Recent advances in the synthesis and antimalarial activity of 1,2,4-trioxanes.

The increasing resistance of various malarial parasite strains to drugs has made the production of a new, rapid-acting, and efficient antimalarial drug more necessary, as the demand for such drugs is growing rapidly. As a major global health concern, various methods have been implemented to address the problem of drug resistance, including the hybrid drug concept, combination therapy, the development of analogues of existing medicines, and the use of drug resistance reversal agents. Artemisinin and its derivatives are currently used against multidrug- resistant P. falciparum species. However, due to its natural origin, its use has been limited by its scarcity in natural resources. As a result, finding a substitute becomes more crucial, and the peroxide group in artemisinin, responsible for the drugs biological action in the form of 1,2,4-trioxane, may hold the key to resolving this issue. The literature suggests that 1,2,4-trioxanes have the potential to become an alternative to current malaria drugs, as highlighted in this review. This is why 1,2,4-trioxanes and their derivatives have been synthesized on a large scale worldwide, as they have shown promising antimalarial activity in vivo and in vitro against Plasmodium species. Consequently, the search for a more convenient, environment friendly, sustainable, efficient, and effective synthetic pathway for the synthesis of 1,2,4-trioxanes continues. The aim of this work is to provide a comprehensive analysis of the synthesis and mechanism of action of 1,2,4-trioxanes. This systematic review highlights the most recent summaries of derivatives of 1,2,4-trioxane compounds and dimers with potential antimalarial activity from January 1988 to 2023.

Spiking neural network-based computational modeling of episodic memory.

In this research article, a spiking neural network-based simulation of the hippocampus is performed to model the functionalities of episodic memory. The purpose of the simulation is to find a computational model through the biological architecture of the hippocampus and correct values for their architectural biological parameters to support the episodic memory functionalities. The episodic store of the model is represented by the collection of events, where each event is further subdivided into coactive activities of experience. The model has tried to mimic the three functionalities of episodic memory, which are pattern separation, pattern association, and their recallings. In pattern separation model used the dentate biological connectivity to generate almost different output patterns corresponding to similar input patterns to reduce interference between two similar memory traces so that ambiguity can be reduced during recalling. In pattern association, an STDP based event encoding and forgetting mechanism are used to mimic the encoding function of the CA3 region in which the coactive activities get associated with each other. A decoder is proposed based on CA1, which can answer the stored event related queries. Along with these functionalities model also supports recalling and encoding based forgetting. Experimental work is performed on the model for the given set of events to check for the pattern separation efficiency, pattern completion efficiency and to check the capability of decoding the answer. An empirical analysis of the results is done and compared with the SMRITI model of episodic memory.

Transcending the challenge of evolving resistance mechanisms in Pseudomonas aeruginosa through ß-lactam-enhancer-mechanism-based cefepime/zidebactam.

Multi-drug resistant (MDR) Pseudomonas aeruginosa harbor a complex array of ß-lactamases and non-enzymatic resistance mechanisms. In this study, the activity of a ß-lactam/ß-lactam-enhancer, cefepime/zidebactam, and novel ß-lactam/ß-lactamase inhibitor combinations was determined against an MDR phenotype-enriched, challenge panel of P. aeruginosa (n = 108). Isolates were multi-clonal as they belonged to at least 29 distinct sequence types (STs) and harbored metallo-ß-lactamases, serine ß-lactamases, penicillin binding protein (PBP) mutations, and other non-enzymatic resistance mechanisms. Ceftazidime/avibactam, ceftolozane/tazobactam, imipenem/relebactam, and cefepime/taniborbactam demonstrated MIC90s of >128 mg/L, while cefepime/zidebactam MIC90 was 16 mg/L. In a neutropenic-murine lung infection model, a cefepime/zidebactam human epithelial-lining fluid-simulated regimen achieved or exceeded a translational end point of 1-log10 kill for the isolates with elevated cefepime/zidebactam MICs (16-32 mg/L), harboring VIM-2 or KPC-2 and alterations in PBP2 and PBP3. In the same model, to assess the impact of zidebactam on the pharmacodynamic (PD) requirement of cefepime, dose-fractionation studies were undertaken employing cefepime-susceptible P. aeruginosa isolates. Administered alone, cefepime required 47%-68% fT >MIC for stasis to ~1 log10 kill effect, while cefepime in the presence of zidebactam required just 8%-16% for >2 log10 kill effect, thus, providing the pharmacokinetic/PD basis for in vivo efficacy of cefepime/zidebactam against isolates with MICs up to 32 mg/L. Unlike ß-lactam/ß-lactamase inhibitors, ß-lactam enhancer mechanism-based cefepime/zidebactam shows a potential to transcend the challenge of ever-evolving resistance mechanisms by targeting multiple PBPs and overcoming diverse ß-lactamases including carbapenemases in P. aeruginosa.IMPORTANCECompared to other genera of Gram-negative pathogens, Pseudomonas is adept in acquiring complex non-enzymatic and enzymatic resistance mechanisms thus remaining a challenge to even novel antibiotics including recently developed ß-lactam and ß-lactamase inhibitor combinations. This study shows that the novel ß-lactam enhancer approach enables cefepime/zidebactam to overcome both non-enzymatic and enzymatic resistance mechanisms associated with a challenging panel of P. aeruginosa. This study highlights that the ß-lactam enhancer mechanism is a promising alternative to the conventional ß-lactam/ß-lactamase inhibitor approach in combating ever-evolving MDR P. aeruginosa.

