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Dentin hypersensitivity (DH) is a rising concern in clinical dentistry that causes pain and discomfort and negatively affects the quality of life of patients. Indian Society of Periodontology conducted a nationwide survey, involving 3000 dentists in December 2020, which revealed significant knowledge gaps regarding DH, viz., under-diagnosis, incorrect differential diagnosis, and treatment strategies/recommendations for the management of DH patients in daily clinical practice. The current paper has been envisioned and conceptualized to update the practicing Indian dentists regarding the so-called enigma of dentistry "Dentin Hypersensitivity," based on the best available contemporary evidence. An expert panel was constituted comprising 30 subject experts from across the country, which after extensive literature review and group discussions formulated these recommendations. The panel advocated routine screening of all dentate patients for exposed dentin areas and DH to avoid under-diagnosis of the condition and suggested an early preventive management. Consensus guidelines/recommendations for the use of desensitizing agents (DAs) at home, including the use of herbal agents, are also provided within the backdrop of the Indian context. The guidelines recommend that active management of DH shall be accomplished by a combination of at home and in-office therapies, starting with the simplest and cost-effective home use of desensitizing toothpastes. A diagnostic decision tree and a flowchart for application in daily practice are designed to manage the patients suffering from DH or presenting with exposed dentin areas in dentition. Various treatment methods to manage DH have been discussed in the paper, including the insights from previously published treatment guidelines. Further, a novel system of classification of DH patients based on specific case definitions has been developed for the first time. Explicit charts regarding the available treatment options and the chronology of institution of the agent, for the management in different case categories of DH, have been provided for quick reference. The management strategy takes into account a decision algorithm based on hierarchy of complexity of treatment options and intends to improve the quality of life of the patient by long-term maintenance with an innovatively defined triple C's or 3Cs approach., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Indian Society of Periodontology.)

Effective broad-spectrum antivirals are critical to prevent and control emerging human coronavirus (hCoV) infections. Despite considerable progress made toward identifying and evaluating several synthetic broad-spectrum antivirals against hCoV infections, a narrow therapeutic window has limited their success. Enhancing the endogenous interferon (IFN) and IFN-stimulated gene (ISG) response is another antiviral strategy that has been known for decades. However, the side effects of pegylated type-I IFNs (IFN-Is) and the proinflammatory response detected after delayed IFN-I therapy have discouraged their clinical use. In contrast to IFN-Is, IFN-λ, a dominant IFN at the epithelial surface, has been shown to be less proinflammatory. Consequently, we evaluated the prophylactic and therapeutic efficacy of IFN-λ in hCoV-infected airway epithelial cells and mice. Human primary airway epithelial cells treated with a single dose of IFN-I (IFN-α) and IFN-λ showed similar ISG expression, whereas cells treated with two doses of IFN-λ expressed elevated levels of ISG compared to that of IFN-α-treated cells. Similarly, mice treated with two doses of IFN-λ were better protected than mice that received a single dose, and a combination of prophylactic and delayed therapeutic regimens completely protected mice from a lethal Middle East respiratory syndrome CoV (MERS-CoV) infection. A two-dose IFN-λ regimen significantly reduced lung viral titers and inflammatory cytokine levels with marked improvement in lung inflammation. Collectively, we identified an effective regimen for IFN-λ use and demonstrated the protective efficacy of IFN-λ in MERS-CoV-infected mice. IMPORTANCE Effective antiviral agents are urgently required to prevent and treat individuals infected with SARS-CoV-2 and other emerging viral infections. The COVID-19 pandemic has catapulted our efforts to identify, develop, and evaluate several antiviral agents. However, a narrow therapeutic window has limited the protective efficacy of several broad-spectrum and CoV-specific antivirals. IFN-λ is an antiviral agent of interest due to its ability to induce a robust endogenous antiviral state and low levels of inflammation. Here, we evaluated the protective efficacy and effective treatment regimen of IFN-λ in mice infected with a lethal dose of MERS-CoV. We show that while prophylactic and early therapeutic IFN-λ administration is protective, delayed treatment is detrimental. Notably, a combination of prophylactic and delayed therapeutic administration of IFN-λ protected mice from severe MERS. Our results highlight the prophylactic and therapeutic use of IFN-λ against lethal hCoV and likely other viral lung infections.

