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The degradation of oncoproteins mediated by proteolysis-targeting chimera (PROTAC) has emerged as a potent strategy in cancer therapy. However, the clinical application of PROTACs is hampered by challenges such as poor water solubility and off-target adverse effects. Herein, we present an ultrasound (US)-activatable PROTAC prodrug termed NPCe6+PRO for actuating efficient sono-immunotherapy in a spatiotemporally controllable manner. Specifically, US irradiation, which exhibits deep-tissue penetration capability, results in Ce6-mediated generation of ROS, facilitating sonodynamic therapy (SDT) and inducing immunogenic cell death (ICD). Simultaneously, the generated ROS cleaves the thioketal (TK) linker through a ROS-responsive mechanism, realizing the on-demand activation of the PROTAC prodrug in deep tissues. This prodrug activation results in the degradation of the target protein BRD4, while simultaneously reversing the upregulation of PD-L1 expression associated with the SDT process. In the orthotopic mouse model of pancreatic tumors, NPCe6+PRO effectively suppressed tumor growth in conjunction with US stimulation.
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Inmunoterapia , Neoplasias Pancreáticas , Profármacos , Animales , Profármacos/farmacología , Profármacos/uso terapéutico , Profármacos/química , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/inmunología , Ratones , Humanos , Línea Celular Tumoral , Proteolisis/efectos de los fármacos , Terapia por Ultrasonido/métodos , Antígeno B7-H1 , Factores de Transcripción , Proteínas de Ciclo Celular , Especies Reactivas de Oxígeno/metabolismo , Proteínas que Contienen BromodominioRESUMEN
Neuropathy is a disturbance of function or a pathological change in nerves causing poor health and quality of life. A proportion of chronic pain patients in the community suffer persistent neuropathic pain symptoms because current drug therapies may be suboptimal so there is a need for new therapeutic modalities. This study investigated the neuroprotective flavonoid, 6-methoxyflavone (6MF), as a potential therapeutic agent and gabapentin as the standard comparator, against neuropathic models. Thus, neuropathic-like states were induced in Sprague-Dawley rats using sciatic nerve chronic constriction injury (CCI) mononeuropathy and systemic administration of streptozotocin (STZ) to induce polyneuropathy. Subsequent behaviors reflecting allodynia, hyperalgesia, and vulvodynia were assessed and any possible motoric side-effects were evaluated including locomotor activity, as well as rotarod discoordination and gait disruption. 6MF (25-75 mg/kg) antagonized neuropathic-like nociceptive behaviors including static- (pressure) and dynamic- (light brushing) hindpaw allodynia plus heat/cold and pressure hyperalgesia in the CCI and STZ models. 6MF also reduced static and dynamic components of vulvodynia in the STZ induced polyneuropathy model. Additionally, 6MF reversed CCI and STZ suppression of locomotor activity and rotarod discoordination, suggesting a beneficial activity on motor side effects, in contrast to gabapentin. Hence, 6MF possesses anti-neuropathic-like activity not only against different nociceptive modalities but also impairment of motoric side effects.
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Flavonas , Hiperalgesia , Neuralgia , Ratas Sprague-Dawley , Animales , Ratas , Neuralgia/tratamiento farmacológico , Neuralgia/etiología , Flavonas/farmacología , Flavonas/uso terapéutico , Hiperalgesia/tratamiento farmacológico , Masculino , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Gabapentina/farmacología , Gabapentina/uso terapéutico , Nocicepción/efectos de los fármacos , Neuropatías Diabéticas/tratamiento farmacológico , Neuropatías Diabéticas/metabolismo , Femenino , Ácido gamma-Aminobutírico/metabolismo , Aminas/farmacología , Aminas/uso terapéutico , Nervio Ciático/lesiones , Nervio Ciático/efectos de los fármacos , Vulvodinia/tratamiento farmacológico , Constricción , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Analgésicos/farmacología , Analgésicos/uso terapéuticoRESUMEN
Cancer is one of the most serious threats to human health. Over the past few years, researchers have incrementally uncovered the pivotal role of tumor acidity in tumor formation, development and treatment through in-depth scientific research. In addition, bioorthogonal reactions have been widely used in tumor diagnosis and therapy, owing to their advantageous characteristics, including small ligand size, biocompatibility, fast reaction kinetics, and high chemospecificity. Consequently, bioorthogonal reactions triggered by tumor acidity have become an emerging strategy in biomedical applications. On this basis, we introduce the concept and major strategies of tumor acidity-triggered bioorthogonal reactions, and review their progress in biomedical applications, with a particular focus on their importance in disease diagnosis and treatment. Finally, clinical challenges and future trends are also outlooked.