Comparative proteomic investigation unravels the pathobiology of Mycobacterium fortuitum biofilm.

Biofilm formation by Mycobacterium fortuitum causes serious threats to human health due to its increased contribution to nosocomial infections. In this study, the first comprehensive global proteome analysis of M. fortuitum was reported under planktonic and biofilm growth states. A label-free Q Exactive Quadrupole-Orbitrap tandem mass spectrometry analysis was performed on the protein lysates. The differentially abundant proteins were functionally characterized and re-annotated using Blast2GO and CELLO2GO. Comparative analysis of the proteins among two growth states provided insights into the phenotypic switch, and fundamental pathways associated with pathobiology of M. fortuitum biofilm, such as lipid biosynthesis and quorum-sensing. Interaction network generated by the STRING database revealed associations between proteins that endure M. fortuitum during biofilm growth state. Hypothetical proteins were also studied to determine their functional alliance with the biofilm phenotype. CARD, VFDB, and PATRIC analysis further showed that the proteins upregulated in M. fortuitum biofilm exhibited antibiotic resistance, pathogenesis, and virulence. Heatmap and correlation analysis provided the biomarkers associated with the planktonic and biofilm growth of M. fortuitum. Proteome data was validated by qPCR analysis. Overall, the study provides insights into previously unexplored biochemical pathways that can be targeted by novel inhibitors, either for shortened treatment duration or for eliminating biofilm of M. fortuitum and related nontuberculous mycobacterial pathogens. KEY POINTS: • Proteomic analyses of M. fortuitum reveals novel biofilm markers. • Acetyl-CoA acetyltransferase acts as the phenotype transition switch. • The study offers drug targets to combat M. fortuitum biofilm infections.

COVID-19 Booster Dose Coverage and Hesitancy among Older Adults in an Urban Slum and Resettlement Colony in Delhi, India.

BACKGROUND: The high prevalence of vaccine booster hesitancy, with the concomitant waning of humoral vaccine or hybrid immunity, and the emergence of SARS-CoV-2 variants of concern can accentuate COVID-19 morbidity and mortality. The study objective was to ascertain the COVID-19 vaccination coverage, including the administration of precaution (booster) dose vaccination, among the older population in an urban slum and resettlement colony population in Delhi, India. METHODS: We conducted a cross-sectional survey in an urban resettlement colony, slum, and village cluster in the Northeast district of Delhi among residents aged ≥50 years. RESULTS: A total of 2217 adults (58.28%) had obtained a COVID-19 booster (precaution) dose vaccine, 1404 (36.91%) had received two doses of a COVID-19 vaccine without booster dose, 121 (3.18%) were unvaccinated, while 62 (1.63%) participants received a single dose. Based on adjusted analysis, older adults (>65 years), higher education, and higher per-capita income were statistically significant predictors of booster dose vaccination. CONCLUSIONS: More than four in ten adults in an urban slum and resettlement colony in Delhi lacked COVID-19 booster dose vaccination despite high rates of double-dose vaccination (~95%). Public health programming should provide an enhanced focus on reducing complacency with renewed prioritization for improving ease of access to COVID-19 vaccination services, particularly in underserved areas.

