Isotretinoin-induced myositis.

Retinoid-induced myositis is a phenomenon recognised in multiple case reports. We report a case of isotretinoin-induced myositis in an 18-year-old male patient. This case adds to the published literature as it demonstrates (i) myositis may occur after extended periods of isotretinoin use, (ii) should be considered as a differential diagnosis even when presenting asymmetrically and (iii) can continue to progress clinically and biochemically initially following the suspension of isotretinoin before being effectively treated with corticosteroids.

Contrasting Distribution of SARS-CoV-2 Lineages across Multiple Rounds of Pandemic Waves in West Bengal, the Gateway of East and North-East States of India.

The evolution of viral variants and their impact on viral transmission have been an area of considerable importance in this pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We analyzed the viral variants in different phases of the pandemic in West Bengal, a state in India that is important geographically, and compared the variants with other states like Delhi, Maharashtra, and Karnataka, located in other regions of the country. We have identified 57 pango-lineages in 3,198 SARS-CoV-2 genomes, alteration in their distribution, as well as contrasting profiles of amino acid mutational dynamics across different waves in different states. The evolving characteristics of Delta (B.1.617.2) sublineages and alterations in hydrophobicity profiles of the viral proteins caused by these mutations were also studied. Additionally, implications of predictive host miRNA binding/unbinding to emerging spike or nucleocapsid mutations were highlighted. Our results throw considerable light on interesting aspects of the viral genomic variation and provide valuable information for improved understanding of wave-defining mutations in unfolding the pandemic. IMPORTANCE Multiple waves of infection were observed in many states in India during the coronavirus disease 2019 (COVID19) pandemic. Fine-scale evolution of major SARS-CoV-2 lineages and sublineages during four wave-window categories: Pre-Wave 1, Wave 1, Pre-Wave 2, and Wave 2 in four major states of India: Delhi (North), Maharashtra (West), Karnataka (South), and West Bengal (East) was studied using large-scale virus genome sequencing data. Our comprehensive analysis reveals contrasting molecular profiles of the wave-defining mutations and their implications in host miRNA binding/unbinding of the lineages in the major states of India.

Anakinra treats fulminant myocarditis from Neisseria meningitidis septicaemia and haemophagocytic lymphohistiocytosis: a case report.

BACKGROUND: Fulminant myocarditis is a life-threatening condition characterized by acute cardiac dysfunction requiring pharmacological or mechanical circulatory support. Haemophagocytic lymphohistiocytosis (HLH) is an uncommon state of immune dysregulation and overactivation. Inflammation mediated by interleukin-1 (IL-1) is thought to play a role in the pathogenesis of myocarditis and HLH, and there is some evidence that the IL-1 receptor antagonist Anakinra may play a role in treating both these conditions. CASE SUMMARY: A 26-year-old previously healthy male presented to the Emergency Department with a 3-day history of malaise, headache, vomiting, diarrhoea, and fever. He was profoundly hypotensive on arrival, diagnosed with septic shock, and commenced on broad-spectrum antibiotics and vasopressors. Blood tests showed lymphopenia, thrombocytopenia, low fibrinogen and elevated high sensitivity troponin T, ferritin, and C-reactive protein. Echocardiography demonstrated severely impaired biventricular systolic function and a diagnosis of fulminant myocarditis was made. His condition deteriorated and he required intubation and additional inotropic support. A diagnosis of HLH was made and he was commenced on Anakinra and Methylprednisolone. His condition improved rapidly thereafter. Polymerase chain reaction testing subsequently confirmed infection with Neisseria meningitidis. DISCUSSION: In this case, fulminant myocarditis and HLH were life-threatening manifestations of meningococcal septicaemia, and the patient's condition improved rapidly following administration of the IL-1 receptor antagonist Anakinra. These complications should be borne in mind in septic patients with marked haemodynamic instability and multiorgan dysfunction, and treatment with Anakinra should be considered in those who fail to respond to conventional therapy.

dbGENVOC: database of GENomic Variants of Oral Cancer, with special reference to India.

Oral cancer is highly prevalent in India and is the most frequent cancer type among Indian males. It is also very common in southeast Asia. India has participated in the International Cancer Genome Consortium (ICGC) and some national initiatives to generate large-scale genomic data on oral cancer patients and analyze to identify associations and systematically catalog the associated variants. We have now created an open, web-accessible database of these variants found significantly associated with Indian oral cancer patients, with a user-friendly interface to enable easy mining. We have value added to this database by including relevant data collated from various sources on other global populations, thereby providing opportunities of comparative geographical and/or ethnic analyses. Currently, no other database of similar nature is available on oral cancer. We have developed Database of GENomic Variants of Oral Cancer, a browsable online database framework for storage, retrieval and analysis of large-scale data on genomic variants and make it freely accessible to the scientific community. Presently, the web-accessible database allows potential users to mine data on ∼24 million clinically relevant somatic and germline variants derived from exomes (n = 100) and whole genomes (n = 5) of Indian oral cancer patients; all generated by us. Variant data from The Cancer Genome Atlas and data manually curated from peer-reviewed publications were also incorporated into the database for comparative analyses. It allows users to query the database by a single gene, multiple genes, multiple variant sites, genomic region, patient ID and pathway identities. Database URL: http://research.nibmg.ac.in/dbcares/dbgenvoc/.