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Microbes represent the most common organisms on Earth; however, less than 2% of microbial species in the environment can undergo cultivation for study under laboratory conditions, and the rest of the enigmatic, microbial world remains mysterious, constituting a kind of "microbial dark matter" (MDM). In the last two decades, remarkable progress has been made in culture-dependent and culture-independent techniques. More recently, studies of MDM have relied on culture-independent techniques to recover genetic material through either unicellular genomics or shotgun metagenomics to construct single-amplified genomes (SAGs) and metagenome-assembled genomes (MAGs), respectively, which provide information about evolution and metabolism. Despite the remarkable progress made in the past decades, the functional diversity of MDM still remains uncharacterized. This review comprehensively summarizes the recently developed culture-dependent and culture-independent techniques for characterizing MDM, discussing major challenges, opportunities, and potential applications. These activities contribute to expanding our knowledge of the microbial world and have implications for various fields including Biotechnology, Bioprospecting, Functional genomics, Medicine, Evolutionary and Planetary biology. Overall, this review aims to peel off the layers from MDM, shed light on recent advancements, identify future challenges, and illuminate the exciting opportunities that lie ahead in unraveling the secrets of this intriguing microbial realm.
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Mungbean, Vigna radia (L.) R. Wilczek, is ranked 2nd next to chickpea (Cicer arietinum) in total cultivation and production in Pakistan. In August of 2022 and 2023, mungbean plants (cv. PRI Mung-2018) were found wilting in a field at the Ayub Agricultural Research Institute, Faisalabad, Pakistan. Wilted leaves turned yellow, died, but remained attached to the stem. Vascular tissue at the base of the stem showed light to dark brown discoloration. Roots were stunted with purplish brown to black discoloration. Symptomatic mungbean plants were collected from fields at five different locations (20 samples/location). Disease incidence was similar among the five fields, ranging from 5 to 10% at each location depending upon type of germplasm and date of sowing. For fungal isolation and morphological identification, symptomatic stem and root tissues were cut into ~5 mm2 pieces with a sterilized blade. Tissues were surface-sterilized for one min in a 0.5% sodium hypochlorite solution, rinsed twice in sterilized water, air dried on sterilized filter paper, and aseptically placed on potato dextrose agar (PDA) containing 0.5 g/L-1 streptomycin sulphate. Plates were incubated for 3-4 days at 25 ± 2°C with a 12-h photoperiod. Single-spore cultures were used for morphological and molecular analyses. Isolates on PDA grew rapidly and produced abundant white aerial mycelium that turned off-white to beige with age. Macroconidia were hyaline, falcate, typically 3-to-6 septate with a pointed apical cell and a foot-shaped basal cell, measuring 24.5-49.5 x 2.7-4.7 µm (n = 40). Globose to obovate chlamydospores measuring 5.8 ± 0.5 µm (n = 40) were produced singly or in chains and were intercalary or terminal and possessed roughened walls. The morphological data indicated the isolates were members of the genus Fusarium (Leslie and Summerell 2006). To obtain a species-level identification, a portion of translation elongation factor 1-α (TEF1), the largest subunit of RNA polymerase (RPB1), and the second largest subunit of RNA polymerase (RPB2) region were PCR amplified and sequenced using EF1/EF2 (O'Donnell et al. 1998), Fa/G2R (Hofstetter et al. 2007), and 5f2/7cr (Liu et al. 1999) primers, respectively. DNA sequences of these genes were deposited in GenBank under accession numbers MW059021, MW059017 and MW059019, respectively. The partial TEF1, RPB1 and RPB2 sequences were queried against the Fusarium MLST database (https://fusarium.mycobank.org/page/Fusarium_identification), using the polyphasic identification tool. The BLASTn search revealed 99.9% identity of the isolate to F. nanum (Xia et al. 2019), formerly FIESC 25 of the F. incarnatum-equiseti species complex (MRC 2610, NRRL 54143; O'Donnell et al. 2018). To confirm pathogenicity, roots of 3-5 leaf stage mungbean seedlings were soaked in a 106 spores ml-1 conidial suspension of the fungus for 15 min and then planted in 10 cm pots containing sterilized soil. Mock-inoculated plants with sterile water served as a negative control. Twenty pots that were used for each inoculated and control treatment were maintained at 25 ± 2°C, 14:8 h photoperiod, and 80% relative humidity in a growth