Enhanced Sensing of Weak Anharmonicities through Coherences in Dissipatively Coupled Anti-PT Symmetric Systems.

In the last few years, the great utility of exceptional points in sensing linear perturbations has been recognized. However, physical systems are inherently anharmonic and macroscopic physics is most accurately described by nonlinear models. Considering the multitude of semiclassical and quantum effects ensuing from nonlinear interactions, the sensing of anharmonicities is a prerequisite to the primed control of these effects. Here, we propose an expedient sensing scheme relevant to dissipatively coupled anti parity-time (anti-PT) symmetric systems and customized for the fine-grained estimation of anharmonic perturbations. The sensitivity to anharmonicities is derived from the coherence between two modes induced by a common vacuum. Owing to this coherence, the linear response acquires a pole on the real axis. We demonstrate how this singularity can be exploited for the enhanced sensing of very weak anhamonicities at low pumping rates. Our results are applicable to a wide class of systems, and we specifically illustrate the remarkable sensing capabilities in the context of a weakly anharmonic yttrium iron garnet sphere interacting with a cavity via a tapered fiber waveguide. A small change in the anharmonicity leads to a substantial change in the induced spin current.

Genetic analysis of Enterovirus D68 associated with pneumonia in children from South India.

EV-D68 is an emerging enterovirus infection associated with severe acute respiratory illness (SARI), acute flaccid myelitis (AFM) and acute flaccid paralysis (AFP). While EV-D68 outbreaks and sporadic cases are reported globally, a single case has been reported from India. The present study aims to investigate the molecular epidemiology and clinical characteristics of EV-D68-associated SARI cases from South India. We screened influenza-negative archived throat swab specimens from Influenza-Like Illness (ILI) and SARI cases (n=959; 2016 to 2018 period) for enteroviruses by pan-enterovirus real-time RT-PCR. Thirteen samples positive for enteroviruses were typed by PCR and sequencing based on VPI, VP2 and/or 5'NCR regions. One EV-D68 RNA sample was subjected to next-generation sequencing for whole genome characterisation. Among 13 enterovirus cases, four were ECHO-11, three EV-D68, two CV-A16 and one each EV-71, CV-B1, CV-B2 and CV-A9. All three cases of EV-D68 infection were reported in children below 2 years of age from Kerala state of South India during June and July 2017. The patients developed pneumonia without any neurological complications. Sequencing based on VPI and 5'NCR regions showed that EV-D68 strains belong to the novel subclade B3. The EV-D68 complete genome identified with two unique amino acid substitutions in VP1 (T-246-I) and 3D (K-344-R) regions. This study reiterates the EV-D68 novel subclade B3 circulation in India and indicates the urgent need for structured EV-D68 surveillance in the country to describe the epidemiology.

Snake bite mortality in children: beyond bite to needle time.

OBJECTIVE: To study the clinical characteristics and predictors of mortality from snake bite envenomation in children. DESIGN: Prospective observational study with a one-group cohort design. SETTING: Paediatric intensive care unit of a tertiary care hospital in South India. SUBJECTS: The study cohort consisted of 145 children (55 girls and 90 boys) <12 years of age with snake bite envenomation. METHODS: Demographic and clinical details were recorded in a semistructured pro forma. Children were treated with polyvalent antisnake venom (ASV) as per WHO protocol. Details of treatment, complications and outcomes were recorded. Univariate analysis was done to identify statistical significance, and those variables found to be significant were analysed using binary logistic regression. RESULTS: Russell's viper was the most common offending snake followed by hump-nosed pit viper. Features of haemotoxicity, neurotoxicity and combined haemotoxicity and neurotoxicity occurred in 68 (47%), 39 (26.9%) and 9 (6%) children, respectively. Acute kidney injury (AKI) occurred in 36 (25%) children. The mortality rate was 10.3%. On univariate analysis, nocturnal bites, severe leucocytosis on day 1, AKI, capillary leak syndrome and a need for more than 20 vials of ASV were significantly associated with mortality. On multivariate analysis, only severe leucocytosis on day 1 (OR 35.29; 95% CI 1.37 to 911.89) and AKI (OR 35.05 95% CI 1.74 to 706.93) were found to be independent predictors of mortality. CONCLUSIONS: This study has identified two hitherto unrecognised risk factors-severe leucocytosis on day 1 and capillary leak syndrome. These findings need to be taken into consideration when planning management strategies for snake bite envenomation in children.

