Novel ANOVA-Statistic-Reduced Deep Fully Connected Neural Network for the Damage Grade Prediction of Post-Earthquake Buildings.

Earthquakes are cataclysmic events that can harm structures and human existence. The estimation of seismic damage to buildings remains a challenging task due to several environmental uncertainties. The damage grade categorization of a building takes a significant amount of time and work. The early analysis of the damage rate of concrete building structures is essential for addressing the need to repair and avoid accidents. With this motivation, an ANOVA-Statistic-Reduced Deep Fully Connected Neural Network (ASR-DFCNN) model is proposed that can grade damages accurately by considering significant damage features. A dataset containing 26 attributes from 762,106 damaged buildings was used for the model building. This work focused on analyzing the importance of feature selection and enhancing the accuracy of damage grade categorization. Initially, a dataset without primary feature selection was utilized for damage grade categorization using various machine learning (ML) classifiers, and the performance was recorded. Secondly, ANOVA was applied to the original dataset to eliminate the insignificant attributes for determining the damage grade. The selected features were subjected to 10-component principal component analysis (PCA) to scrutinize the top-ten-ranked significant features that contributed to grading the building damage. The 10-component ANOVA PCA-reduced (ASR) dataset was applied to the classifiers for damage grade prediction. The results showed that the Bagging classifier with the reduced dataset produced the greatest accuracy of 83% among all the classifiers considering an 80:20 ratio of data for the training and testing phases. To enhance the performance of prediction, a deep fully connected convolutional neural network (DFCNN) was implemented with a reduced dataset (ASR). The proposed ASR-DFCNN model was designed with the sequential keras model with four dense layers, with the first three dense layers fitted with the ReLU activation function and the final dense layer fitted with a tanh activation function with a dropout of 0.2. The ASR-DFCNN model was compiled with a NADAM optimizer with the weight decay of L2 regularization. The damage grade categorization performance of the ASR-DFCNN model was compared with that of other ML classifiers using precision, recall, F-Scores, and accuracy values. From the results, it is evident that the ASR-DFCNN model performance was better, with 98% accuracy.

Genomic and computational analysis of four novel variants of MPL gene in Congenital Amegakaryocytic Thrombocytopenia.

Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare, genetic, autosomal recessive disorder characterized by severe thrombocytopenia, due to inefficient bone marrow megakaryopoiesis eventually leading to aplasia. Majority of the cases are due to homozygous or compound heterozygous mutations in MPL gene encoding for thrombopoietin (THPO) receptor protein. CAMT can be diagnosed at early phase of life, with major complication of transfusion dependency and hematopoietic transplantation as only curative treatment. We have investigated the sequence variations in MPL gene of 7 bone marrow failure (BMF) subjects, who presented with clinically diverse phenotypes, through next generation sequencing (NGS). Plasma THPO levels were estimated using ELISA. Insilico sequence and structure-based analyses were performed to understand the structural and functional implications of mutations, identified through NGS. We studied 7 CAMT subjects suspected of BMF, who presented with severe thrombocytopenia followed by pancytopenia, bleeding manifestation and physical anomalies. The plasma THPO levels were significantly elevated (p<0.05) in all the cases. Molecular analysis by NGS identified 9 genomic mutations in MPL gene. These included 7 non-synonymous substitution, 1 nonsense substitution and 1 in-del mutations, of which 4 are novel mutations. Insilico analysis predicted damaging effects on THPO-R and its reduced affinity for THPO for all the identified mutations. CAMT is a rare disorder with diverse clinical phenotypes and diagnosis is challenging. The elevated plasma THPO levels should be considered for the primary diagnosis and prognosis of the disease. However, molecular analysis of MPL gene is important for the diagnosis and management of the disease through genetic counselling. Though the cytokines, THPO-R agonist are used for the treatment of CAMT, HSCT is the only curative therapy.

A comprehensive molecular study identified 12 complementation groups with 56 novel FANC gene variants in Indian Fanconi anemia subjects.