chamber. After 15 days, leaf yellowing, internal browning from the base of stems and root discoloration was observed in all the inoculated plants. The uninoculated negative control plants remained asymptomatic. Fusarium nanum was re-isolated from artificially inoculated plants and identified by colony growth, conidial characteristics on PDA and molecular analyses (TEF1). To our knowledge, this is the first report of wilt caused by F.nanum on mungbean in Pakistan. In Pakistan, mungbean cultivation in irrigated areas has increased in recent years. It has been introduced frequently in citrus orchards, crop rotation of maize and sesame, intercropping with sugarcane and as green manure. However, citrus, maize, sesame and sugarcane are also hosts of Fusarium spp. Therefore, this information warrants sustainable crop protection and may have an impact on further interaction of F. nanum with other wilt pathogens.
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Streptococcus mutans, the primary cause of dental caries, relies on its ability to create and sustain a biofilm (dental plaque) for survival and pathogenicity in the oral cavity. This study was focused on the antimicrobial biofilm formation control and biofilm dispersal potential of Coumaric acid (CA) against Streptococcus mutans on the dentin surface. The biofilm was analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) viability assay, microtiter plate assay, production of extracellular polymeric substances (EPSs), florescence microscopy (surface coverage and biomass µm2) and three-dimensional (3D) surface plots. It was observed that CA at 0.01 mg/mL reduced bacterial growth by 5.51%, whereases at 1 mg/mL, a significant (p < 0.05) reduction (98.37%) was observed. However, at 1 mg/mL of CA, a 95.48% biofilm formation reduction was achieved, while a 73.45% biofilm dispersal (after 24 h. treatment) was achieved against the preformed biofilm. The MTT assay showed that at 1 mg/mL of CA, the viability of bacteria in the biofilm was markedly (p < 0.05) reduced to 73.44%. Moreover, polysaccharide (EPS) was reduced to 24.80 µg/mL and protein (EPS) to 41.47 µg/mL. ImageJ software (version 1.54 g) was used to process florescence images, and it was observed that the biofilm mass was reduced to 213 (µm2); the surface coverage was reduced to 0.079%. Furthermore, the 3D surface plots showed that the untreated biofilm was highly dense, with more fibril-like projections. Additionally, molecular docking predicted a possible interaction pattern of CA (ligand) with the receptor Competence Stimulating Peptide (UA159sp, PDB ID: 2I2J). Our findings suggest that CA has antibacterial and biofilm control efficacy against S. mutans associated with dental plaque under tested conditions.
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Caries Dental , Placa Dental , Humanos , Ácidos Cumáricos , Caries Dental/tratamiento farmacológico , Placa Dental/tratamiento farmacológico , Simulación del Acoplamiento Molecular , Streptococcus mutans , Biopelículas , DentinaRESUMEN
The outbreak of SARS-CoV-2, also known as the COVID-19 pandemic, is still a critical risk factor for both human life and the global economy. Although, several promising therapies have been introduced in the literature to inhibit SARS-CoV-2, most of them are synthetic drugs that may have some adverse effects on the human body. Therefore, the main objective of this study was to carry out an in-silico investigation into the medicinal properties of Petiveria alliacea L. (P. alliacea L.)-mediated phytocompounds for the treatment of SARS-CoV-2 infections since phytochemicals have fewer adverse effects compared to synthetic drugs. To explore potential phytocompounds from P. alliacea L. as candidate drug molecules, we selected the infection-causing main protease (Mpro) of SARS-CoV-2 as the receptor protein. The molecular docking analysis of these receptor proteins with the different phytocompounds of P. alliacea L. was performed using AutoDock Vina. Then, we selected the three top-ranked phytocompounds (myricitrin, engeletin, and astilbin) as the candidate drug molecules based on their highest binding affinity scores of -8.9, -8.7 and -8.3 (Kcal/mol), respectively. Then, a 100 ns molecular dynamics (MD) simulation study was performed for their complexes with Mpro using YASARA software, computed RMSD, RMSF, PCA, DCCM, MM/PBSA, and free energy landscape (FEL), and found their almost stable binding performance. In addition, biological activity, ADME/T, DFT, and drug-likeness analyses exhibited the suitable pharmacokinetics properties of the selected phytocompounds. Therefore, the results of this study might be a useful resource for formulating a safe treatment plan for SARS-CoV-2 infections after experimental validation in wet-lab and clinical trials.
