Missing Values in Longitudinal Proteome Dynamics Studies: Making a Case for Data Multiple Imputation.

Temporal proteomics data sets are often confounded by the challenges of missing values. These missing data points, in a time-series context, can lead to fluctuations in measurements or the omission of critical events, thus hindering the ability to fully comprehend the underlying biomedical processes. We introduce a Data Multiple Imputation (DMI) pipeline designed to address this challenge in temporal data set turnover rate quantifications, enabling robust downstream analysis to gain novel discoveries. To demonstrate its utility and generalizability, we applied this pipeline to two use cases: a murine cardiac temporal proteomics data set and a human plasma temporal proteomics data set, both aimed at examining protein turnover rates. This DMI pipeline significantly enhanced the detection of protein turnover rate in both data sets, and furthermore, the imputed data sets captured new representation of proteins, leading to an augmented view of biological pathways, protein complex dynamics, as well as biomarker-disease associations. Importantly, DMI exhibited superior performance in benchmark data sets compared to single imputation methods (DSI). In summary, we have demonstrated that this DMI pipeline is effective at overcoming challenges introduced by missing values in temporal proteome dynamics studies.

Mango (Mangifera indica L.): a magnificent plant with cancer preventive and anticancer therapeutic potential.

Mangifera indica L. (mango), a long-living evergreen plant belonging to the Anacardiaceae family, has been cultivated for thousands of years in the Indian subcontinent for its excellent fruits which represent a rich source of fiber, vitamin A and C, essential amino acids, and a plethora of phytochemicals. M. indica is extensively used in various traditional systems of medicine to prevent and treat several diseases. The health-promoting and disease-preventing effects of M. indica are attributed to a number of bioactive phytochemicals, including polyphenols, terpenoids, carotenoid and phytosterols, found in the leaf, bark, edible flesh, peel, and seed. M. indica has been shown to exhibit various biological and pharmacological activities, such as antioxidant, anti-inflammatory, immunomodulatory, antimicrobial, antidiabetic, antiobesity, and anticancer effects. There are a few studies conducted that have indicated the nontoxic nature of mango constituents. However, while there are numerous individual studies investigating anticancer effects of various constituents from the mango tree, an up-to-date, comprehensive and critical review of available research data has not been performed according to our knowledge. The purpose of this review is to present a comprehensive and critical evaluation of cancer preventive and anticancer therapeutic potential of M. indica and its phytochemicals with special focus on the cellular and molecular mechanisms of action. The bioavailability, pharmacokinetics, and safety profile of individual phytocomponents of M. indica as well as current limitations, challenges, and future directions of research have also been discussed.

Patient's perspective and awareness of materials used in dentistry.

OBJECTIVE: To assess patients' knowledge and attitude towards different dental materials used in private and public dental facilities in an urban setting. METHODS: The cross-sectional study was conducted at the Islamabad Dental and Medical College, Islamabad, Pakistan, from February to July 2019, and comprised individuals at private dental clinics and teaching hospitals. Data was collected using a pre-validated structured questionnaire that recorded socio-demographic information as well as patients' perception on evidence-based dentistry using visual analogue, trust on the dentist, quality of materials and the source of information. Data was analysed using SPSS 21. RESULTS: Of the 269 participants, 151(56.1%) were females with a mean age of 33.87±12.63 years, and 118(43.9%) were males with a mean age of 33.28±13.71 years. Overall, 208(77.3%) respondents were in favour of using materials with long-term scientific data; 201(74.7%) recognised a difference in quality of materials used at private clinics and teaching hospitals; 128(63.7%) believed that poor quality materials were used in teaching hospitals; 229(85%) trusted their dentists for using high-quality materials; and 108(40%) identified dentists as the source of information. There was a significant relationship between patient's education level and realising the importance of using dental materials supported by scientific evidence (p≤0.01). CONCLUSIONS: Majority of subjects believed that poor quality materials were used in teaching hospitals compared to private dental facilities.

Identifying temporal molecular signatures underlying cardiovascular diseases: A data science platform.