Introduction: Diarrhea is common in persons living with HIV (PLWH)/AIDS. With the increasing utilization of multiplex gastrointestinal PCR panel (GI panel) testing, we aimed to characterize the roles of CD4 count and hospitalization in GI panel assessments of PLWH with acute diarrhea., Methods: We performed a cross-sectional study of adult PLWH with acute diarrhea who underwent GI panel testing at two urban academic centers. Demographic, HIV disease, GI panel result, and hospitalization data were collected, and patients were cohorted by CD4 count (CD4 < 200, CD4 200-499, CD4 > = 500). The primary outcome was enteric infection as detected by GI panel, and hospitalization., Results: Of 298 PLWH, 119 (39.9%) had a CD4 count below 200, 195 (65.4%) were hospitalized, and 137 (46.0%) had enteric infection. Bacterial infection correlated with higher CD4 count (41.9% (CD4 > = 500) vs 31.2% (CD4 200-499) vs 25.2% (CD4 < 200), p  = 0.041). Hospitalization correlated with poorly controlled HIV and fewer enteric infections (34.4% vs 68.0%, p  < 0.001). After adjusting for HIV disease severity, a negative GI panel remained independently associated with hospitalization (adjusted odds ratio (aOR) 5.32, 95% confidence interval (CI) 2.72-10.9), even in patients tested within 72 hours of hospitalization. Despite better HIV control, men who have sex with men (MSM) had more frequent infectious diarrhea, including from E. coli , giardiasis, and multiple pathogens. MSM status independently predicted enteric infection (aOR 1.93, 95% CI: 1.02-3.67)., Conclusions: GI panel results vary by HIV disease severity and hospitalization in PLWH. Clinicians - especially in the inpatient setting - should carefully consider these factors when interpreting GI panel results. Further characterization of diarrheal etiology in PLWH with a negative GI panel is needed., Plain Language Summary: PCR stool test results are affected by certain factors in HIV-related diarrhea Diarrhea is common in people living with HIV (PLWH) and has a variety of causes, including infections, medications, and HIV itself. Multiplex polymerase chain reaction (PCR) stool testing simultaneously evaluates for a variety of common viral, bacterial, and parasitic infections of the gastrointestinal tract, and is increasingly being used in patients with diarrhea. However, patients with HIV and diarrheal illness may have uncommon infections not typically present in those with normal immune function - and thus not routinely evaluated for in stool testing. It is not known what factors, if any, might affect the results of PCR testing in HIV-related diarrhea.In this study, we examined all PLWH who underwent stool PCR testing for diarrhea over a 4-year period. We separated the patients into groups based on HIV disease severity as measured by CD4 T-cell count, or the count of the immune cells affected by HIV. We examined whether there were differences among groups in infection rates as detected by PCR stool testing. Separately, we studied the role of hospitalization in stool PCR test results.Of 298 PLWH who underwent stool PCR testing for diarrhea, 119 had a CD4 count less than 200 (low CD4 count), 195 were hospitalized at time of testing, and 137 had a positive stool PCR test. Compared to those with a low CD4 count, subjects with less severe HIV disease were more likely to have a bacterial infection on stool PCR testing and less likely to be hospitalized. Hospitalized patients were more likely to have a negative PCR stool test, regardless of CD4 count. Many patients with a low CD4 count had diarrheal etiologies not evaluated by multiplex stool PCR. In PLWH who experience diarrhea, stool PCR testing results vary by CD4 count and hospitalization. Providers should be mindful of these factors when interpreting stool PCR test results., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: JEA receives research support from BioFire Diagnostics and has received consultancy fees from Janssen, Abbvie, and BioFire Diagnostics. JEA receives research support from the Crohn’s and Colitis Foundation and The National Institute of Diabetes and Digestive and Kidney Diseases [Grant Number: K23DK124570]. AV: No disclosures. AMH: No disclosures. AJ: No disclosures. RM: No disclosures. BL: No disclosures., (© The Author(s), 2022.)

This research aims to find out whether the 1, 2, 4-triazine and its derivatives have antifungal effects and can protect humans from infection with Candida albicans . Molecular docking and molecular dynamic simulation are widely used in modern drug design to target a particular protein with a ligand. We are interested in using molecular docking and molecular dynamics modeling to investigate the interaction between the derivatives of 1, 2, 4-triazine with enzyme Lanosterol 14-demethylase (CYP51) of Candida albicans . The inhibition of Candida albicans CYP51 is the main goal of our research. The 1, 2, 4-triazine and its derivatives have been docked to the CYP51 enzyme, which is involved in Candida albicans Multidrug Drug Resistance (MDR). Autodock tools were used to identify the binding affinities of molecules against the target proteins. Compared to conventional fluconazole, the molecular docking results indicated that each drug has a high binding affinity for CYP51 proteins and forms unbound interactions and hydrogen bonds with their active residues and surrounding allosteric residues. The docking contacts were made using a 10 ns MD simulation with nine molecules. RMSD, RMSF, hydrogen bonds, and the Rg all confirm these conclusions. In addition, these compounds were expected to have a favorable pharmacological profile and low toxicity. The compounds are being offered as scaffolds for the development of new antifungal drugs and as candidates for future in vitro testing., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor DJ declared a past collaboration with the author AB., (Copyright © 2022 Verma, Majid, Hossain, Ahmed, Ashid, Bhojiya, Upadhyay, Vishvakarma and Alam.)

