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Background and Objective Ceftriaxone is a cornerstone antibiotic for critically ill children with severe infections. Despite its widespread use, information on the pharmacokinetics of ceftriaxone is lacking in this population. We aimed to determine ceftriaxone pharmacokinetics in critically ill children and to propose ceftriaxone dosing guidelines resulting in adequate target attainment using population pharmacokinetic modeling and simulation. Methods Critically ill children (aged 0–18 years) treated with intravenous ceftriaxone (100 mg/kg once daily, infused in 30 minutes) and a central or arterial line in place were eligible. Opportunistic blood sampling for total and unbound ceftriaxone concentrations was used. Population pharmacokinetic analysis was performed using non-linear mixed-effects modeling on NONMEM™ Version 7.4.3. Simulations were performed to select optimal doses using probability of target attainment for two pharmacokinetic targets of the minimum inhibitory concentration (MIC) reflecting the susceptibility of pathogens (f T > MIC 100% and fT > 4 × MIC 100%). Results Two hundred and five samples for total and 43 time-matched samples for unbound plasma ceftriaxone concentrations were collected from 45 patients, median age 2.5 (range 0.1–16.7) years. A two-compartment model with bodyweight as the co-variate for volume of distribution and clearance, and creatinine-based estimated glomerular filtration rate as an additional covariate for clearance, best described ceftriaxone pharmacokinetics. For a typical patient (2.5 years, 14 kg) with an estimated glomerular filtration rate of 80 mL/min/1.73 m2, the current 100-mg/kg once-daily dose results in a probability of target attainment of 96.8% and 60.8% for a MIC of 0.5 mg/L and 4 × MIC (2 mg/L), respectively, when using fT > MIC 100% as a target. For a 50-mg/kg twice-daily regimen, the probability of target attainment was 99.9% and 93.4%, respectively. Conclusions The current dosing regimen of ceftriaxone provides adequate exposure for susceptible pathogens in most critically ill children. In patients with an estimated glomerular filtration rate of > 80 mL/min/1.73 m2 or in areas with a high prevalence of less-susceptible pathogens (MIC ≥ 0.5 mg/L), a twice-daily dosing regimen of 50 mg/kg can be considered to improve target attainment. Clinical Trial Registration POPSICLE study (ClinicalTrials.gov, NCT03248349, registered 14 August, 2017), PERFORM study (ClinicalTrials.gov, NCT03502993, registered 19 April, 2018). Supplementary Information The online version contains supplementary material available at 10.1007/s40262-021-01035-9.

Development of a novel inhibitor targeting Gyrase B and Topoisomerase IV offers a potential opportunity to combat the drug resistance. In the present study, we extensively investigated the efficacy of RBx 10080758, a novel fluorobenzothiazole, against skin and respiratory infections caused by Staphylococci and Streptococci in in vitro and in vivo models. RBx 10080758 showed a potent IC50 of 0.06 μM against Gyrase and Topoisomerase IV and also exhibited a strong whole cell in vitro activity with MIC ranges of 0.015-0.06, 0.015-0.03, 0.008-0.03, 0.008-0.03, 0.008-0.0.06, 0.015-0.06 μg/ml against Staphylococcus. aureus, Streptococcus pneumoniae, Coagulase negative Staphylococci, Streptococcus viridans, Streptococcus pyogenes and Enterococcus, respectively. As expected from the novel class of molecule, it retains potent even against linezolid and vancomycin resistant strains. Interesting, in mouse systemic infection 10 mg/kg, IV dose protected 100% mice from lethal infections. In rat thigh infection model with MRSA WCUH29 at 45 mg/kg exhibited >3-log10 cfu reduction in thigh muscles. RBx 10080758 displayed potent in vitro and in vivo activity against a panel of MDR Gram-positive bacteria. As a novel chemical class, the fluorobenzothiazoles have the potential to become clinically viable antibiotics, to address the drug resistance problem by its unique dual targeting mechanism of action.

Aim: To investigate the antileishmanial activity of novel azole compounds against Leishmania donovani, which causes deadly visceral leishmaniasis disease. Materials & methods: A focused azole-based library was screened against both promastigotes and amastigotes forms of L. donovani strains in flat-bottomed 96-well tissue culture plates and J774A.1 macrophage cell-line infected with L. donovani. The comprehensive screening of azole-based library against L. donovani strains provided novel hits, which can serve as a good starting point to initiate hit to lead optimization campaign. Results: Hits identified from azole-based library exhibited potent in vitro activity against promastigotes and amastigotes of L. donovani. Conclusion: These potent novel azole hits could be a good starting point to carry out for further medicinal chemistry exploration for antileishmania program.

Pharmacometric modeling can capture tumor growth inhibition (TGI) dynamics and variability. These approaches do not usually consider covariates in high‐dimensional settings, whereas high‐dimensional molecular profiling technologies (“omics”) are being increasingly considered for prediction of anticancer drug treatment response. Machine learning (ML) approaches have been applied to identify high‐dimensional omics predictors for treatment outcome. Here, we aimed to combine TGI modeling and ML approaches for two distinct aims: omics‐based prediction of tumor growth profiles and identification of pathways associated with treatment response and resistance. We propose a two‐step approach combining ML using least absolute shrinkage and selection operator (LASSO) regression with pharmacometric modeling. We demonstrate our workflow using a previously published dataset consisting of 4706 tumor growth profiles of patient‐derived xenograft (PDX) models treated with a variety of mono‐ and combination regimens. Pharmacometric TGI models were fit to the tumor growth profiles. The obtained empirical Bayes estimates‐derived TGI parameter values were regressed using the LASSO on high‐dimensional genomic copy number variation data, which contained over 20,000 variables. The predictive model was able to decrease median prediction error by 4% as compared with a model without any genomic information. A total of 74 pathways were identified as related to treatment response or resistance development by LASSO, of which part was verified by literature. In conclusion, we demonstrate how the combined use of ML and pharmacometric modeling can be used to gain pharmacological understanding in genomic factors driving variation in treatment response.

