Synthesis, spectroscopic characterization and pharmacological evaluation of oxazolone derivatives

A series of 4-aryl methylidene-2-phenyl/methyl-5-(4H)-oxazolone derivatives (2-7) have been synthesized using the reported method by condensation of aldehydes with N-benzoyl / N-acetyl glycine in the presence of zinc oxide as a catalyst and acetic anhydride at room temperature in ethanol. The compounds (2-6) are new derivatives. The structures of compounds were evaluated on the basis of 1H-NMR, 13C-NMR, EIMS, FT-IR and elemental analysis. All the compounds were screened for their antibacterial and urease inhibition activity. Antibacterial activity was tested by agar well diffusion method using Mueller Hinton Agar medium. Compound (2) showed excellent activity against S. aureus which has 16 mm (80%) inhibition and above 24 mm (70%) against S. typhi. The most active compound against E. coli was compound (6) having 20 mm (80%) inhibition followed by compound (5) having above 18 mm (70%) inhibition. Urease inhibition activity of all the compounds was determined by indophenol method. Compounds (3, 6) and (7) showed significant inhibition against Jacks bean urease

Extreme purifying selection against point mutations in the human genome

Large-scale genome sequencing has enabled the measurement of strong purifying selection in protein-coding genes. Here we describe a new method, called ExtRaINSIGHT, for measuring such selection in noncoding as well as coding regions of the human genome. ExtRaINSIGHT estimates the prevalence of "ultraselection" by the fractional depletion of rare single-nucleotide variants, after controlling for variation in mutation rates. Applying ExtRaINSIGHT to 71,702 whole genome sequences from gnomAD v3, we find abundant ultraselection in evolutionarily ancient miRNAs and neuronal protein-coding genes, as well as at splice sites. By contrast, we find much less ultraselection in other noncoding RNAs and transcription factor binding sites, and only modest levels in ultraconserved elements. We estimate that ~0.4-0.7% of the human genome is ultraselected, implying ~ 0.26-0.51 strongly deleterious mutations per generation. Overall, our study sheds new light on the genome-wide distribution of fitness effects by combining deep sequencing data and classical theory from population genetics

Usability and acceptability of a mobile app for behavior change and to improve immunization coverage among children in Pakistan: A mixed-methods study

Background: Pakistan\u27s immunization uptake rates are still significantly lower than anticipated despite several initiatives. Lack of awareness, forgetting about vaccination schedule, and vaccine misconception/misinformation are a few of the major drivers that mitigate the rates of immunization. The current COVID-19 pandemic emphasizes the importance of immunization. The significant reductions in regular childhood vaccination during pandemic have increased the risk of outbreaks of vaccine-preventable diseases. Concerns among parents over possibly exposing their children to COVID-19 during child visits may have contributed to the reported declines. Innovative and cost-effective mHealth interventions must be implemented in order to address the problem of inadequate immunization rates. In addition, it is also critical to understand the end user needs in order to reflect on the highly relevant essence of the customized healthcare experience.Objective: The aim of this study was to learn about caregivers\u27 attitudes toward the usability and acceptability of behavior-change smartphone applications (mobile phones) for improving immunization coverage in Pakistan.Methods: A mixed-method design was employed for this study. The study was conducted at Aga Khan University, Hospital. Parents visiting the Community Health Center for 6-week vaccination of their children were recruited. The study was conducted in two stages. Stage 1 consisted of qualitative interviews that grasped the parent\u27s attitudes and challenges to immunization, as well as their acceptability and accessibility of the smartphone-based behavior-change application to increase vaccine uptake. Stage 1 was followed by stage 2, in which data were collected through a questionnaire designed by using data from qualitative interviews.Results: The majority of participants agreed that immunization serves an important role in protecting their child from illnesses that cause morbidity and mortality. Almost all of them emphasized the importance of using a pre-appointment method at vaccination center in order to reduce the waiting time. Furthermore, participants were also interested in AI-based behavior modification applications related to immunization. They also wanted to have applications in their native language for better understanding and communication of related information. In our study, approximately 95.2 percent of participants agreed to accept SMS immunization updates, which was also reasonably high. Lastly, the majority of them identified forgetfulness as a significant contributor to regular immunization.Conclusion: To enhance the uptake of childhood vaccines, overall vaccination rates, and overcome barriers related to vaccination coverage, cost-effective and user-friendly mHealth AI-based smart phone applications are required to raise awareness regarding the continuation of vaccination service and the importance of timely vaccination. Parents\u27 experiences and attitudes must be considered while designing and evaluating the efficacy of mHealth-based interventions

