1,3-C-H bond activation on a transient gallium(I)/isocyanate adduct.

Reaction of NacNacGa with phenylisocyante generates a transient species amenable to unusual 1,3-C-H bond addition of unactivated sp3 C-H and sp2 C-H bonds of substrates featuring a hard donor atom. This reaction proceeds for pyridine oxide, dimethylsulfoxide, and dimethylacetamide, but not for pyridine, cyclohexanone, and ethyl acetate. C-H activation was also not observed for reactions with triethylphosphine oxide but, interestingly, in the presence of this compound isocyanate undergoes self-coupling on Ga(I) with a regioselectivity that is different when carried out in the absence of Et3PO.

Spatiotemporal pattern of thyroid cancer incidence in South Kerala: A population-based study.

Background: Thyroid cancer (TC) is the most common endocrine cancer and has been increasing over the past decades worldwide. A notable finding is that Kerala's capital Thiruvananthapuram ranks the first among men and the second highest among women in the incidence of TC in India. Reasons for this increase have not been established. Objectives: Here, we investigated the spatiotemporal pattern of TC incidence in Thiruvananthapuram. Materials and Methods: TC incidence data (n = 1937) of Population Based Cancer Registry Thiruvananthapuram, Kerala, India, between 2012 and 2016, were analyzed for identifying geographical patterns by spatial methods, temporal methods for studying spatial variation in TC incidence, distribution of age, gender, and histology in lowland (coastal), midland, and highland. Results: Spatial clustering of TC incidence was identified consistently near the coastal region based on all geospatial analyses. 56.9%, 23.9%, and 19.2% of TC cases were observed in the coastal, midland, and highland areas, respectively. A significant clustered pattern of TC incidence was revealed by Moran's index I (0.49), high-high clusters by local Moran's, hotspot by Getis-Ord-Gi* (P < 0.05), point pattern analysis by nearest neighbor ratio and kernel density estimation. The relative risk of the significant cluster was obtained as 1.60 (95% confidence interval: 1.03-1.84) by SaTScan analysis. Conclusion: This study identified spatial variations in the pattern of TC cases with significant clusters near the coastal region of Thiruvananthapuram. This would help to pinpoint the high-risk geographical areas of TC and for more effective cancer control programs.

Novel Immunotherapies for Myasthenia Gravis.

Myasthenia gravis (MG), a prototype autoimmune neurological disease, had its therapy centred on corticosteroids, non-steroidal broad-spectrum immunotherapy and cholinesterase inhibitors for several decades. Treatment-refractory MG and long-term toxicities of the medications have been major concerns with the conventional therapies. Advances in the immunology and pathogenesis of MG have ushered in an era of newer therapies which are more specific and efficacious. Complement inhibitors and neonatal Fc receptor blockers target disease-specific pathogenic mechanisms linked to myasthenia and have proven their efficacy in pivotal clinical studies. B cell-depleting agents, specifically rituximab, have also emerged as useful for the treatment of severe MG. Many more biologicals are in the pipeline and in diverse stages of development. This review discusses the evidence for the novel therapies and the specific issues related to their clinical use.

Tryptanthrin-malononitrile adduct for highly efficient turn-off fluorescent sensing of aniline.

The fluorescence quenching of 2-(8-chloro-12-oxo-12H-indolo[2,1-b]quinazolin-6-ylidene)-malononitrile (5a) by aniline was studied in detail. Time correlated single photon counting measurements (TCSPC) indicated that the quenching involved both static and dynamic mechanisms without ground state complex formation. The selectivity towards aniline sensing in presence of other amines/aromatics and the anti-interference studies together with the low LOD value indicates the potential of 5a as a molecular probe for aniline sensing which is unaffected by pH alteration as well.

Resting-State Functional Connectivity in Relapsing-Remitting Multiple Sclerosis with Mild Disability: A Data-Driven, Whole-Brain Multivoxel Pattern Analysis Study.

