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Purpose: This study aims to meticulously analyse the trends and recurrent challenges that emerge from Warning Letters (WLs) issued by the United States Food and Drug Administration (USFDA), focusing on current Good Manufacturing Practices (cGMP) voilations. By investigating the organizational, procedural, and systemic factors that precipitate these non-compliances, the research provides a comprehensive overview of the obstacles to cGMP adherence. Methods: The framework for this study involved a detailed statistical analysis of WLs issued from 2019 to 2024, accessible through the USFDA database. Each letter was categorized and analysed according to violation type, frequency, and underlying causes. This approach facilitated a nuanced understanding of the major and minor compliance issues affecting the pharmaceutical industry. Results: The analysis of total 186 WLs reveals a predominance of violations related to cGMP standards and adulteration of drug products, pinpointing these areas as significant compliance. The study further categorizes and discusses minor violations to offer a holistic view of the compliance landscape in pharmaceutical insdustries. Conclusion: The findings from the WLs suggests a critical need for enhanced regulatory vigilance and quality assurance processes within pharmaceutical companies. The recurrent nature of certain violations highlights potential systemic flaws in how cGMP guidelines are implemented and adhered to across the industry. This research advocates for a proactive regulatory strategy by forecasting regulatory trends and identifying cGMP enforcement challenges, aiming to strengthen quality, streamline inspections, reduce compliance discrepancies, and improve public health outcomes. [ABSTRACT FROM AUTHOR]

Background: Coagulase-negative staphylococci (CoNS) are evolving as major reservoirs and vectors of unusual and critical antimicrobial resistance (AMR) mechanisms., Materials and Methods: In this study, the genomic characterization of 26 multidrug-resistant (MDR)-CoNS (S. borealis, S. saprophyticus, S. sciuri, S. hominis, S. epidermidis, S. pasteuri, S. hyicus, S. simulans, S. haemolyticus, and S. arlettae) previously obtained from the nasal cavity of healthy nestling storks, humans who had no contact with animals, pigs, and pig farmers, as well as dogs and dog owners from Spain was performed. High-quality draft genomes obtained by Illumina sequencing technology were used to determine their resistome, virulome, mobile genetic elements, and CRISPR-Cas types. The relatedness of three CoNS species with publicly available genomes was assessed by core-genome single nucleotide polymorphisms (SNPs)., Results: AMR genes to all classes of antibiotics in staphylococci were detected including unusual ones (mecC, ermT, and cfr), of which their corresponding genetic organizations were analyzed. About 96.1% of the MDR-CoNS strains harbored diverse adherence or immune evasion genes. Remarkably, one enterotoxin-C and -L-carrying S. epidermidis-ST595 strain from a nestling stork was detected. Moreover, various plasmid bound-biocide resistance genes (qacACGJ) were identified in 34.6% of the MDR-CoNS. Two genes that encode for cadmium and zinc resistance (cadD, czrC) were found, of which czrC predominated (42.3%). Complete CRISPR-Cas system was detected in 19.2% of the CoNS strains, of which cas-1, -2, and -9 predominated, especially in 75% of the S. borealis strains. The phylogenetic analysis identified clusters of related S. epidermidis lineages with those of other countries (SNP < 100). Also, highly related S. borealis isolates (SNP < 10) from pigs was confirmed for the first time in Spain., Conclusion: These findings showed that various ecological niches harbor CoNS that presented MDR phenotypes mediated by multiple AMR genes carried by mobile genetic elements with relatively low frequency of intact CRISPR-Cas systems. Furthermore, the transmission of some CoNS species in humans and animals is strongly suggested., (© 2024. The Author(s).)

The well-known perturbed-chain-statistical-association-fluid-theory (PC-SAFT) EoS was employed to model CO2 and H2S absorption in some protic ammonium-based ionic liquids, including Methyl-diethanol-ammonium Formate, Methyl-diethanol-ammonium Acetate, Dimethyl-ethanol-ammonium Formate, and Dimethyl-ethanol-ammonium Acetate. In this way, all the acidic gases and the ILs were considered as associative compounds so that they can establish hydrogen bonding by their own or other molecules. Accordingly, 4C, 2B, and 1A association schemes were assumed for H2S, the ILs, and CO2, respectively. Moreover, to estimate the liquid phase concentrations, a complex formation reaction (CFR) approach was followed. In this concept, acidic gases are supposed to form chemical complexes with the ILs. To show the importance of the reactions, the solubilities were calculated with and without using them, and the achieved results were compared. As the outputs show, considering the reactions, the excellent overall AADs% equal to 1.38 and 0.17 were obtained for H2S and CO2 absorption, respectively. While without them, these values were about 5.05 and 8.57. In the second part of the work, the viscosity of the used ILs was estimated through a new approach that combines the free-volume-theory (FVT) and the PC-SAFT, CPA, and mSRK EoSs. Accordingly, the density of the ILs computed using the EoSs, and then FVT was applied to estimate the dynamic viscosity. Based on the outputs, all the EoSs illustrate good ability to calculate viscosities, precisely, so that all the models present AAD% of about 2.5. This is because of the high ability of the FVT to obtain a precise estimation of viscosity using a rough estimation of the density. [ABSTRACT FROM AUTHOR]

