Methionine Sulfoxide Speciation in Mouse Hippocampus Revealed by Global Proteomics Exhibits Age- and Alzheimer's Disease-Dependent Changes Targeted to Mitochondrial and Glycolytic Pathways.

Methionine oxidation to the sulfoxide form (MSox) is a poorly understood post-translational modification of proteins associated with non-specific chemical oxidation from reactive oxygen species (ROS), whose chemistries are linked to various disease pathologies, including neurodegeneration. Emerging evidence shows MSox site occupancy is, in some cases, under enzymatic regulatory control, mediating cellular signaling, including phosphorylation and/or calcium signaling, and raising questions as to the speciation and functional nature of MSox across the proteome. The 5XFAD lineage of the C57BL/6 mouse has well-defined Alzheimer's and aging states. Using this model, we analyzed age-, sex-, and disease-dependent MSox speciation in the mouse hippocampus. In addition, we explored the chemical stability and statistical variance of oxidized peptide signals to understand the needed power for MSox-based proteome studies. Our results identify mitochondrial and glycolytic pathway targets with increases in MSox with age as well as neuroinflammatory targets accumulating MSox with AD in proteome studies of the mouse hippocampus. Further, this paper establishes a foundation for reproducible and rigorous experimental MSox-omics appropriate for novel target identification in biological discovery and for biomarker analysis in ROS and other oxidation-linked diseases.

Posterior fixation of gastric tube with fibrin sealant in laparoscopic sleeve gastrectomy: a promising method to prevent revision surgeries.

BACKGROUND: We aim to assess the effects of gastric posterior fixation with fibrin sealant in laparoscopic sleeve gastrectomy in aspects of 12th-month body mass index and gastric volume. METHODS: The patients who underwent laparoscopic sleeve gastrectomy between January 2019 and February 2021 were divided into two groups preoperatively. The first 75 patients were appointed to the posterior fixation group, and the second 75 were to the control group. Changes in gastric volume and body mass index were assessed in the postoperative 12th month. RESULTS: There were 110 patients in the final analysis. Fifty-four patients had posterior fixation, and 56 had only laparoscopic sleeve gastrectomy. The posterior fixation group was superior in terms of total weight loss rate (39.1% vs. 34.5%, p<0.001) and less gastric volume increase rate (39.8% vs. 164.7%, p<0.001) in the postoperative 12th month. CONCLUSION: Our study suggests that posterior fixation with fibrin sealant in laparoscopic sleeve gastrectomy is a promising method for preventing weight regain and creating a need for revision surgery.

Exploring Temporal and Sex-Linked Dysregulation in Alzheimer's Disease Phospho-Proteome.

This study aims to characterize dysregulation of phosphorylation for the 5XFAD mouse model of Alzheimer's disease (AD). Employing global phosphoproteome measurements, we analyze temporal (3, 6, 9 months) and sex-dependent effects on mouse hippocampus tissue to unveil molecular signatures associated with AD initiation and progression. Our results indicate 1.9 to 4.4 times higher phosphorylation prevalence compared to protein expression across all time points, with approximately 4.5 times greater prevalence in females compared to males at 3 and 9 months. Moreover, our findings reveal consistent phosphorylation of known AD biomarkers APOE and GFAP in 5XFAD mice, alongside novel candidates BIG3, CLCN6 and STX7, suggesting their potential as biomarkers for AD pathology. In addition, we identify PDK1 as a significantly dysregulated kinase at 9 months in females, and the regulation of gap junction activity as a key pathway associated with Alzheimer's disease across all time points. AD-Xplorer, the interactive browser of our dataset, enables exploration of AD-related changes in phosphorylation, protein expression, kinase activities, and pathways. AD-Xplorer aids in biomarker discovery and therapeutic target identification, emphasizing temporal and sex-specific nature of significant phosphoproteomic signatures. Available at: https://yilmazs.shinyapps.io/ADXplorer.

Analysis of factors related to the decision of Hartmann's procedure and its reversal: a single-center experience.

