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Ghana Medical Journal Mar 2024This study aims to examine the frequency of Paratyphi found in blood cultures and evaluate the antibiotic susceptibility pattern of isolates to different antibiotics....
OBJECTIVE
This study aims to examine the frequency of Paratyphi found in blood cultures and evaluate the antibiotic susceptibility pattern of isolates to different antibiotics. Additionally, the study aims to assess the paradigm shift in the trend of enteric fever caused by Typhi (. Typhi) to Paratyphi(. Paratyphi) .
STUDY DESIGN
Retrospective study.
PARTICIPANT
The study enrolled patients aged 12 years and above diagnosed with enteric fever (positive blood culture) and admitted to Peelamedu Samanaidu Govindasamy Naidu (PSG) Hospital.
INTERVENTIONS
The study analyzed demographic and antibiotic susceptibility profiles of isolates collected from 106 enteric fever patients in the hospital between 2010 and 2022. The susceptibility profiles of isolates to multiple antibiotics were assessed.
RESULTS
There were 106 participants, and 95 (89.62%) of them had enteric fever linked to Typhi, while only 11 (10.38%) had enteric fever linked to Paratyphi A. From 2010 to 2022, the study discovered a general decline in the prevalence of enteric fever caused by species. But between 2014 and 2022, the incidence of enteric fever linked to rapidly increased. Azithromycin (100% , n = 106) and ceftriaxone (99% , n = 105) were highly effective against the isolates, whereas nalidixic acid was resisted by 3 isolates (4.72%, n = 3).
CONCLUSION
The study observed a higher incidence of Typhi in comparison to Paratyphi A and a greater susceptibility of males to enteric fever.
FUNDING
None declared.
Topics: Humans; Male; Female; Anti-Bacterial Agents; Typhoid Fever; Retrospective Studies; Salmonella typhi; Microbial Sensitivity Tests; Salmonella paratyphi A; Adult; Adolescent; Child; Middle Aged; Young Adult; Paratyphoid Fever; Incidence; Drug Resistance, Bacterial; Azithromycin; Ceftriaxone; Aged; Prevalence
PubMed: 38957275
DOI: 10.4314/gmj.v58i1.12 -
Genome Medicine Jul 2024Restraining or slowing ageing hallmarks at the cellular level have been proposed as a route to increased organismal lifespan and healthspan. Consequently, there is great...
BACKGROUND
Restraining or slowing ageing hallmarks at the cellular level have been proposed as a route to increased organismal lifespan and healthspan. Consequently, there is great interest in anti-ageing drug discovery. However, this currently requires laborious and lengthy longevity analysis. Here, we present a novel screening readout for the expedited discovery of compounds that restrain ageing of cell populations in vitro and enable extension of in vivo lifespan.
METHODS
Using Illumina methylation arrays, we monitored DNA methylation changes accompanying long-term passaging of adult primary human cells in culture. This enabled us to develop, test, and validate the CellPopAge Clock, an epigenetic clock with underlying algorithm, unique among existing epigenetic clocks for its design to detect anti-ageing compounds in vitro. Additionally, we measured markers of senescence and performed longevity experiments in vivo in Drosophila, to further validate our approach to discover novel anti-ageing compounds. Finally, we bench mark our epigenetic clock with other available epigenetic clocks to consolidate its usefulness and specialisation for primary cells in culture.
RESULTS
We developed a novel epigenetic clock, the CellPopAge Clock, to accurately monitor the age of a population of adult human primary cells. We find that the CellPopAge Clock can detect decelerated passage-based ageing of human primary cells treated with rapamycin or trametinib, well-established longevity drugs. We then utilise the CellPopAge Clock as a screening tool for the identification of compounds which decelerate ageing of cell populations, uncovering novel anti-ageing drugs, torin2 and dactolisib (BEZ-235). We demonstrate that delayed epigenetic ageing in human primary cells treated with anti-ageing compounds is accompanied by a reduction in senescence and ageing biomarkers. Finally, we extend our screening platform in vivo by taking advantage of a specially formulated holidic medium for increased drug bioavailability in Drosophila. We show that the novel anti-ageing drugs, torin2 and dactolisib (BEZ-235), increase longevity in vivo.
CONCLUSIONS
Our method expands the scope of CpG methylation profiling to accurately and rapidly detecting anti-ageing potential of drugs using human cells in vitro, and in vivo, providing a novel accelerated discovery platform to test sought after anti-ageing compounds and geroprotectors.
Topics: Humans; Animals; DNA Methylation; Longevity; Aging; Epigenesis, Genetic; Drug Discovery; Cellular Senescence; Drug Evaluation, Preclinical; Drosophila; Cells, Cultured; Sirolimus
PubMed: 38956711
DOI: 10.1186/s13073-024-01349-w -
Scientific Reports Jul 2024The intestinal epithelium dynamically controls cell cycle, yet no experimental platform exists for directly analyzing cell cycle phases in non-immortalized human...
The intestinal epithelium dynamically controls cell cycle, yet no experimental platform exists for directly analyzing cell cycle phases in non-immortalized human intestinal epithelial cells (IECs). Here, we present two reporters and a complete platform for analyzing cell cycle phases in live primary human IECs. We interrogate the transcriptional identity of IECs grown on soft collagen, develop two fluorescent cell cycle reporter IEC lines, design and 3D print a collagen press to make chamber slides for optimal imaging while supporting primary human IEC growth, live image cell cycle dynamics, then assemble a computational pipeline building upon free-to-use programs for semi-automated analysis of cell cycle phases. The PIP-FUCCI construct allows for assigning cell cycle phase from a single image of living cells, and our PIP-H2A construct allows for semi-automated direct quantification of cell cycle phase lengths using our publicly available computational pipeline. Treating PIP-FUCCI IECs with oligomycin demonstrates that inhibiting mitochondrial respiration lengthens G1 phase, and PIP-H2A cells allow us to measure that oligomycin differentially lengthens S and G2/M phases across heterogeneous IECs. These platforms provide opportunities for future studies on pharmaceutical effects on the intestinal epithelium, cell cycle regulation, and more.