The emergence of methicillin-resistant staphylococci necessitated the search for alternative agents as linezolid, introduced to treat infections due to multidrug-resistant bacteria. Linezolid resistance has since emerged, yet its global prevalence remains low. In Egypt, little is known about the situation. We investigated the prevalence and mechanisms of resistance among Egyptian staphylococcal clinical isolates. Linezolid resistance among 232 staphylococcal isolates obtained from Alexandria Main Hospitals between 2011 and 2016 was assessed using disc diffusion and minimum inhibitory concentration. Resistant isolates were checked for cfr presence using polymerase chain reaction. The V domain of different alleles of 23S rRNA gene was investigated for mutations. Selection for linezolid-resistant mutants was performed in vitro through serial passages in linezolid sub-inhibitory concentrations. Combinations of linezolid with imipenem or anti-inflammatory agents were investigated using time-kill and modified checkerboard assays. Three Staphylococcus haemolyticus isolates (1.3%) from 2015 to 2016 were linezolid-resistant. One isolate carried cfr which was plasmid-borne, and together with another isolate which had a G2603T point mutation in the V domain of 23S rRNA gene. Successive exposure to linezolid sub-inhibitory concentrations was selected for three resistant Staphylococcus aureus mutants out of ten susceptible isolates. These mutants were more resistant towards different antibiotic classes than their susceptible parents. Linezolid combinations with imipenem, ibuprofen, or aspirin were synergistic against the isolates and mutants. Despite unregulated use of linezolid, resistance remains fairly low among the Egyptian isolates. Strict antimicrobial stewardship guidelines are needed in hospitals and the community to guard against further evolution of resistant mutants. [ABSTRACT FROM AUTHOR]

Linezolid is considered as a last-resort antimicrobial agent, the resistance of which is of great concern. The aim of this study was to investigate the mechanisms and transferability of linezolid resistance and molecular epidemiology of linezolid-resistant enterococcal isolates in Wenzhou, China. A collection of 1623 enterococcal strains, including 789 Enterococcus faecalis and 834 Enterococcus faecium, were isolated from our hospital during 2011-2016. Antimicrobial susceptibility testing and clinical data analysis were performed. Molecular mechanisms of linezolid resistance, including the existence of resistance genes cfr and optrA, as well as the mutations in 23S rRNA and ribosomal proteins L3, L4, and L22, were investigated by PCR and sequencing. Conjugation experiments were conducted, and epidemiological characteristics were analyzed by PFGE and MLST. In our study, 31 (3.93%) E. faecalis and 2 (0.24%) E. faecium exhibited resistance to linezolid. Risk factors correlated with linezolid-resistant enterococcal infections included gastrointestinal surgery hospitalization, urogenital disorders, tumor, diabetes, and polymicrobial infections. Among these isolates, 6 (18.18%) harbored cfr, 9 (27.27%) harbored optrA, and 18 (54.55%) co-harbored cfr and optrA. However, mutational mechanisms were not found in this study. Conjugation experiments demonstrated the transferability of cfr and optrA between Gram-positive and Gram-negative bacteria. The clone of these isolates was diverse and scattered. It is noteworthy that cfr and optrA were the main mechanisms of linezolid resistance in this study, posing a potential risk of spread of linezolid resistance. Strikingly, it reported firstly that the two transferable resistance genes cfr and optrA coexisted in the same E. faecalis isolates. [ABSTRACT FROM AUTHOR]

