Revealing third-order interactions through the integration of machine learning and entropy methods in genomic studies.

BACKGROUND: Non-linear relationships at the genotype level are essential in understanding the genetic interactions of complex disease traits. Genome-wide association Studies (GWAS) have revealed statistical association of the SNPs in many complex diseases. As GWAS results could not thoroughly reveal the genetic background of these disorders, Genome-Wide Interaction Studies have started to gain importance. In recent years, various statistical approaches, such as entropy-based methods, have been suggested for revealing these non-additive interactions between variants. This study presents a novel prioritization workflow integrating two-step Random Forest (RF) modeling and entropy analysis after PLINK filtering. PLINK-RF-RF workflow is followed by an entropy-based 3-way interaction information (3WII) method to capture the hidden patterns resulting from non-linear relationships between genotypes in Late-Onset Alzheimer Disease to discover early and differential diagnosis markers. RESULTS: Three models from different datasets are developed by integrating PLINK-RF-RF analysis and entropy-based three-way interaction information (3WII) calculation method, which enables the detection of the third-order interactions, which are not primarily considered in epistatic interaction studies. A reduced SNP set is selected for all three datasets by 3WII analysis by PLINK filtering and prioritization of SNP with RF-RF modeling, promising as a model minimization approach. Among SNPs revealed by 3WII, 4 SNPs out of 19 from GenADA, 1 SNP out of 27 from ADNI, and 4 SNPs out of 106 from NCRAD are mapped to genes directly associated with Alzheimer Disease. Additionally, several SNPs are associated with other neurological disorders. Also, the genes the variants mapped to in all datasets are significantly enriched in calcium ion binding, extracellular matrix, external encapsulating structure, and RUNX1 regulates estrogen receptor-mediated transcription pathways. Therefore, these functional pathways are proposed for further examination for a possible LOAD association. Besides, all 3WII variants are proposed as candidate biomarkers for the genotyping-based LOAD diagnosis. CONCLUSION: The entropy approach performed in this study reveals the complex genetic interactions that significantly contribute to LOAD risk. We benefited from the entropy-based 3WII as a model minimization step and determined the significant 3-way interactions between the prioritized SNPs by PLINK-RF-RF. This framework is a promising approach for disease association studies, which can also be modified by integrating other machine learning and entropy-based interaction methods.

Toward Precision Oncology in Glioblastoma with a Personalized Cancer Genome Reporting Tool and Genetic Changes Identified by Whole Exome Sequencing.

Precision/personalized medicine in oncology has two key pillars: molecular profiling of the tumors and personalized reporting of the results in ways that are clinically contextualized and triangulated. Moreover, neurosurgery as a field stands to benefit from precision/personalized medicine and new tools for reporting of the molecular findings. In this context, glioblastoma (GBM) is a highly aggressive brain tumor with limited treatment options and poor prognosis. Precision/personalized medicine has emerged as a promising approach for personalized therapy in GBM. In this study, we performed whole exome sequencing of tumor tissue samples from six newly diagnosed GBM patients and matched nontumor control samples. We report here the genetic alterations identified in the tumors, including single nucleotide variations, insertions or deletions (indels), and copy number variations, and attendant mutational signatures. Additionally, using a personalized cancer genome-reporting tool, we linked genomic information to potential therapeutic targets and treatment options for each patient. Our findings revealed heterogeneity in genetic alterations and identified targetable pathways, such as the PI3K/AKT/mTOR pathway. This study demonstrates the prospects of precision/personalized medicine in GBM specifically, and neurosurgical oncology more generally, including the potential for genomic profiling coupled with personalized cancer genome reporting. Further research and larger studies are warranted to validate these findings and advance the treatment options and outcomes for patients with GBM.

Low grade oligodendroglioma seeding around the 4th ventricle.

We report a 45 years old female patient with a left temporal grade II oligodendroglioma that recurred on the wall of the fourth ventricle at grade II oligodendroglioma.

Assessment of the severity of temporomandibular disorders in females: Validity and reliability of the Fonseca anamnestic index.

