Intellectual Disability and Blended Phenotypes: Insights from a Centre in North India.

Intellectual disability (ID) is seen in around 2.5% of global population and can vary from mild to severe and profound ID. There can be multiple affected family members if it is inherited, though many autosomal dominant ID cases would be due to de novo mutations are very less likely to recur in families. A confirmatory diagnosis is facilitated by genetic testing like chromosomal microarray and next generation sequencing. We describe here our cohort of 15 patients: children and adolescents with ID diagnosed by using sequencing technologies and parental segregation studies. Most of the variants identified were de novo variants and consistent with sporadic occurrence, and blended phenotypes were identified. Appropriate genetic counseling was performed and options for prenatal diagnosis were discussed. Thus, advanced sequencing technologies enable identification of likely causative de novo variants associated with intellectual disability and dysmorphism.

Percutaneous Thrombectomy using a Computer Assisted Aspiration Device for Deep Vein Thrombosis.

PURPOSE: To demonstrate the safety and effectiveness of a computer-assisted large bore thrombectomy (CA-LBT) device aspiration thrombectomy device for treatment of deep vein thrombosis (DVT). MATERIALS AND METHODS: A single institutional retrospective review was performed to include 16 consecutive patients (median age 51.1 years, range 19-77; 5 men and 11 women) who underwent percutaneous thrombectomy using a 16 Fr CA-LBT device (Lightning Flash Aspiration System,Penumbra Inc., Alameda, California, USA) for DVT (12 iliofemoral with or without caval extension [75.0%], 3 axillosubclavian [18.8%], and 1 caval [6.3%) between January 2023 and August 2023. RESULTS: Thrombectomy was performed via the popliteal (n=10, 62.5%), femoral (n=3, 18.8%), saphenous (n=1, 6.3%), brachial (n=1, 6.3%), femoral and brachial (n=1, 6.3%) veins, with a median fluoroscopy time of 17 min (range 7.2-61min) and contrast agent volume of 110 ml (30-175 ml). Restoration of anterograde flow was achieved in all cases (100%, 16/16). Thirteen patients (81.2%) received venoplasty after thrombectomy for residual stenosis. Stents were placed in seven patients (43.8%). With a median clinical follow-up of 77 days (range 3-278 days), symptom improvement was achieved among 13/15 (86.7%) patients that initially presented with DVT associated symptoms. In 14 patients with imaging follow-up, patency was confirmed in 12 patients (85.7%). Of the two patients with complete thrombosis on follow-up imaging (14.3%), one patient was successfully treated with repeated thrombectomy using Flash technology, while the other patient was treated with systemic anticoagulation. CONCLUSIONS: Aspiration thrombectomy with this 16 Fr CA-LBT device may be a feasible option for treatment of proximal or large volume DVT.

Imaging for Interventional Radiology Liver-Directed Therapies for Neuroendocrine Liver Metastases.

Neuroendocrine tumors are an indolent, heterogeneous group of tumors that primarily arise from the gastropancreatic tract and lungs. Most patients present with liver metastases at the time of diagnosis, which cause significant morbidity and mortality due to excess hormone secretion, bile duct obstruction, and liver damage. A small percentage of these patients are eligible for potential cure through surgical resection. However, interventional radiology provides liver-directed therapies, such as percutaneous ablation, transarterial embolization, chemoembolization, and radioembolization, for palliative care and potential bridging to debulking and surgical resection of neuroendocrine liver metastases. This article aims to provide a brief overview of these liver-directed therapies focusing on the pre-, intra-, and postprocedural imaging findings.

Qualitative, Quantitative, In Vitro Antioxidant Activity and Chemical Profiling of Leptadenia pyrotechnica (Forssk.) Decne Using Advanced Analytical Techniques.

Leptadenia pyrotechnica Forssk. Decne (LP) is a medicinal herb from the Asclepiadaceae family with many advantageous properties. The goal of this research is to identify, quantify, and evaluate the antioxidant potential of LP to validate its remarkable therapeutic advantages. The hot soxhlet extraction method was employed to prepare different extracts of LP (stem and root). These extracts were evaluated physiochemically to check their impurity, purity, and quality; qualitatively to detect different phytochemicals; and quantitatively for phenol, saponin, tannin, flavonoid, and alkaloid contents. Then, the in vitro antioxidant potential was estimated by DPPH, NO, H2O2 scavenging assays, and MC and FRAP assays. The most prevalent phytochemicals of LP were then analysed by AAS, FT-IR, UV-visible, and GC-MS techniques. A higher extractive yield was shown by LPSE and LPRE (7.37 ± 0.11 and 5.70 ± 0.02). The LP stem showed better physicochemical and qualitative results than the root. The quantitative and in vitro antioxidant results indicated maximal phenols, tannins, and alkaloid contents in LPSE, which was further confirmed by UV-visible, FT-IR, and GC-MS results. The extraction methods (soxhlation or ultrasonication) were optimized by utilizing RSM to determine the impacts of multiple parameters. The study concluded that the plant has remarkable therapeutic advantages to promote additional clinical investigations and the mechanisms of its action.