Fluvoxamine's (FLX's) anticancer potential was investigated in pre-clinical research utilizing a DMH-induced colorectal cancer (CRC) rat model. qRT-PCR and immunoblotting validated the mechanistic investigation. The CRC condition was induced in response to COX-2 and IL-6, however, following FLX therapy, the condition returned to normal. FLX's anti-CRC potential may be attributable to COX-2 inhibition since this molecular activity was more apparent for COX-2 than IL-6. FLX repaired the altered metabolites linked to CRC rats, according to 1 H-NMR analysis. FLX was shown to be similar to 5-FU in terms of tumor protection, which may be useful in future medication development., Competing Interests: The authors declare that they have no conflict of interests., (©2022TheAuthor(s).PublishedbyElsevierB.V.)

Background and Aims: Thirty percent of inflammatory bowel disease (IBD) patients hospitalized with flare require salvage therapy or surgery. Additionally, 40% experience length of stay (LOS) > 7 days. No emergency department (ED)-based indices exist to predict these adverse outcomes at admission for IBD flare. We examined whether clinical, laboratory, and endoscopic markers at presentation predicted prolonged LOS, inpatient colectomy, or salvage therapy in IBD patients admitted with flare., Methods: Patients with ulcerative colitis (UC) or colonic involvement of Crohn's disease (CD) hospitalized with flare and tested for Clostridioides difficile infection (CDI) between 2010 and 2020 at two urban academic centers were studied. The primary outcome was complex hospitalization, defined as: LOS > 7 days, inpatient colectomy, or inpatient infliximab or cyclosporine. A nested k-fold cross-validation identified predictive factors of complex hospitalization., Results: Of 164 IBD admissions, 34% (56) were complex. Predictive factors included: tachycardia in ED triage (odds ratio [OR] 3.35; confidence interval [CI] 1.79-4.91), hypotension in ED triage (3.45; 1.79-5.11), hypoalbuminemia at presentation (2.54; 1.15-3.93), CDI (2.62; 1.02-4.22), and endoscopic colitis (4.75; 1.75-5.15). An ED presentation score utilizing tachycardia and hypoalbuminemia predicted complex hospitalization (area under curve 0.744; CI 0.671-0.816). Forty-four of 48 (91.7%) patients with a presentation score of 0 (heart rate < 99 and albumin ≥ 3.4 g/dL) had noncomplex hospitalization., Conclusions: Over 90% of IBD patients hospitalized with flare with an ED presentation score of 0 did not require salvage therapy, inpatient colectomy, or experience prolonged LOS. A simple ED-based score may provide prognosis at a juncture of uncertainty in patient care., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Background and objective A significant proportion of the adult population in the United States (US) live with some form of mental illness. The more prevalent conditions of depression and anxiety are typically managed in primary care settings rather than specialty care. The aim of this study was to determine the efficacy of a novel, measurement-driven psychiatric treatment platform delivered via an online telemental health platform as compared to treatment as usual (TAU). Methods The TAU dataset and the telemental health platform (Brightside) dataset were constructed based on the total populations of adult patients receiving care for depression from January 2018 through December 2020 (November 2018 through March 2021 for the Brightside group). Patients in both groups had a primary mental health diagnosis of depression and the presence of a positive screen for depression as measured by the Patient Health Questionnaire-9 (PHQ-9) upon initiation of treatment. HITLAB, an independent digital health verification and testing lab, conducted comparative analyses of the two groups using the Chi-square test of independence. Results Close to 80% of telemental health platform patients experienced a reduction of 5 or more points from their baseline PHQ-9 score as compared to 52% of TAU patients. The mean reduction in PHQ-9 score was slightly higher in the Brightside group (-11.5) versus the TAU group (-10.1). Chi-square tests of independence [x2 (1, n=6281) = 256.75, p≤0.001] for meaningful reduction and for remission [x2 (1, n=6281) = 105.50 p≤0.001] were highly significant. Conclusion The telemental health platform patients performed significantly better than those under psychiatric TAU in terms of reduction in symptoms of depression in adults., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2022, Chokshi et al.)

Methicillin-Resistant Staphylococcus aureus (MRSA), a pathogenic bacterium that causes life-threatening outbreaks such as community-onset and nosocomial infections as emerging 'superbug'. Time and motion study of its virulent property developed resistance against most of the antibiotics such as Vancomycin. Thereby, to curb this problem entails the development of new therapeutic agents. Plant-derived antimicrobial agents have recently piqued people's interest, so in this research, 186 flavonoids compound selected to unmask the best candidates that can act as potent inhibitors against the Penicillin Binding Protein-2a (PBP-2a) of MRSA. Molecular docking performed using PyRx and GOLD suite to determine the binding affinities and interactions between the phytochemicals and the PBP-2a. The selected candidates strongly interact with the different amino acid residues. The 30 ns molecular dynamics (MD) simulations with five top-ranked compounds such as Naringin, Hesperidin, Neohesperidin, Didymin and Icariin validated the docking interactions. These findings are also strongly supported by root-mean-square deviation, root-mean-square fluctuation and the radius of gyration. ADME/T analysis demonstrates that these candidates appear to be safer inhibitors. Our findings point to natural flavonoids as a promising and readily available source of adjuvant antimicrobial therapy against resistant strains in the future.Communicated by Ramaswamy H. Sarma.

