 81% were mechanically ventilated upon enrollment. MICU participants were significantly older and severely ill with a higher premorbid cognitive and physical dysfunction burden. In univariate analysis, SICU participants had significantly higher mean total CAM-ICU-7 scores, corresponding to delirium severity, (4.15 (2.20) vs 3.60 (2.32), p = 0.02), and a lower mean RASS score (- 1.79 (1.28) vs - 1.53 (1.27), p < 0.001) compared to MICU participants. Following adjustment for benzodiazepines and opioids, delirium severity did not significantly differ between groups. The presence of Feature 3, altered level of consciousness, was significantly associated with the SICU participants, identifying as Black, premorbid functional impairment, benzodiazepines, opioids, and dexmedetomidine. In this secondary analysis examining differences in delirium severity between MICU and SICU participants, we did not identify a difference between participant populations following adjustment for administered benzodiazepines and opioids. We did identify that an altered level of consciousness, core feature 3 of delirium, was associated with SICU setting, identifying as Black, activities of daily living, benzodiazepines and opioid medications. These results suggest that sedation practice patterns play a bigger role in delirium severity than the underlying physiologic insult, and expression of core features of delirium may vary based on individual factors.Item Effects of donor-specific microvascular anatomy on hemodynamic perfusion in human choriocapillaris(Springer Nature, 2023-12-19) An, Senyou; Yu, Huidan; Islam, MD Mahfuzul; Zhang, Xiaoyu; Zhan, Yuting; Olivieri, Joseph J.; Ambati, Jayakrishna; Yao, Jun; Gelfand, Bradley D.; Mechanical and Energy Engineering, Purdue School of Engineering and TechnologyEvidence from histopathology and clinical imaging suggest that choroidal anatomy and hemodynamic perfusion are among the earliest changes in retinal diseases such as age-related macular degeneration (AMD). However, how inner choroidal anatomy affects hemodynamic perfusion is not well understood. Therefore, we sought to understand the influences of choroidal microvascular architecture on the spatial distribution of hemodynamic parameters in choriocapillaris from human donor eyes using image-based computational hemodynamic (ICH) simulations. We subjected image-based inner choroid reconstructions from eight human donor eyes to ICH simulation using a kinetic-based volumetric lattice Boltzmann method to compute hemodynamic distributions of velocity, pressure, and endothelial shear stress. Here, we demonstrate that anatomic parameters, including arteriolar and venular arrangements and intercapillary pillar density and distribution exert profound influences on inner choroidal hemodynamic characteristics. Reductions in capillary, arteriolar, and venular density not only reduce the overall blood velocity within choriocapillaris, but also substantially increase its spatial heterogeneity. These first-ever findings improve understanding of how choroidal anatomy affects hemodynamics and may contribute to pathogenesis of retinal diseases such as AMD.Item Field trials reveal the complexities of deploying and evaluating the impacts of yeast-baited ovitraps on Aedes mosquito densities in Trinidad, West Indie(Springer Nature, 2022-03-08) James, Lester D.; Winter, Nikhella; Stewart, Akilah T. M.; Feng, Rachel Shui; Nandram, Naresh; Mohammed, Azad; Duman‑Scheel, Molly; Romero‑Severson, Ethan; Severson, David W.; Medical and Molecular Genetics, School of MedicineThe use of lure-and-kill, large-volume ovitraps to control Aedes aegypti and Aedes albopictus populations has shown promise across multiple designs that target gravid females (adulticidal) or larvae post-oviposition (larvicidal). Here we report on a pilot trial to deploy 10 L yeast-baited ovitraps at select sites in Curepe, Trinidad, West Indies during July to December, 2019. Oviposition rates among ovitraps placed in three Treatment sites were compared to a limited number of traps placed in three Control areas (no Aedes management performed), and three Vector areas (subjected to standard Ministry of Health, Insect Vector Control efforts). Our goal was to gain baseline information on efforts to saturate the Treatment sites with ovitraps within 20-25 m of each other and compare oviposition rates at these sites with background oviposition rates in Control and Vector Areas. Although yeast-baited ovitraps were highly attractive to gravid Aedes females, a primary limitation encountered within the Treatment sites was the inability to gain access to residential compounds for trap placement, primarily due to residents being absent during the day. This severely limited our intent to saturate these areas with ovitraps, indicating that future studies must include plans to account for these inaccessible zones during trap placement.Item Genetically-predicted placental gene expression is associated with birthweight and adult body mass index(Springer Nature, 2023-01-06) Jasper, Elizabeth A.; Hellwege, Jacklyn N.; Piekos, Jacqueline A.; Jones, Sarah H.; Hartmann, Katherine E.; Mautz, Brian; Aronoff, David M.; Edwards, Todd L.; Velez Edwards, Digna R.; Medicine, School of MedicineThe placenta is critical to human growth and development and has been implicated in health outcomes. Understanding the mechanisms through which the placenta influences perinatal and later-life outcomes requires further investigation. We evaluated the relationships between birthweight and adult body mass index (BMI) and genetically-predicted gene expression in human placenta. Birthweight genome-wide association summary statistics were obtained from the Early Growth Genetics Consortium (N = 298,142). Adult BMI summary statistics were obtained from the GIANT consortium (N = 681,275). We used S-PrediXcan to evaluate associations between the outcomes and predicted gene expression in placental tissue and, to identify genes where placental expression was exclusively associated with the outcomes, compared to 48 other tissues (GTEx v7). We identified 24 genes where predicted placental expression was significantly associated with birthweight, 15 of which were not associated with birthweight in any other tissue. One of these genes has been previously linked to birthweight. Analyses identified 182 genes where placental expression was associated with adult BMI, 110 were not associated with BMI in any other tissue. Eleven genes that had placental gene expression levels exclusively associated with BMI have been previously associated with BMI. Expression of a single gene, PAX4, was associated with both outcomes exclusively in the placenta. Inter-individual variation of gene expression in placental tissue may contribute to observed variation in birthweight and adult BMI, supporting developmental origins hypothesis.