Molecular Epidemiology and Sequence Analysis of Rabies Virus Isolates from North and North East India

In the present study phylogenetic analysis of 30 rabies virus (RV) isolates collected from North and North East India between 2013 and 2016 was carried out. Analysis of two sets of sequence of non-coding G-L intergenic region, based upon a 132-nucleotide region of the cytoplasmic domain (CD) of the G gene (G-CD) and a 549-nucleotide (Psi-L) was done. The phylogenetic tree constructed using 549 nucleotide sequence of hyper variable region (Psi-L) showed the same topology as that obtained on the basis of 132 nucleotide sequence of G-CD region. Four different genetic clusters (GCs) distributed among three geographical regions were identified. Comparison of deduced amino acid (aa) sequences showed four amino acid changes - aa462G, aa465H/R and aa468K in G-CD region. The change observed at position aa465R indicated the spillover of Indian wild strain (mongoose) to domestic animals in Delhi region. The homology among the Indian RV isolates shared >97% nucleotide similarity irrespective of their geographical regions and hosts. The study revealed that the RV isolates are region specific, not host specific and all belonged to genotype 1

Posttranscriptional regulation of PARG mRNA by HuR facilitates DNA repair and resistance to PARP inhibitors

The majority of pancreatic ductal adenocarcinomas (PDAC) rely on the mRNA stability factor HuR (ELAV-L1) to drive cancer growth and progression. Here, we show that CRISPR-Cas9–mediated silencing of the HuR locus increases the relative sensitivity of PDAC cells to PARP inhibitors (PARPi). PDAC cells treated with PARPi stimulated translocation of HuR from the nucleus to the cytoplasm, specifically promoting stabilization of a new target, poly (ADP-ribose) glycohydrolase (PARG) mRNA, by binding a unique sequence embedded in its 30 untranslated region. HuR-dependent upregulation of PARG expression facilitated DNA repair via hydrolysis of polyADP-ribose on related repair proteins. Accordingly, strategies to inhibit HuR directly promoted DNA damage accumulation, inefficient PAR removal, and persistent PARP-1 residency on chromatin (PARP-1 trapping). Immunoprecipitation assays demonstrated that the PARP-1 protein binds and posttranslationally modifies HuR in PARPi-treated PDAC cells. In a mouse xenograft model of human PDAC, PARPi monotherapy combined with targeted silencing of HuR significantly reduced tumor growth compared with PARPi therapy alone. Our results highlight the HuR–PARG axis as an opportunity to enhance PARPi-based therapies. ©2017 AACR

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses

To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1–11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely

The nondermatophyte molds: Emerging as leading cause of onychomycosis in south-east Rajasthan

Background: Onychomycosis is a fungal disease of the nail apparatus caused by both dermatophytic and nondermatophytic strains. Treatment involves long duration antifungal therapy. However, long treatment duration without identifying the causative species may lead to resistance. Confirmation of diagnosis and speciation by culture before administering antifungal therapy is ideal. Aims: To study the clinical and epidemiological aspects of onychomycosis in Hadoti region (south-east Rajasthan) and identify various mycological strains and predisposing factors causing onychomycosis. Materials and Methods: A prospective study of clinically diagnosed cases of onychomycosis attending the outpatient Department of Dermatology in our institute conducted from June 2012 to May 2013. The clippings were subjected to potassium hydroxide (KOH) examination and culture in the appropriate medium. Results: A total of 150 cases were enrolled in our study. There were 110 males (73.33%) and 40 females (26.66%) and male to female ratio was 2.75:1. The total dystrophic onychomycosis was the most common presentation seen in the majority of cases (46%) followed by distal lateral subungual onychomycosis in 52 cases (34.6%), mixed onychomycosis in 16 cases (10.66%), superficial white onychomycosis in 11 cases (7.33%), and proximal subungual onychomycosis in 2 cases. None had the endonyx variant. Direct microscopic examination of the nail clipping mounted with 40% KOH demonstrated fungal elements in 83 (55.33%) cases. Rate of isolation of organisms by culture was 64%. Nondermatophytes were isolated in 53 (35.33%), dermatophytes in 28 (18.66%), and yeasts in 15 (10%) of cases. The most commonly isolated species was Aspergillus in 45 (30%) cases. Aspergillus flavus was more commonly isolated compared to Aspergillus niger. Conclusion: The nondermatophyte molds appear to be more common causative agents of onychomycosis compared to usual dermatophyte species in south-east Rajasthan. Our study re-emphasizes the importance of culture for diagnosis of onychomycosis in every suspected case prior to therapy

Author Correction: Plk1 Regulates the Repressor Function of FoxM1b by inhibiting its Interaction with the Retinoblastoma Protein

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Monitoring the efficacy of antimalarial medicines in India via sentinel sites: Outcomes and risk factors for treatment failure

Background & objectives: To combat the problem of antimalarial drug resistance, monitoring the changes in drug efficacy over time through periodic surveillance is essential. Since 2009, systematic and continuous monitoring is being done through nationwide sentinel site system. Potential early warning signs like partner drug resistance markers were also monitored in the clinical samples from the study areas. Methods: A total of 1864 patients with acute uncomplicated malaria were enrolled in therapeutic efficacy studies of artesunate plus sulphadoxine-pyrimethamine (AS+SP) for Plasmodium falciparum; those infected with P. vivax were given chloroquine (CQ). Polymerase chain reaction (PCR) was used to distinguish post-treatment reinfection from treatment failures. Isolates of P. falciparum were also analysed for dihydropteroate synthase (dhps) and dihydrofolate reductase (dhfr) gene mutations. Results: Overall, 1687 (91.7%) patients completed the follow-up. In most of the falciparum patients the parasitaemia was cleared within 24 h of treatment, except 12 patients who remained parasite positive after 72 h. Presence of dhfr and dhps quintuple mutation was observed predominantly in treatment failure samples. A daily dose of artesunate of 95% cases in all the sentinel sites except in Northeastern region (NE). Chloroquine remained 100% efficacious in case of P. vivax infections. Interpretation & conclusion: Till 2012, India′s national antimalarial drug resistance monitoring system proved highly efficacious and safe towards first-line antimalarials used in the country, except in Northeastern region where a decline in efficacy of AS+SP has been observed. This led to change in first-line treatment for P. falciparum to artemether-lumefantrine in Northeastern region