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Antivirales , Tratamiento Farmacológico de COVID-19 , Proteasas 3C de Coronavirus , Fitoquímicos , SARS-CoV-2 , Humanos , Antivirales/farmacología , Antivirales/química , Antivirales/uso terapéutico , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Proteasas 3C de Coronavirus/metabolismo , Proteasas 3C de Coronavirus/química , COVID-19/virología , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Fitoquímicos/farmacología , Fitoquímicos/química , Fitoquímicos/uso terapéutico , Extractos Vegetales/química , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Inhibidores de Proteasas/farmacología , Inhibidores de Proteasas/química , Inhibidores de Proteasas/uso terapéutico , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/enzimologíaRESUMEN
PURPOSE: Nephrolithiasis (NL) affects 1 in 11 individuals worldwide, leading to significant patient morbidity. NL is associated with nephrocalcinosis (NC), a risk factor for chronic kidney disease. Causative genetic variants are detected in 11% to 28% of NL and/or NC, suggesting that additional NL/NC-associated genetic loci await discovery. Therefore, we employed genomic approaches to discover novel genetic forms of NL/NC. METHODS: Exome sequencing and directed sequencing of the OXGR1 locus were performed in a worldwide NL/NC cohort. Putatively deleterious, rare OXGR1 variants were functionally characterized. RESULTS: Exome sequencing revealed a heterozygous OXGR1 missense variant (c.371T>G, p.L124R) cosegregating with calcium oxalate NL and/or NC disease in an autosomal dominant inheritance pattern within a multigenerational family with 5 affected individuals. OXGR1 encodes 2-oxoglutarate (α-ketoglutarate [AKG]) receptor 1 in the distal nephron. In response to its ligand AKG, OXGR1 stimulates the chloride-bicarbonate exchanger, pendrin, which also regulates transepithelial calcium transport in cortical connecting tubules. Strong amino acid conservation in orthologs and paralogs, severe in silico prediction scores, and extreme rarity in exome population databases suggested that the variant was deleterious. Interrogation of the OXGR1 locus in 1107 additional NL/NC families identified 5 additional deleterious dominant variants in 5 families with calcium oxalate NL/NC. Rare, potentially deleterious OXGR1 variants were enriched in patients with NL/NC compared with Exome Aggregation Consortium controls (χ2 = 7.117, P = .0076). Wild-type OXGR1-expressing Xenopus oocytes exhibited AKG-responsive Ca2+ uptake. Of 5 NL/NC-associated missense variants, 5 revealed impaired AKG-dependent Ca2+ uptake, demonstrating loss of function. CONCLUSION: Rare, dominant loss-of-function OXGR1 variants are associated with recurrent calcium oxalate NL/NC disease.
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Nefrolitiasis , Receptores Purinérgicos P2 , Humanos , Oxalato de Calcio , Nefrolitiasis/genética , Mutación Missense/genética , Transportadores de Sulfato/genética , Receptores Purinérgicos P2/genética , Receptores Purinérgicos P2/metabolismoRESUMEN
Wolbachia are endosymbiotic bacteria found within many arthropods, including insects. A variety of benefits are provided by these bacteria to human and insect hosts, including protection from viruses and parasites and the ability to kill males. In this study, Wolbachia was identified in Aedes aegypti present in Jeddah, Saudi Arabia. A population of mosquitoes was collected from eight different areas, processed, and tested for Wolbachia using 16 S rRNA specific to Wolbachia bacteria and Wolbachia surface protein (wsp) under optimized PCR conditions. In five ecologically diverse sites to determine Wolbachia prevalence, we identified eleven diverse novel resident Wolbachia strains within Ae. Aegypti for the first time in Jeddah, Saudi Arabia. Future studies to evaluate the possible use of Wolbachia as a control agent in Aedes sp. in Saudi Arabia are necessary. Wolbachia prevalence rates and strain characterization through Sanger sequencing with multilocus sequence typing (MLST) and phylogenetic analysis revealed significant diversity. In developing biocontrol strategies, it is beneficial to consider the implications of resident Wolbachia strains.