Background: Multivoxel pattern analysis (MVPA) has emerged as a powerful unbiased approach for generating seed regions of interest (ROIs) in resting-state functional connectivity (RSFC) analysis in a data-driven manner. Studies exploring RSFC in multiple sclerosis have produced diverse and often incongruent results. Objectives: The aim of the present study was to investigate RSFC differences between people with relapsing-remitting multiple sclerosis (RRMS) and healthy controls (HC). Methods: We performed a whole-brain connectome-wide MVPA in 50 RRMS patients with expanded disability status scale ≤4 and 50 age and gender-matched HCs. Results: Significant group differences were noted in RSFC in three clusters distributed in the following regions: anterior cingulate gyrus, right middle frontal gyrus, and frontal medial cortex. Whole-brain seed-to-voxel RSFC characterization of these clusters as seed ROIs revealed network-specific abnormalities, specifically in the anterior cingulate cortex and the default mode network. Conclusions: The network-wide RSFC abnormalities we report agree with the previous findings in RRMS, the cognitive and clinical implications of which are discussed herein. Impact statement This study investigated resting-state functional connectivity (RSFC) in relapsing-remitting multiple sclerosis (RRMS) people with mild disability (expanded disability status scale ≤4). Whole-brain connectome-wide multivoxel pattern analysis was used for assessing RSFC. Compared with healthy controls, we were able to identify three regions of interest for significant differences in connectivity patterns, which were then extracted as a mask for whole-brain seed-to-voxel analysis. A reduced connectivity was noted in the RRMS group, particularly in the anterior cingulate cortex and the default mode network regions, providing insights into the RSFC abnormalities in RRMS.

Clinical Spectrum of Biopsy Proven Mitochondrial Myopathy.

Objectives: Clinical spectrum of mitochondrial myopathy extends beyond chronic progressive external ophthalmoplegia (CPEO). While information on encephalomyopathies is abundant, clinical data on predominant myopathic presentation of mitochondrial disorders are lacking. Materials and Methods: Clinical, electrophysiological, biochemical, and follow-up data of patients with predominant myopathic presentation and muscle biopsy confirmed primary mitochondrial myopathy was obtained. We excluded known syndromes of mitochondrial cytopathies and encephalomyopathies. Results: Among 16 patients, 7 had CPEO, 4 had CPEO with limb-girdle muscle weakness (LGMW), and 5 had isolated LGMW. Systemic features included seizures with photosensitivity (n = 3), diabetes (n = 1), cardiomyopathy (n = 1), and sensorineural hearing loss (n = 1) and were more common in isolated LGMW. Elevated serum creatine kinase (CK) and lactate levels and electromyography (EMG) myopathic potentials were more frequent with LGMW. During follow-up, LGMW had more severe progression of weakness. Conclusion: We identified three subsets of mitochondrial myopathy with distinct clinical features and evolutionary patterns. Isolated LGMW was seen in 30% of patients and would represent severe end of the spectrum.

Genotype-phenotype correlations in valosin-containing protein disease: a retrospective muticentre study.

BACKGROUND: Valosin-containing protein (VCP) disease, caused by mutations in the VCP gene, results in myopathy, Paget's disease of bone (PBD) and frontotemporal dementia (FTD). Natural history and genotype-phenotype correlation data are limited. This study characterises patients with mutations in VCP gene and investigates genotype-phenotype correlations. METHODS: Descriptive retrospective international study collecting clinical and genetic data of patients with mutations in the VCP gene. RESULTS: Two hundred and fifty-five patients (70.0% males) were included in the study. Mean age was 56.8±9.6 years and mean age of onset 45.6±9.3 years. Mean diagnostic delay was 7.7±6 years. Symmetric lower limb weakness was reported in 50% at onset progressing to generalised muscle weakness. Other common symptoms were ventilatory insufficiency 40.3%, PDB 28.2%, dysautonomia 21.4% and FTD 14.3%. Fifty-seven genetic variants were identified, 18 of these no previously reported. c.464G>A (p.Arg155His) was the most frequent variant, identified in the 28%. Full time wheelchair users accounted for 19.1% with a median time from disease onset to been wheelchair user of 8.5 years. Variant c.463C>T (p.Arg155Cys) showed an earlier onset (37.8±7.6 year) and a higher frequency of axial and upper limb weakness, scapular winging and cognitive impairment. Forced vital capacity (FVC) below 50% was as risk factor for being full-time wheelchair user, while FVC <70% and being a full-time wheelchair user were associated with death. CONCLUSION: This study expands the knowledge on the phenotypic presentation, natural history, genotype-phenotype correlations and risk factors for disease progression of VCP disease and is useful to improve the care provided to patient with this complex disease.