Severity Scoring Cutoff for MLPA and Its Diagnostic Yield in 332 North Indian Children with Developmental Delay.

Chromosomal aberrations/rearrangements are the most common cause of intellectual disability (ID), developmental delay (DD), and congenital malformations. Traditionally, karyotyping has been the investigation of choice in such cases, with the advantage of being cheap and easily accessible, but with the caveat of the inability to detect copy number variations of sizes less than 5 Mb. Chromosomal microarray can solve this problem, but again the problems of expense and poor availability are major challenges in developing countries. The purpose of this study is to find the utility of multiplex ligation-dependent probe amplification (MLPA) as a middle ground, in a resource-limited setting. We also attempted to establish an optimum cutoff for the de Vries score, to enable physicians to decide between these tests on a case-to-case basis, using only clinical data. A total of 332 children with DD/ID with or without facial dysmorphism and congenital malformations were studied by MLPA probe sets P245. Assessment of clinical variables concerning birth history, facial dysmorphism, congenital malformations, and family history was done. We also scored the de Vries scoring for all the patients to find a suitable cutoff for MLPA screening. In our study, the overall detection rate of MLPA was 13.5% (45/332). The majority of patients were DiGeorge's syndrome with probe deletion in 22q11.21 in 3.3% (11/332) followed by 15q11.2 del in 3.6% (12/332, split between Angelman's and Prader-Willi's syndromes). Also, 3.0% (10/332) of patients were positive for Williams-Beuren's syndrome 7q11.23, 1.8% (6/332) for Wolf--Hirschhorn's syndrome 4p16.3, 1.2% (4/332) for 1p36 deletion, and 1% for each trichorhinophalangeal syndrome type I 8q23.3 duplication syndrome and cri du chat syndrome. The optimum cutoff of de Vries score for MLPA testing in children with ID and/or dysmorphism came out to be 2.5 (rounded off to 3) with a sensitivity of 82.2% and specificity of 66.7%. This is the largest study from India for the detection of chromosomal aberrations using MLPA common microdeletion kit P245. Our study suggests that de Vries score with a cutoff of 3 or more can be used to offer MLPA as the first tier test for patients with unexplained ID, with or without facial dysmorphism and congenital malformations.

Comparison of Clinical Outcomes of Implantation of Foldable Hydrophobic Acrylic Intraocular Lens With and Without Heparin Surface Modification in Indian Diabetic Patients.

Background This study aimed to compare the clinical outcomes of a heparin surface-modified (HSM) hydrophobic acrylic foldable intraocular lens (IOL) (CT LUCIA 601PY) and non-heparin-modified hydrophobic acrylic foldable IOL (AcrySof IQ SN60WF) in diabetic patients undergoing phacoemulsification. Methodology This randomized, single-surgeon, double-masked controlled trial was conducted at Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi. In this randomized controlled trial, 100 eyes of 100 diabetic patients with or without mild-to-moderate diabetic retinopathy were enrolled (HSM IOL, n = 50; non-HSM IOL, n = 50). Outcome measures were aqueous flare, visual acuity, and anterior chamber depth (ACD). These were measured preoperatively as well as one day, one week, one month, three months, six months, and one year postoperatively. Results The HSM IOL group had significantly lower anterior chamber aqueous flare values (photon count/ms) than the non-HSM IOL group on postoperative day one (9.97 ± 5.2 vs. 17.56 ± 11.3, p < 0.001), postoperative week one (11.47 ± 7.78 vs. 17.06 ± 9.4, p = 0.02), and postoperative month three (7.7 ± 4.1 vs. 12.5 ± 5.6, p = 0.004) of phacoemulsification. The corrected distance visual acuity (CDVA) was significantly better in the HSM IOL group on postoperative day one (uncorrected distance visual acuity: p = 0.022; CDVA; p = 0.005), but there was no significant difference at any other follow-ups. ACD was significantly longer in the HSM IOL group at all follow-ups. Conclusions The implantation of HSM IOL resulted in significantly lower inflammatory reactions in the early postoperative period in diabetics.