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Aedes , Dengue , Wolbachia , Masculino , Animales , Humanos , Wolbachia/genética , Filogenia , Tipificación de Secuencias Multilocus , Mosquitos Vectores , Dengue/epidemiologíaRESUMEN
This study aimed to conduct a detailed study on murine model testing of bacteriophage against Acinetobacter baumannii. These bacteriophages were tested not only for their efficacy in healing wound of murine models infected with multidrug resistant A. baumannii but were also studied for any derangement in hematological parameters as well as liver and kidney function. The study also included any histological changes observed in hepatic and renal tissues of the bacteriophage treated murine animals. This experimental study was conducted at Institute of Basic Medical Sciences, Khyber Medical University, Peshawar and Institute of Pure and Applied Biology, Department of Microbiology and Molecular Genetics, Bahauddin Zakariya University, Multan. A. baumannii isolates were obtained from the Microbiology Department, Armed Forces Institute of Pathology, Rawalpindi. Antimicrobial susceptibility was done by using standard procedures and as per Clinical Laboratory Standards Institute guidelines. Bacteriophages were isolated from sewage water samples collected from different hospitals in Multan. These bacteriophages were characterized and finally used for treating the murine model and efficacy of phage as a therapeutic option was determined by using superficial rat wound model. In this study, the isolated lytic bacteriophage was effective in relatively faster wound healing of the infected animals. Moreover, there were no significant hematological or renal and hepatic profile changes in treated animals. Histology of renal and hepatic tissues was also normal as compared to control animals. Our study concluded that the isolated phage could serve as an attractive therapeutic candidate to combat the deadly multidrug resistant A. baumannii.
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Infecciones por Acinetobacter , Acinetobacter baumannii , Bacteriófagos , Ratones , Ratas , Animales , Infecciones por Acinetobacter/terapia , Infecciones por Acinetobacter/microbiología , Modelos Animales de Enfermedad , Aguas del Alcantarillado , Antibacterianos/farmacología , Farmacorresistencia Bacteriana MúltipleRESUMEN
The objective of smart cities is to improve the quality of life for citizens by using Information and Communication Technology (ICT). The smart IoT environment consists of multiple sensor devices that continuously produce a large amount of data. In the IoT system, accurate inference from multi-sensor data is imperative to make a correct decision. Sensor data are often imprecise, resulting in low-quality inference results and wrong decisions. Correspondingly, single-context data are insufficient for making an accurate decision. In this paper, a novel compound context-aware scheme is proposed based on Bayesian inference to achieve accurate fusion and inference from the sensory data. In the proposed scheme, multi-sensor data are fused based on the relation and contexts of sensor data whether they are dependent or not on each other. Extensive computer simulations show that the proposed technique significantly improves the inference accuracy when it is compared to the other two representative Bayesian inference techniques.
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Comunicación , Calidad de Vida , Teorema de Bayes , Ciudades , Simulación por ComputadorRESUMEN
The multi-sonar distributed fusion system has been pervasively deployed to jointly detect and track marine targets. In the realistic scenario, the origin of locally transmitted tracks is uncertain due to clutter disturbance and the presence of multi-target. Moreover, attributed to the different sonar internal processing times and diverse communication delays between sonar and the fusion center, tracks unavoidably arrive in the fusion center with temporal out-of-sequence (OOS), both problems pose significant challenges to the fusion system. Under the distributed fusion framework with memory, this paper proposes a novel multiple forward prediction-integrated equivalent measurement fusion (MFP-IEMF) method, it fuses the multi-lag OOST with track origin uncertainty in an optimal manner and is capable to be implemented in both the synchronous and asynchronous multi-sonar tracks fusion system. Furthermore, a random central track initialization technique is also proposed to detect the randomly born marine target in time via quickly initiating and confirming true tracks. The numerical results show that the proposed algorithm achieves the same optimality as the existing OOS reprocessing method, and delivers substantially improved detection and tracking performance in terms of both ANCTT and estimation accuracy compared to the existing OOST discarding fusion method and the ANF-IFPFD method.