Phenotype guided characterization and molecular analysis of Indian patients with long QT syndromes.

BACKGROUND: Long QT syndromes (LQTS) are characterized by prolonged QTc interval on electrocardiogram (ECG) and manifest with syncope, seizures or sudden cardiac death. Long QT 1-3 constitute about 75% of all inherited LQTS. We classified a cohort of Indian patients for the common LQTS based on T wave morphology and triggering factors to prioritize the gene to be tested. We sought to identify the causative mutations and mutation spectrum, perform genotype-phenotype correlation and screen family members. METHODS: Thirty patients who fulfilled the criteria were enrolled. The most probable candidate gene among KCNQ1, KCNH2 and SCN5A were sequenced. RESULTS: Of the 30 patients, 22 were classified at LQT1, two as LQT2 and six as LQT3. Mutations in KCNQ1 were identified in 17 (77%) of 22 LQT1 patients, KCNH2 mutation in one of two LQT2 and SCN5A mutations in two of six LQT3 patients. We correlated the presence of the specific ECG morphology in all mutation positive cases. Eight mutations in KCNQ1 and one in SCN5A were novel and predicted to be pathogenic by in-silico analysis. Of all parents with heterozygous mutations, 24 (92%) of 26 were asymptomatic. Ten available siblings of nine probands were screened and three were homozygous and symptomatic, five heterozygous and asymptomatic. CONCLUSIONS: This study in a cohort of Asian Indian patients highlights the mutation spectrum of common Long QT syndromes. The clinical utility for prevention of unexplained sudden cardiac deaths is an important sequel to identification of the mutation in at-risk family members.

Heat shock protein 70 gene polymorphisms' influence on the electrophysiology of long QT syndrome.

PURPOSE: Long QT syndrome (LQTS) is a rare cardiac disorder caused due to mutations in genes encoding ion channels responsible for generation of electrical impulses. The heat shock protein (HSP)-70 gene, expressed under conditions of stress, plays a cardioprotective role when overexpressed and helps in the proper folding of the nascent proteins synthesized by the cellular machinery. We aimed to identify the role played by HSP-70 gene polymorphisms in the pathogenesis of LQTS. METHODS: Study included 49 LQTS patients, 71 family members, and 219 healthy individuals recruited from an ethnically matched population. Genotyping of the single-nucleotide polymorphisms (SNPs) rs1043618 (HSP-70-1, +190G/C), rs1061581 (HSP-70-2, +1267A/G), and rs2227956 (HSP-70-hom, +2437T/C) was performed by PCR-RFLP analysis, and the results were analyzed statistically at 95 % confidence interval and p ≤ 0. 05. RESULTS: The "C" allele of HSP-70-1 (+190G/C) and "G" allele of HSP-70-2 (+1267A/G) showed strong association with LQTS phenotype. The haplotype group C-G-T consisting of two risk alleles was significantly associated with the disease condition. Multifactor dimensionality reduction analysis further substantiated that the three-allele model influences the outcome of the phenotype highlighting the effect of modifiers in the etiology of LQTS. CONCLUSIONS: As HSP-70 influences the channel assembly and maturation/trafficking of the ion channel proteins, the alleles C of the HSP-70-1 and G of the HSP-70-2 loci and the haplotype group C-G-T could be considered a diagnostic biomarker in the identification of the LQTS phenotype with a potential to affect the progression and modification of the disease phenotype.

Mutational analysis of SCN5A gene in long QT syndrome.