The increasing demand for compact and functional electronics has led to significant rise in research interest in the development of versatile energy storage systems. With this perspective notion, herein, we fabricated electrically conducting polymer-based flexible carbon cloth (CC) electrodes and assessed their electrochemical performance. Briefly, polyaniline nanofibers (Pani-NFs) and polypyrrole nanotubes (PPy-NTs) were synthesized by interfacial polymerization and reactive self-degrade template method, respectively. The physico-chemical properties of the as-synthesized nanostructured conducting polymers were characterized with the help of X-ray diffraction (XRD), field emission scanning electron microscope (FESEM), field emission transmission electron microscope (FETEM) and Raman spectroscopy. The electrochemical performance of the Pani-NFs and PPy-NTs coated flexible CC electrodes was evaluated in 1 M H2SO4 electrolyte with a potential window of −0.2 to 0.8 V versus saturated calomel electrode (SCE). The Pani-NFs and PPy-NTs coated electrodes yielded the maximum areal capacitance of 0.79 and 0.74 F.cm−2, respectively at a constant discharge current density of 10 mA.cm−2, which was determined from the charge-discharge curve during the discharging period. The results demonstrate the potential of the nanostructured conducting polymer-based flexible electrodes for portable and wearable energy storage applications.

Background:Diabetic nephropathy is the major cause for chronic renal failure (CRF) and proteinuria is an independent risk factor for end stage renal disease. Hence, early identification and quantification of proteinuria is of prime importance in the diagnosis and management. Method: The present study is a prospective observational study conducted amongst 50 diabetic subjects in Medicine department & IKDRC,Civil Hospital Ahmedabad.The study carried out during the period between July 2017 to October 2019. All patients were treated as per standard treatment protocol. 24-hour urine protein and random urine protein to creatinine ratio (P:C) was determined. Result: Total 50(24 male &26 female) patients were studied. A strong correlation was found between 24 hours urine protein and protein- Creatinine ratio, especially in patient with eGFR >30 (CKD stage I to III) with coefficient of correlation of 0.973.However correlation weaken as the GFR worsens and is weakest in patients with stage 5 CKD Conclusion: The random urine Protein:Creatinine ratio predicts the amount of 24-hour urinary protein excretion with high accuracy.Hence it can be used as a faster substitute test for 24-hour urinary protein estimation.

The mounting evidence supporting the capacity of Plasmodium vivax to cause severe disease has prompted the need for a better characterization of the resulting clinical complications. India is making progress with reducing malaria, but epidemics of severe vivax malaria in Gujarat, one of the main contributors to the vivax malaria burden in the country, have been reported recently and may be the result of a decrease in transmission and immune development. Over a period of one year, we enrolled severe malaria patients admitted at the Civil Hospital in Ahmedabad, the largest city in Gujarat, to investigate the morbidity of severe vivax malaria compared to severe falciparum malaria. Patients were submitted to standard thorough clinical and laboratory investigations and only PCR-confirmed infections were selected for the present study. Severevivax malaria (30 patients) was more frequent than severe falciparum malaria (8 patients) in our setting, and it predominantly affected adults (median age 32 years, interquartile range 22.5 years). This suggests a potential age shift in anti-malarial immunity, likely to result from the recent decrease in transmission across India. The clinical presentation of severe vivax patients was in line with previous reports, with jaundice as the most common complication. Our findings further support the need for epidemiological studies combining clinical characterization of severe vivax malaria and serological evaluation of exposure markers to monitor the impact of elimination programmes.

It is common to study the strong decay of a heavy nucleus as a tunneling phenomenon where the $\alpha$ ($^4$He) or a light nuclear cluster tunnels through the Coulomb barrier formed by its interaction with the heavier daughter nucleus. The position and width of the Coulomb barrier are determined by the total interaction potential between the two daughter nuclei. We examine the effects of including nonlocality and deformation in the interaction potential by calculating the half-lives, $t_{1/2}$, and thereby phenomenological preformation factors of several nuclei which have the possibility of decaying by emitting either an $\alpha$ or a light nuclear cluster. The effect of deformation manifests itself by a decrease in $t_{1/2}$ for all the decays studied. The effect of nonlocality is studied within two different models of the nuclear potential: the energy-independent but angular momentum ($l$) dependent Mumbai (M) potential and the energy-dependent Perey-Buck (PB) potential. The nonlocal nuclear interaction leads to a decrease in all half-lives studied. Though the decrease is larger due to the Perey-Buck potential, half-lives evaluated using the Mumbai potential show a strong sensitivity to the $l$ value in the decay. This feature of the $\alpha$ and cluster decay half-lives can provide a complementary tool in addition to scattering data which are more commonly used to fix the parameters of a nonlocal potential in literature., Comment: 19 pages, 5 figures