SARS-CoV-2 mutation 614G creates an elastase cleavage site enhancing its spread in high AAT-deficient regions.

SARS-CoV-2 was first reported from China. Within three months, it evolved to 10 additional subtypes. Two evolved subtypes (A2 and A2a) carry a non-synonymous Spike protein mutation (D614G). We conducted phylodynamic analysis of over 70,000 SARS-CoV-2 coronaviruses worldwide, sequenced until July2020, and found that the mutant subtype (614G) outcompeted the pre-existing type (614D), significantly faster in Europe and North-America than in East Asia. Bioinformatically and computationally, we identified a novel neutrophil elastase (ELANE) cleavage site introduced in the G-mutant, near the S1-S2 junction of the Spike protein. We hypothesised that elevation of neutrophil elastase level at the site of infection will enhance the activation of Spike protein thus facilitating host cell entry for 614G, but not the 614D, subtype. The level of neutrophil elastase in the lung is modulated by its inhibitor α1-antitrypsin (AAT). AAT prevents lung tissue damage by elastase. However, many individuals exhibit genotype-dependent deficiency of AAT. AAT deficiency eases host-cell entry of the 614G virus, by retarding inhibition of neutrophil elastase and consequently enhancing activation of the Spike protein. AAT deficiency is highly prevalent in European and North-American populations, but much less so in East Asia. Therefore, the 614G subtype is able to infect and spread more easily in populations of the former regions than in the latter region. Our analyses provide a molecular biological and evolutionary model for the higher observed virulence of the 614G subtype, in terms of causing higher morbidity in the host (higher infectivity and higher viral load), than the non-mutant 614D subtype.

Assessment of the Hemophagocytic Lymphohistiocytosis HScore in Patients With Coronavirus Disease 2019.

The clinical manifestation of moderate to severe coronavirus disease 2019 (COVID-19) has parallels to secondary hemophagocytic lymphohistiocytosis (HLH) both clinically and based on molecular inflammatory response. We found no evidence to support the utility of risk-stratifying COVID-19 patients using risk scoring methodology designed for HLH.

Safety of intravenous anakinra in COVID-19 with evidence of hyperinflammation, a case series.

OBJECTIVES: Anakinra is a selective IL-1 inhibitor, which has been used in the context of secondary haemophagocytic lymphohistiocytosis. Although usually given in the s.c. form, previous anecdotal reports have emphasized its utility when given i.v. Our aim is to report our experience on the beneficial effects of anakinra i.v. in patients with SARS-CoV-2 and evidence of hyperinflammation. METHODS: We report four patients with severe COVID-19 infection requiring intensive care admission and ventilatory support. RESULTS: All four patients showed evidence of deterioration, with hyperferritinaemia and increasing oxygen requirements and with superadded bacterial infections. Upon commencement of anakinra i.v., there was subsequent improvement in the patients clinically, with reduction in ventilatory support and inotropic support, and biochemically, with rapid improvement in inflammatory markers. CONCLUSION: Anakinra is safe to use i.v. in patients with COVID-19 and evidence of superadded bacterial infection. Although its utility has not been confirmed in a randomized trial, current research in the COVID-19 pandemic aims to establish the utility of immunosuppression, including IL-1 blockade, on the outcomes of patients with moderate to severe disease. Our case series supports its use in patients with severe, life-threatening COVID-19 and evidence of hyperinflammation.

Mutations in SARS-CoV-2 viral RNA identified in Eastern India: Possible implications for the ongoing outbreak in India and impact on viral structure and host susceptibility.

Direct massively parallel sequencing of SARS-CoV-2 genome was undertaken from nasopharyngeal and oropharyngeal swab samples of infected individuals in Eastern India. Seven of the isolates belonged to the A2a clade, while one belonged to the B4 clade. Specific mutations, characteristic of the A2a clade, were also detected, which included the P323L in RNA-dependent RNA polymerase and D614G in the Spike glycoprotein. Further, our data revealed emergence of novel subclones harbouring nonsynonymous mutations, viz. G1124V in Spike (S) protein, R203K, and G204R in the nucleocapsid (N) protein. The N protein mutations reside in the SR-rich region involved in viral capsid formation and the S protein mutation is in the S2 domain, which is involved in triggering viral fusion with the host cell membrane. Interesting correlation was observed between these mutations and travel or contact history of COVID-19 positive cases. Consequent alterations of miRNA binding and structure were also predicted for these mutations. More importantly, the possible implications of mutation D614G (in SD domain) and G1124V (in S2 subunit) on the structural stability of S protein have also been discussed. Results report for the first time a bird's eye view on the accumulation of mutations in SARS-CoV-2 genome in Eastern India.