BACKGROUND: Hartmann's procedure (HP) is commonly applied to resolve acute clinical conditions in most cases with colonic obstruction or perforation. HP and the closure of the end colostomy are associated with high morbidity-mortality rates. In our study, we aimed to report our clinical experience in HP. METHODS: Demographic data and outcomes of Hartmann procedures performed between 2015 and 2023 were retrospectively reviewed. RESULTS: The median age of our study was 63 (18-94) years; 65 of the patients were female, and 97 were male. Colorectal malig-nancies were the primary etiology in 50% of patients who underwent HP, with 70% presenting with obstruction and 30% with perfora-tion. Two-thirds of the patients were American Society of Anesthesiologists-2 or higher. Postoperative complications did not develop in 74.7% of patients. Our mortality rate was 33.3%. The colostomy was closed in 59 patients during an average 2-year follow-up. The median closure time was 311 (57-1319) days. A stapler was used in 89.8% of patients during the closure. A diverting ileostomy was created in only two patients. The median hospital stay was 8 (5-70) days. Post-operative complications did not develop in 25.4% of patients, while four patients died. CONCLUSION: In our population, HP was more commonly performed for colorectal cancer. The procedure and closure of the ostomy result in low stoma closure rates, high morbidity, and mortality rates, as well as surgical difficulties.

Comprehensive Analysis of Electronic Health Records to Characterize The Association Between Intimate Partner Violence and Mental Health.

Intimate partner violence (IPV) involves physical, emotional, and sexual harm to the survivor. To characterize the relationship between mental health and IPV, we utilized electronic health records (EHR) data from IBM Explorys. Focusing on 15 mental health conditions and IPV, we queried cohorts of patients with these conditions to discover additional medical terms, including symptoms, findings, and diagnoses that are prevalent in these cohorts. We then systematically assessed the (i) direct association (co-occurrence, i.e., relative prevalence of a medical term in a cohort compared to the background population) and (ii) indirect association (the similarity between co-occurrence profiles) between all pairs of these mental health conditions. Our results showed that direct and indirect measures of association provide complementary insights into the relationship between pairs of conditions. Using this framework, we discovered several patterns of association among 16 different mental health related conditions.

Adverse health correlates of intimate partner violence against older women: Mining electronic health records.

Intimate partner violence (IPV) is often studied as a problem that predominantly affects younger women. However, studies show that older women are also frequently victims of abuse even though the physical effects of abuse are harder to detect. In this study, we mined the electronic health records (EHR) available through IBM Explorys to identify health correlates of IPV that are specific to older women. Our analyses suggested that diagnostic terms that are co-morbid with IPV in older women are dominated by substance abuse and associated toxicities. When we considered differential co-morbidity, i.e., terms that are significantly more associated with IPV in older women compared to younger women, we identified terms spanning mental health issues, musculoskeletal issues, neoplasms, and disorders of various organ systems including skin, ears, nose and throat. Our findings provide pointers for further investigation in understanding the health effects of IPV among older women, as well as potential markers that can be used for screening IPV.

Appendiceal neoplasms: Suspected findings and reports of 14 cases.

Background: Neoplastic lesions of the vermiform appendix are still considered to be rare, some studies suggest that appendix cancer may be on the rise, with an estimated incidence of 0.08-0.1% of all appendiceal specimens. The lifetime incidence of malignant appendiceal tumors ranges from 0.2 to 0.5%. Patients and Methods: Our study is applied at the Department of General Surgery at tertiary training and research hospital; 14 patients who had appendectomy or right hemicolectomy between December 2015 and April 2020 were evaluated. Results: The mean age of the patients was 52.3 ± 15.1 (range, 26-79) years. Gender of the patients were: five (35.7%) men and nine (64.3%) women. The clinical diagnosis was appendicitis without suspected findings in 11 (78.6%), appendicitis with suspected findings (appendiceal mass, etc.) in three (21.4%) of the patients, and there is no patient with asymptomatic or other rare findings. Surgeries applied for the patients were: nine (64.3%) underwent open appendectomy, four (28.6%) underwent laparoscopic appendectomy, and one (7.1%) underwent open right hemicolectomy. Histopathologic results were as follows: five (35.7%) neuroendocrine neoplasm, eight (57.1%), noninvasive mucinous neoplasm, and one (7.1%) adenocarcinoma. Conclusion: While diagnosis and management of appendiceal pathology, surgeons should be familiar with suspected findings of appendiceal tumors and discuss them with patients to the possibility of histopathologic results.