OBJECTIVE: During cardiovascular disease progression, molecular systems of myocardium (e.g., a proteome) undergo diverse and distinct changes. Dynamic, temporally-regulated alterations of individual molecules underlie the collective response of the heart to pathological drivers and the ultimate development of pathogenesis. Advances in high-throughput omics technologies have enabled cost-effective, temporal profiling of targeted systems in animal models of human diseases. However, computational analysis of temporal patterns from omics data remains challenging. In particular, bioinformatic pipelines involving unsupervised statistical approaches to support cardiovascular investigations are lacking, which hinders one's ability to extract biomedical insights from these complex datasets. APPROACH AND RESULTS: We developed a non-parametric data analysis platform to resolve computational challenges unique to temporal omics datasets. Our platform consists of three modules. Module I preprocesses the temporal data using either cubic splines or principal component analysis (PCA), and it simultaneously accomplishes the tasks on missing data imputation and denoising. Module II performs an unsupervised classification by K-means or hierarchical clustering. Module III evaluates and identifies biological entities (e.g., molecular events) that exhibit strong associations to specific temporal patterns. The jackstraw method for cluster membership has been applied to estimate p-values and posterior inclusion probabilities (PIPs), both of which guided feature selection. To demonstrate the utility of the analysis platform, we employed a temporal proteomics dataset that captured the proteome-wide dynamics of oxidative stress induced post-translational modifications (O-PTMs) in mouse hearts undergoing isoproterenol (ISO)-induced hypertrophy. CONCLUSION: We have created a platform, CV.Signature.TCP, to identify distinct temporal clusters in omics datasets. We presented a cardiovascular use case to demonstrate its utility in unveiling biological insights underlying O-PTM regulations in cardiac remodeling. This platform is implemented in an open source R package (https://github.com/UCLA-BD2K/CV.Signature.TCP).

Unsupervised classification of multi-omics data during cardiac remodeling using deep learning.

Integration of multi-omics in cardiovascular diseases (CVDs) presents high potentials for translational discoveries. By analyzing abundance levels of heterogeneous molecules over time, we may uncover biological interactions and networks that were previously unidentifiable. However, to effectively perform integrative analysis of temporal multi-omics, computational methods must account for the heterogeneity and complexity in the data. To this end, we performed unsupervised classification of proteins and metabolites in mice during cardiac remodeling using two innovative deep learning (DL) approaches. First, long short-term memory (LSTM)-based variational autoencoder (LSTM-VAE) was trained on time-series numeric data. The low-dimensional embeddings extracted from LSTM-VAE were then used for clustering. Second, deep convolutional embedded clustering (DCEC) was applied on images of temporal trends. Instead of a two-step procedure, DCEC performes a joint optimization for image reconstruction and cluster assignment. Additionally, we performed K-means clustering, partitioning around medoids (PAM), and hierarchical clustering. Pathway enrichment analysis using the Reactome knowledgebase demonstrated that DL methods yielded higher numbers of significant biological pathways than conventional clustering algorithms. In particular, DCEC resulted in the highest number of enriched pathways, suggesting the strength of its unified framework based on visual similarities. Overall, unsupervised DL is shown to be a promising analytical approach for integrative analysis of temporal multi-omics.

Integrated Dissection of Cysteine Oxidative Post-translational Modification Proteome During Cardiac Hypertrophy.

Cysteine oxidative modification of cellular proteins is crucial for many aspects of cardiac hypertrophy development. However, integrated dissection of multiple types of cysteine oxidative post-translational modifications (O-PTM) of proteomes in cardiac hypertrophy is currently missing. Here we developed a novel discovery platform that encompasses a customized biotin switch-based quantitative proteomics pipeline and an advanced analytic workflow to comprehensively profile the landscape of cysteine O-PTM in an ISO-induced cardiac hypertrophy mouse model. Specifically, we identified a total of 1655 proteins containing 3324 oxidized cysteine sites by at least one of the following three modifications: reversible cysteine O-PTM, cysteine sulfinylation (CysSO2H), and cysteine sulfonylation (CysSO3H). Analyzing the hypertrophy signatures that are reproducibly discovered from this computational workflow unveiled four biological processes with increased cysteine O-PTM. Among them, protein phosphorylation, creatine metabolism, and response to elevated Ca2+ pathways exhibited an elevation of cysteine O-PTM in early stages, whereas glucose metabolism enzymes were increasingly modified in later stages, illustrating a temporal regulatory map in cardiac hypertrophy. Our cysteine O-PTM platform depicts a dynamic and integrated landscape of the cysteine oxidative proteome, through the extracted molecular signatures, and provides critical mechanistic insights in cardiac hypertrophy. Data are available via ProteomeXchange with identifier PXD010336.