Fanconi anemia (FA) is a rare autosomal or X-linked genetic disorder characterized by chromosomal breakages, congenital abnormalities, bone marrow failure (BMF), and cancer. There has been a discovery of 22 FANC genes known to be involved in the FA pathway. This wide number of pathway components makes molecular diagnosis challenging for FA. We present here the most comprehensive molecular diagnosis of FA subjects from India. We observed a high frequency (4.42 ± 1.5 breaks/metaphase) of chromosomal breakages in 181 FA subjects. The major clinical abnormalities observed were skin pigmentation (70.2%), short stature (46.4%), and skeletal abnormalities (43.1%), along with a few minor clinical abnormalities. The combination of Sanger sequencing and Next Generation Sequencing could molecularly characterize 164 (90.6%) FA patients and identified 12 different complementation groups [FANCA (56.10%), FANCG (16.46%), FANCL (12.80%), FANCD2 (4.88%), FANCJ (2.44%), FANCE (1.22%), FANCF (1.22%), FANCI (1.22%), FANCN (1.22%), FANCC (1.22%), FANCD1 (0.61%) and FANCB (0.61%)]. A total of 56 novel variants were identified in our cohort, including a hotspot variant: a deletion of exon 27 in the FANCA gene and a nonsense variant at c.787 C>T in the FANCG gene. Our comprehensive molecular findings can aid in the stratification of molecular investigation in the diagnosis and management of FA patients.

Acute neurological complications during acute lymphoblastic leukemia therapy: A single-center experience over 10 years.

BACKGROUND: Acute neurological complications occur in 3.6-11% of children treated for acute lymphoblastic leukemia (ALL). This analysis aimed to evaluate the profile of acute neuro-toxicity and its etiology in children with ALL. METHODS: A retrospective case analysis of central nervous system events in children treated for ALL at our center was performed. Details of events were retrieved from the case records (January 2006-December 2015) and analyzed. RESULTS: Ninety (9.5%) neurological events occurred in 923 patients treated for ALL. Phase of therapy were: induction (38), consolidation (5), interim maintenance (5), intensification (15) and maintenance (27). Seizures and neurological deficits were the presenting features in 64 and 40 children, respectively. Events included : neuro-infections in 18, posterior reversible encephalopathy syndrome (PRES) in 7, epilepsy in 6, intracranial bleed in 5, systemic infection with neurological complication in 4, hydrocephalus and aseptic meningitis in 3 each, methotrexate encephalopathy and metabolic seizures in 2 children each. Seizures and status epilepticus of unknown etiology and neurological deficits of unknown etiology was observed in 26 and 13 children, respectively. Seizures occurred mainly in induction (12) and intensification phase (9). Status epilepticus transpired in maintenance phase in 9/14 patients. Induction phase was complicated by PRES in 7, intracranial bleed in 5 and cerebral sinus venous thrombosis in 1 patient. Neuroimaging was done in 86% of events. There were 18 (20.6%) deaths: neuro-infections (8), status epilepticus (6), systemic infection (2), bleed (1), and unexplained encephalopathy (demyelination)(1). At last follow-up, 53 patients were well and 7 children persist to have a neurological disability. CONCLUSION: Ten percent of children on treatment for ALL suffered an acute neuro-toxicity. Morbidity and high-incidence of neuroinfections are major concerns.

Nitric oxide synthase-2 (NOS2) gene polymorphism c.1832C>T (Ser608Leu) associated with nitrosative stress in Fanconi anaemia.

