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.

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.

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.

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.

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).

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.

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.

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.

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.

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.

Varied Presentation of Congenital Segmental Dilatation of the Intestine in Neonates: Report of Three Cases.

Congenital segmental dilatation (CSD) of the intestine is a rare developmental anomaly characterized by sharply demarcated dilatation of a gastrointestinal segment and may present with intestinal obstruction. We report three cases of CSD of the intestine in neonates with varied presentation. First patient was mistaken as pneumoperitoneum on abdominal radiograph, which led to initial abdominal drain placement. The 2nd patient was a case of anorectal malformation associated with congenital pouch colon (CPC) and CSD of ileum; and the third case presented as neonatal intestinal obstruction and found to have CSD of ileum. All the patients were successfully managed in our department.

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.

Preduodenal Portal Vein Associated with Duodenal Obstruction of other Etiology: A Case Series.

DuodenalPreduodenal portal vein is a rare and interesting entity which often causes duodenal obstruction. It is also associated with other congenital anomalies. We report here three cases of preduodenal portal vein associated with other anomalies causing duodenal obstruction not related to direct compression by portal vein itself.

Persistent mullerian duct syndrome: A 24-year experience.

BACKGROUND: Persistence of mullerian duct derivatives in otherwise normal male child is a very rare disorder. This may lead to diagnostic as well as management dilemma. MATERIALS AND METHODS: The medical record of 27 cases of persistent mullerian duct syndrome (PMDS) operated in three teaching hospitals more than a period of 24years is retrieved and analyzed for demography, clinical presentation, investigations, and treatment. RESULTS: There were a total of twenty seven male children with PMDS. The age was ranged between 3months and 19years. Ten patients presented with isolated bilateral UDT, six patients with bilateral UDT and unilateral inguinal hernia (4 left and 2 right sided inguinal hernia), and eight patients presented with right inguinal hernia and left sided UDT. Eight of 27 patients showed familial trends i.e. four pairs of brothers had PMDS in our series. In 21 patients, the diagnosis was made incidentally while operating for UDT and inguinal hernia. At operation 5 patients had female type of PMDS and 22 patients had male type PMDS. In 6 patients (male type), the PMDS was associated with transverse testicular ectopia. In 18 patients the initial operation was performed through inguinal incision with excision of mullerian remnants in the same settings in 12 patients. In 4 patients, straightforward laparotomy performed (familial cases) to excise mullerian remnants. In 5 patients, the PMDS was diagnosed on laparoscopy; initially biopsy of these remnants and gonads was done followed by excision of remnants by laparotomy approach. Biopsies taken from gonads in each patient revealed testicular tissue with variable degree of immaturity and dysplasia. The biopsy of mullerian remnants did not reveal any malignancy. All patients were genotypically male. CONCLUSION: Isolated undescended testes, left UDT and right inguinal hernia, bilateral UDT and unilateral inguinal hernia are the main presenting features of PMDS. About 30% of the patients showed familial tendency. Inguinal exploration for UDT or inguinal hernia, and laparoscopy for UDT reveal incidental findings of mullerian remnants. PMDS can be managed as single stage procedure however two stage procedure including gonadal biopsies in first stage followed by mullerian remnants excision and orchidopexy in the second stage can be opted if there is doubt about gonads and genotype.

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.

Hernia of umbilical cord: report of three unusual cases.

Congenital hernia of umbilical cord is a less frequent entity in newborns and occasionally associated with other maladies. Herein, we report three unusual cases of hernia of umbilical cord. First case was associated with in-utero evisceration of entire small bowel through the presumably ruptured hernia of umbilical cord and other two cases had associated patent vitellointestinal duct (PVID). All of the cases were managed successfully.