The SCN5A gene encodes for the INa channel implicated in long QT syndrome type-3 (LQTS-type-3). Clinical symptoms of this type are lethal as most patients had a sudden death during sleep. Screening of SCN5A in South Indian cohort by PCR-SSCP analyses revealed five polymorphisms - A29A (exon-2), H558R (exon-12), E1061E and S1074R (exon-17) and IVS25 + 65G > A (exon-25) respectively. In-silico and statistical analyses were performed on all the polymorphisms. Exon-2 of SCN5A gene revealed A282G polymorphism (rs6599230), resulting in alanine for alanine (A29A) silent substitution in the N-terminus of SCN5A protein. Exon-12 showed A1868G polymorphism (H558R - rs1805124) and its 'AA' genotype and 'A' allele frequency were found to be higher in LQTS patients pointing towards its role in LQTS etiology. Two polymorphisms A3378G (E1061E) and the novel C3417A (S1074R) were identified as compound heterozygotes/genetic compounds in exon-17 of SCN5A located in the DIIS6-DIIIS1 domain of the SCN5A transmembrane protein. IVS25 + 65G > A was identified in intron-25 of SCN5A. The 'G' allele was identified as the risk allele. Variations were identified in in-silico analyses which revealed that these genetic compounds may lead to downstream signaling variations causing aberrations in sodium channel functions leading to prolonged QTc. The compound heterozygotes of SCN5A gene polymorphisms revealed a significant association which may be deleterious/lethal leading to an aberrant sodium ion channel causing prolonged QTc.

Genotype-phenotype correlation in long QT syndrome families.

Heterogeneity in clinical manifestations is a well-known feature in Long QT Syndrome (LQTS). The extent of this phenomenon became evident in families wherein both symptomatic and asymptomatic family members are reported. The study hence warrants genetic testing and/or screening of family members of LQTS probands for risk stratification and prediction. Of the 46 families screened, 18 probands revealed novel variations/compound heterozygosity in the gene/s screened. Families 1-4 revealed probands carrying novel variations in KCNQ1 gene along with compound heterozygosity of risk genotypes of the SCN5A, KCNE1 and NPPA gene/s polymorphisms screened. It was also observed that families- 5, 6 and 7 were typical cases of "anticipation" in which both mother and child were diagnosed with congenital LQTS (cLQTS). Families- 16 and 17 represented aLQTS probands with variations in IKs and INa encoding genes. First degree relatives (FDRs) carrying the same haplotype as the proband were also identified which may help in predictive testing and management of LQTS. Most of the probands exhibiting a family history were found to be genetic compounds which clearly points to the role of cardiac genes and their modifiers in a recessive fashion in LQTS manifestation.

Atrial natriuretic peptide gene - a potential biomarker for long QT syndrome.

This study highlights the possible implication of NPPA (natriuretic peptide precursor A) gene in the etiology of Long QT syndrome (LQTS) by population-based as well as familial study. Three SNPs of NPPA - C-664G, C1363A and T1766C were examined by molecular analyses in LQTS, controls and first degree relatives (FDRs). This study revealed a possible association of 1364 C>A SNP 'C' allele with LQTS (p = 0.0013). All three SNPs were in tight linkage disequilibrium. The familial study highlights the association of NPPA SNP with cLQTS and implicating it as a potential biomarker in South Indian population.

Novel mutations of KCNQ1 in Long QT syndrome.

BACKGROUND: Autosomal recessive Long QT syndrome is characterized by prolonged QTc along with congenital bilateral deafness depends on mutations in K(+) channel genes. A family of a Long QT syndrome proband from India has been identified with novel indel variations. METHODS: The molecular study of the proband revealed 4 novel indel variations in KCNQ1. In-silico analysis revealed the intronic variations has led to a change in the secondary structure of mRNA and splice site variations. The exonic variations leads to frameshift mutations. DNA analysis of the available family members revealed a carrier status. RESULTS AND CONCLUSION: It is thus predicted that the variations may lead to a change in the position of the splicing enhancer/inhibitor in KCNQ1 leading to the formation of a truncated S2-S3 fragment of KCNQ1 transmembrane protein in cardiac cells as well as epithelial cells of inner ear leading to deafness and aberrant repolarization causing prolonged QTc.