Fanconi anemia (FA) occurs due to genomic instability with predisposition to bone marrow failure, phenotypic abnormalities and cancers. Though mutations in 22 genes leading to DNA repair defect have been identified, the cellular factor such as oxidative stress has also shown to be associated with FA. Nitrosative Stress (NS) is biochemically correlated to many oxidative stress related disorders and the NS as a pathological hallmark in FA has been so far overlooked. We carried out the study first time in Indian patients with FA with an objective to understand the role of NS in the pathogenesis of FA. The study was carried out in 70 FA subjects. The FA subjects were diagnosed by chromosomal breakage analysis. Molecular study was carried out by Next Generation Sequencing and Sanger sequencing. The 3-nitrotyrosine [3-NT] levels were estimated through enzyme-linked immuno-sorbent assay (ELISA) and the nitric oxide synthase genes- NOS1 (c.-420-34221G>A (rs1879417), c.-420-10205C>T (rs499776), c.4286+720G>C (rs81631)) and NOS2 (c.1823C>T (p. Ser608Leu) (rs2297518)) polymorphism were studied by direct sequencing. Chromosomal breakage analysis revealed a high frequency of chromosomal breaks (Mean chromosomal breakage-4.13 ± 1.5 breaks/metaphase) in 70 FA patients as compared to the control. Molecular studies revealed FANCA (58.34%), FANCG (18.34%) and FANCL (16.6%) complementation groups. The 3-nitrotyrosine [3-NT] levels showed to be significantly (p < 0.05) elevated in FA subjects when compared to the age match controls. Genotyping of the NOS2 gene c.1823C>T (p. Ser608Leu) (rs2297518), showed statistically significant (P < 0.05) association with FA. Elevated level of 3-NT is one of the cause of NS and NOS2 gene polymorphism associated with FA is an important target in the treatment regimen.

Severe telomere shortening in Fanconi anemia complementation group L.

Fanconi Anemia (FA) is a rare genetic disease with the incidence of 1 in 360,000 and is characterised by bone marrow failure, physical abnormalities, pancytopenia, and high frequency of chromosomal breakage and increased risk of evolving into malignancy. Telomere plays an important role in genomic stability, ageing process and cancers. Telomere shortening has been reported in FA. We studied telomere length in FA subjects and compared with complementation groups. Chromosomal breakage analysis from PHA stimulated, MMC induced peripheral blood culture was carried out in 37 clinically diagnosed FA. Molecular study of FANCA, G, and L was done through Sanger sequencing and next generation sequencing. Telomere length was estimated using real time quantitative polymerase chain reaction (qPCR) method. Student t-test was applied to test the significance. A high frequency of chromosomal breakage was observed in all the patients compared to healthy controls. We found significantly shorter telomere length in all the three complementation groups compare to age matched healthy controls. Among all complementation groups, FANCL showed severe telomere shortening (P value 0.0001). A negative correlation was observed between telomere length and chromosomal breakage frequency (R = -0.3116). Telomere shortening is not uncommon in FA subjects. However the telomere length shortening is different in complementation groups as FANCL showed severe telomere shortening in FA subjects. Though BM transplantation is essential for the management of the FA subjects, the telomere length can be considered as biological marker to understand the prognosis of the disease as FA subjects primarily treated with androgens.

Novel pathogenic variant c.2714C>A (p. Thr905Lys) in the HK1 gene causing severe haemolytic anaemia with developmental delay in an Indian family.

Hexokinase (EC 2.7.1.1, Adenosine Tri Phosphate (ATP): D-hexose-6-phosphotransferase) is a crucial regulatory enzyme of the glycolytic pathway (Embden-Meyerhof pathway). Hexokinase deficiency is associated with chronic non-spherocytic haemolytic anaemia (HA) with some exceptional cases showing psychomotor/mental retardation and fetus death. The proband is a four-and-half-year-old female child born of a four-degree consanguineous marriage hailing from South India with autosomal recessive congenital HA associated with developmental delay. She was well till 3 months of her age post an episode of diarrhoea when she was noted to be severely anaemic and requiring regular transfusions. The common causes of HA, haemoglobinopathies, red cell membranopathies and common red cell enzymopathies (G6PD, GPI, PK and P5N) were ruled out. Targeted analysis of whole exome sequencing (WES) using an insilico gene panel for hereditary anaemia was performed to identify pathogenic variants in the patient. Next-generation sequencing revealed a novel homozygous variant in hexokinase gene c.2714C>A (p. Thr905Lys) in exon-18. The pathogenic nature of the variant p. Thr905Lys in the HK1 gene was confirmed collectively by biochemical and molecular studies. Insilico analysis (PolyPhen-2, Provean, Mutation Taster) predicted the variant to be severe disease causing. Multiple sequence alignment demonstrated the conservation of p. Thr905 across the species. The impact of the mutation on the protein structure was studied by PyMOL and Swiss Protein databank viewer.