Restoring the Ocular Integrity of Perforated Corneal Ulcer Using Living Surgical Donor Tissues Derived From Keratoplasty in the COVID-19 Pandemic.

The coronavirus disease 2019 (COVID-19) caused an unprecedented crisis for corneal surgeons who were forced to strategize for an acute shortage of tissues. Here, we report the initial clinical outcomes of utilizing host corneal buttons derived from optical penetrating keratoplasties of pseudophakic bullous keratoplasty (PBK) patients. Two patients presented to our department with a perforated fungal corneal ulcer in one eye during the COVID-19 pandemic. One eye of each of the patients was operated on with non-vascularized host cut tissues preserved in glycerin. The tissues were secured using 10-0 nylon sutures. Good anatomical integrity was achieved in both eyes. An optical penetrating keratoplasty (PK) was done in both eyes after one year for visual rehabilitation, with a final visual acuity of 20/120 and 20/80, respectively, at six months. In conclusion, therapeutic PK using host tissues obtained from the recipients of optical PK is a safe and effective option to restore ocular integrity during a shortage of fresh or glycerol-preserved corneas. However, optical PK is required for the final visual rehabilitation.

Estrone-Based Derivatives Stabilize the c-MYC and c-KIT G-Quadruplex DNA Structures.

G-rich sequences are present across the genome and can fold to form dynamic secondary structures, namely, G-quadruplexes (G4). These structures play a pivotal role in regulating numerous biological processes including replication, transcription, and translation. Therefore, targeting these structures using molecular scaffolds is an attractive approach to modulating their functions. Herein, we report the synthesis of three estrone-based derivatives (Est-1, Est-2, and Est-3) with a nonplanar core and a cationic alkyl side chain as G4 stabilizers. CD melting and polymerase stop assay results indicate that these ligands preferentially stabilize parallel c-MYC and c-KIT1 G4s over the other G4s and duplex DNAs. The ligand Est-3 shows cytotoxicity against cancer cell lines and effectively downregulates the c-KIT gene in HepG2 cell lines. Molecular modeling and dynamics studies showed that the ligand prefers stacking over the 5'-quartet of c-MYC G4 using the aromatic ring of the ligand. Overall, the findings of this study demonstrate that even G4 ligands can accommodate nonplanar scaffolds, which opens up new avenues for ligand design.

Non-insulinoma pancreatogenous hypoglycemia syndrome (NIPHS)/Nesidioblastosis as the underlying cause of recurrent hypoglycemia in a diabetic adult.

Non-insulinoma pancreatogenous hypoglycemia syndrome (NIPHS), without previous bariatric surgery, is a rare form of hypoglycemia in adult patients and is associated with nesidioblastosis. Adult-onset nesidioblastosis in diabetic patients is rare and histologically identical to "non-insulinoma pancreatogenous hypoglycemia syndrome (NIPHS)". Nesidioblastosis is rare in adults and clinically and biochemically mimics Insulinoma. In the literature, there have only been four cases of adult nesidioblastosis that followed diabetes mellitus. We report a case of nesidioblastosis in a 36-year-old diabetic female presenting with dizziness, sweating, and palpitations for three years. Selective non-invasive techniques failed to detect a tumor. Based on the pursuit of an insulinoma, a distal pancreatectomy specimen was received at our laboratory, and a diagnosis of nesidioblastosis was made. She is currently on follow-up with a favorable outcome. The definitive diagnosis of nesidioblastosis is made on a histological basis. The preferred form of treatment is pancreatic surgical resection. Nesidioblastosis should be taken into consideration in cases where diabetes transforms into hyperinsulinemic hypoglycemia.

Isolation and characterization of emerging Mpox virus from India.

Mpox (previously known as Monkeypox) has recently re-emerged, primarily through human-to-human transmission in non-endemic countries including India. Virus isolation is still considered as the gold standard for diagnosis of viral infections. Here, the qPCR positive skin lesion sample from a patient was inoculated in Vero E6 cell monolayer. Characteristic cytopathic effect exhibiting typical cell rounding and detachment was observed at passage-02. The virus isolation was confirmed by qPCR. The replication kinetics of the isolate was determined that revealed maximum viral titre of log 6.3 PFU/mL at 72 h postinfection. Further, whole genome analysis through next generation sequencing revealed that the Mpox virus (MPXV) isolate is characterized by several unique SNPs and INDELs. Phylogenetically, it belonged to A.2 lineage of clade IIb, forming a close group with all other Indian MPXV along with few from USA, UK, Portugal, Thailand and Nigeria. This study reports the first successful isolation and phenotypic and genotypic characterization of MPXV from India.