OBJECTIVE: To evaluate the validity and reliability of the Fonseca anamnestic index (FAI) over time in Turkish females. METHODS: Four hundred-fourteen patients who visited the otorhinolaryngology clinic were initially included in the study between January 1, 2018 and January 1, 2019. The Turkish version of the FAI is a self-report instrument that was completed by all of the patients after a brief explanation from the clinician. Cronbach's alpha was calculated using data from the first questionnaire. RESULTS: The results of the first assessment showed 243 patients had no TMD (58.7%), 40 had mild TMD (9.7%), 87 had moderate TMD (21%), and 44 had severe TMD (10.6%). At the second assessment, the respective values were 243 (58.7%), 37 (8.9%), 98 (23.7%), and 36 (8.7%). The internal consistency of the first test was high. CONCLUSION: The FAI can be used to collect a large amount of data easily, at minimal cost.

A new method for quantification of frontal retrusion and complex skull shape in metopic craniosynostosis: a pilot study of a new outcome measure for endoscopic strip craniectomy.

OBJECTIVE: The objective of this study was to propose a new skull outline-based method to objectively quantify complex 3D skull shapes and frontal and supraorbital retrusion in metopic craniosynostosis using 3D photogrammetry. METHODS: A standard section from 3D photogrammetry, which represents the trigonocephalic shape, was used in this study. From the midpoint of the area of this section, half diagonals were calculated to the skull outline at 5° increments in the anterior half of the head. These half diagonals were used to create a sinusoidal curve, and the area under the sinusoidal curve (AUC) was used to represent the mathematical expression of the trigonocephalic head shape. The AUC from 0° to 180° (90° from the midline to each side) was calculated and is referred to as AUC0→180. The AUC from 60° to 120° (30° from the midline to each side) was also calculated and is referred to as AUC60→120. A total of 24 patients who underwent endoscopic strip craniectomy and 13 age- and sex-matched controls were included in the study. The AUC values obtained in patients at different time points and controls were analyzed. RESULTS: The mean preoperative AUC60→120 and AUC0→180 in the patients were significantly lower than those in control individuals. The increase in both AUC60→120 and AUC0→180 values is statistically significant at the discontinuation of helmet therapy and at final follow-up. Receiver operating characteristic curve analysis indicated that AUC60→120 is a more accurate classifier than AUC0→180. CONCLUSIONS: The proposed method objectively quantifies complex head shape and frontal retrusion in patients with metopic craniosynostosis and provides a quantitative measure for follow-up after surgical treatment. It avoids ionizing radiation exposure.

Past, Present, and Future of Therapies for Pituitary Neuroendocrine Tumors: Need for Omics and Drug Repositioning Guidance.

Innovation roadmaps are important, because they encourage the actors in an innovation ecosystem to creatively imagine multiple possible science future(s), while anticipating the prospects and challenges on the innovation trajectory. In this overarching context, this expert review highlights the present unmet need for therapeutic innovations for pituitary neuroendocrine tumors (PitNETs), also known as pituitary adenomas. Although there are many drugs used in practice to treat PitNETs, many of these drugs can have negative side effects and show highly variable outcomes in terms of overall recovery. Building innovation roadmaps for PitNETs' treatments can allow incorporation of systems biology approaches to bring about insights at multiple levels of cell biology, from genes to proteins to metabolites. Using the systems biology techniques, it will then be possible to offer potential therapeutic strategies for the convergence of preventive approaches and patient-centered disease treatment. Here, we first provide a comprehensive overview of the molecular subtypes of PitNETs and therapeutics for these tumors from the past to the present. We then discuss examples of clinical trials and drug repositioning studies and how multi-omics studies can help in discovery and rational development of new therapeutics for PitNETs. Finally, this expert review offers new public health and personalized medicine approaches on cases that are refractory to conventional treatment or recur despite currently used surgical and/or drug therapy.

Intermediate-Grade Meningeal Melanocytoma in a 19-Month- Old Child with Difficulties in Differential Diagnosis and Management.

