A Rare Case of Mosaic 3pter and 5pter Deletion-Duplication with Autism Spectrum Disorder and Dyskinesia.

Introduction: There is evidence that neurodevelopmental disorders are associated with chromosomal abnormalities. Current genetic testing can clinch an exact diagnosis in 20-25% of such cases. Case Description. A 3 years and 11 months old boy with global developmental delay had repetitive behaviors and hyperkinetic movements. He was stunted and underweight. He had ataxia, limb dyskinesia, triangular face, microcephaly, upward slanting palpebral fissure, hypertelorism, retrognathia, posteriorly rotated ears, long philtrum, thin lips, broad nasal tip, polydactyly, tappering fingers, and decreased tone in the upper and lower limbs with normal deep tendon reflexes. Magnetic resonance imaging of the brain, ultrasound of the abdomen, and ophthalmological evaluation were normal. Brain evoked response auditory revealed bilateral moderate hearing loss. He fulfilled the Diagnostic Statistical Manual 5 criteria for autism. In the Vineland Social Maturity Scale, his score indicated a severe delay in social functioning. His genetic evaluation included karyotyping, fluorescence in situ hybridization (FISH), and chromosomal microarray analysis (CMA). The karyotype report from high-resolution lymphocyte cultures was mos 46, XY, der(3)t(3; 5)(p26; p15.3)[50]/46, XY,der(5) t(3;5) (p26;p15.3)[50].ish. His karyotype report showed a very rare and abnormal mosaic pattern with two cell lines (50% each). Cell-line#1: 3pter deletion with 5pter duplication (3pter-/5pter+) and cell-line#2: 3pter duplication with 5pter deletion (3pter+/5pter-) derived from a de novo reciprocal translocation t(3; 5)(p26; p15.3) which was confirmed by FISH. The chromosomal microarray analysis report was normal. The two cell lines (50% each) seem to have balanced out at the whole genome level. Occupational, sensory integration, and behavior modification therapy were initiated for his autistic features, and anticholinergic trihexiphenidyl was prescribed for hyperkinetic movements. Conclusion: This case highlights a rare genetic finding and the need for timely genetic testing in a child with dysmorphism and autism with movement disorder to enable appropriate management and genetic counselling.

Detection and Mitigation of Neurovascular Uncoupling in Brain Gliomas.

Functional magnetic resonance imaging (fMRI) with blood oxygen level-dependent (BOLD) technique is useful for preoperative mapping of brain functional networks in tumor patients, providing reliable in vivo detection of eloquent cortex to help reduce the risk of postsurgical morbidity. BOLD task-based fMRI (tb-fMRI) is the most often used noninvasive method that can reliably map cortical networks, including those associated with sensorimotor, language, and visual functions. BOLD resting-state fMRI (rs-fMRI) is emerging as a promising ancillary tool for visualization of diverse functional networks. Although fMRI is a powerful tool that can be used as an adjunct for brain tumor surgery planning, it has some constraints that should be taken into consideration for proper clinical interpretation. BOLD fMRI interpretation may be limited by neurovascular uncoupling (NVU) induced by brain tumors. Cerebrovascular reactivity (CVR) mapping obtained using breath-hold methods is an effective method for evaluating NVU potential.

Investigation of the intraoperative cortical responses to spinal motor mapping in a patient with chronic pain.