Conformational analysis and interaction of the Staphylococcus aureus transmembrane peptidase AgrB with its AgrD propeptide substrate.

Virulence gene expression in the human pathogen, S. aureus is regulated by the agr (accessory gene regulator) quorum sensing (QS) system which is conserved in diverse Gram-positive bacteria. The agr QS signal molecule is an autoinducing peptide (AIP) generated via the initial processing of the AgrD pro-peptide by the transmembrane peptidase AgrB. Since structural information for AgrB and AgrBD interactions are lacking, we used homology modelling and molecular dynamics (MD) annealing to characterise the conformations of AgrB and AgrD in model membranes and in solution. These revealed a six helical transmembrane domain (6TMD) topology for AgrB. In solution, AgrD behaves as a disordered peptide, which binds N-terminally to membranes in the absence and in the presence of AgrB. In silico, membrane complexes of AgrD and dimeric AgrB show non-equivalent AgrB monomers responsible for initial binding and for processing, respectively. By exploiting split luciferase assays in Staphylococcus aureus, we provide experimental evidence that AgrB interacts directly with itself and with AgrD. We confirmed the in vitro formation of an AgrBD complex and AIP production after Western blotting using either membranes from Escherichia coli expressing AgrB or with purified AgrB and T7-tagged AgrD. AgrB and AgrD formed stable complexes in detergent micelles revealed using synchrotron radiation CD (SRCD) and Landau analysis consistent with the enhanced thermal stability of AgrB in the presence of AgrD. Conformational alteration of AgrB following provision of AgrD was observed by small angle X-ray scattering from proteodetergent micelles. An atomistic description of AgrB and AgrD has been obtained together with confirmation of the AgrB 6TMD membrane topology and existence of AgrBD molecular complexes in vitro and in vivo.

Genetic Defects in Children with Cardiac Anomalies/Malformations: Noonan and CFC Syndromes.

Cardiac defects presenting in childhood show significant phenotypic and genetic heterogeneity. With availability of advanced genetic technologies, these can be detected early using specialized testing. Prenatal testing is currently feasible with improved ultrasonography and fetal echocardiography. Here, we report two cases of Noonan's and cardiofaciocutaneous syndromes in patients seen in the genetic unit of a tertiary care center presenting with cardiac defect with or without developmental delay, short stature, and dysmorphism. In these conditions, there is also increased risk of malignancy such as juvenile myelomonocytic leukemia. With the advent of next-generation sequencing, definitive diagnosis and counseling is possible in this group of conditions.

Genome survey sequencing and mining of genome-wide microsatellite markers in yellow-billed babbler (Turdoides affinis).

Turdoides affinis is a species of group dwelling old world passerine of family Leiothrichidae. Unavailability of genome-wide sequence and species-specific molecular markers have hindered comprehensive understanding of cooperative breeding behaviour in T. affinis. Therefore, we generated genome-wide microsatellite markers through whole genome short read sequencing of T. affinis. A total of 68.8 gigabytes of paired-end raw data were sequenced containing 195,067,054 reads. Total sequenced reads spanned a coverage of 17X with genome size of 1.18 Gb. A large number of microsatellite markers (265,297) were mined in the T. affinis genome using Krait, and 50 most informative markers were identified and validated further. In-silico PCR results validated 47 markers. Of these 47 markers, five were randomly selected and validated in-vitro in twelve individuals of T. affinis. Genotyping data on these five loci estimated observed heterozygosity (H0) and expected heterozygosity (He) ratios between 0.333 - 0.833 and 0.851-0.906, respectively. Effective allele size ranged from 6.698 to 10.667, inbreeding coefficient of the population ranged from 0.080 to 0.631 and null allele frequency was calculated at 0.055 to 0.303. Polymorphic information content of all the five loci varied between 0.850 and 0.906. Probabilities of exclusion and identity across 5 loci was estimated to be 0.95 and 0.0036, respectively. All the loci showed significant adherence to Hardy-Weinberg equilibrium. The microsatellite markers reported in this study will facilitate future population genetics studies on T. affinis and other congeneric species.

A Review of Professional Liability in IR: Sweeping the Mines.

Medical professional liability (MPL) is becoming a substantial issue in interventional radiology (IR), with both impact on health care costs and negative psychological effects on physicians. MPL presents special challenges within IR because of the field's complex and innovative therapies that are provided to a diverse group of patients and complicated by the off-label use of devices and drugs that is pervasive in the field. This review discusses the principles and practices to avoid and manage MPLs that are specific to the field of IR.