Intermediate-grade meningeal melanocytoma (IGM) is a rare tumor that has not been reported in children so far. It is speculated to have more aggressive clinical behavior with undefined best management options. In this study, we present a 19-month-old girl as the first case with IGM in English literature. Preoperative diagnosis was ambiguous, given the unclear patient history and radiological features resembling a growing skull fracture or a congenital parietal bone agenesis subtype. During surgery, a dark gray-black dural area (5 × 7 cm in size) was found and then excised. However, the surgery was complicated due to brain edema and swelling, warranting a second surgery for reconstruction and dural repair. Of the 16 reported adult patients, 14 showed a high recurrence rate without adjuvant radiotherapy; 2 showed no recurrence with adjuvant radiotherapy. No adjuvant radiotherapy was given to our patient since she was 19 months old at the time of diagnosis and showed no recurrence at 48-month follow-up until now. Close monitoring with radiological imaging is of paramount importance for such cases.

A new biomarker that predicts ventricular arrhythmia in patients with ischemic dilated cardiomyopathy: Galectin-3.

INTRODUCTION: Ventricular arrhythmias are caused by scar tissue in patients with ischemic dilated cardiomyopathy. The gold standard imaging technique for detecting scar tissue is magnetic resonance imaging (MRI). However, MRI is not feasible for use as a screening test, and also cannot be used in patients who have received an implantable cardioverter-defibrillator (ICD). In this study, we aimed to assess the association between levels of galectin-3 (Gal-3), which is known to be secreted by scar tissue, and the history of ventricular arrhythmias in patients with ischemic dilated cardiomyopathy who received an ICD. METHODS: Nineteen healthy controls and 32 patients who had previously undergone VVI-ICD implantation due to ischemic dilated cardiomyopathy were enrolled in the study. Patients were divided into three groups: the first group including patients who had received no ICD therapies, the second including patients with arrhythmia requiring therapies with no arrhythmia storm, and the third including patients who had arrhythmia storm. We assessed the association between Gal-3 levels and the history of ventricular arrhythmias in these patients. RESULTS: Gal-3 levels were significantly higher in the patient groups than in the control group (p<0.01). Gal-3 levels of patients with arrhythmias requiring ICD therapies were significantly higher than in patients with ICD not requiring therapies (p=0.02). They were also higher in patients with a history of arrhythmia storm than in patients without shocks (p=0.05). Receiver operating curve analysis showed with 84% sensitivity and 75% specificity that Gal-3 levels over 7 ng/ml indicated ventricular arrhythmia that required therapies. CONCLUSION: Gal-3 may be used to further improve risk stratification in patients with ischemic cardiomyopathy who are more prone to developing life-threatening arrhythmias.

Non-vitamin K antagonist oral anticoagulant use at doses inappropriately lower than recommended in outpatient older adults: a real-life data.

BACKGROUND/PURPOSE: There has been a rapid increase in the use of non-vitamin K-antagonist oral anticoagulants (NOAC). Current guidelines recommend dose adjustments be made in accordance with certain criteria for each NOAC. This study is aimed at determining whether or not NOAC were prescribed for non-valvular atrial fibrillation (AF) in guideline-recommended doses in community-dwelling older adults. METHODS: Older adults taking NOAC for non-valvular AF presenting to a cardiology outpatient clinic for the first time were included in the study. The NOAC dose for each patient was assessed based on the recommendations of the European Society of Cardiology and were categorized as appropriate or inappropriate (low or high dose). The patients were also evaluated for demographic data, diseases, CHA2DS2-VASc score, HASBLED score, frailty and falls in the previous year. RESULTS: A total of 302 older adults were included in the study, with a mean age of 75.5 ± 7.5 years. One hundred eighty-four patients (60.9%) were found to be on appropriate doses of NOAC, while 109 (36.1%) were on inappropriately low doses and nine (2.98%) were on inappropriately high doses. Accordingly, 39.1% of the AF patients were found to be on inappropriate doses of NOAC, 92.4% of which were inappropriately low. A multivariate logistic regression analysis revealed that the only factor associated with inappropriate low-dose NOAC use was patient age (OR = 1.061, 95% CI = 1.009-1.116, p = 0.022). CONCLUSION: Our study suggests that the inappropriate use of lower dose NOAC may emerge as a significant problem in outpatient older adults. This inappropriate practice seems to be associated with older age rather than the diseases, CHA2DS2-VASc/HASBLED scores, frailty and presence of falls.

The relationship between T-wave peak-to-end interval and hemodynamic parameters in patients with pulmonary arterial hypertension.