Prediction of Kinase-Substrate Associations Using The Functional Landscape of Kinases and Phosphorylation Sites.

Protein phosphorylation is a key post-translational modification that plays a central role in many cellular processes. With recent advances in biotechnology, thousands of phosphorylated sites can be identified and quantified in a given sample, enabling proteome-wide screening of cellular signaling. However, for most (> 90%) of the phosphorylation sites that are identified in these experiments, the kinase(s) that target these sites are unknown. To broadly utilize available structural, functional, evolutionary, and contextual information in predicting kinase-substrate associations (KSAs), we develop a network-based machine learning framework. Our framework integrates a multitude of data sources to characterize the landscape of functional relationships and associations among phosphosites and kinases. To construct a phosphosite-phosphosite association network, we use sequence similarity, shared biological pathways, co-evolution, co-occurrence, and co-phosphorylation of phosphosites across different biological states. To construct a kinase-kinase association network, we integrate protein-protein interactions, shared biological pathways, and membership in common kinase families. We use node embeddings computed from these heterogeneous networks to train machine learning models for predicting kinase-substrate associations. Our systematic computational experiments using the PhosphositePLUS database shows that the resulting algorithm, NetKSA, outperforms two state-of-the-art algorithms, including KinomeXplorer and LinkPhinder, in overall KSA prediction. By stratifying the ranking of kinases, NetKSA also enables annotation of phosphosites that are targeted by relatively less-studied kinases.Availability: The code and data are available at compbio.case.edu/NetKSA/.

Barriers to Coronavirus Disease 19 vaccination in patients with obesity.

BACKGROUND: Patients with obesity are at a high risk of severe disease and death from Coronavirus Disease 2019 (COVID-19). Vaccination offers a safe and effective means of reducing this risk. The rate of COVID-19 vaccine refusal in patients with obesity is unknown. METHODS: Patients with obesity were administered validated questionnaires assessing COVID-19 fear, general vaccine hesitancy, and COVID-19-specific vaccine hesitancy. RESULTS: 507 participants completed the study. COVID-19 vaccine hesitancy was high: Fifteen percent of patients refused COVID-19 vaccine. Hesitancy related to other vaccines was also high: Eight percent of patients refused a vaccine in the past, and 15% delayed a vaccine. Fear of side effects and doubts regarding effectiveness were the most common reasons for vaccine refusal. CONCLUSIONS: Despite high risk for complications, vaccine hesitancy is high among patients with obesity. Targeted public health interventions are critical to reduce vaccine hesitancy and improve vaccination rates.

Extrahepatic Biliary Tract Variations is an Effect for Acute Calculous Cholecystitis.

OBJECTIVE: To evaluate the anatomy of the extrahepatic bile duct and to reveal its importance in the formation of acute calculous cholecystitis (ACC). STUDY DESIGN: Case-control study. PLACE AND DURATION OF STUDY: Department of General Surgery and Radiology, Kanuni Sultan Suleyman Training and Research Hospital of the University of Health Sciences, Turkey, between January 2016 and December 2021. METHODOLOGY: The data of the patients treated with ACC were analysed on MRCP by an experienced radiologist. The patients were divided into two groups; asymptomatic gallstones (AsGS, control group) and ACC. The cystic duct, common hepatic duct, and common bile duct lengths and variations in cystic duct opening were measured. Receiver operating characteristics (ROC) analysis was conducted to define a cut-off value and compared categorical results of the two groups by Mann-Whitney U test. RESULTS: One-hundred and seventy-three patients were analysed, one-hundred and seven were females, and 66 were males. The median age was 46 years in the AsGS group and 53 years in the ACC group. It was statistically significant that ACC had a higher median age value than AsGS (p=0.014). In the analysis of extrahepatic variations, cystic duct, common hepatic duct, and common bile duct length, were statistically longer in the calculous cholecystitis group (p<0.001, p=0.022, and p=0.019 respectively). ROC analysis was performed for cystic, common hepatic, and common bile duct length, respectively. Cut-off values ​​were 30.5 mm, 36.5 mm, and 42.5 mm. CONCLUSION: Extrahepatic bile duct variations are of critical importance in ACC surgery. In the data, as the cystic duct and common bile duct lengthens, the possibility of ACC increases. There is need for studies with larger samples. KEY WORDS: Acute calculous cholecystitis, Extrahepatic biliary tract, Anatomical variations, Cholelithiasis.