Intraoperative neurophysiological monitoring (IONM) in spinal cord stimulation (SCS) surgery for chronic pain is shown to provide effective guidance during device placement. Electromyography (EMG) is used to determine the laterality of the paddle. In some SCS cases, laterality cannot be obtained via EMG due to patient physiology. Electroencephalography (EEG) is already used in IONM to monitor cortical responses. Here, we show proof-of-concept of assessing the responses of epidurally evoked EMGs simultaneously with EEGs to determine laterality during IONM using a high-resolution (HR) SCS paddle. An 8-column HR-SCS paddle was acutely placed at T9-T10 interspace in patients with failed back surgery syndrome. EMG signals from 18 muscle groups were recorded simultaneously with 60-channel EEG signals at various stimulation amplitudes (0-10 mA). Particular attention was paid to regions associated with pain including the somatosensory cortex (S1), prefrontal cortex (PFC), and motor cortex (M1). When left and right lateral contacts were stimulated at low amplitudes (1-2 mA), significant changes were seen in θ, α, and ß powers in the contralateral PFC but not in M1 or S1. There was a significant correlation between M1 and contralateral contacts in α power. At higher currents (7-8 mA), right-sided contacts resulted in α power change. We found significant differences in α, θ, and ß powers in PFC for contralateral stimulation of the lateral SCS contacts at low amplitudes and in α power at higher amplitudes. The changes in PFC suggest the potential of EEG for understanding a cortical mechanism of action of SCS and provide insight into the pathophysiology of chronic pain.NEW & NOTEWORTHY Here, we present proof of concept of assessing the responses of epidurally evoked electromyography simultaneously with scalp electroencephalography to determine whether both laterality and insights into pain mechanisms can be elucidated. With stimulation, significant changes were seen in θ, α, and ß band power in the contralateral prefrontal cortex and in α power in the motor cortex. We provide insight into the mechanism of action of SCS in preventing pain in this patient.

Extracorporeal irradiation in malignant bone tumors: Single institution experience and review of literature.

In the last couple of decades, the management of malignant bone tumor (MBT) has seen a sea change. With the advent in surgical technics, radiation therapy, and chemotherapy, it has moved from disabling amputation to limb salvage surgery. Extracorporeal irradiation (ECI) and re-implantation of resected bone is a useful method of limb salvage of MBTs. In our study, we analyzed and presented the results of 8 cases of MBTs treated with this modality. Between 2014 and 2017, 8 patients with primary MBT were enrolled for ECI technique who are meeting the eligibility criteria. Before taking the patient for ECI treatment, a multispecialty tumor board discussion was done for each patient. All of them received neo-adjuvant and adjuvant chemotherapy except the patients with histology of giant cell tumor. Following neoadjuvant chemotherapy bone excision surgery was performed, and the resected bone was taken for ECI with the dose of 50 Gray in a single fraction. After ECI, bone segment was re-implanted at osteotomy site in the same setting. After completion of adjuvant chemotherapy, the patients were then followed up for any sequelae, local and systemic control, ambulation, and functional outcome. Out of 8 patients, there were 5 males and 3 females with mean age of 22 (range 13-36). The involved bone was the tibia in 6 patients, ischium in 1 patient, and femur in 1 patient. Histopathologically, the malignancies included 3 osteosarcoma, 3 Giant cell tumor, 1 Ewing's sarcoma and 1 chondrosarcoma. At median follow-up of 12 months (range 6-26 months), local control rate was 87.5% and systemic control rate was 75%. Perioperative ECI and re-implantation is a useful, convenient, and inexpensive technique. The overall treatment time is reduced. The patient's own bone fits perfectly to the resection site with reduced risk of graft site infection. The risk of local recurrence due to tumor re-implantation is negligible with tumoricidal radiation doses of ECI, and it is usually associated with manageable sequelae. Recurrence rates are acceptable and salvageable with surgery.

Epidemiological characteristics of endometrial cancer patients treated at a tertiary health center in National Capital Territory of India.