Background Cefotaxime is frequently used in critically ill children, however pharmacokinetic (PK) studies to support adequate dosing in this patient population are limited. Objectives To characterize cefotaxime PK in critically ill children and evaluate exposures achieved by current and alternative dosing regimens. Methods Children (0–18 years) admitted to the paediatric ICU, receiving intravenous cefotaxime (100–150 mg/kg/day, interval 6–8 h) were included (Clinicaltrials.gov NCT03248349). Total plasma cefotaxime concentrations were measured on multiple study days. Population-PK analysis was performed using nonlinear mixed effects modelling (NONMEM™). Dose evaluations were performed using typical patients across the paediatric age range and target attainment was determined for MICs of 0.5, 2 and 4 mg/L. Results 479 cefotaxime plasma concentrations from 52 children (median age 1.6, range 0.03–17.7 years) were used to describe cefotaxime PK. We describe a two-compartment structural model with interindividual variability, including bodyweight as covariate for volume of distribution and clearance. Model predicted exposure for 150 mg/kg/day (current dose) showed trough concentrations 4 years of age. The maximum cefotaxime doses (200 mg/kg/day, interval 6 h) proved adequate for MICs ≤0.5 mg/L across the whole age range. Similar daily doses with increased frequency (interval 4 h) covered MICs up to 2 mg/L, while a loading dose followed by continuous infusion regimens are needed to adequately treat MICs of 4 mg/L. Conclusions Higher cefotaxime doses are required for adequate exposure for most pathogens in critically ill children. A higher dose frequency or continuous infusion is advisable to improve target attainment for intermediately susceptible pathogens.

Polypyrrole (PPy) nanotubes and polyaniline (Pani) nanofibers have been synthesized using chemical routes. The nanostructures are probed by X-ray diffraction (XRD), field emission scanning electron microscope (FESEM), field emission transmission electron microscope (FETEM) and Fourier transform infrared spectroscopy (FT-IR). The electrochemical performance of the nanostructures is determined by cyclic voltammetry (CV), galvanostatic charge–discharge and impedance measurements. The CV test has been performed using different electrolytes in order to get a superior electrode–electrolyte combination. The maximum specific capacitance for PPy nanotubes has been measured around 49.53F/g in 2 M KCl solution and that of 70F/g in 2 M H2SO4 solution in case of Pani nanofibers at a current density of 0.1 A/g. The higher specific capacitance of Pani nanofiber is attributed to its low charge transfer resistance as revealed from the Nyquist plot.

We have reported surface functionalization and characterization of electrically conductive polyaniline:chitosan (PAni:Ch) nanocomposites to investigate the combined effect of nanofibre structures and surface modification on cell-biomaterial interactions. The surface of the chemically synthesized PAni:Ch nanocomposites was modified with a glycine N-hydroxysuccinimide (NHS) ester to incorporate bioactivity for better cell-biomaterial interactions. X-ray photoelectron spectroscopy (XPS) and attenuated total reflection fourier transform infrared (ATR FTIR) spectroscopy confirmed incorporation of carboxyl and amine functionality after modification. Probable interaction mechanisms between unprotected glycine NHS and the nanocomposites surface were also proposed based on XPS and ATR FTIR results. The biocompatibility of the materials were evaluated by Hemolysis assay, MTS assay and live/dead assay. Surface functionalized PAni:Ch nanocomposites promoted improved fibroblast adhesion, spreading, proliferation and morphology as revealed by confocal microscopy and scanning electron microscopy. This study reveals potential of nanostructured conductive PAni based materials as potential biomaterial for tissue engineering applications.

Background RBx 14255 is a fluoroketolide in pre-clinical evaluation with potent activity against MDR Gram-positive pathogens. Objectives To investigate the efficacy of RBx 14255 against bacterial meningitis caused by Streptococcus pneumoniae, Neisseria meningitidis or Haemophilus influenzae in an experimental murine meningitis model. Methods In vitro activity of RBx 14255 was evaluated against clinical isolates of S. pneumoniae, N. meningitidis and H. influenzae. The in vivo efficacy of RBx 14255 was evaluated against bacterial meningitis, induced with S. pneumoniae 3579 erm(B), S. pneumoniae MA 80 erm(B), N. meningitidis 1852 and H. influenzae B1414 in a murine meningitis model. Results RBx 14255 showed strong in vitro bactericidal potential against S. pneumoniae, N. meningitidis and H. influenzae with MIC ranges of 0.004-0.1, 0.03-0.5 and 1-4 mg/L, respectively. In a murine meningitis model, a 50 mg/kg dose of RBx 14255, q12h, resulted in significant reduction of bacterial counts in the brain compared with the pretreatment control. The concentration of RBx 14255 in brain tissue correlated well with the efficacy in this mouse model. Conclusions RBx 14255 showed superior bactericidal activity in time-kill assays in vitro and in vivo in an experimental murine meningitis model. RBx 14255 could be a promising candidate for future drug development against bacterial meningitis.

Background: Perinatal mortality rate (PNMR) serves as the most sensitive index, directly reflecting prenatal; intrapartum and newborn care. In order to reduce perinatal mortality, it is necessary to study the various factors influencing perinatal deaths.Methods: It was a retrospective study done over the period of 1 year from January 2021 to December 2021. Total 4389 deliveries were included out of which 228 perinatal deaths occurred. Causes of perinatal deaths were identified and studied.Results: Results showed that perinatal mortality rate was 17.5 per 1000 live births. Incidence of early neonatal death was 17.5% per total admissions. Majority of perinatal deaths occurred due to preterm, low birth weight. Maternal factor associated with perinatal mortality were antepartum haemorrhage, eclampsia, obstructed labour, malpresentation, medical problems in pregnancy.Conclusions: The perinatal mortality could be prevented with strengthening of antenatal care screening, educating pregnant women to recognize the signs of complications of pregnancy, timely access to obstetric care, monitoring of labour for fetal distress, and proper newborn resuscitation. With proper coordination of neonatologist and obstetrician, sizeable reduction in perinatal mortality can be achieved.