ß-Lactam Resistance in ESKAPE Pathogens Mediated Through Modifications in Penicillin-Binding Proteins: An Overview.

Bacteria acquire ß-lactam resistance through a multitude of mechanisms among which production of ß-lactamases (enzymes that hydrolyze ß-lactams) is the most common, especially in Gram-negatives. Structural changes in the high-molecular-weight, essential penicillin-binding proteins (PBPs) are widespread in Gram-positives and increasingly reported in Gram-negatives. PBP-mediated resistance is largely achieved by accumulation of mutation(s) resulting in reduced binding affinities of ß-lactams. Herein, we discuss PBP-mediated resistance among ESKAPE pathogens that cause diverse hospital- and community-acquired infections globally.

Determinants of Treatment Adherence and Health Outcomes in Patients With Type 2 Diabetes and Hypertension in a Low-Income Urban Agglomerate in Delhi, India: A Qualitative Study.

Background Diabetes and hypertension (HTN) are increasing threats to global public health. Despite evidence of effective management of diabetes and HTN by medications that help in the prevention and reducing mortality of the disease, a large proportion of people either remain undiagnosed or untreated, especially in low-resource countries. This study was conducted to explore the patient treatment pathway and their health-seeking behavior in a low-income urban area. Methodology We conducted 45 in-depth interviews of adult patients affected by type 2 diabetes mellitus (DM) and/or HTN on treatment for at least two years and attended the weekly clinic catering to an urban resettlement colony in the Northeast district of Delhi. Interviews were conducted and transcribed into Hindi and translated into English. Data analysis was done using Microsoft Excel. The patient treatment pathways were mapped, and their health-seeking behavior, treatment adherence, and experiences were described. Results Most patients reported taking treatment from the government primary health facilities due to optimal healthcare accessibility as the prescribed drugs for DM/HTN control were available free of cost at these healthcare facilities. Those who visited private facilities thought of shorter waiting times and the quality of drugs. Patients also had little knowledge of complications of diabetes and hypertensive disorders. Nearly 25% of patients had poor adherence to the medications, and lifestyle modification was rarely practiced by patients although they were aware of the same. Conclusions Expanding the role of community health workers or volunteers in providing information on noncommunicable diseases might help improve patient treatment pathways to care.

Development of an Artificial Intelligence-Guided Citizen-Centric Predictive Model for the Uptake of Maternal Health Services Among Pregnant Women Living in Urban Slum Settings in India: Protocol for a Cross-sectional Study With a Mixed Methods Design.

BACKGROUND: Pregnant women are considered a "high-risk" group with limited access to health facilities in urban slums in India. Barriers to using health services appropriately may lead to maternal and child mortality, morbidity, low birth weight, and children with stunted growth. With the increase in the use of artificial intelligence (AI) and machine learning in the health sector, we plan to develop a predictive model that can enable substantial uptake of maternal health services and improvements in adverse pregnancy health care outcomes from early diagnostics to treatment in urban slum settings. OBJECTIVE: The objective of our study is to develop and evaluate the AI-guided citizen-centric platform that will support the uptake of maternal health services among pregnant women seeking antenatal care living in urban slum settings. METHODS: We will conduct a cross-sectional study using a mixed methods approach to enroll 225 pregnant women aged 18-44 years, living in the urban slums of Delhi for more than 6 months, seeking antenatal care, and who have smartphones. Quantitative and qualitative data will be collected using an Open Data Kit Android-based tool. Variables gathered will include sociodemographics, clinical history, pregnancy history, dietary history, COVID-19 history, health care facility data, socioeconomic status, and pregnancy outcomes. All data gathered will be aggregated into a common database. We will use AI to predict the early at-risk pregnancy outcomes (in terms of the type of delivery method, term, and related complications) depending on the needs of the beneficiaries translating into effective service-delivery improvements in enhancing the use of maternal health services among pregnant women seeking antenatal care. The proposed research will help policy makers to prioritize resource planning, resource allocation, and the development of programs and policies to enhance maternal health outcomes. The academic research study has received ethical approval from the University Research Ethics Committee of Dehradun Institute of Technology (DIT) University, Dehradun, India. RESULTS: The study was approved by the University Research Ethics Committee of DIT University, Dehradun, on July 4, 2021. Enrollment of the eligible participants will begin by April 2022 followed by the development of the predictive model by October 2022 till January 2023. The proposed AI-guided citizen-centric tool will be designed, developed, implemented, and evaluated using principles of human-centered design that will help to predict early at-risk pregnancy outcomes. CONCLUSIONS: The proposed internet-enabled AI-guided prediction model will help identify the potential risk associated with pregnancies and enhance the uptake of maternal health services among those seeking antenatal care for safer deliveries. We will explore the scalability of the proposed platform up to different geographic locations for adoption for similar and other health conditions. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/35452.