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Algoritmos , Ambiente , Sonido , Agua , Simulación por ComputadorRESUMEN
Pongamia pinnata (L.) Pierre (Pongamia) is a tree native to Southeast Asia. Recently, interest in Pongamia focused on its potential as a biofuel source as its seeds contain around 40% oil. However, Pongamia has multiple applications beyond biofuel production. It is a legume, can form symbiotic associations with mycorrhizal fungi, has been shown to be tolerant to drought, salinity, and heavy metals in soil, and has potential to mitigate climate change. Additionally, Pongamia oil has medicinal properties, can be used as biopesticide, insect repellent, to produce soap, and as a source of edible grade vegetable oil. The seed cake can be used as a source of bioenergy, food and feed protein, and organic fertiliser, and the flowers are a good source of pollen and nectar. Pongamia can also bring socio-economic benefits as its ability to restore degraded and contaminated land provides opportunities for local communities through novel valorisation pathways. These multiple applications have potential to form part of a circular bioeconomy in line with sustainable development goals. Although research on the multiple applications of Pongamia has grown considerably, knowledge gaps remain and these need to be addressed so that the full potential of Pongamia can be achieved. Further understanding of the mechanisms underlying its resilience to abiotic stresses, phytoremediation potential and biotic interactions should be a priority, and co-ordinated breeding efforts will be key. Here, we critically review the available literature on Pongamia and highlight gaps in knowledge in which future research should focus on to ensure that the full potential of this versatile tree can be achieved. We conclude that Pongamia can potentially form part of a circular bioeconomy and that harnessing the multiple applications of Pongamia in a holistic manner, with collaboration among key stakeholders, is crucial for the successful application of its benefits far beyond biofuel production.
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Millettia , Pongamia , Millettia/metabolismo , Secuestro de Carbono , Biocombustibles , Fitomejoramiento , Árboles/metabolismo , Factores SocioeconómicosRESUMEN
Objectives: To study prevalence and resistance pattern to azoles of candida species causing vulvovaginitis in reproductive age women. Methods: Samples were collected from Hayatabad Medical Complex from November 2018 to May 2019. This cross-sectional study was conducted at the department of Microbiology, Institute of Pathology and Diagnostic Medicine, Khyber Medical University Peshawar, Pakistan. A total of 369 high vaginal swabs were collected. Candida was isolated by vaginal swabs inoculation on Sabouraud's dextrose agar (SDA). Colonies on SDA were inoculated on Candida CHROM agar to identify candida species. Wet film microscopy and Gram staining were performed. Biochemical identification was done with 20C AUX. Antifungal susceptibility testing was done by disc diffusion and broth micro-dilution methods to find the resistance pattern of azole drugs. Fluconazole, Clotrimazole, Miconazole, Voriconazole and Itraconazole were the azoles drugs used. Results: Among 43%(n=158) positive candida cases, 44%(n=85) were non pregnant women while 41%(n=73) were pregnant. The Candida species distribution of 158 isolates was as follow; Candida albicans (C. albicans) 46.2%(n=73), Candida krusei (C. krusei) 29.1%(n=46), Candida parapsilosis (C. parapsilosis) 19%(n=30) and Candida glabrata (C. glabrata) 5.7%(n=9). Overall Candida isolates were highly resistant 72%(n=113) to Fluconazole while least resistant 21.5 % (n=34) to Itraconazole. Conclusion: C. albicans is the most prevalent specie involved in Vulvovaginal candidiasis. Candida species were found to be least resistant to Itraconazole followed by Voriconazole, Miconazole, Clotrimazole and Fluconazole.