COVID19 in children with cancer in low- and middle-income countries: Experience from a cancer center in Chennai, India.

Crowded outpatient clinics and common wards in many hospitals in low and middle-income countries predispose children, caregivers, and health care workers to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We report on the clinical features and outcomes of 15 children with cancer at our center who tested positive for SARS-CoV-2. Five out of 15 patients were symptomatic, and one patient required intensive care and respiratory support. All the patients in the study have recovered from the SARS-CoV-2 infection without any sequelae and have resumed their cancer treatment.

Mitochondrial DNA variations and mitochondrial dysfunction in Fanconi anemia.

In-vitro studies with different Fanconi anemia (FA) cell lines and FANC gene silenced cell lines indicating involvement of mitochondria function in pathogenesis of FA have been reported. However, in-vivo studies have not been studied so far to understand the role of mitochondrial markers in pathogenesis of FA. We have carried out a systematic set of biomarker studies for elucidating involvement of mitochondrial dysfunction in disease pathogenesis for Indian FA patients. We report changes in the mtDNA number in 59% of FA patients studied, a high frequency of mtDNA variations (37.5% of non-synonymous variations and 62.5% synonymous variations) and downregulation of mtDNA complex-I and complex-III encoding genes of OXPHOS (p<0.05) as strong biomarkers for impairment of mitochondrial functions in FA. Deregulation of expression of mitophagy genes (ATG; p>0.05, Beclin-1; p>0.05, and MAP1-LC3, p<0.05) has also been observed, suggesting inability of FA cells to clear off impaired mitochondria. We hypothesize that accumulation of such impaired mitochondria in FA cells therefore may be the principal cause for bone marrow failure (BMF) and a plausible effect of inefficient clearance of impaired mitochondria in FA.

Clinical, Immunological, and Molecular Features of Severe Combined Immune Deficiency: A Multi-Institutional Experience From India.

Background: Severe Combined Immune Deficiency (SCID) is an inherited defect in lymphocyte development and function that results in life-threatening opportunistic infections in early infancy. Data on SCID from developing countries are scarce. Objective: To describe clinical and laboratory features of SCID diagnosed at immunology centers across India. Methods: A detailed case proforma in an Excel format was prepared by one of the authors (PV) and was sent to centers in India that care for patients with primary immunodeficiency diseases. We collated clinical, laboratory, and molecular details of patients with clinical profile suggestive of SCID and their outcomes. Twelve (12) centers provided necessary details which were then compiled and analyzed. Diagnosis of SCID/combined immune deficiency (CID) was based on 2018 European Society for Immunodeficiencies working definition for SCID. Results: We obtained data on 277 children; 254 were categorized as SCID and 23 as CID. Male-female ratio was 196:81. Median (inter-quartile range) age of onset of clinical symptoms and diagnosis was 2.5 months (1, 5) and 5 months (3.5, 8), respectively. Molecular diagnosis was obtained in 162 patients - IL2RG (36), RAG1 (26), ADA (19), RAG2 (17), JAK3 (15), DCLRE1C (13), IL7RA (9), PNP (3), RFXAP (3), CIITA (2), RFXANK (2), NHEJ1 (2), CD3E (2), CD3D (2), RFX5 (2), ZAP70 (2), STK4 (1), CORO1A (1), STIM1 (1), PRKDC (1), AK2 (1), DOCK2 (1), and SP100 (1). Only 23 children (8.3%) received hematopoietic stem cell transplantation (HSCT). Of these, 11 are doing well post-HSCT. Mortality was recorded in 210 children (75.8%). Conclusion: We document an exponential rise in number of cases diagnosed to have SCID over the last 10 years, probably as a result of increasing awareness and improvement in diagnostic facilities at various centers in India. We suspect that these numbers are just the tip of the iceberg. Majority of patients with SCID in India are probably not being recognized and diagnosed at present. Newborn screening for SCID is the need of the hour. Easy access to pediatric HSCT services would ensure that these patients are offered HSCT at an early age.