Eugenol and geraniol impede Csu-pilus assembly and evades multidrug-resistant Acinetobacter baumannii biofilms: In-vitro and in-silico evidence.

Acinetobacter baumannii forms robust biofilms, which aid protection against antimicrobials and account for adaptation in hospital settings. Biofilm formation by A. baumannii has worsens the scenario of drug resistance. Therefore, new strategies are required to tackle biofilm-forming multidrug-resistant A. baumannii. The present study investigated compounds with antimicrobials and antibiofilm properties against A. baumannii. Different antimicrobials were selected from available reports. Initially, comparative antimicrobial activity against A. baumannii isolates was assessed. Most potent antimicrobial compounds were further analyzed for time-kill kinetics, biofilm inhibition, and exopolysaccharide (EPS) reduction in their presence and absence. The antibiofilm potentials were also confirmed with SEM analysis. The relative gene expression of the csuE gene and molecular docking was carried out to investigate the molecular mechanism of mature biofilm disruption. The results demonstrated eugenol and geraniol as the most potent inhibitors with MICs of 6.08 mM and 3.24 mM, respectively, with the potential to significantly inhibit growth and EPS production. Complete inhibition of A. baumannii mature biofilms was observed with a maximum of 60.89 mM and 129.6 mM concentrations of eugenol and geraniol, respectively. The SEM analysis and lower expression of the csuE gene showed the effectiveness of potent antibiofilm agents. In-silico docking showed efficient binding of eugenol and geraniol with the csuE protein of archaic pilus. The findings of molecular docking concordant the assumption that these molecules may prevent the assembly of mature pilus, which results in abolished biofilms. In conclusion, the antibiofilm virtues of eugenol and geraniol were elucidated to be used in the future to control the persistence of biofilm-forming drug-resistant A. baumannii.

Acinetobacter baumannii Biofilm Formation: Association with Antimicrobial Resistance and Prolonged Survival under Desiccation.

Biofilm-forming multidrug-resistant Acinetobacter baumannii has emerged as a global pathogen. This study investigated the impact of biofilm formation by A. baumannii on antimicrobial resistance and prolonged survival under desiccation, which is essential for effective infection control of A. baumannii in hospital settings. Seventy-eight clinical isolates of A. baumannii were identified, and antibiotic susceptibility profiles were assessed. All the isolates were investigated for their biofilm-forming abilities at 24 and 48 h. The biofilm inhibitory concentrations of antibiotics were evaluated for selected biofilm-forming isolates to determine the influence of biofilm on antibiotic tolerance. The impact of biofilm formation on desiccation tolerance was also evaluated for up to 48 days. The results revealed that out of 78 A. baumannii clinical isolates, 83% were MDR and 17% non-MDR. Overall, 79% of isolates formed high biofilm after 24 h. The extent of biofilm formation gets significantly increased after 48 h, and 87% of isolates formed high biofilm. It was observed that eradicating mature biofilm requires up to a thousandfold higher concentration of antibiotics than MICs, and biofilm-forming isolates can survive for a prolonged period under desiccation. In conclusion, our findings revealed that both MDR and non-MDR isolates of A. baumannii could form biofilms on abiotic surfaces. A. baumannii biofilms contribute to endurance in the presence of antimicrobials and desiccation conditions, which are significant trouble for hospital patient care management. The present findings may offer insights for developing preventive measures to tackle biofilm-associated A. baumannii infection.

Knockdown of the Type-II Fatty acid synthase gene hadC in mycobacterium fortuitum does not affect its growth, biofilm formation, and survival under stress.