Insidious Onset of Localised Small Intestinal Perforation by Ingested Plastic Fork.

Ingestion of a foreign body is generally observed in the psychiatric patients and children. Healthy adult individuals may also swallow a foreign body unintentionally. Here, we report a case of a patient who swallowed a plastic fork and treated with laparoscopic repair. A 46-year man was admitted to the emergency room with the abdominal pain. His physical evaluation and diagnostic imaging revealed free air in the abdomen. Further imaging with CT scan showed a foreign body in the proximal ileum. On taking details of his swallowing history, he remembered swallowing a broken part of a plastic fork unwittingly during dinner. Following the removal of the foreign body, the perforation area was primarily repaired in double layers. The postoperative course was uneventful. An accurate diagnosis of the small intestinal perforation caused by the ingested foreign bodies, particularly in cases where the patient is unaware of the ingestion, can be difficult. CT scan is a useful tool when available to establish the diagnosis before the surgical intervention. Key Words: Small intestine, Perforation, Foreign body, Laparoscopic surgery.

Functional characterization of co-phosphorylation networks.

MOTIVATION: Protein phosphorylation is a ubiquitous regulatory mechanism that plays a central role in cellular signaling. According to recent estimates, up to 70% of human proteins can be phosphorylated. Therefore, the characterization of phosphorylation dynamics is critical for understanding a broad range of biological and biochemical processes. Technologies based on mass spectrometry are rapidly advancing to meet the needs for high-throughput screening of phosphorylation. These technologies enable untargeted quantification of thousands of phosphorylation sites in a given sample. Many labs are already utilizing these technologies to comprehensively characterize signaling landscapes by examining perturbations with drugs and knockdown approaches, or by assessing diverse phenotypes in cancers, neuro-degerenational diseases, infectious diseases and normal development. RESULTS: We comprehensively investigate the concept of 'co-phosphorylation' (Co-P), defined as the correlated phosphorylation of a pair of phosphosites across various biological states. We integrate nine publicly available phosphoproteomics datasets for various diseases (including breast cancer, ovarian cancer and Alzheimer's disease) and utilize functional data related to sequence, evolutionary histories, kinase annotations and pathway annotations to investigate the functional relevance of Co-P. Our results across a broad range of studies consistently show that functionally associated sites tend to exhibit significant positive or negative Co-P. Specifically, we show that Co-P can be used to predict with high precision the sites that are on the same pathway or that are targeted by the same kinase. Overall, these results establish Co-P as a useful resource for analyzing phosphoproteins in a network context, which can help extend our knowledge on cellular signaling and its dysregulation. AVAILABILITY AND IMPLEMENTATION: github.com/msayati/Cophosphorylation. This research used the publicly available datasets published by other researchers as cited in the manuscript. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Partial cecum resection using endostapler in acute complicated appendicitis with appendiceal base necrosis.

INTRODUCTION: The method of stump closure is controversial in complicated patients, especially with appendix base necrosis or perforation. AIM: To evaluate the efficacy and safety of partial cecum resection technique with an endostapler in patients with appendix base necrosis or perforation. MATERIAL AND METHODS: Thirty-six patients who underwent laparoscopic partial cecum resection due to appendix base necrosis or perforation between 2015 and 2020 were retrospectively analyzed. In acute complicated appendicitis with appendiceal base necrosis or perforation, it was performed by laparoscopic partial cecum resection using an endostapler within a safe surgical margin. Demographic characteristics, duration of operation, days of hospital stay, and intra- and post-operative complications were evaluated. RESULTS: The mean age of the patients is 42.72 ±16.69, female/male ratio was 19/17 (52.8%/47.2%). No intraoperative complications developed. Mean operative time and hospital stay were 104.75 ±34.96, 4.58 ±2.82 days, respectively. Post-operative complications developed in 5 (13.7%) patients. One of them was wound infection (2.7%), 2 of them were ileus (5.5%) and 2 patients had an intraabdominal abscess (5.5%). Stapler line leak was not observed in any of the patients. CONCLUSIONS: The use of an endostapler in laparoscopic appendectomy is a safe and effective technique in cases where appendix base necrosis, appendix perforation or severe inflammation affects the base of the cecum.