Acute disseminated encephalomyelitis presenting as depressive episode.

A 9-year-old girl presented to the Child Guidance Clinic with clinical features suggestive of depressive episode of 1 week duration. There was history of short febrile illness 3 weeks prior to the onset of the depressive symptoms. MRI scan of brain showed features of acute disseminated encephalomyelitis.

Rickettsial infection with hemophagocytosis.

A five-year-old girl admitted with scrub typhus developed multiple organ dysfunction associated with hyperferritinaemia, hypofibrinogenaemia and hyperlipidaemia. Bone marrow aspiration studies confirmed haemophagocytic lymphohistiocytosis (HLH). HLH is a syndrome characterized by the uncontrolled activation and proliferation of macrophages and T-cells and can occur together with infections, connective tissue disorders, malignancies and genetic disorders.

Clinical profile of acute disseminated encephalomyelitis in children.

AIM: To study the clinical profile of acute disseminated encephalomyelitis (ADEM) in children. MATERIALS AND METHODS: All children admitted with ADEM during a period of one and a half years were included in the study. The diagnosis of ADEM was made based on the clinical presentation and suggestive MRI findings. All children were treated with intravenous methyl prednisolone, followed by oral prednisolone and followed up for varying periods up to three and a half years. RESULTS: The sample consisted of 14 children with 11(79%) girls and 3 (21%) boys. The oldest child was 12 years and the youngest was a six-month-old infant. Acute febrile illness preceded the onset of neurological symptoms in 64% of children. The interval between the preceding illness and symptoms of ADEM varied from 7 days to 28 days (mean 12 days). The common presenting symptoms were fever, vomiting, headache, gait disturbance and generalized seizures. Neurological manifestations included altered sensorium, multiple cranial nerve involvement, quadriplegia and paraplegia, dystonia and choreiform movements, nystagmus, bladder involvement (both incontinence and retention), speech defect and double vision. Facial nerve was the most common cranial nerve involved. Psychological manifestations included aggressive behavior, psychotic symptoms and mood changes. One child each had features of acute psychotic episode and depressive episode. All children recovered fully. One child had multiphasic disseminated encephalomyelitis (MDEM) on follow up. CONCLUSION: Despite the serious neuropsychiatric manifestations, ADEM in children generally has good immediate outcome. Children with ADEM need long-term follow up for cognitive impairments.

Acute disseminated encephalomyelitis presenting as acute psychotic disorder.

A 5 year old boy and a 10 year old girl presented with acute onset of psychotic disorder, which occurred one week after an upper respiratory infection. MRI images of brain were consistent with the diagnosis of acute disseminated encephalomyelitis (ADEM) in both cases. ADEM is one of the differential diagnoses to be considered when acute psychotic disorder occurs during childhood.

Revesz syndrome.

A 5-year-old girl was admitted with pallor, hypopigmented sparse hair, tongue ulcers, atrophic nail changes, hypoplastic anemia and bilateral exudative retinopathy. A diagnosis of Revesz syndrome was made. She had the additional features of retinal detachment and retinitis pigmentosa, which are hitherto unreported in this syndrome.

Macroscopic T wave alternans in long QT syndrome.

A 6 year old girl was admitted with recurrent episodes of loss of consciousness. ECG showed prolonged QT interval and macroscopic T Wave alternans. Identification of this ECG pattern is important since it can lead to potentially lethal arrhythmias.

Spectrum of clinical presentations of vein of galen aneurysm.

Aneurysm of the vein of Galen is a rare intracranial vascular malformation. It is known to have diverse manifestations and varying severity. Four cases with different modes of presentation and outcome are reported. A mortality of 50 per cent was encountered. Among the survivors, one had neurologic sequelae whereas the other had attained age-appropriate developmental milestones. The former was a rare case of spontaneous thrombosis of the aneurysm while the latter was a boy who underwent therapeutic embolization.