Background: Mycobacterial fatty acid synthase Type-II (FAS-II) components are major virulence factors exploited as potential targets for developing novel antimycobacterial drugs. The FAS-II enzyme 3-hydroxyacyl-ACP dehydratase (HadC) is important for biofilm development and pathogenesis of Mycobacterium tuberculosis and other mycobacterial species. Methods: Literature review and homology search led to the identification of Mycobacterium fortuitum MFhadC gene. Functional interaction study of MFHadC protein was done using STRING. M. fortuitum MFhadC over-expressing (HS) and knockdown (HA) strains were constructed and validated by expression analysis using quantitative polymerase chain reaction. The strains were analyzed for growth behavior and surface spreading ability. Biofilm formation was assayed through crystal violet assay, viability count, and basic fuchsin staining. In addition, survival of the strains was studied under in vitro nutrient starvation and detergent stress. Results: STRING analysis showed the interaction of HadC with proteins involved in biofilm formation. The strains HS and HA showed spreading ability on the agarose surface, exhibiting translocation patterns similar to the vector control strain. All three strains showed a similar amount of biofilm formation when analyzed using crystal violet assay, viability count, and basic fuchsin staining. The strains showed no deviation in survival when incubated under nutrient starvation and detergent stress. Conclusion: Our results suggest that MFhadC may not be important for the formation and maintenance of biofilm, a factor critically important in M. fortuitum pathogenicity. However, not essential for survival and growth, MFhadC maintains the viability of M. fortuitum under a nutrient-starved environment. Collectively, MFhadC may not be used as a biofilm-specific marker for M. fortuitum.

Mycobacterium fortuitum fabG4 knockdown studies: Implication as pellicle and biofilm specific drug target.

The fatty acid biosynthesis pathway is crucial for the formation of the mycobacterial cell envelope. The fatty acid synthase type-II (FAS-II) components are attractive targets for designing anti-biofilm inhibitors. Literature review, bioinformatics analysis, cloning, and sequencing led to the identification of a novel Mycobacterium fortuitum FAS-II gene MFfabG4 which interacts with mycobacterial proteins involved in biofilm formation. A manually curated M. fortuitum fatty acid biosynthesis pathway has been proposed exploiting functional studies from the Kyoto Encyclopedia of Genes and Genomes and Mycobrowser databases for MFFabG4. M. fortuitum MFfabG4 knockdown strain (FA) was constructed and validated by quantitative polymerase chain reaction. The FA strain displayed unstructured smooth colony architecture, correlating with decreased pathogenicity and virulence. MFfabG4 knockdown resulted in diminished pellicle and attenuated biofilm formation, along with impaired sliding motility, and reduced cell sedimentation. The FA strain showed lowered cell surface hydrophobicity, indicating attenuation in M. fortuitum intracellular infection-causing ability. Stress survival studies showed the requirement of MFfabG4 for survival in a nutrient-starved environment. The results indicate that MFfabG4 maintains the physiology of the cell envelope and is required for the formation of M. fortuitum pellicle and biofilm. The study corroborates the role of MFfabG4 as a pellicle- and biofilm-specific drug target and a potential diagnostic marker for M. fortuitum and related pathogenic mycobacteria.

Sero-Surveillance to Monitor the Trend of SARS-CoV-2 Infection Transmission in India: Study Protocol for a Multi Site, Community Based Longitudinal Cohort Study.

Introduction: Large-scale sero-prevalence studies with representation from all age groups are required to estimate the true burden of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in the community. Serial serological surveys in fixed cohorts enable study of dynamics of viral transmission and correlates of immune response over time in the context of gradual introduction of COVID-19 vaccines and repeated upsurge of cases during the pandemic. Methods: This longitudinal study will involve follow-up of a cohort of 25,000 individuals (5,000 per site) aged 2 years and above recruited from five existing demographic surveillance sites in India. The cohort will be tested for the presence of IgG antibodies against S1/S2 spike protein subunits of SARS-CoV-2 in four rounds; once at baseline and subsequently, at intervals of 4 months for a year between January 2021 and January 2022. Neutralization assays will be carried out in a subset of seropositive samples in each round to quantify the antibody response and to estimate the durability of antibody response. Serial serological surveys will be complemented by fortnightly phone based syndromic surveillance to assess the burden of symptomatic acute febrile illness/ influenza like illness in the same cohort. A bio-repository will also be established to store the serum samples collected in all rounds of serological surveys. Discussion: The population based sero-epidemiological studies will help to determine the burden of COVID-19 at the community level in urban and rural Indian populations and guide in monitoring the trends in the transmission of SARS-CoV-2 infection. Risk factors for infection will be identified to inform future control strategies. The serial serological surveys in the same set of participants will help determine the viral transmission dynamics and durability of neutralizing immune response in participants with or without symptomatic COVID infection.