The benefits of organizing multichannel communications by fragmenting the data in bonded or in aggregated channels have been usually assessed at the media access control layer, being the network traffic the purpose of the studies. Despite the importance of the different kinds of channel organizations over the transmit signal peak-to average power ratio (PAPR) to size the back-off value of the power amplifier, little attention has been paid to it. In this paper the key aspect is the PAPR, which is fundamental to face transmitter designs optimizing the trade-off between linearity and the time-of-life of the batteries. The results are of interest not only in ad hoc cognitive radio networks, but also in some of the latest European Telecommunications Standards Institute and Institute of Electrical and Electronics Engineers standards supporting mobility in either wireless local area network environments or in cellular communications. A standardized radio link is used to model a realistic scenario to study different settings of the aggregate channels and to compare them with channel bonding alternatives. Besides, the suitability of some crest factor reduction techniques is here considered for different channel organizations. The results show how the channel organization (contiguous, regular and random spaced), either with bonded or aggregated strategies, affects the PAPR. [ABSTRACT FROM AUTHOR]

Background: Cardiac positron emission tomography (PET) can lead to flow impairment quantification using PET coronary flow reserve (CFR: ratio of stress flow to rest flow) and is superior to the current standard, single-photon emission computed tomography. In this study, our first aim was to assess the benefit of CFR in place of invasive CFR (CFR) by comparing the correlations of each of the indices with combined pressure and flow index CDP, and combined functional (pressure-flow) and anatomical (%area stenosis, %AS) index, LFC. The second aim was to test the correlation between CFR and CFR. Methods: N-13 ammonia PET scans were performed and CFR was obtained using a 1-compartment 2K-dynamic volume (DV)-constant kinetic model in Flowquant. During catheterization, simultaneous pressure and flow readings were obtained in 10 vessels (three vessels in one patient, one vessel each in 7 patients) using a dual sensor tipped Combowire, and CFR, CDP, LFC, and FFR were computed. %AS was obtained using quantitative coronary angiography. CDP was correlated with invasive pressure index (FFR) and CFR and with FFR and CFR. LFC was correlated with the %AS, FFR, and CFR/CFR, individually and in combination. Correlation analysis was done in SAS; p < 0.05 was used for statistical significance. Results: The correlations between CDP vs FFR and CFR ( r = 0.62, p = 0.19) in combination, as well as CDP vs FFR and CFR in combination ( r = 0.58, p = 0.24) remained similar. The correlation between LFC vs FFR, CFR and %AS in combination improved ( r = 0.82) with a near-significant p = 0.06, in comparison to the correlation between LFC vs FFR, CFR and %AS in combination ( r = 0.75, p = 0.15). CFR correlated strongly and significantly ( r = 0.82, p = 0.003) with CFR, and the values were within 11 %. Conclusion: The novelty of the PET procedure in this study is that the noninvasive CFR can be used instead of invasive CFR for the functional diagnosis of CAD. Therefore, a PET scan can reduce procedure time and cost while simplifying the diagnostic protocol for assessing coronary artery disease, thus benefitting both the patients and clinicians. [ABSTRACT FROM AUTHOR]

The assessment of functional coronary lesion severity using intracoronary hemodynamic parameters like the pressure-derived fractional flow reserve and the flow-derived coronary flow reserve are known to rely critically on the establishment of maximal hyperemia. We evaluated a hyperemia-free index, basal pressure drop coefficient (bCDP), that combines pressure and velocity for simultaneous assessment of the status of both epicardial and microvascular circulations. In 23 pigs, simultaneous measurements of distal coronary arterial pressure and flow were performed using a dual-sensor tipped guidewire in the settings of both normal and abnormal microcirculation with the presence of epicardial lesions of area stenosis (AS) < 50% and AS > 50%. The bCDP, a parameter based on fundamental fluid dynamics principles, was calculated as the transtenotic pressure-drop divided by the dynamic pressure in the distal vessel, measured under baseline (without hyperemia) conditions. The group mean values of bCDP for normal (84 ± 18) and abnormal (124.5 ± 15.6) microcirculation were significantly different. Similarly, the mean values of bCDP from AS < 50% (72.5 ± 16.1) and AS > 50% (136 ± 17.2) were also significantly different ( p < 0.05). The bCDP could significantly distinguish between lesions of AS < 50% to AS > 50% under normal microcirculation (52.1 vs. 85.8; p < 0.05) and abnormal microcirculation (84.9 vs. 172; p < 0.05). Further, the bCDP correlated linearly and significantly with the hyperemic parameters FFR ( r = 0.42, p < 0.05) and CDP ( r = 0.50, p < 0.05). The bCDP is a promising clinical diagnostic parameter that can independently assess the severity of epicardial stenosis and microvascular impairment. We believe that it has an immediate appeal for detection of coronary artery disease if validated clinically. [ABSTRACT FROM AUTHOR]