SGK1 (Serum and Glucocorticoid Regulated Kinase 1), a serine/threonine kinase that is activated by various stimuli, including serum and glucocorticoids. It controls inflammation, apoptosis, hormone release, neuro-excitability and cell proliferation, all of which play an important role in cancer progression and metastasis. SGK1 was recently proposed as a potential drug target for cancer, diabetes, and neurodegenerative diseases. In this study, molecular docking, physiochemical, toxicological properties and molecular dynamic simulation of the Bis-[1-N,7-N, Pyrazolo tetraethoxyphthalimido{-4-(3,5-Dimethyl-4-(spiro-3-methylpyazolo)-1,7-dihydro-1H-dipyrazolo[3,4-b;4',3'-e]pyridin-8-yl)}]p-disubstituted phenyl compoundsand reference EMD638683 against new SGK1 target protein. Compared to the reference inhibitor EMD638683, we choose the best compounds (series 2-6) based on the binding energy (in the range from -11.0 to -10.6 kcal/mol). With the exception of compounds 2 and 6, none of the compounds posed a risk for AMES toxicity or carcinogenicity due to their toxicological properties. 100 ns MD simulation accompanied by MM/PBSA energy calculations and PCA. According to MD simulation results, the binding of compounds 3, 4 and 5 stabilizes the SGK1 structure and causes febrile conformational changes compared to EMD638683. As a result of this research, the final selected compounds 3, 4 and 5 can be used as scaffolds to develop promising SGK1 inhibitors for the treatment of related diseases such as cancer.Communicated by Ramaswamy H. Sarma.

Background: The cigarette smoking and its effect on the inflammatory cytokine levels in the smoker's saliva depicted the influence of electronic cigarettes on oral cytokine levels in oral fluids are scarce in the literature., Objectives: The present trial was conducted to compare and determine the proinflammatory and anti-inflammatory cytokines in whole stimulated saliva samples of electronic cigarette smokers, conventional smokers, and participants with no smoke exposure., Materials and Methods: Sixty adult participants were divided into the following four groups of nonsmokers, current smokers, smokers smoking both conventional and e-cigarettes, and e-cigarette smokers. The saliva samples were assessed for Interleukins (IL-1B, 6, 8, 10, and IL-1RA), C-reactive protein (CRP), and tumor necrosis factor-alpha (TNF-α) using enzyme-linked immunosorbent assay. Plaque scores and Gingival Index, and body mass index were also calculated., Results: Statistically significant ( P < 0.05) and remarkable relationship was seen in plaque scores and IL 1RA, 1 β, and 10 with the respective values as-0.285, 0.268, and 0.267. Regarding anti-inflammatory cytokines, CRP, IL-10, and IL-RA had the P-value of 0.073, 0.945, and 0.834 respectively. When these values were evaluated for proinflammatory cytokines, the P values were 0.0001, 0.019, 0.991, and 903 for TNF-α, IL-1 β, IL-6, and IL-8, respectively. These results were statistically significant for TNF-α ( P = 0.001)., Conclusion: Within its limitations, the present study concludes that smoking e-cigarettes whether solely or in combination with conventional smoking increases the levels of proinflammatory cytokines such as TNF-α and IL-1 β with decreased counter IL-1RA levels., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Journal of Pharmacy and Bioallied Sciences.)

Microglia and macrophages initiate and orchestrate the innate immune response to central nervous system (CNS) virus infections. Microglia initiate neurotropic coronavirus clearance from the CNS, but the role of infiltrating macrophages is not well understood. Here, using mice lacking cell-specific expression of DP1, the receptor for prostaglandin D 2 (PGD 2 ), we delineate the relative roles of PGD 2 signaling in microglia and macrophages in murine coronavirus-infected mice. We show that the absence of PGD 2 /DP1 signaling on microglia recapitulated the suboptimal immune response observed in global DP1 -/- mice. Unexpectedly, the absence of the DP1 receptor on macrophages had an opposite effect, resulting in enhanced activation and more rapid virus clearance. However, microglia are still required for disease resolution, even when macrophages are highly activated, in part because they are required for macrophage recruitment to sites of infection. Together, these results identify key differences in the effects of PGD 2 /DP1 signaling on microglia and macrophages and illustrate the complex relationship between the two types of myeloid cells. IMPORTANCE Current understanding about the roles of microglia versus macrophages in viral encephalitis is limited. We previously showed that the signaling of a single prostaglandin, PGD 2 , through its DP1 receptor on myeloid cells is critical for optimal immune responses in infected mice. Here, we demonstrate that the specific ablation of the DP1 receptor on macrophages and microglia had markedly different effects on outcomes. DP1 -/- macrophages exhibited greater phagocytic properties than controls, resulting in enhanced kinetics of virus clearance, while DP1 absence on microglia resulted in increased lethality. Microglia were still required for protection, even when DP1 was not expressed on macrophages. These results suggest that therapeutic strategies directed at specific myeloid subsets in the brain may be useful in the context of viral infections.