Decoding Acinetobacter baumannii biofilm dynamics and associated protein markers: proteomic and bioinformatics approach.

Biofilm formation by Acinetobacter baumannii is one of the major cause of its persistence in hospital environment. Biofilm phenotypes are more resistant to physical as well as chemical stresses than their planktonic counterparts. The present study was carried in quest of biofilm-associated protein markers and their association with various biological pathways of A. baumannii. The study was designed with an aim to highlight the crucial common factor present in the majority of the A. baumannii strains irrespective of its resistance nature. A label-free proteome comparison of biofilm and planktonic phenotypes of A. baumannii was done using QExactive tandem mass spectrometry. Our investigation suggests key elevation of adhesion factors, acetate metabolism, nutrient transporters, and secretion system proteins are required for biofilm formation in A. baumannii. Elevation of biofilm-associated proteins revealed that biofilm is the unique phenotype with the potential to form robust matrix-embedded colonies and defeat stress condition. Further, core protein markers of biofilm phenotypes could be used as targets for new clinical interventions to combat biofilm-associated infections.

Response surface modeling integrated microtiter plate assay for Mycobacterium fortuitum biofilm quantification.

In this study, the effects of agitation, temperature, and pH on biofilm formation by Mycobacterium fortuitum were studied and quantified through response surface modeling. The microtiter plate assay was optimized to achieve conditions favoring maximum mycobacterial biofilm quantification. Optical density (OD) measurement using a crystal violet assay was performed to estimate the amount of biofilm formed. Response surface methodology (RSM) results revealed an R2 value of 96.18%, exhibiting a maximum OD of 2.119 (λ570 nm) at a temperature of 37 °C and pH 7.0, under a static environment. The conditions were experimentally validated. Statistically significant results showed that the maximum biofilm was produced 96 h after mycobacterial inoculation. Thus, the results provide a basis for using RSM as an efficient optimization method for M. fortuitum biofilm assays. This approach can also be incorporated into strategies for screening anti-biofilm compounds, synthetic chemicals, drugs, or inhibitors against pathogenic mycobacteria.

In silico identification of promising inhibitor against RNA-dependent RNA polymerase target of SARS-CoV-2.

The severe acute respiratory syndrome is a viral respiratory disease recognised as COVID-19, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Formerly, no precise remedies are available, and many studies regarding COVID-19 prevention and treatment are under development. Several targets for the design of drugs are identified, and studies are in headway to explore the potential target. RNA-dependent RNA polymerase (RdRp) protein identified as a promising target against SARS-CoV-2 infection for the drug design due to its significant role in viral replication. The present study focuses on identifying the binding effect of previously known RdRp inhibitors with RdRp of SARS-CoV-2 using molecular docking and molecular dynamics simulation approaches. Molecular docking and binding free energy calculations against RdRp enzyme identified suramin as a potential compound that showed the highest docking score of -7.83 Kcal/mole and binding energy of -80.83 Kcal/mole as a comparison to other compounds. Further, molecular dynamics simulation studies were moreover showed the stable binding behaviour of suramin docked complex in the protein active site. Thus, the study concludes that suramin might be helpful as a potential inhibitor against RNA-dependent RNA polymerase of SRAS-CoV-2. However, further investigation is needed to assess the possible effect of inhibitors on RdRp through in vitro and in vivo experiments.

Synthesis of novel 1,2,4-trioxanes and antimalarial evaluation against multidrug-resistant Plasmodium yoelii nigeriensis.

Malaria epidemics represent one of the life-threatening diseases to low-income lying countries which subsequently affect the economic and social condition of mankind. In continuation in the development of a novel series of 1,2,4-trioxanes 13a1-c1, 13a2-c2, and 13a3-c3 have been prepared and further converted into their hemisuccinate derivatives 14a1-c1, 14a2-c2, and 14a3-c3 respectively. All these new compounds were evaluated for their antimalarial activity against multidrug-resistant Plasmodium yoelii nigeriensis in mice by both oral and intramuscular (im) routes. Hydroxy-functionalized trioxane 13a1 showed 80% protection and its hemisuccinate derivative 14a1 showed 100% protection at a dose of 48 mg/kg × 4 days by both routes, which is twice active than artemisinin by oral route.