Extreme purifying selection against point mutations in the human genome

Genome sequencing of tens of thousands of humans has enabled the measurement of large selective effects for mutations to protein-coding genes. Here we describe a new method, called ExtRaINSIGHT, for measuring similar selective effects in noncoding as well as in coding regions of the human genome. ExtRaINSIGHT estimates the prevalance of strong purifying selection, or “ultraselection” (λs), as the fractional depletion of rare single-nucleotide variants in target genomic sites relative to matched sites that are putatively free from selection, after controlling for local variation and neighbor-dependence in mutation rate. We show using simulations that λs is closely related to the average site-specific selection coefficient against heterozygous point mutations, as predicted at mutation-selection balance. Applying ExtRaINSIGHT to 71,702 whole genome sequences from gnomAD v3, we find strong evidence of ultraselection in evolutionarily ancient miRNAs and neuronal protein-coding genes, as well as at splice sites. By contrast, we find weak evidence in other noncoding RNAs and transcription factor binding sites, and only modest evidence in ultraconserved elements and human accelerated regions. We estimate that ~0.3–0.5% of the human genome is ultraselected, implying ~0.3–0.4 lethal or nearly lethal de novo mutations per potential human zygote. Overall, our study sheds new light on the genome-wide distribution of fitness effects for new point mutations by combining deep new sequencing data sets and classical theory from population genetics

Intravenous vs intravenous plus aerosolized colistin for treatment of ventilator-associated pneumonia - A matched case-control study in neonates

Background: Recently intravenous (IV) and aerosolized (ASZ) colistin have been used for treating ventilator-associated pneumonia (VAP) due to colistin susceptible multidrug-resistant Gram-negative bacteria (MDR-GNB). Colistin has limited lung penetration. We compared the efficacy and safety of IV-alone versus IV+ASZ-colistin for treating VAP in neonates.Methods: This retrospective matched case-control-study was performed at NICU of the Aga Khan University Hospital, Pakistan between January 2015 and December 2018. Sixteen neonates with MDR-GNB associated VAP received IV-ASZ-colistin and were matched for date of birth, gestational age, birth weight, Apgar score, antenatal steroid history, disease severity and duration of mechanical ventilation with 16 control neonates who received IV-colistin alone.Results: Both groups had similar MDR-GNB isolates and Acinetobacter baumannii (78%) was the most common pathogen. No colistin-resistant strain was isolated. Duration of IV-colistin and concomitant antibiotics use was significantly (p \u3c 0.05) shorter in IV-ASZ-colistin group. Significantly (p \u3c 0.05) higher clinical cure and microbial eradication, along with lower ventilatory requirements, mortality rate, and colistin induced nephrotoxicity and electrolyte imbalance was observed in IV-ASZ-colistin group.Conclusions: With better lung penetration, ASZ-colistin offers effective and safe microbiological and clinical benefits as adjunctive or alternate treatment of VAP due to colistin susceptible MDR-GNB in neonates

An artificial intelligence-based, personalized smartphone app to improve childhood immunization coverage and timelines among children in Pakistan: Protocol for a randomized controlled trial

Background: The immunization uptake rates in Pakistan are much lower than desired. Major reasons include lack of awareness, parental forgetfulness regarding schedules, and misinformation regarding vaccines. In light of the COVID-19 pandemic and distancing measures, routine childhood immunization (RCI) coverage has been adversely affected, as caregivers avoid tertiary care hospitals or primary health centers. Innovative and cost-effective measures must be taken to understand and deal with the issue of low immunization rates. However, only a few smartphone-based interventions have been carried out in low- and middle-income countries (LMICs) to improve RCI.Objective: The primary objectives of this study are to evaluate whether a personalized mobile app can improve children\u27s on-time visits at 10 and 14 weeks of age for RCI as compared with standard care and to determine whether an artificial intelligence model can be incorporated into the app. Secondary objectives are to determine the perceptions and attitudes of caregivers regarding childhood vaccinations and to understand the factors that might influence the effect of a mobile phone-based app on vaccination improvement.Methods: A mixed methods randomized controlled trial was designed with intervention and control arms. The study will be conducted at the Aga Khan University Hospital vaccination center. Caregivers of newborns or infants visiting the center for their children\u27s 6-week vaccination will be recruited. The intervention arm will have access to a smartphone app with text, voice, video, and pictorial messages regarding RCI. This app will be developed based on the findings of the pretrial qualitative component of the study, in addition to no-show study findings, which will explore caregivers\u27 perceptions about RCI and a mobile phone-based app in improving RCI coverage.Results: Pretrial qualitative in-depth interviews were conducted in February 2020. Enrollment of study participants for the randomized controlled trial is in process. Study exit interviews will be conducted at the 14-week immunization visits, provided the caregivers visit the immunization facility at that time, or over the phone when the children are 18 weeks of age.Conclusions: This study will generate useful insights into the feasibility, acceptability, and usability of an Android-based smartphone app for improving RCI in Pakistan and in LMICs.Trial registration: ClinicalTrials.gov NCT04449107; https://clinicaltrials.gov/ct2/show/NCT04449107.International registered report identifier (irrid): DERR1-10.2196/22996