Pseudomonas aeruginosaforms biofilms in the lungs of chronically infected cystic fibrosis patients, which are tolerant to both the treatment of antibiotics and the host immune system. Normally, antibiotics are less effective against bacteria growing in biofilms; azithromycin has shown a potent efficacy in cystic fibrosis patients chronically infected withP. aeruginosaand improved their lung function. The present study was conducted to evaluate the effect of azithromycin onP. aeruginosabiofilm. We show that azithromycin exhibited a potent activity againstP. aeruginosabiofilm, and microscopic observation revealed that azithromycin substantially inhibited the formation of solid surface biofilms. Interestingly, we observed that azithromycin restrictedP. aeruginosabiofilm formation by inhibiting the expression ofpelgenes, which has been previously shown to play an essential role in bacterial attachment to solid-surface biofilm. In a rat model of chronicP. aeruginosalung infection, we show that azithromycin treatment resulted in the suppression of quorum sensing-regulated virulence factors, significantly improving the clearance ofP. aeruginosabiofilms compared to that in the placebo control. We conclude that azithromycin attenuatesP. aeruginosabiofilm formation, impairs its ability to produce extracellular biofilm matrix, and increases its sensitivity to the immune system, which may explain the clinical efficacy of azithromycin in cystic fibrosis patients.

Objectives FtsZ is an essential bacterial protein and an unexplored target for the development of antibacterial drugs. The development of a novel inhibitor targeting FtsZ offers a potential opportunity to combat drug resistance. DS01750413, a new derivative of PC190723, is a novel FtsZ inhibitor with improved in vitro and in vivo activity. The objective of this study was to investigate the efficacy of DS01750413 against Staphylococcus spp., including MRSA, in in vitro and in vivo models. Methods In vitro activities of DS01750413 and standard-of-care antibiotics were evaluated against clinical isolates of Gram-positive pathogens. The in vivo efficacy was evaluated in a murine systemic infection model caused by MRSA. Results DS01750413 showed potent in vitro activity against MRSA clinical isolates with MIC ranges of 0.5–1 mg/L and also demonstrated concentration-dependent bactericidal killing. In the murine bacteraemia infection model of MRSA, treatment with DS01750413 resulted in prolonged survival of animals compared with placebo-treated animals and exhibited a significant reduction in the bacterial load in liver, spleen, lungs and kidneys. Conclusions DS01750413 showed encouraging in vitro and in vivo activity against MRSA. As a novel chemical class, DS01750413 has the potential to become clinically viable antibiotics to address the drug resistance problem by its unique novel targeting mechanism of action.

Highlights • That Sphingolipid derivatives are promising drug candidates for the management of novel COVID-19 disease. • C-1P based tailoring of Th1 effector immunity for the eradication of infection is a translationally viable approach and deserves immediate attention. • That C-1P would promote the killing of infected cells and resolve infection in moderate to severely infected cases. • Ceramide derivatives can be exploited as drug candidates for controlling SARS-CoV-2 against novel COVID-19 disease., Sphingolipids are potent bioactive agents involved in the pathogenesis of various respiratory bacterial infections. To date, several sphingolipid derivatives are known, but S1P (Sphingosine-1-phosphate) and Ceramide are the best-studied sphingolipid derivatives in the context of human diseases. These are membrane-bound lipids that influence host-pathogen interactions. Based on these features, we believe that sphingolipids might control SARS-CoV-2 infection in the host. SARS-CoV-2 utilizes the ACE-II receptor (Angiotensin-converting enzyme II receptor) on epithelial cells for its entry and replication. Activation of the ACE-II receptor is indirectly associated with the activation of S1P Receptor 1 signaling which is associated with IL-6 driven fibrosis. This is expected to promote pathological responses during SARS-CoV-2 infection in COVID-19 cases. Given this, mitigating S1P signaling by application of either S1P Lyase (SPL) or S1P analog (Fingolimod / FTY720) seems to be potential approach for controlling these pathological outcomes. However, due to the immunosuppressive nature of FTY720, it can modulate hyper-inflammatory responses and only provide symptomatic relief, which may not be sufficient for controlling the novel COVID-19 infection. Since Th1 effector immune responses are essential for the clearance of infection, we believe that other sphingolipid derivatives like Cermaide-1 Phosphate with antiviral potential and adjuvant immune potential can potentially control SARS-CoV-2 infection in the host by its ability in enhancing autophagy and antigen presentation by DC to promote T cell response which can be helpful in controlling SARS-CoV-2 infection in novel COVID-19 patients.