The risk of hardware infection in deep brain stimulation surgery is greater at impulse generator replacement than at the primary procedure.

BACKGROUND/AIMS: Infection of implanted hardware after deep brain stimulation (DBS) has a significant impact on patient morbidity. We examined all patients who underwent DBS procedures over the last 9 years in our centre to assess the infection rate and possible factors related to surgery that may predispose to infection. METHODS: Surgical reports and clinical notes were reviewed in 273 consecutive patients who underwent a total of 519 DBS-related procedures in our institute between November 2002 and September 2011. RESULTS: Sixteen separate hardware-related infections occurred in 11 patients. Infections occurred in 3% of all procedures and 4% of all patients. The infection rate after implantable pulse generator (IPG) replacement surgery was more than three times higher than after de novo DBS surgery. In addition, male patients were more likely to develop device-related infections. CONCLUSIONS: It is unclear why infection rates should be more than three times higher after IPG replacement surgery than after the de novo procedure. The former is a shorter and simpler procedure to conduct. Perhaps the use of better antimicrobial protection and rechargeable batteries may be useful strategies to reduce infections following IPG revision surgery.

Proposal for evaluating the quality of reports of surgical interventions in the treatment of trigeminal neuralgia: the Surgical Trigeminal Neuralgia Score.

OBJECT: The aim of this study was to design a checklist with a scoring system for reporting on studies of surgical interventions for trigeminal neuralgia (TN) and to validate it by a review of the recent literature. METHODS: A checklist with a scoring system, the Surgical Trigeminal Neuralgia Score (STNS), was devised partially based on the validated STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) criteria and customized for TN after a literature review and then applied to a series of articles. These articles were identified using a prespecified MEDLINE and Embase search covering the period from 2008 to 2010. Of the 584 articles found, 59 were studies of interventional procedures for TN that fulfilled the inclusion criteria and 56 could be obtained in full. The STNS was then applied independently by 3 of the authors. RESULTS: The maximum STNS came to 30, and was reliable and reproducible when used by the 3 authors who performed the scoring. The range of scores was 6-23.5, with a mean of 14 for all the journals. The impact factor scores of the journals in which the papers were published ranged from 0 to 4.8. Twenty-four of the studies were published in the Journal of Neurosurgery or in Neurosurgery. Studies published in neurosurgical journals ranked higher on the STNS scale than those published in nonneurosurgical journals. There was no statistically significant correlation between STNS and impact factors. Stereotactic radiosurgery (n = 25) and microvascular decompression (n = 15) were the most commonly reported procedures. The diagnostic criteria were stated in 35% of the studies, and 4 studies reported subtypes of TN. An increasing number of studies (46%) used the recommended Kaplan-Meier methodology for pain survival outcomes. The follow-up period was unclear in 8 studies, and 26 reported follow-ups of more than 5 years. Complications were reported fairly consistently but the temporal course was not always indicated. Direct interview, telephone conversation, and questionnaires were used to measure outcomes. Independent assessment of outcome was only clearly stated in 7 studies. Only 2 studies used the 36-Item Short Form Health Survey to measure quality of life and 4 studies reported on the severity of preoperative pain. The Barrow Neurological Institute pain questionnaire was the most commonly used outcome measure (n = 13), followed by the visual analog scale. CONCLUSIONS: Similar to the STROBE criteria that provide a checklist of items that should be included in reports of observational studies in general, the authors' suggested checklist for the STNS could help editors and reviewers ensure that quality reports are published, and could prove useful for colleagues when reporting their results specifically on the surgical management of TN. It would help the patient and clinicians make a decision about selecting the appropriate neurosurgical procedure.