Substituent-Guided Palladium-Ene Reaction for the Synthesis of Carbazoles and Cyclopenta[ b]indoles.

An efficient palladium-catalyzed intramolecular Trost-Oppolzer type Alder-ene strategy was developed for the synthesis of carbazoles and cyclopenta[ b]indoles from easily accessible(3-allyl-1 H-indol-2-yl)methyl acetates. This strategy was extended for the synthesis of naphthalenes and dibenzobenzofurans as well. In addition, a short synthesis of antibacterial and antifungal natural product glycozoline and its analogues was also achieved.

Emergence of severe spondyloarthropathy-related entheseal pathology following successful vedolizumab therapy for inflammatory bowel disease.

OBJECTIVES: Vedolizumab (VDZ) blocks α4ß7 integrin and is licenced for the treatment of IBD. It has been associated with mild SpA-related features, including sacroiliitis and synovitis. Herein we report a series of cases demonstrating the emergence of severe SpA-associated enthesitis/osteitis following successful IBD therapy with VDZ. METHODS: We evaluated 11 VDZ-treated patients with IBD across seven centres who developed severe active SpA and/or enthesopathy, with the aim of characterizing the VDZ-associated SpA or entheseal flares. Imaging features demonstrating particularly severe disease were recorded. RESULTS: De novo SpA developed in 9 of 11 patients and flare of known SpA in 2 patients, with 4 patients requiring hospitalization due to disease severity. Available data showed that one of seven cases were HLA-B27 positive. The median time from VDZ initiation to flare was 12 weeks, with IBD well controlled in 7 of 10 patients (no data for 1 patient) at flare. Severe SpA enthesitis/osteitis was evident on MRI or US, including acute sacroiliitis (n = 5), extensive vertebral osteitis (n = 1), peri-facetal oedema (n = 1) and isolated peripheral enthesitis (n = 3). Due to arthritis severity, VDZ was discontinued in 9 of 11 patients and a change in therapy, including alternative anti-TNF, was initiated. CONCLUSION: Severe SpA, predominantly HLA-B27 negative, with osteitis/enthesitis may occur under successful VDZ treatment for IBD, including in subjects with prior anti-TNF therapy for intestinal disease.

Toward a quantitative description of microscopic pathway heterogeneity in protein folding.

How many structurally different microscopic routes are accessible to a protein molecule while folding? This has been a challenging question to address experimentally as single-molecule studies are constrained by the limited number of observed folding events while ensemble measurements, by definition, report only an average and not the distribution of the quantity under study. Atomistic simulations, on the other hand, are restricted by sampling and the inability to reproduce thermodynamic observables directly. We overcome these bottlenecks in the current work and provide a quantitative description of folding pathway heterogeneity by developing a comprehensive, scalable and yet experimentally consistent approach combining concepts from statistical mechanics, physical kinetics and graph theory. We quantify the folding pathway heterogeneity of five single-domain proteins under two thermodynamic conditions from an analysis of 100 000 folding events generated from a statistical mechanical model incorporating the detailed energetics from more than a million conformational states. The resulting microstate energetics predicts the results of protein engineering experiments, the thermodynamic stabilities of secondary-structure segments from NMR studies, and the end-to-end distance estimates from single-molecule force spectroscopy measurements. We find that a minimum of ∼3-200 microscopic routes, with a diverse ensemble of transition-path structures, are required to account for the total folding flux across the five proteins and the thermodynamic conditions. The partitioning of flux amongst the numerous pathways is shown to be subtly dependent on the experimental conditions that modulate protein stability, topological complexity and the structural resolution at which the folding events are observed. Our predictive methodology thus reveals the presence of rich ensembles of folding mechanisms that are generally invisible in experiments, reconciles the contradictory observations from experiments and simulations and provides an experimentally consistent avenue to quantify folding heterogeneity.

Systemic Inflammatory Response Syndrome Following Percutaneous Nephrolithotomy: Assessment of Risk Factors and Their Impact on Patient Outcomes.