Background Thirty-four CCHF cases (17 fatal; 17 survived) were confirmed from Gujarat state, India during the year 2019. We aimed to find out the viral load, antibody kinetics, cytokine profile and phylogenetic analysis between fatal and non- fatal cases. Methods Thirty four cases were included in this study. Blood and urine samples were collected from all the cases on the day of admission to hospital. Non-fatal cases were followed weekly for understanding the profile of viral kinetics, anti-CCHFV IgM and IgG antibodies. We also quantified the cytokines in both fatal and non-fatal cases. For epidemiological correlation, livestock were screened for anti-CCHF IgG antibodies and the tick pool specimens were tested by real time RT-PCR. Virus isolation was attempted on tick pools and human specimens and phylogenetic analysis performed on human and ticks complete genome sequences. Results CCHF cases were detected throughout year in 2019 with the peak in August. Out of 34 cases, eight secondary CCHF cases were reported. Cases were predominantly detected in males and in 19–45 years age group (55.88%). The persistence of viremia was observed till 76th POD (post onset date) in one case whereas anti-CCHFV IgM and IgG was detected amongst these cases from the 2nd and 20th POD respectively. Positivity observed amongst livestock and tick pools were was 21.57% and 7.4% respectively. The cytokine analysis revealed a significant increase in the level of serum IL-6, IL-10 and IFN-γ during the acute phase of the infection, but interestingly IL-10 lowered to normal upon clearance of the virus in the clinically recovered case. Fatal cases had high viral RNA copy numbers. Bleeding from one or two mucosal sites was significantly associated with fatality (OR-16.47;p-0.0034 at 95% CI). We could do CCHF virus isolation from two cases. Phylogenetic analysis revealed circulation of re-assortment of Asian-West African genotypes in humans and ticks. Conclusions The persistence of CCHF viral RNA was detected till 76th POD in one of the survivors. The circulation of a re-assortment Asian-West African genotype in a CCHF case is also reported first time from India., Author summary Crimean Congo hemorrhagic fever is a zoonotic tick-borne viral hemorrhagic disease. This disease is reported from Europe, Mediterranean, north-western China, central Asia, Africa, and the Middle East. Several outbreaks of CCHF were reported from Gujarat and Rajasthan states, India from 2011 to 2019. In this study, we discuss the clinical, molecular, serological, and the cytokine data of 34 CCHF cases (17 fatal and 17 survived) which were detected from Gujarat state in the year 2019. A sequential weekly follow up of the CCHF survivors was performed to understand the viral kinetics and the antibody profile. Interestingly, the presence of persistence CCHF viral RNA was observed till 76th POD in one of the survivors. To our knowledge, we are reporting this long term persistence of viremia for the first time. We also observed that the anti-CCHFV IgM detection in the serum samples starts as soon as 2nd POD but anti-CCHFV IgG antibody could be detected in the majority of the cases only after the 28th POD. The cytokine analysis revealed a significant increase in the level of serum IL-6, IL-10 and IFN-γ during the acute phase of the infection, but interestingly IL-10 lowered to normal upon clearance of the virus in the clinically recovered case. We did the phylogenetic analysis and concluded the circulation of the Asian-West African re-assortment genotype in humans, which has not been reported from India prior to this study.

Aim In critically ill mechanically ventilated children, midazolam is used first line for sedation, however its sedative effects have been difficult to quantify for which novel quantification methods are still required. In this analysis, we use parametric time-to-event (PTTE) analysis to quantify the effects of midazolam in critically ill children. Methods For the PTTE analysis, data was analyzed from a published sedation interruption study in mechanically ventilated critically ill children. In this study, blinded midazolam or placebo infusions were administered during the sedation interruption phase until, based on COMFORT-B and NISS scores, patients became undersedated and unblinded midazolam was restarted. Using NONMEM® v.7.4.3.,the restart of unblinded midazolam was analysed as a clinical event, followed by internal and external validation. Results Data contained 138 events from 79 individuals (37 blinded midazolam; 42 blinded placebo). In the PTTE model, a constant function best described the baseline hazard. The use of midazolam reduced the hazard for restart of unblinded midazolam due to undersedation by 51%. In the blinded midazolam group, time to midazolam restart was 26 h versus 58 h in patients with low versus high disease severity upon admission (PRISM II 21), respectively. For blinded placebo these times were 14 h and 33 h, respectively. The model performed well in an external validation with 42 individuals. Conclusion The PTTE analysis effectively quantified the effect of midazolam and the influence of disease severity on sedation in mechanically ventilated critically ill children and provides a valuable tool to quantify sedative efficacy

Background: Different human populations across the globe responded in a different way against the SARS-CoV-2 infection. Therefore, it is anticipated that host genetic variants have straight association with the COVID-19. Genome Wide Association Study (GWAS) may help to understand this aspect. Methods: We carried out GWAS analysis with 571 SARS-CoV-2 infected patients from Gujarat state of India with different phases of COVID-19 severity. After quality filtering, total 94, 320 and 147, deceased, recovered (after admitting in intensive care unit), and asymptomatic, patients were included in the final analysis using three tools i.e. PLINK, OrdinalGWAS·jl and SAIGE. Findings: We identified total ten, thirteen, and ten unique genomic loci for deceased vs recovered, deceased vs asymptomatic and recovered vs asymptomatic groups, respectively. TNFSF4, LRRC56 and TUBD1 genes have shown an association in deceased vs recovered. Similarly, genomic markers where nearby genes are OR7C2, OR7A17, PAX5, etc. are significant for disease vs asymptomatic comparison. For recovered vs asymptomatic comparison, a strong signal at chromosome 6, locus 6p21·32 where HLA group of genes, which are key regulators of the immune system, is found. Unfavorable alleles in AX-11318356, AX-11403743, and AX-11509434 have shown the higher frequency in European compared to the South Asian population and it is reversed for AX-40266551, AX-40266553, AX-38975337, AX-11258333, and AX-30353919. Interpretation: Unfavorable alleles of the markers showing association with the disease severity and outcome can be used for risk prediction in the SARS-CoV-2 infections. GWAS study in other populations may help to further strengthen the outcome of this study. Funding: Department of Science and Technology, Government of Gujarat, India. Conflict of Interest: All the authors of this manuscript declare no competing interests. Ethical Approval: The present studies involving human participants were reviewed and approved by Institutional Ethical Committee of Gujarat Biotechnology Research Centre (GBRC), Gandhinagar, and B. J. Medical College and Civil hospital, Ahmedabad, reference No. EC/Approval/38/2020.