Settings and Design: A retrospective study which analyzed the data of female patients attending a tertiary care center in National Capital Territory for the treatment of endometrial cancer. Materials and Methods: Eighty-six histopathologically confirmed cases of carcinoma endometrium were taken from January 2016 to December 2019. Detailed information was collected regarding patient's case history, sociodemographic data (age of presentation, occupation, religion, residence, and substance addiction), clinical presentation, diagnostic and therapeutic procedures, and known risk factors (age at menarche and menopause, parity, obesity, use of oral contraceptive pills, hormone replacement therapy, and comorbidities such as hypertension and diabetes). Statistical Analysis Used: After analysis, results were presented as mean ± standard deviation and frequency. Results: Eighty-six percent of the patients (n = 73) were in the age group of 40-70 years; the mean age of the patients at diagnosis of endometrial cancer was 54 years. Eighty-one percent (n = 70) of the patients were from urban areas. Sixty-seven percent of the females (n = 54) were Hindu. All the patients were housewives with nonsedentary lifestyles. Most patients (88%; n = 76) presented with bleeding per vaginum. Fifty-nine percent (n = 51) had stage I disease, followed by 15% (n = 13) with stage II, 14% (n = 12) with stage III, and 12% (n = 10) with stage IV disease. Eighty-two percent (n = 72) of the patients had endometrioid carcinoma. Other less common variants were mixed Mullerian malignant tumor, squamous, adenosquamous, serous, and endometrioid stromal. Forty-four percent (n = 38), 39% (n = 34), and 16% (n = 14) of the patients had grade I, grade II, and grade III tumor, respectively. 53.5% of the cases (n = 46) had >50% myometrial invasion at the time of presentation. Eighty-two percent (n = 71) of the patients were postmenopausal. The mean age at menarche and menopause was 13 years and 47 years, respectively. Fifteen percent (n = 13) of the females were nulliparous. Forty-six percent (n = 40) of the patients were overweight. Most patients (82%) had no history of addiction. Twenty-five percent (n = 22) of the patients had hypertension, and 27% (n = 23) has diabetes as comorbidity. Conclusions: The incidence of endometrium cancer is showing a steady rise in the recent past. Early age of menarche, late age of menopause, nulliparity, obesity, and diabetes mellitus are well-documented risk factors for uterine cancer. Better outcome and control of disease is possible by understanding of endometrial cancer etiology, risk factors, and its preventive measures. Thus, a robust screening program is warranted to detect the disease in early stage and for increased survival.

Marginal Adaptation of Veneers: A Systematic Review.

This study aimed to systematically review the literature to evaluate the marginal adaptation of veneers using different fabrication methods, namely, conventional feldspathic porcelain laminate veneers (PLVs), computer-aided design-computer-aided machining (CAD-CAM) veneers, and pressed veneers. A comprehensive literature search was performed using electronic databases (PubMed and Google Scholar) as well as hand searches to identify all relevant studies related to veneers and marginal adaptation. The identified studies were screened for assessing the inclusion and exclusion criteria. The included articles were then subjected to data extraction and analysis. The search resulted in 130 articles, of which six were included in this systematic review. All included articles were assessed for adaptation of margins. Based on the findings of this systematic review, no significant differences were found in the marginal adaptation of CAD-CAM and conventional feldspathic PLVs. The marginal fidelity of ceramic veneers issuing from the various fabrication techniques was clinically acceptable.

Can we accurately diagnose endometriosis without a diagnostic laparoscopy?

Endometriosis is a progressive, estrogen-dependent, chronic inflammatory disease that affects approximately 6-10% of reproductive age women. Patients usually presents with symptoms, such as non-menstrual pelvic and abdominal pain, ovulatory pain, dyspareunia, dysmenorrhea, dyschezia, and/or changes to bowel or bladder function, which can be exacerbated during ovulation or menses. Endometriosis is a leading cause of unexplained infertility, accounting for up to 50-80% of cases. Currently, altered endometrial receptivity and progesterone resistance are some of the leading theories that could explain endometriosis-related implantation failure. In the endometrium, the B-cell chronic lymphocytic leukemia/lymphoma 6 (BCL-6) protein forms a complex that binds to and inactivates regulators of the progesterone pathway, leading to progesterone resistance, aberrant decidualization, implantation failure, and recurrent miscarriages in women diagnosed with endometriosis. Surgical diagnosis consisting of laparoscopy, with or without histologic confirmation, is still considered the gold standard for diagnosis of endometriosis. Development of noninvasive screening and diagnostic tests to accurately identify patients with endometriosis has become increasing popular. A screening test for endometriosis has been developed to detect endometrial BCL-6 overexpression in asymptomatic women with unexplained infertility or recurrent pregnancy loss. Positive endometrial BCL-6 testing has been associated with recurrent miscarriages and poor in vitro fertilization outcomes. When the underlying cause of endometrial inflammation secondary to endometriosis was treated, an improvement in subsequent live birth rates was seen. Endometrial BCL-6 testing has a high positive predictive value that could help physicians and patients undergoing infertility treatment to seek surgical evaluation for endometriosis, to improve their reproductive outcomes.

Integrated Proteomics-Based Physical and Functional Mapping of AXL Kinase Signaling Pathways and Inhibitors Define Its Role in Cell Migration.

