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Alzheimer's disease (AD) is the most common cause of dementia with advancing age as its strongest risk factor. AD neuropathologic change (ADNC) is known to be associated with numerous DNA methylation changes in the human brain, but the oldest old (> 90 years) have so far been underrepresented in epigenetic studies of ADNC. Our study participants were individuals aged over 90 years (n = 47) from The 90+ Study. We analyzed DNA methylation from bulk samples in eight precisely dissected regions of the human brain: middle frontal gyrus, cingulate gyrus, entorhinal cortex, dentate gyrus, CA1, substantia nigra, locus coeruleus and cerebellar cortex. We deconvolved our bulk data into cell-type-specific (CTS) signals using computational methods. CTS methylation differences were analyzed across different levels of ADNC. The highest amount of ADNC related methylation differences was found in the dentate gyrus, a region that has so far been underrepresented in large scale multi-omic studies. In neurons of the dentate gyrus, DNA methylation significantly differed with increased burden of amyloid beta (Aβ) plaques at 5897 promoter regions of protein-coding genes. Amongst these, higher Aβ plaque burden was associated with promoter hypomethylation of the Presenilin enhancer 2 (PEN-2) gene, one of the rate limiting genes in the formation of gamma-secretase, a multicomponent complex that is responsible in part for the endoproteolytic cleavage of amyloid precursor protein into Aβ peptides. In addition to novel ADNC related DNA methylation changes, we present the most detailed array-based methylation survey of the old aged human brain to date. Our open-sourced dataset can serve as a brain region reference panel for future studies and help advance research in aging and neurodegenerative diseases., (© 2022. The Author(s).)

Neurodegenerative disorders are characterized by phenotypic changes and hallmark proteopathies. Quantifying these in archival human brain tissues remains indispensable for validating animal models and understanding disease mechanisms. We present a framework for nanometer-scale, spatial proteomics with multiplex ion beam imaging (MIBI) for capturing neuropathological features. MIBI facilitated simultaneous, quantitative imaging of 36 proteins on archival human hippocampus from individuals spanning cognitively normal to dementia. Customized analysis strategies identified cell types and proteopathies in the hippocampus across stages of Alzheimer's disease (AD) neuropathologic change. We show microglia-pathologic tau interactions in hippocampal CA1 subfield in AD dementia. Data driven, sample independent creation of spatial proteomic regions identified persistent neurons in pathologic tau neighborhoods expressing mitochondrial protein MFN2, regardless of cognitive status, suggesting a survival advantage. Our study revealed unique insights from multiplexed imaging and data-driven approaches for neuropathologic analysis and serves broadly as a methodology for spatial proteomic analysis of archival human neuropathology. TEASER: Multiplex Ion beam Imaging enables deep spatial phenotyping of human neuropathology-associated cellular and disease features., (© 2022. The Author(s).)

Background: The laparoscopic view of extrahepatic biliary tract and cystic artery is different anatomically from open approach. Consequently iatrogenic injuries due to inadverent damage to cystic artery are not uncommon. These complications can be prevented by careful dissection in Calots triangle and better knowledge of laparoscopic anatomy of cystic artery and its variations. The aim of this study is to establish the prevalence of variation in position of cystic artery in relation to cystic duct. This will help identify the safe area for dissecting peritoneum in Calots triangle and thus help young surgeons overcome the long learning curve associated with laparoscopy., Materials and Methods: During a 10 year period from January 2009 to January 2019, 1850 laparoscopic cholecystectomies that were performed at a tertiary care hospital were studied. Patients with history of previous abdominal surgery were excluded from the study. Cystic artery was divided into four groups based on its relative position to cystic duct. It includes superomedial, superolateral, anterior and absent cystic artery relative to the cystic duct., Results: Out of 1850 cases of laparoscopic cholecystectomy 1676 (90.59%) patients had cystic artery superomedial to cystic duct and 96 (5.19%) had a cystic artery at superolateral position to cystic duct. In 48 (2.59%) patients it was found anterior to cystic duct and in 30 (1.62%) patients it was absent., Conclusions: It is concluded that the most common position of cystic artery is superomedial while the least common position was found to be anterior to cystic duct. Hence it is postulated that blind dissection from anterior side is the safest approach to avoid injury to cystic artery.

Background: The implementation of the Electronic Medical Record (EMR) system initiated a significant transition in the healthcare system from traditional paper-based medical records to a digital version. Though EMR offers several benefits compared to Paper Medical Records (PMR), patient satisfaction with the EMR has been an area of concern. The objective of this study is to explore patient satisfaction with the EMR compared to the PMR of patients attending five Primary Healthcare Centers in the Western Region of Saudi Arabia., Methods: A cross-sectional survey was conducted with patients who attended five Primary Health Care centers (PHCs) in the Western Region during 2018. A sample of 377 participants was invited to complete a self-developed structured questionnaire with multiple choice and Likert Scale questions. The questionnaire was distributed to participants in the PHC waiting areas., Results: The sample size realized as (n = 377) participants, the majority (65.0%) were female. The overall patient satisfaction was 3.708. Patient satisfaction with the EMR was statistically significant compared to the PMR (3.7241 vs. 3.6919, p < 0.001). Several factors provided evidence of the overall satisfaction with the implementation of the EMR, including an increase in physician attention during the clinical consultation (82.3%), increased explanation of tests and medication (85.8%), increased time spent with the patient during the consultation (80.4%) and increased active listening by the physician (77.3%). Besides, the patients felt confident to ask the physician question related to health during clinical consultation (84.0%)., Conclusion: Patient satisfaction during the clinical consultation and overall satisfaction with various PHC services improved with the implementation of EMR.

Background: mRNA polyadenylation is an essential step of pre-mRNA processing in eukaryotes. Accurate prediction of the pre-mRNA 3'-end cleavage/polyadenylation sites is important for defining the gene boundaries and understanding gene expression mechanisms., Results: 28761 human mapped poly(A) sites have been classified into three classes containing different known forms of polyadenylation signal (PAS) or none of them (PAS-strong, PAS-weak and PAS-less, respectively) and a new computer program POLYAR for the prediction of poly(A) sites of each class was developed. In comparison with polya&#95;svm (till date the most accurate computer program for prediction of poly(A) sites) while searching for PAS-strong poly(A) sites in human sequences, POLYAR had a significantly higher prediction sensitivity (80.8% versus 65.7%) and specificity (66.4% versus 51.7%) However, when a similar sort of search was conducted for PAS-weak and PAS-less poly(A) sites, both programs had a very low prediction accuracy, which indicates that our knowledge about factors involved in the determination of the poly(A) sites is not sufficient to identify such polyadenylation regions., Conclusions: We present a new classification of polyadenylation sites into three classes and a novel computer program POLYAR for prediction of poly(A) sites/regions of each of the class. In tests, POLYAR shows high accuracy of prediction of the PAS-strong poly(A) sites, though this program's efficiency in searching for PAS-weak and PAS-less poly(A) sites is not very high but is comparable to other available programs. These findings suggest that additional characteristics of such poly(A) sites remain to be elucidated. POLYAR program with a stand-alone version for downloading is available at http://cub.comsats.edu.pk/polyapredict.htm.