Background: Inflammatory bowel disease (IBD) patients who have Clostridioides difficile infection (CDI) have worse outcomes., Aims: We aimed to determine whether such outcomes are the result of CDI or whether CDI occurs in patients who have more severe IBD., Methods: This was a retrospective study of patients hospitalized for ≥ 2 IBD flares from 2010 to 2019. The primary outcome was time to IBD flare between hospitalizations. First, time to flare was compared between patients who were hospitalized for a flare complicated by CDI and subsequently for a CDI-negative flare (cohort A, denoted +/-) versus patients who were hospitalized for two CDI-negative flares (cohort B, -/-). Second, time between flares was compared within the subset of cohort A patients who had three flares (cohort C, -/+/-) before and after CDI., Results: Time between flares was a median of 4 months (IQR 1-9) among 51 cohort A patients versus 12 months (IQR 6-38) among 51 cohort B patients (log-rank P < 0.01). In contrast, the median time between flares was similar within cohort C before and after CDI (log-rank P = 0.54). At time of the second IBD flare, patients in cohort A (+/-) were more likely to have moderate or severe disease compared to patients in cohort B (-/-)., Conclusions: Patients with prior CDI had shorter time to subsequent IBD flare relative to their CDI-negative counterparts. This is not likely due to CDI itself because there was no difference in time between flares before versus after acquiring CDI. Rather, patients who acquire CDI may have more severe IBD., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Background & Aims: Alterations in microRNA (miRNA) and in the intestinal barrier are putative risk factors for irritable bowel syndrome (IBS). We aimed to identify differentially expressed colonic mucosal miRNAs, their targets in IBS compared to healthy controls (HCs), and putative downstream pathways., Methods: Twenty-nine IBS patients (15 IBS with constipation [IBS-C], 14 IBS with diarrhea [IBS-D]), and 15 age-matched HCs underwent sigmoidoscopy with biopsies. A nCounter array was used to assess biopsy specimen-associated miRNA levels. A false discovery rate (FDR) < 10% was considered significant. Real-time polymerase chain reaction (PCR) was used to validate differentially expressed genes. To assess barrier function, trans-epithelial electrical resistance (TEER) and dextran flux assays were performed on Caco-2 intestinal epithelial cells that were transfected with miRNA-inhibitors or control inhibitors. Protein expression of barrier function associated genes was confirmed using western blots., Results: Four out of 247 miRNAs tested were differentially expressed in IBS compared to HCs (FDR < 10%). Real-time PCR validation suggested decreased levels of miR-219a-5p and miR-338-3p in IBS (P = .026 and P = .004), and IBS-C (P = .02 and P = .06) vs. HCs as the strongest associations. Inhibition of miR-219a-5p resulted in altered expression of proteasome/barrier function genes. Functionally, miR-219a-5p inhibition enhanced the permeability of intestinal epithelial cells as TEER was reduced (25-50%, P < .05) and dextran flux was increased (P < .01). Additionally, inhibition of miR-338-3p in cells caused alterations in the mitogen-activated protein kinase (MAPK) signaling pathway genes., Conclusion: Two microRNAs that potentially affect permeability and visceral nociception were identified to be altered in IBS patients. MiR-219a-5p and miR-338-3p potentially alter barrier function and visceral hypersensitivity via neuronal and MAPK signaling and could be therapeutic targets in IBS., (Copyright © 2021 AGA Institute. All rights reserved.)

Background: The use of membrane with the guided bone regeneration (GBR) has been a controversial aspect of the implant placement, which helps achieve the primary graft stabilization and inhibit early graft loss., Objectives: The present clinical trial was aimed to determine the results of GBR with nonresorbable (expanded polytetrafluoroethylene [e-PTFE]) and resorbable (collagen) membrane both clinically and radiographically for 2 years with dental implant placement., Materials and Methods: 16 subjects having 32 sites for implant placement in a split-mouth pattern were included in the study. The sites for implant was prepared and grafted with the autogenous graft procured from the mandibular ramus area followed by graft coverage with either e-PTFE or collagen membrane. Various radiographic and clinical parameters were assessed for 2 years at an interval of 6 months each. The collected data were recorded for each study subject for all the implant sites and were statistically analyzed., Results: The mean values for periodontal probing depth at 6 months, 12 months, 18 months, and 24 months were 2.25 ± 0.17, 2.67 ± 1.84, 2.64 ± 1.21, and 3.01 ± 0.52, respectively, for the e-PTFE group. For the collagen group, the probing depth mean values at 6 months, 12 months, 18 months, and 24 months were 2.30 ± 0.14, 2.59 ± 1.76, 2.62 ± 1.30, and 2.98 ± 0.81, respectively. The corresponding clinical and radiographic parameters at all time intervals were nonsignificant on the intergroup comparison., Conclusion: Dental implants placed with simultaneous GBR have an acceptable survival rate at the end of 2 years irrespective of the resorbable or non-resorbable membrane used., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Journal of Pharmacy and Bioallied Sciences.)