Pheochromocytoma and Hypertrophic Cardiomyopathy Leading to Cardiac Arrest.

A 33-year-old female with no known past medical history presented to the hospital for a witnessed cardiac arrest. The patient was emergently intubated and sedated. Further investigation demonstrated an 8.5 cm x 7.6 cm mass in the adrenal region, which was subsequently found to be a pheochromocytoma by biopsy. She was transferred to a tertiary care center for further evaluation. We wish to raise awareness of this condition among clinicians and encourage further research into the connections between pheochromocytoma and further cardiac complications.

MuSyC dosing of adjuvanted cancer vaccines optimizes antitumor responses.

With the clinical approval of T-cell-dependent immune checkpoint inhibitors for many cancers, therapeutic cancer vaccines have re-emerged as a promising immunotherapy. Cancer vaccines require the addition of immunostimulatory adjuvants to increase vaccine immunogenicity, and increasingly multiple adjuvants are used in combination to bolster further and shape cellular immunity to tumor antigens. However, rigorous quantification of adjuvants' synergistic interactions is challenging due to partial redundancy in costimulatory molecules and cytokine production, leading to the common assumption that combining both adjuvants at the maximum tolerated dose results in optimal efficacy. Herein, we examine this maximum dose assumption and find combinations of these doses are suboptimal. Instead, we optimized dendritic cell activation by extending the Multidimensional Synergy of Combinations (MuSyC) framework that measures the synergy of efficacy and potency between two vaccine adjuvants. Initially, we performed a preliminary in vitro screening of clinically translatable adjuvant receptor targets (TLR, STING, NLL, and RIG-I). We determined that STING agonist (CDN) plus TLR4 agonist (MPL-A) or TLR7/8 agonist (R848) as the best pairwise combinations for dendritic cell activation. In addition, we found that the combination of R848 and CDN is synergistically efficacious and potent in activating both murine and human antigen-presenting cells (APCs) in vitro. These two selected adjuvants were then used to estimate a MuSyC-dose optimized for in vivo T-cell priming using ovalbumin-based peptide vaccines. Finally, using B16 melanoma and MOC1 head and neck cancer models, MuSyC-dose-based adjuvating of cancer vaccines improved the antitumor response, increased tumor-infiltrating lymphocytes, and induced novel myeloid tumor infiltration changes. Further, the MuSyC-dose-based adjuvants approach did not cause additional weight changes or increased plasma cytokine levels compared to CDN alone. Collectively, our findings offer a proof of principle that our MuSyC-extended approach can be used to optimize cancer vaccine formulations for immunotherapy.

Dental caries experience in preschool children: is it related to a child's place of residence and family income?

PURPOSE: To assess the caries prevalence in 3- to 5-year-old children and determine whether urbanisation and income are associated with the dental decay status of these preschool children residing in the district of Lahore, Pakistan. MATERIALS AND METHODS: Multistage random sampling was done to collect the sample of children from urban and rural areas. A list of children 3 to 5 years of age was prepared, and every 2nd child on the list was randomly selected until a total of 700 children were enrolled in the study. Lady Health Workers (LHWs) were trained to conduct this survey after permission from the pertinent authorities. The data of the children and their mothers regarding their age, gender, socioeconomic status (SES) and area of residence were collected. The caries status of children was recorded using the dmft index as per WHO criteria. RESULTS: The prevalence of dental caries in preschool children of Lahore was found to be 40.5%. Within this group, caries prevalence was 33.3% in 3-year-old children, 47.6% in 4-year-old children and 75% in the 5-year-old children. The mean dmft score for the entire child population was 1.85 ± 3.26. A significant association was found between caries prevalence, low socioeconomic status, female gender and rural residence. CONCLUSION: Preschool children in Lahore, Pakistan have average dmft scores of 1.85 (± 3.26), which are mostly related to untreated carious lesions. Lower caries experience was found to be associated with rural residence and low family income.

Stereotactic radiotherapy and radiosurgery in pediatric patients: analysis of indications and outcome.