To better understand the signaling complexity of AXL, a member of the tumor-associated macrophage (TAM) receptor tyrosine kinase family, we created a physical and functional map of AXL signaling interactions, phosphorylation events, and target-engagement of three AXL tyrosine kinase inhibitors (TKI). We assessed AXL protein complexes using proximity-dependent biotinylation (BioID), effects of AXL TKI on global phosphoproteins using mass spectrometry, and target engagement of AXL TKI using activity-based protein profiling. BioID identifies AXL-interacting proteins that are mostly involved in cell adhesion/migration. Global phosphoproteomics show that AXL inhibition decreases phosphorylation of peptides involved in phosphatidylinositol-mediated signaling and cell adhesion/migration. Comparison of three AXL inhibitors reveals that TKI RXDX-106 inhibits pAXL, pAKT, and migration/invasion of these cells without reducing their viability, while bemcentinib exerts AXL-independent phenotypic effects on viability. Proteomic characterization of these TKIs demonstrates that they inhibit diverse targets in addition to AXL, with bemcentinib having the most off-targets. AXL and EGFR TKI cotreatment did not reverse resistance in cell line models of erlotinib resistance. However, a unique vulnerability was identified in one resistant clone, wherein combination of bemcentinib and erlotinib inhibited cell viability and signaling. We also show that AXL is overexpressed in approximately 30% to 40% of nonsmall but rarely in small cell lung cancer. Cell lines have a wide range of AXL expression, with basal activation detected rarely. IMPLICATIONS: Our study defines mechanisms of action of AXL in lung cancers which can be used to establish assays to measure drug targetable active AXL complexes in patient tissues and inform the strategy for targeting it's signaling as an anticancer therapy.

Boutique Egg Freezing: Empowering Technology or Marketing Phenomenon? A Word of Caution.

The introduction of oocyte vitrification has propelled the field of oncofertility. However, it is becoming increasingly common to offer planned oocyte cryopreservation to healthy, fertile women due to a lack of a partner or other personal issues. The aim of this article is to discuss the pros and cons of planned oocyte cryopreservation along with potential exploitation issues by unregulated clinics and international agencies. This article further encourages obstetricians and gynecologists to discuss these issues of planned oocyte cryopreservation with their patients to empower them to make an educated decision based on research and science rather than be susceptible to entities that stand to gain monetarily by prompting women to fear a childless future.

Automated eloquent cortex localization in brain tumor patients using multi-task graph neural networks.

Localizing the eloquent cortex is a crucial part of presurgical planning. While invasive mapping is the gold standard, there is increasing interest in using noninvasive fMRI to shorten and improve the process. However, many surgical patients cannot adequately perform task-based fMRI protocols. Resting-state fMRI has emerged as an alternative modality, but automated eloquent cortex localization remains an open challenge. In this paper, we develop a novel deep learning architecture to simultaneously identify language and primary motor cortex from rs-fMRI connectivity. Our approach uses the representational power of convolutional neural networks alongside the generalization power of multi-task learning to find a shared representation between the eloquent subnetworks. We validate our method on data from the publicly available Human Connectome Project and on a brain tumor dataset acquired at the Johns Hopkins Hospital. We compare our method against feature-based machine learning approaches and a fully-connected deep learning model that does not account for the shared network organization of the data. Our model achieves significantly better performance than competing baselines. We also assess the generalizability and robustness of our method. Our results clearly demonstrate the advantages of our graph convolution architecture combined with multi-task learning and highlight the promise of using rs-fMRI as a presurgical mapping tool.

Identification of the Somatomotor Network from Language Task-based fMRI Compared with Resting-State fMRI in Patients with Brain Lesions.