BACKGROUND: T-wave peak-to-end interval (TPEI) is a measure of repolarization dispersion on surface electrocardiogram (ECG). TPEI has been reported as a prognostic parameter with heart disorders. In this study, we aimed to evaluate the relationship between echocardiogram-derived right heart parameters, right heart catheterization (RHC) measurements, and TPEI in patients with precapillary pulmonary arterial hypertension (PAH). METHODS: Thirty-eight patients (29 females and 9 males, mean age of 54.9 ± 10.9 years) who had undergone RHC for a preliminary diagnosis of pulmonary hypertension (PH) were included in the study. We performed transthoracic echocardiography (TTE), and resting 12-lead ECG was recorded before RHC. TPEI was measured from leads of V1-V6, DII, DIII, and aVF, and these values are averaged to obtain the global TPEI. RESULTS: Duration of TPEI was significantly correlated with mean PAP, pulmonary vascular resistance (PVR), and cardiac index (CI). Longer TPEI was associated with higher N terminal probrain natriuretic peptide (NT pro-BNP) level, lower 6-min walk distance (6MWD), and lower tricuspid annular plane systolic excursion (TAPSE). CONCLUSION: Prolongation of TPEI could be a new predictor of adverse outcome in PAH and may provide additional prognostic information for patients with PAH.

Endoscopic Third Ventriculostomy in an Untreated Vein of Galen Malformation Presenting Lately with Acute Obstructive Hydrocephalus.

BACKGROUND: Mural-type vein of Galen malformations (VoGMs) mostly manifest in later stages of infancy as macrocephaly, hydrocephalus, or failure to thrive unless previously diagnosed and treated. Literature is extremely limited on the success and safety of endoscopic third ventriculostomy (ETV) in acute obstructive hydrocephalus caused by an untreated VoGM. Thus, we aimed to present a case for demonstrating the possible efficacy and safety of ETV under such conditions. CASE DESCRIPTION: A 22-month-old boy presenting with acute-onset headache, vomiting, and lethargy was diagnosed with a mural-type VoGM and acute obstructive hydrocephalus. He was treated satisfactorily with ETV and endovascular embolization. We observed a shrinkage in malformation sac diameter of >20 mm in the magnetic resonance imaging angiography at postoperative year 1. The child showed normal motor and mental development at his outpatient clinic visit at postoperative month 15. CONCLUSIONS: To the best of our knowledge, this is the first case in the literature with an untreated VoGM presenting with acute obstructive hydrocephalus who was treated with the combination of ETV and endovascular embolization and had an adequate follow-up period.

Analyses of Copy Number Variations in Myxopapillary Ependymomas of Cauda Equina.

AIM: To identify the copy number variations that are specific to myxopapillary ependymomas (MPEs) of the cauda equina. MATERIAL AND METHODS: The patient cohort included five patients who underwent resection of histologically confirmed MPEs. Tumor samples collected during surgery and stored in liquid nitrogen as well as corresponding blood samples collected were analyzed. Genomic DNA from the venous blood and tumor samples was obtained using standard techniques and hybridized to a Cytoscan 750K Array in accordance with the manufacturer’s introductions. RESULTS: As a novel finding, amplification on chromosome 14q32.33 was detected in all tumor and blood samples, except one tumor sample. All tumor tissues also showed amplification on chromosomes 5, 7, 9, and 16. CONCLUSION: Although further studies with larger cohorts are required to identify genes involved in MPE tumorigenesis and to validate our results, these findings provide a basis for advanced molecular biological and genetic studies of MPEs.

Effects of vaginal birth versus caesarean section on hearing screening results in a large series from the Aegean region.

Objective: To evaluate the effects of caesarian section (CS) versus vaginal birth (VB) delivery techniques on results from neonatal hearing screening tests (NHSTs).Design: Retrospective analysis.Study sample: A total of 10,767 neonates divided into two groups according to delivery technique underwent NHSTs. Those who failed TEOAE or AABR were sent for diagnostic ABR examination.Results: A total of 5620 of 6044 (92.9%) of the neonates in the CS group passed the TEOAE test bilaterally and 424 (7.1%) failed either unilaterally or bilaterally. In the VB group, 4496 of 4723 (95.1%) neonates passed the TEOAE test bilaterally, while the remaining 227 (4.9%) failed the test either unilaterally or bilaterally. Bilateral passing rate of TEOAE test results was significantly higher in the VB group than the CS group (p < 0.05). The AABR failure rate (unilaterally or bilaterally) was 1% in the CS group, which was significantly higher than that in the VB group (0.6%). Diagnostic ABR bilateral pass rate was not statistically different between the groups.Conclusions: Delivery method was shown to affect the results of NHSTs. We found that the rates of failing the TEOAE and screening AABR examinations were higher among neonates born by CS compared to VB.