INTRODUCTION: We describe indications, outcomes, and risk profiles of fractionated stereotactic radiotherapy (SRT) and single fraction "radiosurgery" (SRS) in pediatric patients compared to the adult population and evaluate the causal role of SRS and SRT in inducing new neurological complications. MATERIALS AND METHODS: Six children with AVMs and 12 children with neoplastic diseases were prospectively followed for >2 years after SRT/S. The survival, control of pathology, and specified neurological complications were analyzed. In tumor patients, the median overall survival time was 45 months (range 5-103) and the median progression free survival time was 35 months (range 5-98). RESULTS: Control or regression of the tumor was obtained in 83% of patients with neoplastic disease. Three patients with malignant tumors died from disease progression. In AVMs the median time follow up was 52 months (range 27-100). All AVMs were obliterated. New neurological deficits occurred in 67%. SRT/S was considered the direct cause in 25%. All the neurological deficiencies related to SRT/S were focal and related to the irradiated areas. In tumor patients, midline lesions, malignant diagnosis, and additional treatment with surgery, chemotherapy, and craniospinal irradiation seemed to increase the risk of new deficits after SRT/S. In AVM patients, a high Spetzler-Martin grade seemed to carry a higher complication risk. CONCLUSION: The risk of uncontrolled tumor disease or the risk of hemorrhage of non-obliterated AVM must be balanced against the overall risks and benefits of SRT/S. Following SRT/S, the risk of worsening pre-existing deficits is relatively high. The risk of inducing new long-term deficits is relatively low.

Bidirectional relationship between diabetes and periodontal disease: review of evidence.

Presently there are 170 million diabetic patients worldwide. Pakistan ranks sixth in the world with approximately 6.2 million in the 20-79 year age affected by the diabetes. 6-10% of the 35-44year old diabetic patients have been reported to be affected by moderate form of periodontal disease in Pakistan. Periodontal disease is referred to as sixth complication of diabetes. The association between diabetes and periodontal disease has been reported for more than 40 years but reverse has not been the focus of researchers until recently. Studies have suggested a bidirectional relationship between periodontal disease and glycaemic control with each disease having a potential impact on the other.

Mesenteric Lipoma with Volvulus: A Rare Cause of Acute Abdomen in a Child.

Lipoma is benign tumor of mature fat cells and is reported to develop anywhere in the body, e.g. trunk and extremities; however, lipoma in the mesentery of gut is rare, particularly in children. Mesenteric lipomas may be asymptomatic or may present with acute abdomen by leading to volvulus of gut. We report a 6-year female with intestinal obstruction. Exploratory laparotomy revealed a large mesenteric lipoma in the mesentery of small bowel causing volvulus of ileum. Lipoma was excised and postoperative recovery remained uneventful both in the hospital and on subsequent follow up. We believe mesenteric lipoma should be considered as a cause of volvulus and in differential diagnosis of acute abdomen in children. Key Words:  Mesentery, Lipoma, Volvulus, Ileum, Intestinal obstruction.

Acute Kidney Injury after Congenital Heart Disease Surgery: A Single-Center Experience in a Low- to Middle-Income Country.

Background Acute kidney injury (AKI) is a commonly recognized clinical problem after congenital heart disease (CHD) surgery. Increased perioperative morbidity, development of chronic kidney disease, and increased mortality are the major concerns. We investigated frequency, risk factors, and outcomes of AKI after CHD surgery at our hospital. Methods This study was a retrospective analytic review conducted from January 2013 to October 2016 on patients aged between 1 month and 45 years who underwent cardiopulmonary bypass (CPB) for CHD surgery. The modified Kidney Disease Improving Global Outcomes criteria based on serum creatinine value was adopted to diagnose AKI. We assessed AKI frequency and its staging, and outcomes as AKI resolution, length of stay, and mortality. Stages II and III (plasma creatinine level two or more times the baseline) were labeled as severe AKI. Univariate and multivariate logistic regression analyses were conducted, and results were reported as mean with standard deviation and as frequencies with percentage. Odds ratios (ORs) with 95% confidence intervals (CIs) were reported for factors associated with the development of AKI. Results Of the 840 patients who underwent CHD surgery, 237 (28%) developed AKI. AKI stages II1 and III were seen in 101 (42%) and 103 (43%) patients, respectively. Prolonged CPB time > 120 minutes (adjusted OR [AOR]: 1.87; 95% CI: 1.22-2.88; p = 0.004) and hemoglobin > 16 gm/dL (AOR: 1.80; 95% CI: 1.16-2.78; p = 0.008) were associated with the development of AKI on multivariate analysis. AKI resolved spontaneously in 222 (94%) patients, and 10 (4%) patients who developed AKI died. Conclusions Most patients with AKI showed spontaneous resolution. Prolonged CPB time and increased hemoglobin were found to be significant risk factors. Our study found spontaneous resolution of AKI in most cases. However, preplanning and careful monitoring in patients with expected prolonged CPB time and increased baseline hemoglobin can prevent and identify AKI at an early stage.