The ongoing coronavirus disease 2019 (COVID-19) pandemic is associated with substantial morbidity and mortality. Although much has been learned in the first few months of the pandemic, many features of COVID-19 pathogenesis remain to be determined. For example, anosmia is a common presentation, and many patients with anosmia show no or only minor respiratory symptoms 1 . Studies in animals infected experimentally with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of COVID-19, provide opportunities to study aspects of the disease that are not easily investigated in human patients. Although the severity of COVID-19 ranges from asymptomatic to lethal 2 , most experimental infections provide insights into mild disease 3 . Here, using K18-hACE2 transgenic mice that were originally developed for SARS studies 4 , we show that infection with SARS-CoV-2 causes severe disease in the lung and, in some mice, the brain. Evidence of thrombosis and vasculitis was detected in mice with severe pneumonia. Furthermore, we show that infusion of convalescent plasma from a recovered patient with COVID-19 protected against lethal disease. Mice developed anosmia at early time points after infection. Notably, although pre-treatment with convalescent plasma prevented most signs of clinical disease, it did not prevent anosmia. Thus, K18-hACE2 mice provide a useful model for studying the pathological basis of both mild and lethal COVID-19 and for assessing therapeutic interventions.

In this paper, we propose a quadtree based approach to capture the spatial information of medical images for explaining nonlinear SVM prediction. In medical image classification, interpretability becomes important to understand why the adopted model works. Explaining an SVM prediction is difficult due to implicit mapping done in kernel classification is uninformative about the position of data points in the feature space and the nature of the separating hyperplane in the original space. The proposed method finds ROIs which contain the discriminative regions behind the prediction. Localization of the discriminative region in small boxes can help in interpreting the prediction by SVM. Quadtree decomposition is applied recursively before applying SVMs on sub images and model identified ROIs are highlighted. Pictorial results of experiments on various medical image datasets prove the effectiveness of this approach. We validate the correctness of our method by applying occlusion methods., (© Springer Science+Business Media, LLC, part of Springer Nature 2020.)

The study deals with the synthesis and characterization of chitosan-g-Poly (Acrylic acid-co-Acrylamide) [chit-g-Poly (AA-co-Am)] for sustained release of curcumin. The formation of chit-g-Poly (AA-co-Am) was ascertained through various spectral, thermal, microscopic methods and zeta potential. The potential of chit-g-Poly (AA-co-Am) for drug delivery applications were investigated through pH regulated kinetic models, in vitro antibacterial assay and molecular docking studies. The study reveals antibacterial activity of chit-g-Poly (AA-co-Am) against Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa along with enhanced binding with bacterial receptors. In this study, nanoparticle of curcumin drug with grafted chitosan (NpCGC) was developed as effective nano therapeutic drug delivery system. Kinetic data of NpCGC reveals that the enhanced release of curcumin from NpCGC has been occurred at pH 5.4. The present study provides an economical and eco-friendly approach towards the preparation of chit-g-Poly (AA-co-Am) for sustained drug delivery applications., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Microarray technology to isolate living cells using external fields is a facile way to do phenotypic analysis at the cellular level. We have used alternating current dielectrophoresis (AC-DEP) to drive the assembly of live pathogenic Salmonella typhi (S.typhi) and Escherichia coli (E.coli) bacteria into miniaturized single cell microarrays. The effects of voltage and frequency were optimized to identify the conditions for maximum cell capture which gave an entrapment efficiency of 90% in 60 min. The chip was used for calibration-free estimation of cellular loads in binary mixtures and further applied for rapid and enhanced testing of cell viability in the presence of drug via impedance spectroscopy. Our results using a model antimicrobial sushi peptide showed that the cell viability could be tested down to 5 μg/mL drug concentration under an hour, thus establishing the utility of our system for ultrafast and sensitive detection., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Chandipura Virus (CHPV), a negative-stranded RNA virus belonging to the Rhabdoviridae family, has been previously reported to bring neuronal apoptosis by activating several factors leading to neurodegeneration. Following virus infection of the central nervous system, microglia, the ontogenetic and functional equivalents of macrophages in somatic tissues gets activated and starts secreting chemokines, thereby recruiting peripheral leukocytes into the brain parenchyma. In the present study, we have systemically examined the effect of CHPV on microglia and the activation of cellular signalling pathways leading to chemokine expression upon CHPV infection. Protein and mRNA expression profiles of chemokine genes revealed that CHPV infection strongly induces the expression of CXC chemokine ligand 10 (CXCL10) and CC chemokine ligand 5 (CCL5) in microglia. CHPV infection triggered the activation of signalling pathways mediated by mitogen-activated protein kinases, including p38, JNK 1 and 2, and nuclear factor κB (NF-kappaB). CHPV-induced expression of CXCL10 and CCL5 was achieved by the activation of p38 and NF-kappaB pathways. Considering the important role of inflammation in neurodegeneration, we have targeted NF-kappaB using a newly synthesised natural product nitrosporeusine analogue and showed incapability of microglial supernatant of inducing apoptosis in neurons after treatment., Competing Interests: The authors declare that they have no conflict of interest.