Effects of carbamate pesticides intermediates on Escherichia coli membrane architecture: An in vitro and in silico approach.

Methyl isocyanate (MIC), a low molecular weight synthetic aliphatic compound, having an isocyanate group (-NCO), has industrial application. In this study, the effects of methyl isocyanate and its mechanism on outer membrane protein of Escherichia coli were observed using experimental and computational methods. In vitro exposure of N-succinimidyl N-methylcarbamate (NSNM) a synthetic analogue of MIC on E. coli to a final concentration of 2 mM was found to affect the growth curve pattern and changes in cell morphology. Molecular docking studies of MIC and NSNM with E. coli outer membrane protein (OmpW, OmpX, OmpF OmpA), and periplasmic domain (PAL) were performed. The in-silico results revealed that outer membrane protein OmpF showed the highest negative binding energy, i.e. ∆G -4.11 kcal/mole and ∆G -3.19 kcal/mole by NSNM and MIC as compared to other proteins. Our study concludes that methyl isocyanate retains lethal toxicity which leads to cell death due to the membrane protein damage of E. coli membrane.

Specialist to non-specialist teleconsultations in chronic respiratory disease management: A systematic review.

BACKGROUND: Chronic respiratory diseases (CRD), are common public health problems with high prevalence, disability and mortality rates worldwide. Further uneven distribution of the health workforce is a major barrier to the effective diagnosis and treatment of CRDs. Teleconsultation between a specialist and non-specialist could possibly bridge the gap in access to health care and decrease CRD burden in remote areas. This review investigates the evidence for the effective use of specialist to non-specialist teleconsultation in the management of CRDs in remote areas and identifies instances of good practice and knowledge gaps. METHODS: We searched for articles till November 2020, which focused on specialist to non-specialist teleconsultations for CRD diagnosis or management. Two independent reviewers conducted the title and abstract screening and extracted data from the selected papers and the quality was assessed by Joanna Briggs Institute's (JBI) tool. A descriptive and narrative approach was used due to the heterogeneous nature of the selected studies. RESULTS: We found 1715, articles that met the initial search criteria, but after excluding duplicates and non-eligible articles, we included 10 research articles of moderate quality. These articles were from nine different studies, all of which, except one, were conducted in high-income countries. The studies reported results in terms of impact on the patients, and the health care providers including primary care physicians (PCP) and specialists. The teleconsulting systems used in all the selected papers primarily used audio modes in addition to other modes like the audio-video medium. The included studies reported primarily non-clinical outcomes including effectiveness, feasibility, acceptability and usability of the teleconsultation systems and only three described the clinical outcomes. The teleconsultation was predominantly conducted in the PCP's office with the specialist located remotely. CONCLUSIONS: We found relatively few, papers which explored specialist to non-specialist teleconsultation in management of CRDs, and no controlled trials. Two of the included papers described systems, which were used for other diseases in addition to the CRD. The available literature although not generalisable, encourages the use of specialist to non-specialist teleconsultation for diagnosis and management of CRDs.

Activity of ß-lactam plus ß-lactam-enhancer combination cefepime/zidebactam against Klebsiella pneumoniae harbouring defective OmpK35/36 porins and carbapenemases.

Cefepime/zidebactam is a ß-lactam/ß-lactam-enhancer based novel antibiotic which is in clinical development for treating infections caused by multidrug-resistant Gram-negative bacteria. Here, in vitro activity of cefepime/zidebactam was determined against multicentre Klebsiella pneumoniae clinical isolates co-expressing serine and/or metallo-carbapenemases and defective OmpK35 and OmpK36 porins. The MICs were determined using the reference broth microdilution method. Outer membrane protein expression was assessed using SDS-PAGE and mutations in the genes encoding OmpK35 and OmpK36 were identified by DNA sequencing. Among 34 isolates studied, carbapenemase genes, blaKPC and blaOXA-48-like, were present in 18 and 11 isolates, respectively; 5 isolates harboured both blaOXA-48-like and blaNDM. Point mutations, insertions, and duplications in OmpK35 and OmpK36, which are known to impact the activity of carbapenems, were detected. Against these isolates, cefepime/zidebactam (1:1) showed a consistent activity (MICs ≤4 mg/L). In conclusion, cefepime/zidebactam overcomes enzymatic, and non-enzymatic carbapenem-impacting resistance mechanisms concurrently expressed in K. pneumoniae.