Uncovering complementary sets of variants for predicting quantitative phenotypes.

MOTIVATION: Genome-wide association studies show that variants in individual genomic loci alone are not sufficient to explain the heritability of complex, quantitative phenotypes. Many computational methods have been developed to address this issue by considering subsets of loci that can collectively predict the phenotype. This problem can be considered a challenging instance of feature selection in which the number of dimensions (loci that are screened) is much larger than the number of samples. While currently available methods can achieve decent phenotype prediction performance, they either do not scale to large datasets or have parameters that require extensive tuning. RESULTS: We propose a fast and simple algorithm, Macarons, to select a small, complementary subset of variants by avoiding redundant pairs that are likely to be in linkage disequilibrium. Our method features two interpretable parameters that control the time/performance trade-off without requiring parameter tuning. In our computational experiments, we show that Macarons consistently achieves similar or better prediction performance than state-of-the-art selection methods while having a simpler premise and being at least two orders of magnitude faster. Overall, Macarons can seamlessly scale to the human genome with ∼107 variants in a matter of minutes while taking the dependencies between the variants into account. AVAILABILITYAND IMPLEMENTATION: Macarons is available in Matlab and Python at https://github.com/serhan-yilmaz/macarons. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Minimally Invasive Parathyroidectomy: Are Auxiliary Methods Necessary?

OBJECTIVE: To determine the success rate of minimally invasive parathyroidectomies (MIPs) with preoperative scintigraphy and ultrasonography, and to assess whether these imaging modalities are sufficient. STUDY DESIGN:  Observational study. PLACE AND DURATION OF STUDY:   Department of General Surgery, University of Health Sciences, Kanuni Sultan Süleyman Training and Research Hospital, Istanbul, Turkey between March 2017 and December 2019. METHODOLOGY: Medical records of 61 patients, who underwent MIP to treat primary hyperparathyroidism, were examined. Age, gender, and pre- and postoperative calcium, parathormone, and phosphorus levels were obtained from patient records. For all patients, the parathyroid (PT) glands were localised, using ultrasonography and Tc-99m methoxyisobutylisonitrile (MIBI) scintigraphy. RESULTS:  The average patient age was 56.89 ± 13.47 years. Of the patients, 83.6% (n = 51) were females. Localisation of the PT glands with preoperative scintigraphy had an accuracy rate of 100%. However, ultrasonographic localisation was unsuccessful in five patients. Adenomas were noted in 44 patients (72.1%), hyperplasia in 15 patients (24.6%), and neoplasia in two patients (3.3%). Serum parathormone and calcium levels were measured 24 hours after surgery, and were found to be significantly reduced compared to the corresponding preoperative levels (p <0.001). Hypocalcaemia developed in four patients (6.6%), two (3.3%) of which were symptomatic. After three months, persistent hyperparathyroidism developed in five patients (8.2%). CONCLUSION: Parathyroid scintigraphy has been demonstrated to be the gold standard for the preoperative localisation of PT glands. In the absence of scintigraphy, ultrasound guidance is the next useful technique for PT gland localisation. Key Words: Minimal invasive parathyroidectomy, Parathyroid scintigraphy, Ultrasonography, Parathormone.

Data-driven identification of subtypes of intimate partner violence.

Intimate partner violence (IPV) is a complex problem with multiple layers of heterogeneity. We took a data-driven approach to characterize this heterogeneity. We integrated data from different studies, representing 640 individuals from various backgrounds. We used hierarchical clustering to systematically group cases in terms of their similarities according to violence variables. Results suggested that the cases can be clustered into 12 hierarchically organized subgroups, with verbal abuse and negotiation being the main discriminatory factors at higher levels. The presence of physical assault, injury, and sexual coercion was discriminative at lower levels of the hierarchy. Subgroups also exhibited significant differences in terms of relationship dynamics and individual factors. This study represents an attempt toward using integrative data analysis to understand the etiology of violence. These results can be useful in informing treatment efforts. The integrative data analysis framework we develop can also be applied to various other problems.

Co-occurrence Patterns of Intimate Partner Violence.