Native tissues and organs coordinate and execute their activities via dynamic, interlinked clusters of biochemical and biophysical attributes, which are differed throughout biological processes spatiotemporally. Passive biomaterials, developed with tunable structural, mechanical and biochemical properties, cannot mimic the dynamic features of the cellular environment and therefore, often lack of efficiency in tissue regeneration to restore full functionality. With the perspective to address this notion, stimuli responsive biomaterials have evolved as effective tool that replicate essential static and dynamic features of native tissues due to their capacity to alter physicochemical characteristics in response to physical/chemical/biological stimuli compatible to tissues and organs, facilitating on demand cell microenvironmental manipulation. The current chapter focuses on trends of stimuli responsive biomaterials explored for tissue engineering (TE) applications. Special emphasize has been devoted to those stimuli responsive biomaterials (e.g. electroactive biomaterials), which are sensitive to the stimuli that match with the native biophysical cues of tissues and can regulate those biophysical cues to modulate the regeneration associated cellular processes for faster and efficient tissue regeneration. Each category of stimuli responsive biomaterials has been discussed with a brief introduction and the mechanism of functionality followed by its applications in various TE applications. Biomaterials that respond to chemical and biological stimuli, have also been briefly addressed in the light of TE potential. The chapter also highlights the advantages-limitations and future directions of stimuli responsive biomaterials at the end.

Aim In critically ill mechanically ventilated children, midazolam is used first line for sedation, however its exact sedative effects have been difficult to quantify. In this analysis, we use parametric time-to-event (PTTE) analysis to quantify the effects of midazolam in critically ill children. Methods In the PTTE analysis, data was analyzed from a published study in mechanically ventilated children in which blinded midazolam or placebo infusions were administered during a sedation interruption phase until, based on COMFORT-B and NISS scores, patients became undersedated and unblinded midazolam was restarted. Using NONMEM® v.7.4.3., restart of unblinded midazolam was analysed as event. Patients in the trial were divided into internal and external validation cohorts prior to analysis. Results Data contained 138 events from 79 individuals (37 blinded midazolam; 42 blinded placebo). In the PTTE model, the baseline hazard was best described by a constant function. Midazolam reduced the hazard for restart of unblinded midazolam due to undersedation by 51%. In the blinded midazolam group, time to midazolam restart was 26 h versus 58 h in patients with low versus high disease severity upon admission (PRISM II 21), respectively. For blinded placebo, these times were 14 h and 33 h, respectively. The model performed well in an external validation with 42 individuals. Conclusion The PTTE analysis effectively quantified the effect of midazolam in prolonging sedation and also the influence of disease severity on sedation in mechanically ventilated critically ill children, and provides a valuable tool to quantify the effect of sedatives. Clinical trial number and registry URL: Netherlands Trial Register, Trial NL1913 (NTR2030), date registered 28 September 2009 https://www.trialregister.nl/trial/1913.

Virus disease spreads effortlessly mechanically or through minute insect vectors that are extremely challenging to avoid. Emergence and reemergence of new viruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), H1N1 influenza virus, avian influenza virus, dengue virus, Citrus tristeza virus, and Tomato yellow leaf curl virus have paralyzed the economy of many countries. The cure for major viral diseases is not feasible; however, early detection and surveillance of the disease can obstruct their spread. Therefore, advances in the field of virus diagnosis and the development of new point-of-care testing kits become necessary globally. Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas) is an emerging technology for gene editing and diagnostics development. Several rapid nucleic acid diagnostic kits have been developed and validated using Cas9, Cas12, and Cas13 proteins. This review summarizes the CRISPR/Cas-based next-generation molecular diagnostic techniques and portability of devices for field-based utilization.

ObjectivesTo investigate the anti-leishmanial activity of novel azole compounds against Leishmania donovani, which causes deadly visceral leishmaniasis disease.MethodsA focused azole-based library was screened both against promastigotes and amastigotes forms of L. donovani strains in flat-bottomed 96-well tissue-culture plates and J774A.1 macrophages infected with L. donovani. The comprehensive screening azole-based library against L. donovani strains provided novel hits, which can serve as a good starting point to initiate hit to lead optimization campaign.ResultsHits identified from azole-based library exhibited potent in vitro activity against promastigotes and amastigotes of L. donovani.ConclusionsThese potent novel azole hits could be a good starting point to carry out for further medicinal chemistry exploration for anti-leishmania program.

Biogenic silver nanoparticles (AgNPs) were synthesized by using Citrus grandis (L.) Osbeck fruit extract through a simple one step method by reducing silver nitrate (AgNO3) at room temperature. Citrus grandis (L.) Osbeck is an indigenously available edible citrus fruit tree in Northeast India and sub-Himalayan foot hills. Formation of AgNPs were confirmed primarily by UV–Vis spectrophotometer and extensively characterized by TEM and XRD. The plasmon resonance at 435 nm confirmed the formation of AgNPs and TEM analysis showed AgNPs with average size of 11 ± 3.57 nm. XRD analysis showed crystalline nature of the Ag NPs with fcc lattice points attributed to (111), (200), (222) and (311) planes. The AgNPs showed excellent antimicrobial activities against both Gram positive (Bacillus cereus) and negative (Pseudomonas syringae pv. syringae) plant pathogens. It exerted MIC value of 20 and 30 µg/mL, respectively against B. cereus and P. syringae pv. Syringae, whereas MBC value of 70 and 80 µg/mL were observed against B. cereus and P syringae pv. Syringae, respectively. The Ag NPs showed no considerable cytotoxicity against murine macrophage RAW264.7 cell line which indicates its further possible application for animal model trial.