Chandipura Virus (CHPV) a negative-stranded RNA virus belonging to the Rhabdoviridae family, has been previously reported to bring about neuronal apoptosis by stimulating oxidative stress. Our in silico data suggested the involvement of Angiotensin II in intracellular Ca 2+ secretion within CHPV infected cells that further lead to enhancement of ROS level and mitochondrial dysfunction. ROS is also known to phosphorylate p38 that leads to neuronal apoptosis through FasL-FADD pathway during CHPV infection. Minocycline a broad-spectrum antibiotic well-known for its anti-oxidative and anti-inflammatory role was used in the present study to investigate its efficacy against CHPV. The results obtained from the present study showed minocycline to be effective in mitigating the levels of cytoplasmic Ca 2+ , ROS, phosphorylation of p38 molecules and hence cellular apoptosis. Thus minocycline apart from being an anti-inflammatory and anti-oxidative agent, our study showed that minocycline has an additional Ca 2+ chelation activity.

Background: Endovascular treatment for large-vessel acute ischemic stroke (AIS) has rapidly emerged. However, the understanding of the complex biology involving endothelial cells (ECs) remains scarce., Methods: Using stent retrievers during endovascular thrombectomy (ET) in patients with AIS, ECs were segregated, centrifuged in a dissociation buffer, and suspended in endothelial specific antibody solution. Subsequently, fluorescence-activated cell sorting (FACS) and microscopic analyses were performed., Results: Three stent-retriever devices (2 Solitaire, 1 Trevo) were collected as separate deployments. Of 5.0% (±.48%) total events using FACS, 6.8% (±.68%) of cells were specific for ECs using fluorescent markers and were further visualized on fluorescence microscopy for consistence with the positive controls., Conclusions: We describe a novel, minimally invasive biopsy technique to collect and harvest ECs from stent retrievers during ET and validate the approach in the treatment of AIS. Further work for detailed characterization and viability assessment of ECs is needed to compare their biology with in vitro and animal models., (Copyright © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Nitrosporeusines A and B are two recently isolated marine natural products with novel skeleton and exceptional biological profile. Interesting antiviral activity of nitrosporeusines and promising potential in curing various diseases, evident from positive data from various animal models, led us to investigate their anti-inflammatory potential. Accordingly, we planned and synthesized nitrosporeusines A and B in racemic as well as enantiopure forms. The natural product synthesis was followed by preparation of several analogues, and all the synthesized compounds were evaluated for in vitro and in vivo anti-inflammatory potential. Among them, compounds 25, 29 and 40 significantly reduced levels of nitric oxide (NO), reactive oxygen species (ROS) and pro-inflammatory cytokines. In addition, these compounds suppressed several pro-inflammatory mediators including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), nuclear factor-κB (NF-κB), and thereby can be emerged as potent anti-inflammatory compounds. Furthermore, all possible isomers of lead compound 25 were synthesized, characterized and profiled in same set of assays and found that one of the enantiomer (-)-25a was superior among them., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Neurotropic viruses induce neurodegeneration either directly by activating host death domains or indirectly through host immune response pathways. Chandipura Virus (CHPV) belonging to family Rhabdoviridae is ranked among the emerging pathogens of the Indian subcontinent. Previously we have reported that CHPV induces neurodegeneration albeit the root cause of this degeneration is still an open question. In this study we explored the role of microglia following CHPV infection. Phenotypic analysis of microglia through lectin and Iba-1 staining indicated cells were in an activated state post CHPV infection in cortical region of the infected mouse brain. Cytokine Bead Array (CBA) analysis revealed comparatively higher cytokine and chemokine levels in the same region. Increased level of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), Nitric Oxide (NO) and Reactive Oxygen species (ROS) in CHPV infected mouse brain indicated a strong inflammatory response to CHPV infection. Hence it was hypothesized through our analyses that this inflammatory response may stimulate the neuronal death following CHPV infection. In order to validate our hypothesis supernatant from CHPV infected microglial culture was used to infect neuronal cell line and primary neurons. This study confirmed the bystander killing of neurons due to activation of microglia post CHPV infection.