An Analysis of Otology-Neurotology Articles from Turkey Published in Science Citation Indexed Otolaryngology Journals from 2012 through 2016.

OBJECTIVE: The objective of this study was to review the articles on otology-neurotology submitted from Turkey and published in Science Citation Indexed (SCI) and Science Citation Index-Expanded (SCI-E) journals in the period from 2012 through 2016 in terms of characteristics and quantity, and to analyze the variances in these parameters over the defined time period to profile the national scientific endeavor in the field. METHODS: We searched the papers on otology-neurotology and related subjects that were submitted from Turkey and published in the period from 2012 through 2016 in the relevant journals listed in SCI and SCI-E. We noted the impact factors and quartile rankings of the publishing journals, and reviewed, counted and classified the titles, subjects, types and characteristics of the articles that met our criteria. RESULTS: A total of 546 papers from Turkey were published in 25 SCI and SCI-E listed journals (145 and 401, respectively) in the defined period. The impact factors of these 25 journals ranged from 0.392 to 2.951. Of these papers, 393 (71.97%) were experimental or observational clinical studies, case reports, or surveys; 137 (25.10%) were non-clinical, laboratory or animal experiments; and the remaining 16 (2.93%) were reviews or letters to the editor. CONCLUSION: A substantial number of papers on otology-neurotology submitted from Turkey were published in many prestigious SCI-journals, however, we did not find any significant increase in this number in the given period. We also found concentration of articles in certain journals and inclination to a few subjects and would like to underline that the number of basic science and ecological-epidemiological studies within the confines of our review were relatively few.

The relationship between sarcopenia and urinary incontinence.

PURPOSE: Urinary incontinence (UI) is a common cause of morbidity in the female older adult. Identification of factors associated with UI is necessary to identify risky individuals, to take preventive measures, and to recognize commonly associated co-morbidities. We suggest that sarcopenia may be associated with UI through decrease in muscle mass/strength. In this study, we aimed to investigate the relationship between UI (stress and/or urgency) and sarcopenia. METHODS: Female older adults ≥ 60 years that applied to geriatric outpatient clinic were analyzed cross-sectionally. The presence of UI, UI types, fecal incontinence, and constipation was obtained. Functional status was assessed by basic and instrumental activities of daily living (ADL and IADL), nutrition by mini-nutritional assessment-short form (MNA-SF). Total muscle mass was measured by bioimpedance analysis. Hand grip strength and walking speed were assessed. RESULTS: A total of 802 female adults were included. The prevalence of UI was 48.9%. Associated factors with presence of UI were higher age and BMI, presence of fecal incontinence, constipation, lower activities of ADL and IADL scores, lower grip strength, lower skeletal muscle mass adjusted by weight and BMI, and presence of sarcopenia adjusted by weight and BMI. Independent factors related with UI were presence of fecal incontinence, constipation, IADL dependency, low muscle mass adjusted by weight and body mass index, and sarcopenia adjusted by weight. CONCLUSION: The results of our study suggest that UI is independently associated with sarcopenia when muscle mass was adjusted by weight and also with presence of low muscle mass when muscle mass was adjusted by weight or BMI.

Coronary microvascular dysfunction equivalent to left main coronary artery disease.

Coronary microvascular dysfunction, also known as cardiac syndrome X, is a clinical syndrome presenting with typical angina and evidence of myocardial ischemia in the absence of flow-limiting stenosis on coronary angiography. Of patients undergoing coronary angiography due to suspected myocardial ischemia, 50% are found to have normal or near-normal coronary arteries. Described in this case report is a patient who developed hypotension and ST segment depressions during treadmill exercise test. Left main coronary artery or multivessel disease was suspected. Coronary angiography was normal, but coronary flow reserve measurement revealed severe microvascular dysfunction.