Background Resting-state functional MRI (rs-fMRI) is a potential alternative to task-based functional MRI (tb-fMRI) for somatomotor network (SMN) identification. Brain networks can also be generated from tb-fMRI by using independent component analysis (ICA). Purpose To investigate whether the SMN can be identified by using ICA from a language task without a motor component, the sentence completion functional MRI (sc-fMRI) task, compared with rs-fMRI. Materials and Methods The sc-fMRI and rs-fMRI scans in patients who underwent presurgical brain mapping between 2012 and 2016 were analyzed, using the same imaging parameters (other than scanning time) on a 3.0-T MRI scanner. ICA was performed on rs-fMRI and sc-fMRI scans with use of a tool to separate data sets into their spatial and temporal components. Two neuroradiologists independently determined the presence of the dorsal SMN (dSMN) and ventral SMN (vSMN) on each study. Groups were compared by using t tests, and logistic regression was performed to identify predictors of the presence of SMNs. Results One hundred patients (mean age, 40.9 years ± 14.8 [standard deviation]; 61 men) were evaluated. The dSMN and vSMN were identified in 86% (86 of 100) and 76% (76 of 100) of rs-fMRI scans and 85% (85 of 100) and 69% (69 of 100) of sc-fMRI scans, respectively. The concordance between rs-fMRI and sc-fMRI for presence of dSMN and vSMN was 75% (75 of 100 patients) and 53% (53 of 100 patients), respectively. In 10 of 14 patients (71%) where rs-fMRI did not show the dSMN, sc-fMRI demonstrated it. This rate was 67% for the vSMN (16 of 24 patients). Conclusion In the majority of patients, independent component analysis of sentence completion task functional MRI scans reliably demonstrated the somatomotor network compared with resting-state functional MRI scans. Identifying target networks with a single sentence completion scan could reduce overall functional MRI scanning times by eliminating the need for separate motor tasks. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Field and Birn in this issue.

Prenatal Diagnosis by Chromosome Microarray Analysis, An Indian Experience.

BACKGROUND: Karyotyping has been the gold standard for prenatal chromosome analysis. The resolution should be higher by chromosome microarray analysis (CMA). The challenge lies in recognizing benign and pathogenic or clinically significant copy number variations (pCNV) and variations of unknown significance (VOUS). The aim was to evaluate the diagnostic yield and clinical utility of CMA, to stratify the CMA results in various prenatal referral groups and to accumulate Indian data of pCNVs and VOUS for further interpretation to assist defined genetic counseling. METHODS: Karyotyping and CMA were performed on consecutive referrals of 370 prenatal samples of amniotic fluid (n = 274) and chorionic villi (n = 96) from Indian pregnant women with high maternal age (n = 23), biochemical screen positive (n = 61), previous child abnormal (n = 59), abnormal fetal ultrasound (n = 205) and heterozygous parents (n = 22). RESULTS AND CONCLUSION: The overall diagnostic yield of abnormal results was 5.40% by karyotyping and 9.18% by CMA. The highest percentage of pCNVs were found in the group with abnormal fetal ultrasound (5.40%) as compared to other groups, such as women with high maternal age (0.81%), biochemical screen positive (0.54%), previous abnormal offspring (0.81%) or heterozygous parents group (1.62%). Therefore, all women with abnormal fetal ultrasound must undergo CMA test for genotype-phenotype correlation. CMA detects known and rare deletion/duplication syndromes and characterizes marker chromosomes. Accumulation of CNV data will form an Indian Repository and also help to resolve the uncertainty of VOUS. Pretest and posttest genetic counseling is essential to convey benefits and limitations of CMA and help the patients to take informed decisions.

Role of Functional Magnetic Resonance Imaging in the Presurgical Mapping of Brain Tumors.

When planning for brain tumor resection, a balance between maximizing resection and minimizing injury to eloquent brain parenchyma is paramount. The advent of blood oxygenation level-dependent functional magnetic resonance (fMR) imaging has allowed researchers and clinicians to reliably measure physiologic fluctuations in brain oxygenation related to neuronal activity with good spatial resolution. fMR imaging can offer a unique insight into preoperative planning for brain tumors by identifying eloquent areas of the brain affected or spared by the neoplasm. This article discusses the fMR imaging techniques and their applications in neurosurgical planning.

Perceptual and computational detection of face morphing.

A relatively new type of identity theft uses morphed facial images in identification documents in which images of two individuals are digitally blended to create an image that maintains a likeness to each of the original identities. We created a set of high-quality digital morphs from passport-style photos for a diverse set of people across gender, race, and age. We then examine people's ability to detect facial morphing both in terms of determining if two side-by-side faces are of the same individual or not and in terms of identifying if a face is the result of digital morphing. We show that human participants struggle at both tasks. Even modern machine-learning-based facial recognition struggles to distinguish between an individual and their morphed version. We conclude with a hopeful note, describing a computational technique that holds some promise in recognizing that one facial image is a morphed version of another.