The association between myopia and high intelligence has been the subject of much vexed debate in academic circles, particularly over the last two decades. This debate has risen from the observation that, over recent centuries, the prevalence of myopia amongst most populations has coincided with a marked increase in the average level of intelligence in these populations. The relationship between myopia and intelligence and theories surrounding this association is examined by the authors. Additionally, the various factors that confound the myopia and high intelligence debate, such as genetics, educational levels, ethnicity, and environmental factors were also explored by the authors. Whilst most studies found a positive correlation reaching statistical significance between myopia and high intelligence compared to emmetropes and hyperopes, further research is required to determine whether this association is causal.

Background: Neonatal circumcision is a fairly common surgical procedure that may be carried out for medical reasons, one of them being prevention of urinary tract infections (UTI) in male infants. Circumcision could help in reducing the incidence of UTI by reducing periurethral bacterial colonization, which is accepted as a potential risk factor in UTI. Evidence is needed to inform the benefits or harm for the routine use of this intervention., Objectives: To assess the effectiveness and safety of routine neonatal circumcision for the prevention of UTIs in infancy., Search Methods: We searched the Cochrane Neonatal Review Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We completed this search 30 June 2011., Selection Criteria: Randomised controlled trials and quasi-randomised controlled trials., Data Collection and Analysis: Two review authors had planned to independently screen studies, extract data and assess risk of bias using standard Cochrane Collaboration methodologies. We did not identify any studies for inclusion in this review., Main Results: We did not identify any relevant studies after a comprehensive search of the literature., Authors' Conclusions: We were unable to identify any randomised controlled trials on the use of routine neonatal circumcision for prevention of UTI in male infants. Until further evidence becomes available, clinicians should continue to base their decisions on position statements and recommendations and in conjunction with the opinions of the children's parents.

Dabigatran etexilate was recently approved by the Therapeutic Goods Administration for thromboprophylactic use in adults undergoing elective total hip or knee replacement. Dabigatran etexilate is the prodrug of the active moiety dabigatran, an orally active agent that could replace enoxaparin in some clinical indications. Dabigatran is a direct thrombin inhibitor; it has stable, predictable pharmacokinetics and does not require routine monitoring. Pooled efficacy data from large-scale phase III clinical trials of dabigatran use in orthopaedic thromboprophylaxis have shown non-inferiority to enoxaparin, with total venous thromboembolism results of 3.8% for dabigatran etexilate 150 mg and 3.0% for dabigatran etexilate 220 mg, compared with 3.3% for enoxaparin. Pooled safety results for dabigatran are similar to those for enoxaparin, with major bleeding rates of 1.1% for dabigatran etexilate 150 mg and 1.4% for dabigatran etexilate 220 mg, compared with 1.4% for enoxaparin. Dabigatran failed to demonstrate non-inferiority compared with enoxaparin 30 mg twice daily for orthopaedic thromboprophylaxis. Issues relating to the use of dabigatran include its lack of antidote, limited application in renal disease, and interaction with drugs such as amiodarone and verapamil. Several trials investigating the use of dabigatran for other indications, such as stroke prevention in atrial fibrillation and acute coronary syndromes, are underway. Given its safety profile, efficacy, oral bioavailability and stable pharmacokinetic properties, dabigatran may be a viable alternative to enoxaparin for thromboprophylaxis in orthopaedic surgery.

Warfarin and heparin are the traditional mainstay anticoagulant therapies for treating thromboembolic disease. These drugs, with a documented history of utility, also have inherent difficulties in usage; in particular, the complicated monitoring and numerous drug-drug interactions of warfarin, and the need for parenteral administration of heparins. New agents have recently emerged that target specific elements of the clotting pathway. Rivaroxaban, which inhibits activated factor X (Xa), is currently in clinical trials and is the most advanced factor Xa inhibitor. The drug offers once-daily oral dosing, with no need for injections, dose titration, or frequent blood tests to monitor the international normalised ratio. It has a rapid onset of action and, although there is no specific antidote, it has a short plasma elimination half-life (about 5-9 hours). Evidence from recently published large-scale phase III clinical trials shows rivaroxaban to be superior to enoxaparin for prophylaxis of venous thromboembolism after major orthopaedic surgery. Studies have shown rivaroxaban to have a sound safety profile, with an incidence of bleeding similar to enoxaparin in phase III clinical trials. Few side effects and drug-drug interactions between rivaroxaban and common medications have been found thus far, although some interactions with potent cytochrome P450 3A4 inhibitors have been observed. It is hoped that rivaroxaban may be used as a first-line anticoagulant for prophylaxis of venous thromboembolic disease in postsurgical patients.