Effects of Obstructive Sleep Apnea in Children as a Result of Adenoid and/or Adenotonsillar Hypertrophy on Maternal Psychologic Status.

The authors aimed to evaluate the effects of obstructive sleep apnea in children as a result of adenoid and/or adenotonsillar hypertrophy on maternal psychologic status. The study sample comprised the mothers of 66 children aged 3 to 15 years (mean age: 7.55 ±â€Š2.94 years) who were scheduled to undergo curette adenoidectomy or adenotonsillectomy because of airway obstruction. The mothers completed the 14-item Hospital Anxiety and Depression Scale (HADS), 20-item State-Trait Anxiety Inventory-1 (STAI-1), and 20-item State-Trait Anxiety Inventory-2 (STAI-2) questionnaires before the operation and 10 days afterwards. Mothers who were under psychiatric treatment or declined to fill the questionnaires were excluded from the study. The results obtained postoperatively by day 10, when all the children had considerable improvement in their breathing, were analyzed as control data. The mean postoperative HAD-A and HAD-D scores of the mothers were significantly lower than the mean preoperative scores (P < 0.001). Mothers' mean STAI-1 and STAI-2 scores were also significantly lower postoperatively (P < 0.001). Pediatric adenoidectomy or adenotonsillectomy to relieve airway obstruction has a beneficial effect not only on the health of pediatric patients but also on the psychologic status of their mothers.

Potential contribution of virtual histology plaque composition to hemodynamic-morphologic dissociation in patients with non-ST elevation acute coronary syndrome.

OBJECTIVE: Histologic plaque characteristics may influence the hemodynamic effect generated by physiologically significant unstable coronary lesions where plaque content and surface related factors are expected to contribute to the maximum translesional pressure drop. In this study, we aimed to identify local lesion specific virtual histological characteristics that may potentially affect hemodynamic outcome measures. METHODS: Forty-eight consecutive patients with non-ST-elevation acute coronary syndrome (NSTEACS) having paired hemodynamic and morphological data were enrolled. A dual sensor guide-wire was used for the assessment of fractional flow reserve (FFR) and stenosis resistance (HSR) in the culprit vessel. Virtual histology intravascular ultrasound imaging was performed after obtaining hemodynamic data. RESULTS: In a hemodynamically significant lesion subset (FFR<0.75 [n=34]), after controlling for lesion length, MLA and coronary artery compliance, FFR correlated with necrotic core (NC) area (r=-0.423, p=0.028) at MLA and NC volume (r=-0.497, p=0.008) and dense calcium (DC) volume (r=-0.332, p=0.03) across the entire lesion segment. Likewise, NC (r=-0.544, p=0.005) and DC (r=0.376, p=0.03) areas at MLA and NC (r=0.545, p=0.005) and DC (r=0.576, p=0.003) volumes across the entire lesion segment were associated with HSR in the hemodynamically significant lesion group (HSR>0.80 [n=33]). However, no correlation has been observed between intracoronary hemodynamic end-points and plaque components in hemodynamically insignificant lesions. CONCLUSIONS: This study demonstrated that for a given coronary stenosis geometry and arterial compliance, plaque composition may influence hemodynamic outcome measures in functionally significant stenoses in patients with NSTEACS.

Predicting the disease of Alzheimer with SNP biomarkers and clinical data using data mining classification approach: decision tree.

Single Nucleotide Polymorphisms (SNPs) are the most common genomic variations where only a single nucleotide differs between individuals. Individual SNPs and SNP profiles associated with diseases can be utilized as biological markers. But there is a need to determine the SNP subsets and patients' clinical data which is informative for the diagnosis. Data mining approaches have the highest potential for extracting the knowledge from genomic datasets and selecting the representative SNPs as well as most effective and informative clinical features for the clinical diagnosis of the diseases. In this study, we have applied one of the widely used data mining classification methodology: "decision tree" for associating the SNP biomarkers and significant clinical data with the Alzheimer's disease (AD), which is the most common form of "dementia". Different tree construction parameters have been compared for the optimization, and the most accurate tree for predicting the AD is presented.