OBJECTIVES: To identify perioperative risk factors for postoperative systemic inflammatory response syndrome (SIRS) and suggest possible modifications to reduce morbidity. MATERIAL AND METHODS: We prospectively analysed perioperative data such as history of pervious stone surgery, number and configuration of stones, presence of stent or nephrostomy, any previous positive urine culture, intraoperative renal pelvic urine and stone culture, aspiration of turbid urine on initial puncture, number of tracts required and clearance of stones, operative time and intraoperative hypotension and tachycardia of all patients who underwent percutaneous nephrolithotomy over a period of 15 months. RESULTS: A total of 182 patients were included, average stone size was 2.8 cm, 36.2% had staghorn stones and 15.9% had an indwelling stent or nephrostomy. Despite sterile preoperative urine culture, renal pelvic urine culture (RPUC) was positive in 14.8% (27 patients) and stone culture was positive in 21.9% (40 patients). SIRS developed in 17.5% (32 patients) and septic shock in 1.09% (2 patients). On analysis younger age, positive RPUC and stone culture, longer operative time and intraoperative tachycardia correlated significantly with the development of SIRS. CONCLUSION: Intra-operative cultures are only therapy-guiding cultures during SIRS, as preoperative urine cultures seldom accurately depict bacteriological status of upper tracts and thus should be obtained in all patients.

Adult granulosa cell tumor of the testis masquerading as hydrocele

Adult testicular granulosa cell tumor is a rare, potentially malignant sex cord-stromal tumor, of which 30 cases have been described to date. We report the case of a 43-year-old male who complained of a left testicular swelling. Scrotal ultrasound showed a cystic lesion, suggestive of hydrocele. However, due to a clinical suspicion of a solid-cystic neoplasm, a high inguinal orchidectomy was performed, which, on pathological examination, was diagnosed as adult granulosa cell tumor. Adult testicular granulosa cell tumors have aggressive behaviour as compared to their ovarian counterparts. They may rarely be predominantly cystic and present as hydrocele. Lymph node and distant metastases have been reported in few cases. Role of MIB-1 labelling index in prognostication is not well defined. Therefore, their recognition and documentation of their behaviour is important from a diagnostic, prognostic and therapeutic point of view.

Energetic and topological determinants of a phosphorylation-induced disorder-to-order protein conformational switch.

We show that the phosphorylation of 4E-BP2 acts as a triggering event to shape its folding-function landscape that is delicately balanced between conflicting favorable energetics and intrinsically unfavorable topological connectivity. We further provide first evidence that the fitness landscapes of proteins at the threshold of disorder can differ considerably from ordered domains.

Biliary peritonitis following percutaneous nephrolithotomy: Minimally invasive management.

Percutaneous nephrolithotomy (PCNL) is a standard procedure for large renal calculi but has potential for complications. Rarely, biliary tract injury can occur during PCNL that can lead to biliary peritonitis with sepsis. Such cases are usually managed by emergent cholecystectomy. We present a case of biliary peritonitis resulting from gall bladder injury during PCNL, managed minimally invasively with an abdominal drain and endoscopic retrograde cholangiography with common bile duct stenting.

Adult granulosa cell tumor of the testis masquerading as hydrocele.

Adult testicular granulosa cell tumor is a rare, potentially malignant sex cord-stromal tumor, of which 30 cases have been described to date. We report the case of a 43-year-old male who complained of a left testicular swelling. Scrotal ultrasound showed a cystic lesion, suggestive of hydrocele. However, due to a clinical suspicion of a solid-cystic neoplasm, a high inguinal orchidectomy was performed, which, on pathological examination, was diagnosed as adult granulosa cell tumor. Adult testicular granulosa cell tumors have aggressive behaviour as compared to their ovarian counterparts. They may rarely be predominantly cystic and present as hydrocele. Lymph node and distant metastases have been reported in few cases. Role of MIB-1 labelling index in prognostication is not well defined. Therefore, their recognition and documentation of their behaviour is important from a diagnostic, prognostic and therapeutic point of view.

The role of intracellular organisms in the pathogenesis of inflammatory arthritis.

Inflammatory arthritis is a condition which is characterised by recurrent episodes of joint pain and swelling. It encompasses a spectrum of disorders ranging from rheumatoid arthritis to ankylosing spondylitis. In these conditions, for reasons that are poorly understood, the immune system raises an inflammatory response within the joint space. In some cases, autoantigens have been identified (e.g., anticitrullinated peptides in rheumatoid arthritis), but the absence of these, in the seronegative arthritides, for example, raises question as to the underlying pathogenesis. Interest has, therefore, turned to host-pathogen interactions and whether aberrant immune responses to these could explain the development of arthritis. This has been most widely studied in reactive arthritis (ReA), where an infectious episode precedes the development of the joint symptoms. In this review, we present the evidence for the role of host-bacterial interactions in the pathogenesis of joint inflammation with particular emphasis on ReA. We discuss a range of possible mechanisms including molecular mimicry, persistent low grade infections, and abnormal host responses to common bacterial causes of reactive arthritis as well as discussing some of the clinical challenges that we face in making the diagnosis and in treatment of persistent symptoms.