The mounting evidence supporting the capacity of Plasmodium vivax to cause severe disease has prompted the need for a better characterization of the resulting clinical complications. India is making progress with reducing malaria, but epidemics of severe vivax malaria in Gujarat, one of the main contributors to the vivax malaria burden in the country, have been reported recently and may be the result of a decrease in transmission and immune development. Over a period of one year, we enrolled severe malaria patients admitted at the Civil Hospital in Ahmedabad, the largest city in Gujarat, to investigate the morbidity of severe vivax malaria compared to severe falciparum malaria. Patients were submitted to standard thorough clinical and laboratory investigations and only PCR-confirmed infections were selected for the present study. Severevivax malaria (30 patients) was more frequent than severe falciparum malaria (8 patients) in our setting, and it predominantly affected adults (median age 32 years, interquartile range 22.5 years). This suggests a potential age shift in anti-malarial immunity, likely to result from the recent decrease in transmission across India. The clinical presentation of severe vivax patients was in line with previous reports, with jaundice as the most common complication. Our findings further support the need for epidemiological studies combining clinical characterization of severe vivax malaria and serological evaluation of exposure markers to monitor the impact of elimination programmes.

The changes in the recommended storage conditions of the glycoconjugate vaccines against Neisseria meningitidis (Men) serogroup A and serogroup X can affect its activity or potency. Elevated temperature and the change in pH may result in the physical instability leading to the size degradation of the polysaccharide (PS) and subsequent loss of PS epitopes. Moreover, high temperature may also result in protein aggregation and altered tertiary structure of the protein in the conjugate. Consequently, the construction of a potent glycoconjugate is dependent on optimal temperature and pH. The changes in both these conditions can also affect the production of a capsular polysaccharide (PS) and its conjugation to a protein carrier and may also affect the integrity of the vaccine molecule including the maintenance of the protective epitopes. In our study we have used inhibition ELISA as a tool to assess the impact of temperature and pH alterations on the antigenicity of N. meningitidis serogroup A and X, PS and conjugates and their correlation with the size distribution analysis using high pressure size exclusion chromatography. The studies on pH alterations from 5 to 9 led to minimal impact on size and antigenicity of all antigens, however, an elevated temperature adversely impacted the antigen size as well as antigenicity to varying extent. Results indicate the higher stability of MenX PS and conjugate as compared to that for MenA counterparts at elevated temperatures. Furthermore, both the MenA and MenX conjugates appears to be more stable as compared to the corresponding PSs.

FimH is a type I fimbrial lectin located at the tip of type-1 pili of Gram-negative uropathogenic Escherichia coli (UPEC) guiding its ability to adhere and infect urothelial cells. Accordingly, blocking FimH with small molecule inhibitor is considered as a promising new therapeutic alternative to treat urinary tract infections caused by UPEC. Herein, we report that compounds having the S-glycosidic bond (thiomannosides) had improved metabolic stability and plasma exposures when dosed orally. Especially compound 5h showed the potential to inhibit biofilm formation and also to disrupt the preformed biofilm. And compound 5h showed prophylactic effect in UTI model in mice.

The LINAC at the Los Alamos Neutron Science Center (LANSCE) has been utilizing the Delta-t method to match the RF cavities to the design acceleration parameters since its commissioning in 1972. The differences in time-of-flight between two subsequent Beam Position and Phase Monitors (BPPMs) are measured with both accelerated and drifting beams, depending on the whether the module is set to on or off. The algorithm optimizes the module amplitude and phase via iterative measurements if the initial phase is in the vicinity of the design value. With an upgrade to a faster readout system, a scan over the whole RF cavity phase range requires relatively less time than the classical optimization procedure. The Phase Scan Signature Matching (PSSM) method provides a time-efficient method that ensures the phase selection lands on the bunching side and empowers future analyses to build module-specific models. The PSSM also utilizes a direct model to determine the correct amplitude to sub-percent level instead of using linearized matrices. Furthermore, lacking a reliable energy measurement method in the LINAC, we measure the beam phases at two downstream locations to increase the precision of energy measurements. In this letter, we also discuss the sensitivities of PSSM, error propagation, and the implementation results for the 2019 and 2020 beam cycles.

Fusarium wilt (Fusarium oxysporum f. sp. ciceris) of chickpea is the major limitation to chickpea production worldwide. As the nature of the pathogen is soil borne, exploitation of host plant resistance is the most suitable and economical way to manage this disease. Present study was therefore conducted with an aim to find new, stable and durable sources of resistance of chickpea against Fusarium wilt through multi-environment and multi-year screening. During 2007/2008 crop season, 130 promising genotypes having

DS86760016 is a new leucyl-tRNA-synthetase inhibitor at the preclinical development stage. DS86760016 showed potent activity against extended-spectrum multidrug-resistant Pseudomonas aeruginosa isolated from clinical samples and in vitro biofilms. In a murine catheter-associated urinary tract infection model, DS86760016 treatment resulted in significant eradication of P. aeruginosa from the kidney, bladder, and catheter without developing drug resistance. Our data suggest that DS86760016 has the potential to act as a new drug for the treatment of Pseudomonas infections.