Machine Learning and Integrative Analysis of Biomedical Big Data.

Recent developments in high-throughput technologies have accelerated the accumulation of massive amounts of omics data from multiple sources: genome, epigenome, transcriptome, proteome, metabolome, etc. Traditionally, data from each source (e.g., genome) is analyzed in isolation using statistical and machine learning (ML) methods. Integrative analysis of multi-omics and clinical data is key to new biomedical discoveries and advancements in precision medicine. However, data integration poses new computational challenges as well as exacerbates the ones associated with single-omics studies. Specialized computational approaches are required to effectively and efficiently perform integrative analysis of biomedical data acquired from diverse modalities. In this review, we discuss state-of-the-art ML-based approaches for tackling five specific computational challenges associated with integrative analysis: curse of dimensionality, data heterogeneity, missing data, class imbalance and scalability issues.

Gastric teratoma: Our 17 year experience.

BACKGROUND: Teratomas originating from the stomach are extremely rare and account for less than 1% of all cases of teratomas. This site of occurrence has unique diagnostic and management issues. METHODS: A single centre case-record review of gastric teratomas presenting between January 2000 and April 2017 was performed. RESULTS: Thirteen children were found to have gastric teratomas. Presenting features were abdominal distension in 12 (92%) and palpable abdominal mass in 9 (69%). At operation, 8 (61%) were exogastric tumors. The tumor was excised with partial gastrectomy (n=7, 54%), total gastrectomy (n=1, 8%), partial gastrectomy and limited transverse colectomy (n=2, 15%), and excision of small part of serosa (mucosal sparing) (n=3, 23%). Histopathologically, these were identified as mature gastric teratomas in 8 (61%). Three (23%) children died postoperatively. CONCLUSION: Gastric teratomas are rare, with the majority described as exogastric. Partial gastrectomy is always needed, but occasionally complete gastrectomy is necessary. Overall survival is >75% in our experience. LEVEL OF EVIDENCE: IV.

Meta-cognitive online sequential extreme learning machine for imbalanced and concept-drifting data classification.

In this paper, a meta-cognitive online sequential extreme learning machine (MOS-ELM) is proposed for class imbalance and concept drift learning. In MOS-ELM, meta-cognition is used to self-regulate the learning by selecting suitable learning strategies for class imbalance and concept drift problems. MOS-ELM is the first sequential learning method to alleviate the imbalance problem for both binary class and multi-class data streams with concept drift. In MOS-ELM, a new adaptive window approach is proposed for concept drift learning. A single output update equation is also proposed which unifies various application specific OS-ELM methods. The performance of MOS-ELM is evaluated under different conditions and compared with methods each specific to some of the conditions. On most of the datasets in comparison, MOS-ELM outperforms the competing methods.

Distinct Presentations of Hernia of Umbilical Cord.

Hernia of umbilical cord is a well-known entity which presents with herniation of small bowel into the proximal part of umbilical cord. It has very good prognosis after surgical repair. Occasionally, it can have distinct presentations and varied malformations at the umbilicus which have bearing on the course of treatment and final outcome. Herein, we describe various presentations and malformations associated with hernia of umbilical cord. Embryological extrapolation is attempted for the malformations at umbilicus.