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Objectives: Identification of colistin resistance and its bactericidal activity against gram-negative bacteria isolated from urinary tract infection (UTI) patients. Methods: This 6-month cross sectional study was conducted in Hayatabad Medical Complex Peshawar from January 2019-June2019.. A total of 2000 urine samples were collected and transported to the Health Research Institute, NIH, Research Centre, Khyber Medical College Peshawar. Samples were streaked on different media and incubated at 37C° for 24hrs. Gram negative bacteria were identified through gram staining and Analytical Profile Index (API) 10s. Gram negative bacteria were subjected under antibiotic sensitivity profile through Kirby-Bauer disc diffusion method. Colistin resistance was found through broth microdilution method. Minimum bactericidal activity was performed to find out the lowest concentration of colistin required to kill gram-negative bacteria. Results: A total of 241(12.05%) uropathogenic gram negative bacteria were isolated and identified from 2000 urine samples while excluding intrinsically resistant bacteria. After broth microdilution, colistin resistance was found in 48(19.9%) Escherichia coli, 4(1.6%) Klebsiella pneumoniae and 3(1.3%) Pseudomonas aeruginosa respectively. Colistin resistant Escherichia coli were resistant to 77% Cephalosporins, 81% to Fluoroquinolones and 70% to Penicillin combinations. Colistin resistant Klebsiella pneumoniae were 100% resistant to Cephalosporins, Penicillin combinations and Fluoroquinolones while 75% were resistant to Carbapenems and Monobactams. Pseudomonas aeruginosa isolates were sensitive to all used antibiotics. Conclusion: E.coli was the mainly responsible uropathogen causing UTIs. Colistin resistance was found in 22.8% gram negative uropathogens. Klebsiella pneumoniae isolates exhibited highest resistance to antibiotics.
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ABSTRACT: Patients undergoing percutaneous coronary intervention (PCI) with a clinical indication for oral anticoagulation (OAC) in addition to antiplatelet therapy (APT) necessitate rigorous evaluation of bleeding and ischemic risk to guide therapy. The optimal OAC/APT drug combination and duration of treatment is not known. This study aimed to evaluate the incidence of patients undergoing PCI with an OAC indication and the rationale for post-PCI combined OAC/APT selection in clinical practice. Consecutive patients undergoing PCI with an indication for combined OAC/APT were included in a 12-month retrospective case series. Patient demographics, clinical characteristics, prescribed OAC/APT regimens, and rationale for drug selection were reviewed. PCI was performed in 1650 patients during the study period, with an indication for OAC/APT in 133 (8.1%). A combination of aspirin, P2Y12 inhibitor, and OAC was the most frequently prescribed regime on discharge (n = 103, 81%). Dual antiplatelet therapy (DAPT) in combination with OAC was continued for a mean duration of 6.4 ± 4.4 weeks (range 3-52 weeks) before one antiplatelet was discontinued. There was no significant difference between the mean CHA2DS2-VASc or HAS-BLED score of patients with atrial fibrillation discharged on OAC/DAPT compared with alternate combinations (DAPT alone or OAC/single APT), 3.6 ± 1.3 versus 3.8 ± 1, P = 0.37 and 2.04 ± 0.7 versus 2.05 ± 1.0, P = 0.98, respectively. This case series identifies high variability in OAC/APT treatment duration and limited application of risk scoring systems and high-risk PCI characteristics in the selection of OAC/APT regimens. A more systematic patient assessment is needed to help standardize OAC/APT prescribing for this important patient cohort.