Herein, we fabricated ternary nanocomposites (NCs) of reduced graphene oxide (rGO), ruthenium oxide (RuO2) and polyaniline nanofiber (Pani-NFs) as a flexible electrode for supercapacitor application. NCs and their individual components were characterized using high-resolution transmission electron microscopy (HRTEM), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR). The ternary NCs displayed areal capacitance as high as 1.5 F .cm−2 and thereby, indicated its potential as a supercapacitor electrode material.

RBx 11760, a bi-aryl oxazolidinone, was investigated for antibacterial activity against Gram-positive bacteria. The MIC 90 s of RBx 11760 and linezolid against Staphylococcus aureus were 2 and 4 mg/liter, against Staphylococcus epidermidis were 0.5 and 2 mg/liter, and against Enterococcus were 1 and 4 mg/liter, respectively. Similarly, against Streptococcus pneumoniae the MIC 90 s of RBx 11760 and linezolid were 0.5 and 2 mg/liter, respectively. In time-kill studies, RBx 11760, tedizolid, and linezolid exhibited bacteriostatic effect against all tested strains except S. pneumoniae . RBx 11760 showed 2-log 10 kill at 4× MIC while tedizolid and linezolid showed 2-log 10 and 1.4-log 10 kill at 16× MIC, respectively, against methicillin-resistant S. aureus (MRSA) H-29. Against S. pneumoniae 5051, RBx 11760 showed bactericidal activity, with 4.6-log 10 kill at 4× MIC compared to 2.42-log 10 and 1.95-log 10 kill for tedizolid and linezolid, respectively, at 16× MIC. RBx 11760 showed postantibiotic effects (PAE) at 3 h at 4 mg/liter against MRSA H-29, and linezolid showed the same effect at 16 mg/liter. RBx 11760 inhibited biofilm production against methicillin-resistant S. epidermidis (MRSE) ATCC 35984 in a concentration-dependent manner. In a foreign-body model, linezolid and rifampin resulted in no advantage over stasis, while the same dose of RBx 11760 demonstrated a significant killing compared to the initial control against S. aureus ( P < 0.05) and MRSE ( P < 0.01). The difference in killing was statistically significant for the lower dose of RBx 11760 ( P < 0.05) versus the higher dose of linezolid ( P > 0.05 [not significant]) in a groin abscess model. In neutropenic mouse thigh infection, RBx 11760 showed stasis at 20 mg/kg of body weight, whereas tedizolid showed the same effect at 40 mg/kg. These data support RBx 11760 as a promising investigational candidate.

Background Ever since Crimean-Congo hemorrhagic fever [CCHF] discovered in India, several outbreaks of this disease have been recorded in Gujarat State, India. During the year 2011 to 2015 several districts of Gujarat and Rajasthan state (Sirohi) found to be affected with CCHF including the positivity among ticks and livestock. During these years many infected individuals succumbed to this disease; which subsequently led to nosocomial infections. Herein, we report CCHF cases recorded from Rajasthan state during January 2015. This has affected four individuals apparently associated with one suspected CCHF case admitted in a private hospital in Jodhpur, Rajasthan. Case presentation A 30-year-old male was hospitalized in a private hospital in Jodhpur, Rajasthan State, who subsequently had developed thrombocytopenia and showed hemorrhagic manifestations and died in the hospital. Later on, four nursing staff from the same hospital also developed the similar symptoms (Index case and Case A, B, C). Index case succumbed to the disease in the hospital at Jodhpur followed by the death of the case A that was shifted to AIIMS hospital, Delhi due to clinical deterioration. Blood samples of the index case and Case A, B, C were referred to the National institute of Virology, Pune, India for CCHF diagnosis from the different hospitals in Rajasthan, Delhi and Gujarat. However, a sample of deceased suspected CCHF case was not referred. Subsequently, blood samples of 5 nursing staff and 37 contacts (Case D was one of them) from Pokhran area, Jaisalmer district were referred to NIV, Pune. Conclusions It clearly indicated that nursing staff acquired a nosocomial infection while attending the suspected CCHF case in an Intensive Care Unit of a private hospital in Jodhpur. However, one case was confirmed from the Pokhran area where the suspected CCHF case was residing. This case might have got the infection from suspected CCHF case or through other routes. CCHF strain associated with these nosocomial infections shares the highest identity with Afghanistan strain and its recent introduction from Afghanistan cannot be ruled out. However, lack of active surveillance, unawareness among health care workers leads to such nosocomial infections.

Different models for the nonlocal description of the nuclear interaction are compared through a study of their effects on the half-lives of radioactive nuclei decaying by the emission of alpha particles. The half-lives are evaluated by considering a preformed $\ensuremath{\alpha}$ particle ($^{4}\mathrm{He}$ nucleus), which tunnels through the Coulomb barrier generated by its interaction with the daughter nucleus. An effective potential obtained from a density-dependent double-folding strong potential between the $\ensuremath{\alpha}$ and the daughter nucleus within the nonlocal framework is found to decrease the half-lives as compared to those in the absence of nonlocalities. Whereas the percentage decrease within the older Perey-Buck and S\~ao Paulo models ranges between 20 to 40% for medium to heavy nuclei, a recently proposed effective potential leads to a decrease of only 2 to 4%. In view of these results, we provide a closer examination of the approximations used in deriving the local equivalent potentials and propose that, apart from the scattering data, the $\ensuremath{\alpha}$ decay half-lives can be used as a complementary tool for constraining the nonlocality models.