A founder variant in the South Asian population leads to a high prevalence of FANCL Fanconi anemia cases in India.

Fanconi anemia (FA) is a rare genetic disorder characterized by bone marrow failure, predisposition to cancer, and congenital abnormalities. FA is caused by pathogenic variants in any of 22 genes involved in the DNA repair pathway responsible for removing interstrand crosslinks. FANCL, an E3 ubiquitin ligase, is an integral component of the pathway, but patients affected by disease-causing FANCL variants are rare, with only nine cases reported worldwide. We report here a FANCL founder variant, anticipated to be synonymous, c.1092G>A;p.K364=, but demonstrated to induce aberrant splicing, c.1021_1092del;p.W341_K364del, that accounts for the onset of FA in 13 cases from South Asia, 12 from India and one from Pakistan. We comprehensively illustrate the pathogenic nature of the variant, provide evidence for a founder effect, and propose including this variant in genetic screening of suspected FA patients in India and Pakistan, as well as those with ancestry from these regions of South Asia.

First Counseling Revealing the Diagnosis of Childhood Cancer: Parent Preferences From an Indian Perspective.

BACKGROUND: The first counseling or the exchange between the physician and the parent(s) of children with cancer is of vital importance as it sets the tone for the rest of the treatment. The goal of our study was to find out the preferences among parents of Indian children with cancer regarding communication and breaking of bad news when fully informed about the diagnosis. MATERIALS AND METHODS: A sample of 60 parents who had been counseled within 3 months from diagnosis were interviewed with a prepared questionnaire directed at eliciting their experiences with the physicians who broke the bad news to them and also suggestions to improve the exchange. RESULTS: Sixty parents of children diagnosed with cancer participated in the study. All parents agreed on the importance of first counseling and asked for a second round of counseling to reinforce concepts learned during the first counseling. An overall 83% of parents wanted a comparison with another child having the same diagnosis, 57% wanted immediate or extended family to be present, and 92% did not want support staff to be present during counseling. In all, 68% of parents did not want to reveal the diagnosis to the child, 77% wanted as much information about the disease as possible, including estimated cost of treatment, and 90% wanted access to other information services and information about other centers where treatment was available. CONCLUSIONS: Parents have preferences about the ways in which information is presented to them during the first counseling. Knowing these preferences will help physicians to better their ability to interact with parents in the future during first counseling and help them decide a culturally appropriate course of action.

Parent's Perspectives on the End-of-life Care of their Child with Cancer: Indian Perspective.

CONTEXT: Parents report that end-of-life decisions are the most difficult treatment-related decisions that they face during their child cancer experience. Research from the parent's perspective of the quality of end-of-life care of their cancer children is scarce, particularly in developing countries like India. AIMS: This study aimed to identify the symptoms (medical/social/emotional) that most concerned parents at the end-of-life care of their cancer child and to identify the strategies parents found to be helpful during this period. SETTINGS AND DESIGN: We wanted to conduct this to focus on the parents perspectives on their cancer child's end-of-life care and to address the issues that could contribute to the comfort of the families witnessing their child's suffering. MATERIALS AND METHODS: The study was conducted at Sri Ramachandra University, Chennai, a Tertiary Care Pediatric Hemato Oncology Unit. Parents who lost their child to cancer, treated in our institution were interviewed with a validated prepared questionnaire. Statistical analysis was performed using SAS statistical software package. RESULTS: Toward death, dullness (30%), irritability (30%), and withdrawn from surroundings (10%) were the most common symptoms encountered. About 30% of the children had fear to be alone. About 50% of the children had the fear of death. Pain, fatigue, loss of appetite were the main distressful symptoms that these children suffered from parents' perspective. Though the parents accepted that the child was treated for these symptoms, the symptom relief was seldom successful. CONCLUSION: The conclusion of the study was that at the end of their child's life, parents value obtaining adequate information and communication, being physically present with the child, preferred adequate pain management, social support, and empathic relationships by the health staff members.

Vitamin D insufficiency among children with cancer in India.