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Anticoagulantes/administración & dosificación , Aspirina/administración & dosificación , Fibrilación Atrial/tratamiento farmacológico , Isquemia Miocárdica/terapia , Intervención Coronaria Percutánea , Inhibidores de Agregación Plaquetaria/administración & dosificación , Antagonistas del Receptor Purinérgico P2Y/administración & dosificación , Administración Oral , Anciano , Anciano de 80 o más Años , Anticoagulantes/efectos adversos , Aspirina/efectos adversos , Fibrilación Atrial/complicaciones , Fibrilación Atrial/diagnóstico , Terapia Antiplaquetaria Doble , Femenino , Hemorragia/inducido químicamente , Humanos , Masculino , Persona de Mediana Edad , Isquemia Miocárdica/complicaciones , Isquemia Miocárdica/diagnóstico , Intervención Coronaria Percutánea/efectos adversos , Inhibidores de Agregación Plaquetaria/efectos adversos , Antagonistas del Receptor Purinérgico P2Y/efectos adversos , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
The inevitable COVID-19 global pandemic has severely affected Pakistan's fragile healthcare system. The system was already facing a significant burden of noncommunicable and other infectious diseases, and the pandemic further exacerbated the disease and the healthcare burden in Pakistan. In such a situation, people who live in geographically challenged areas with limited healthcare infrastructure and resources are more vulnerable to the impacts of a pandemic. The authors share the experience of the development of emergency response centres (ERCs) in the rural remote mountainous regions of Pakistan-Chitral, an initiative that the Government of Pakistan and Aga Khan Health Service Pakistan (AKHSP) implemented to manage the increasing rates of COVID-19 cases in these areas. The authors outline the processes that need to be undertaken to develop such healthcare facilities in a short period of time and discusses the challenges of establishing and operating these centres and the lessons learnt during and after the development of these centres in the remote mountainous regions of Pakistan.
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COVID-19 , Urgencias Médicas , Humanos , Pakistán , Pandemias , SARS-CoV-2RESUMEN
This paper presents a novel incentive-based load shedding management scheme within a microgrid environment equipped with the required IoT infrastructure. The proposed mechanism works on the principles of reverse combinatorial auction. We consider a region of multiple consumers who are willing to curtail their load in the peak hours in order to gain some incentives later. Using the properties of combinatorial auctions, the participants can bid in packages or combinations in order to maximize their and overall social welfare of the system. The winner determination problem of the proposed combinatorial auction, determined using particle swarm optimization algorithm and hybrid genetic algorithm, is also presented in this paper. The performance evaluation and stability test of the proposed scheme are simulated using MATLAB and presented in this paper. The results indicate that combinatorial auctions are an excellent choice for load shedding management where a maximum of 50 users participate.
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OBJECTIVE: To determine the impact of musculoskeletal disorders on patients' quality of life. METHODS: The cross-sectional study was conducted at the Khyber Teaching Hospital, Peshawar, Pakistan, from September 2018 to March 2019, and comprised patients of either gender having a variety of musculoskeletal disorders. Data was collected using a validated EuroQol-5-Dimension-3-Level scale. Data was analysed using SPSS 20. RESULTS: Of the 377 participants, 204(54.1%) were males, and 173(45.9%) were females. The overall mean age was 35.9±12.5 years. Muscular weakness was the most commonly encountered problem 153(40.6%), followed by muscle stiffness 49(13.0%) and adhesive capsulitis 39(10.3%). Patients with musculoskeletal disorders had moderately good 'health state today' score of 56.03±20.175 on VAS. CONCLUSION: Musculoskeletal disorders were found to have a negative impact on quality of life and health status of the patients.
Asunto(s)
Enfermedades Musculoesqueléticas , Calidad de Vida , Adulto , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Musculoesqueléticas/epidemiología , Encuestas y Cuestionarios , Centros de Atención Terciaria , Adulto JovenRESUMEN
PURPOSE: To evaluate the genotoxic effects of gold jewellery fumes and its association with GSTM1 and GSTT1 genetic polymorphisms. MATERIALS AND METHODS: We examined 94 subjects including 54 gold jewellery workers and 40 controls. The DNA damage was evaluated by alkaline comet assay and genotyping by PCR. RESULTS: The mean total comet score (TCS) in gold jewellery workers was significantly higher as compared to the control subjects (128.0 ± 60.6 versus 47.7 ± 21.4; p = 0.0001). Duration of occupational exposure had positive correlation (r = 0.453, p < 0.01) with DNA damage. Age and tobacco use had significant effects on the TCS of the exposed group as compared to the control group (p < 0.05). The frequency of the GSTM1-null genotype in the exposed group was significant (p = 0.004) as compared to the control group. No significant association (p > 0.05) between the GSTM1 and GSTT1 genotypes and DNA damage was found. CONCLUSIONS: Our results suggest that there is increased DNA damage in gold jewellery workers due to their occupational surroundings. Hence there is a strong need to educate the workers about the adverse health effects of potentially hazardous chemicals and highlight the importance of using protective measures.