Intimate partner violence (IPV) is an important social and public health problem, affecting millions of women worldwide. Violence in a relationship can occur in multiple ways, including physical violence, psychological aggression, and sexual violence. In this study, utilizing data from the National Intimate Partner and Sexual Violence Survey (NISVS), we comprehensively investigate the interplay between physical, psychological, and sexual violence, in terms of their co-occurrence patterns, their relation to trauma symptoms and overall health of victims. For this purpose, we perform network analysis and develop a visualization technique that enables in-depth navigation of the three-dimensional (physical, psychological, sexual) space of violence. Our findings show that physical violence tends to significantly co-occur with psychological abuse, and violence intensifies when both are present. We also find that sexual violence tends to overlap less with other types of violence, particularly with physical violence. Milder forms of psychological abuse are prominent in the population and seem to represent a separate type of abuse (micro-aggression) in terms of its occurrence patterns. Finally, we observe that trauma symptoms and health problems tend to be reported more by survivors at the presence of intense psychological aggression. Our findings can be useful in developing treatments that target different patterns of IPV.

Robust inference of kinase activity using functional networks.

Mass spectrometry enables high-throughput screening of phosphoproteins across a broad range of biological contexts. When complemented by computational algorithms, phospho-proteomic data allows the inference of kinase activity, facilitating the identification of dysregulated kinases in various diseases including cancer, Alzheimer's disease and Parkinson's disease. To enhance the reliability of kinase activity inference, we present a network-based framework, RoKAI, that integrates various sources of functional information to capture coordinated changes in signaling. Through computational experiments, we show that phosphorylation of sites in the functional neighborhood of a kinase are significantly predictive of its activity. The incorporation of this knowledge in RoKAI consistently enhances the accuracy of kinase activity inference methods while making them more robust to missing annotations and quantifications. This enables the identification of understudied kinases and will likely lead to the development of novel kinase inhibitors for targeted therapy of many diseases. RoKAI is available as web-based tool at http://rokai.io .

Is early anvil placement an alternative technique to reduce anastomotic leak after rectosigmoid cancer resection?

INTRODUCTION: Anastomotic leakage (AL) is one of the most disastrous complications after rectosigmoid cancer operations. The aim of this study is to investigate the effect of the insertion time of circular stapler anvil on assessing the blood supply of the proximal colon segment, and thus to evaluate the prevention of early anastomotic leaks. MATERIAL METHODS: A total of 57 patients were included in the study, 25 patients in group A and 32 patients in group B, respectively. From the beginning of the operation to the time of anvil placement in group A, it was 32.08 (± 7.34) minutes, and in group B it was 92.19 (± 16.63) minutes. None of the patients in group A had AL, and 4 patients in group B had AL. DISCUSSION: Our study shows that the anvil must be placed at the beginning of the dissection to evaluate the anomalies that cause anastomotic leaks. We think that this method increases the reliability of the anastomosis line. Thus, the hospitalization period of the patients was shortened and they returned to their active lives faster. In addition, patients used less antibiotics and they needed less medical treatment. KEY WORDS: Anastomotic leaks, Anvil, Rectosigmoid cancer placement, Stapler colorectal.

SPADIS: An Algorithm for Selecting Predictive and Diverse SNPs in GWAS.

Phenotypic heritability of complex traits and diseases is seldom explained by individual genetic variants identified in genome-wide association studies (GWAS). Many methods have been developed to select a subset of variant loci, which are associated with or predictive of the phenotype. Selecting connected SNPs on SNP-SNP networks have been proven successful in finding biologically interpretable and predictive SNPs. However, we argue that the connectedness constraint favors selecting redundant features that affect similar biological processes and therefore does not necessarily yield better predictive performance. In this paper, we propose a novel method called SPADIS that favors the selection of remotely located SNPs in order to account for their complementary effects in explaining a phenotype. SPADIS selects a diverse set of loci on a SNP-SNP network. This is achieved by maximizing a submodular set function with a greedy algorithm that ensures a constant factor approximation to the optimal solution. We compare SPADIS to the state-of-the-art method SConES, on a dataset of Arabidopsis Thaliana with continuous flowering time phenotypes. SPADIS has better average phenotype prediction performance in 15 out of 17 phenotypes when the same number of SNPs are selected and provides consistent improvements across multiple networks and settings on average. Moreover, it identifies more candidate genes and runs faster.