BACKGROUND: Vitamin D plays an important role in regulating various homeostatic mechanisms and has yet untapped potential in cancer prevention and prognosis. Only a few studies have been done worldwide in relating the Vitamin D levels in pediatric cancer patients to the general population but none so far in an Indian setting to the best of our knowledge. OBJECTIVE: To compare the Vitamin D levels in a group of children with cancer to that of the general pediatric population and to note differences in the prevalence of Vitamin D insufficiency and make inferences arising from demographic and therapeutic variations. MATERIALS AND METHODS: Vitamin D levels were found by immuno-chemilumino-metric assay in 102 children (51 cases and 51 controls) over a 6 months period. RESULTS: In comparing the Vitamin D levels of children with cancer and controls from a healthy population we found an increased incidence of Vitamin D insufficiency in cancer children (80.39%) when compared to controls (50.98%) and a much lower mean Vitamin D value in cancer children (22.8 ng/ml) when compared to controls (33 ng/dl). It was also found that cancer children above 6 years had a greater chance for developing Vitamin D insufficiency (P = 0.038) as did children suffering from hematological malignancies (P = 0.025). CONCLUSION: Our study showed an increased prevalence of Vitamin D insufficiency in children with cancer and hence we suggest routine measurement of Vitamin D levels in children with cancer and subsequent supplementation.

Co-Incidence or Co-Existence? Acute Lymphoblastic Leukaemia in HbE-alpha Thalassaemia: A Case Report with Review of Literature.

Haemoglobin E (HbE) is a Haemoglobin variant that commonly occurs in many places in Asia. As ß thalassaemia and α thalassaemia also occur in the same regions, the co-inheritance of these conditions leads to various phenotypic forms. HbE α thalassaemia is less common and of a milder phenotype than HbE ß thalassaemia. Though malignancies are one of the complications in thalassaemia, occurrence of leukaemia is a rare event. Here we present a case of a two-year-old male child co-presenting with pre B acute lymphoblastic leukaemia (ALL) with MLL rearrangement and HbE alpha thalassaemia. The child is on remission 12 months post-therapy with standard ALL high risk protocol with no minimal residual disease (MRD). Haematological and oncological conditions coexisting at presentation is a challenge to therapy. This case is described for its rarity. Informed consent has been obtained from the parents.

Congenital afibrinogenemia in a new born: a rare cause for bleeding.

Bleeding in the neonates may be a result of thrombocytopenia, sepsis or vitamin K deficiency. Congenital bleeding disorders are a rare cause of bleeding. The umbilical cord bleed is an important clue to underlying bleeding disorders especially factor XIII deficiency and afibrinogenemia. In some laboratories, the routine workup for the bleeding neonate may not always include fibrinogen assays, which may then delay this diagnosis. We report a case of congenital afibrinogenemia in a neonate who presented with umbilical stump bleeding for its rarity and to re-emphasize the need for including fibrinogen assays while assessing a bleeding neonate.

Newly diagnosed immune thrombocytopenia: update on diagnosis and management.

Immune thrombocytopenia (ITP) continues to intrigue pediatricians and hematologists alike. Patients can have a dramatic presentation with wide-spread bleeds over a few days. There is an aura and fear of intra-cranial hemorrhage that drives the physician to recommend and the patient's family to accept drug treatment. Difference of opinion among physicians in the recommendations for treatment is not uncommon, even though recent evidence-based guidelines recommend a conservative, observation-based approach for the majority of patients with newly diagnosed childhood ITP. It is important to note that a specific 'platelet cut-off count', is no longer suggested as an indication by itself to recommend drug therapy. The manuscript is an update on newly diagnosed ITP in children. Recent changes in definitions and recommendations for treatment are highlighted. Pros and cons of 1st line drugs, including corticosteroids, intravenous immunoglobulin and anti-D are listed. Adjunctive therapies for the management of epistaxis and menorrhagia are described. Role of splenic artery embolization and emergency splenectomy in the backdrop of severe thrombocytopenia is discussed. Realistic case scenarios, common errors and frequently asked questions are included for a practical and easy reading.