Usability and Acceptability of a Mobile App for Behavior Change and to Improve Immunization Coverage among Children in Pakistan: A Mixed-Methods Study

Background: Pakistan’s immunization uptake rates are still significantly lower than anticipated despite several initiatives. Lack of awareness, forgetting about vaccination schedule, and vaccine misconception/misinformation are a few of the major drivers that mitigate the rates of immunization. The current COVID-19 pandemic emphasizes the importance of immunization. The significant reductions in regular childhood vaccination during pandemic have increased the risk of outbreaks of vaccine-preventable diseases. Concerns among parents over possibly exposing their children to COVID-19 during child visits may have contributed to the reported declines. Innovative and cost-effective mHealth interventions must be implemented in order to address the problem of inadequate immunization rates. In addition, it is also critical to understand the end user needs in order to reflect on the highly relevant essence of the customized healthcare experience. Objective: The aim of this study was to learn about caregivers’ attitudes toward the usability and acceptability of behavior-change smartphone applications (mobile phones) for improving immunization coverage in Pakistan. Methods: A mixed-method design was employed for this study. The study was conducted at Aga Khan University, Hospital. Parents visiting the Community Health Center for 6-week vaccination of their children were recruited. The study was conducted in two stages. Stage 1 consisted of qualitative interviews that grasped the parent’s attitudes and challenges to immunization, as well as their acceptability and accessibility of the smartphone-based behavior-change application to increase vaccine uptake. Stage 1 was followed by stage 2, in which data were collected through a questionnaire designed by using data from qualitative interviews. Results: The majority of participants agreed that immunization serves an important role in protecting their child from illnesses that cause morbidity and mortality. Almost all of them emphasized the importance of using a pre-appointment method at vaccination center in order to reduce the waiting time. Furthermore, participants were also interested in AI-based behavior modification applications related to immunization. They also wanted to have applications in their native language for better understanding and communication of related information. In our study, approximately 95.2 percent of participants agreed to accept SMS immunization updates, which was also reasonably high. Lastly, the majority of them identified forgetfulness as a significant contributor to regular immunization. Conclusion: To enhance the uptake of childhood vaccines, overall vaccination rates, and overcome barriers related to vaccination coverage, cost-effective and user-friendly mHealth AI-based smart phone applications are required to raise awareness regarding the continuation of vaccination service and the importance of timely vaccination. Parents’ experiences and attitudes must be considered while designing and evaluating the efficacy of mHealth-based interventions

An Artificial Intelligence–Based, Personalized Smartphone App to Improve Childhood Immunization Coverage and Timelines Among Children in Pakistan: Protocol for a Randomized Controlled Trial

Background: The immunization uptake rates in Pakistan are much lower than desired. Major reasons include lack of awareness, parental forgetfulness regarding schedules, and misinformation regarding vaccines. In light of the COVID-19 pandemic and distancing measures, routine childhood immunization (RCI) coverage has been adversely affected, as caregivers avoid tertiary care hospitals or primary health centers. Innovative and cost-effective measures must be taken to understand and deal with the issue of low immunization rates. However, only a few smartphone-based interventions have been carried out in low- and middle-income countries (LMICs) to improve RCI. Objective: The primary objectives of this study are to evaluate whether a personalized mobile app can improve children’s on-time visits at 10 and 14 weeks of age for RCI as compared with standard care and to determine whether an artificial intelligence model can be incorporated into the app. Secondary objectives are to determine the perceptions and attitudes of caregivers regarding childhood vaccinations and to understand the factors that might influence the effect of a mobile phone–based app on vaccination improvement. Methods: A mixed methods randomized controlled trial was designed with intervention and control arms. The study will be conducted at the Aga Khan University Hospital vaccination center. Caregivers of newborns or infants visiting the center for their children’s 6-week vaccination will be recruited. The intervention arm will have access to a smartphone app with text, voice, video, and pictorial messages regarding RCI. This app will be developed based on the findings of the pretrial qualitative component of the study, in addition to no-show study findings, which will explore caregivers’ perceptions about RCI and a mobile phone–based app in improving RCI coverage. Results: Pretrial qualitative in-depth interviews were conducted in February 2020. Enrollment of study participants for the randomized controlled trial is in process. Study exit interviews will be conducted at the 14-week immunization visits, provided the caregivers visit the immunization facility at that time, or over the phone when the children are 18 weeks of age. Conclusions: This study will generate useful insights into the feasibility, acceptability, and usability of an Android-based smartphone app for improving RCI in Pakistan and in LMICs