A real world multi center study on efficacy and safety of natalizumab in Indian patients with multiple sclerosis.

BACKGROUND: Natalizumab (NTZ) is increasingly being used in Indian multiple sclerosis (MS) patients. There are no reports on its safety and efficacy, especially with respect to the occurrence of progressive multifocal leukoencephalopathy (PML). OBJECTIVES: To describe the patient characteristics, treatment outcomes, and adverse events, especially the occurrence of PML in NTZ-treated patients. METHODS: A multicentre ambispective study was conducted across 18 centres, from Jan 2012 to Dec 2021. Patients at and above the age of 18 years treated with NTZ were included. Descriptive and comparative statistics were applied to analyze data. RESULTS: During the study period of 9 years, 116 patients were treated with NTZ. Mean age of the cohort was 35.6 ± 9.7 years; 83/116 (71.6%) were females. Relapse rate for the entire cohort in the year before NTZ was 3.1 ± 1.51 while one year after was 0.20±0.57 (p = 0.001; CI 2.45 -3.35). EDSS of the entire cohort in the year before NTZ was 4.5 ± 1.94 and one year after was 3.8 ± 2.7 (p = 0.013; CI 0.16-1.36). At last follow up (38.3 ± 22.78 months) there were no cases of PML identified. CONCLUSIONS: Natalizumab is highly effective and safe in Indian MS patients, with no cases of PML identified at last follow up.

Impact of the COVID-19 Pandemic on the Frequency, Clinical Spectrum and Outcomes of Pediatric Guillain-Barré Syndrome in India: A Multicentric Ambispective Cohort Study.

Objective: To study impact of COVID-19 pandemic on frequency, clinical/electrophysiological profile and treatment outcomes in pediatric Guillain-Barré syndrome (GBS). Background: GBS is the most frequent cause of pediatric acute flaccid paralysis. The effect of the COVID-19 pandemic on pediatric GBS is unclear in the literature. Methods: We conducted an ambispective, multicentric, cohort study involving 12 of 27 centres in GBS Consortium, during two periods: pre-COVID-19 (March-August 2019) and during COVID-19 (March-August 2020). Children ≤12 years who satisfied National Institute of Neurological Diseases and Stroke criteria for GBS/variants were enrolled. Details pertaining to clinical/laboratory parameters, treatment and outcomes (modified Rankin Scale (mRS) at discharge, GBS Disability score at discharge and 3 months) were analysed. Results: We enrolled 33 children in 2019 and 10 in 2020. Children in 2020 were older (median 10.4 [interquartile range 6.75-11.25] years versus 5 (2.5-8.4) years; P = 0.022) and had more sensory symptoms (50% versus 18.2%; P = 0.043). The 2020 group had relatively favourable mRS at discharge (median 1 (1-3.5) versus 3 (2-4); P = 0.042) and GBS disability score at 3 months (median 0 (0-0.75) versus 2 (0-3); P = 0.009) compared to 2019. Multivariate analysis revealed bowel involvement (P = 0.000) and ventilatory support (P = 0.001) as independent predictors of disability. No child in 2020 had preceding/concurrent SARS-CoV2 infection. Conclusions: The COVID-19 pandemic led to a marked decline in pediatric GBS presenting to hospitals. Antecedent illnesses, clinical and electrophysiological profile of GBS remained largely unchanged from the pre-pandemic era.

Isolated Myelitis and Intramedullary Spinal Cord Abscess in Melioidosis-A Case Report.

Neuromelioidosis is a severe tropical infection with high morbidity and mortality. Isolated myelitis is an extremely rare manifestation of melioidosis which may evade diagnosis. We report a 69-year-old diabetic male patient who presented with acute flaccid paraplegia and longitudinally extensive myelitis and no systemic symptoms. MRI of spinal cord showed lower dorsal cord and conus T2 hyperintensity and microabscesses with dural enhancement. The diagnosis was clinched with blood culture growing Burkholderia pseudomallei. He rapidly developed colitis, septicemia and multiorgan dysfunction and succumbed to the illness in spite of antibiotics and aggressive supportive care. The case highlights that melioidosis should be considered as a differential diagnosis of infectious myelitis, especially in the tropics. Presence of a neutrophilic blood and cerebrospinal fluid picture and microabscesses in spinal cord are important diagnostic clues. The outcome is dismal unless the diagnosis is considered early in the disease course and managed expeditiously with sensitive antibiotics.

Assessing quality of obturation and instrumentation time using Kedo-SG blue, Kedo-SH, and reciprocating hand K-files in primary mandibular molars: A double-blinded randomized controlled trial.

BACKGROUND: Pulpectomy is the treatment of choice for severely infected primary molars. The aim of the study is to evaluate the instrumentation time and obturation quality using Kedo SG blue, Kedo SH, and reciprocating hand K files in primary mandibular molars. To evaluate the instrumentation time and obturation quality using Kedo-SG blue, Kedo-SH, and reciprocating hand K-files in primary mandibular molars. MATERIALS AND METHODS: A double-blinded randomized controlled trial was conducted on 45 mandibular molars and were randomly assigned to three experimental groups (n = 15). Group I was instrumented using Kedo-SG blue pediatric rotary files, Group II with Kedo-SH pediatric hand files, and Group III with reciprocating hand K-files. Standardized digital radiographs were taken before and after root canal instrumentation. Root canal preparation time was also recorded. Statistical analysis of the obtained data was done using SPSS software version 17.0. An intergroup comparison of the instrumentation time and the quality of obturation were done using ANOVA and Chi-square test with the level of significance set at 5%. P < 0.05 was considered statistically significant. RESULTS: No significant differences were noted with regard to the quality of obturation between the three groups (P < 0.14). However, a statistically significant difference was noted in the instrumentation time between the three groups (P = 0.000). Kedo-SG blue rotary file had significantly lesser instrumentation time when compared to that of Kedo-SH hand files and reciprocating hand K-files. CONCLUSION: On comparative evaluation,Kedo-SG blue pediatric rotary file showed a marked reduction in instrumentation time, followed by Kedo-SH pediatric hand files and reciprocating hand K-files.

Recurrent painful ophthalmoplegic neuropathy: a cause for recurrent third nerve palsy in a child.

Recurrent painful ophthalmoplegic neuropathy (RPON), previously called ophthalmoplegic migraine, is a rare condition characterised by recurrent episodes of headache and ophthalmoplegia. We report a case of 11-year-old girl with recurrent painful ophthalmoplegia due to isolated right oculomotor nerve involvement. MR brain imaging showed enhancing lesion of cisternal segment of right oculomotor nerve. A possibility of Tolosa Hunt syndrome was considered and she was treated with glucocorticoids, followed by azathioprine due to recurrence. In the fourth episode, she developed migraine headache followed by right third nerve palsy, after which the diagnosis was revised to RPON. She was started on flunarizine along with short-term glucocorticoids. At 1-year follow-up, she remained asymptomatic. RPON should be considered in patients with recurrent third nerve palsy to avoid inadvertent long-term exposure to immunosuppressive agents.

Myoneuropathic presentation of limb girdle muscular dystrophy R8 with a novel TRIM32 mutation.

TRIM 32-related Limb Girdle Muscular Dystrophy (LGMD R8/2H) is a rare genetic muscle disease reported in fewer than 100 patients worldwide. Here, we report a male patient with progressive proximo-distal lower limb weakness with onset in the third decade who had mixed myopathic and neurogenic pattern in electrophysiology and muscle biopsy. Clinical exome sequencing revealed a homozygous pathogenic single base pair insertion in exon 2 of the TRIM32 gene confirming the diagnosis of LGMD R8. This is a novel frameshift mutation and one of the very few cases of LGMD R8 reported from India.