Topics: Humans; Epithelial Cells; Intestinal Mucosa; Cell Cycle; Oligomycins; Cells, Cultured
PubMed: 38956443
DOI: 10.1038/s41598-024-66042-9 -
Scientific Reports Jul 2024Rapamycin slows cystogenesis in murine models of polycystic kidney disease (PKD) but failed in clinical trials, potentially due to insufficient drug dosing. To improve...
Rapamycin slows cystogenesis in murine models of polycystic kidney disease (PKD) but failed in clinical trials, potentially due to insufficient drug dosing. To improve drug efficiency without increasing dose, kidney-specific drug delivery may be used. Mesoscale nanoparticles (MNP) selectively target the proximal tubules in rodents. We explored whether MNPs can target cystic kidney tubules and whether rapamycin-encapsulated-MNPs (RapaMNPs) can slow cyst growth in Pkd1 knockout (KO) mice. MNP was intravenously administered in adult Pkd1KO mice. Serum and organs were harvested after 8, 24, 48 or 72 h to measure MNP localization, mTOR levels, and rapamycin concentration. Pkd1KO mice were then injected bi-weekly for 6 weeks with RapaMNP, rapamycin, or vehicle to determine drug efficacy on kidney cyst growth. Single MNP injections lead to kidney-preferential accumulation over other organs, specifically in tubules and cysts. Likewise, one RapaMNP injection resulted in higher drug delivery to the kidney compared to the liver, and displayed sustained mTOR inhibition. Bi-weekly injections with RapaMNP, rapamycin or vehicle for 6 weeks resulted in inconsistent mTOR inhibition and little change in cyst index, however. MNPs serve as an effective short-term, kidney-specific delivery system, but long-term RapaMNP failed to slow cyst progression in Pkd1KO mice.
Topics: Animals; Sirolimus; Mice; Polycystic Kidney Diseases; Mice, Knockout; Nanoparticles; Disease Models, Animal; TOR Serine-Threonine Kinases; TRPP Cation Channels; Kidney; Drug Delivery Systems; Male
PubMed: 38956234
DOI: 10.1038/s41598-024-65830-7 -
Zhonghua Yu Fang Yi Xue Za Zhi [Chinese... Jun 2024To study the carriage status of drug susceptibility, clonal complex groups, serotypes, surface proteins and virulence genes of e from respiratory specimen sources. A...
To study the carriage status of drug susceptibility, clonal complex groups, serotypes, surface proteins and virulence genes of e from respiratory specimen sources. A total of 35 strains of meeting the criteria were collected from 3 hospitals in 2 locations, Tangshan and Jinan. The age span of the patients was 3 days-92 years, and the percentage of elderly patients≥60 years was 71.5%.The susceptibility to 9 antimicrobial drugs was measured and analyzed using the micro broth dilution method. The strains were 100.0% sensitive to penicillin, linezolid, vancomycin, and ceftriaxone; However, it exhibits high resistance rates to erythromycin, clindamycin and levofloxacin, at 97.1%, 85.7% and 82.9% respectively; and the resistance rates to tetracycline and chloramphenicol were 34.3% and 14.2%, respectively. Genome sequence determination and analysis showed that 16 resistance genes were detected in 35 strains, among which: macrolide and lincosamide resistance genes were mainly B, with a carrying rate of 74.2%; tetracycline resistance genes were mainly M, with a carrying rate of 25.7%; in addition, the mutation rates of the quinolone resistance determinants A and C were 88.5% and 85.7%, respectively. 35 strains belonged to 6 ST types and 4 clonal groups, with CC10/ST10 as the main one, accounting for 62.8%; they contained 4 serotypes of Ⅰb, Ⅱ, Ⅲ, and Ⅴ, as well as 1 untyped strain, with serotype Ⅰb as the main one, accounting for 65.7%. The strains carried three pilus types, PI1+PI2a, PI2a and PI2b types, respectively, and detected five surface proteins, , 1, , , and r_0594, and seven virulence factors, E, A, B, l, and A. Overall, isolated from respiratory tract specimens is predominantly sourced from elderly patients, with CC10 strains being most prevalent. These strains harbor multiple drug-resistant and virulence genes, demonstrating elevated resistance rates to macrolides, lincosamides, and quinolones. This emphasizes the necessity for vigilant attention to the health threat posed by from respiratory tract speciments of elderly patients.
Topics: Streptococcus agalactiae; Humans; Aged; Anti-Bacterial Agents; Middle Aged; Microbial Sensitivity Tests; Aged, 80 and over; Adult; Child; Adolescent; Child, Preschool; Infant; Young Adult; Infant, Newborn; Drug Resistance, Bacterial; Streptococcal Infections
PubMed: 38955738
DOI: 10.3760/cma.j.cn112150-20231214-00446 -
Zhonghua Er Ke Za Zhi = Chinese Journal... Jul 2024
Review
Topics: Humans; Pneumonia, Mycoplasma; China; Mycoplasma pneumoniae; Child; Macrolides; Anti-Bacterial Agents; Child, Preschool; Drug Resistance, Bacterial
PubMed: 38955692
DOI: 10.3760/cma.j.cn112140-20240407-00247 -
Medical Microbiology and Immunology Jul 2024Streptococcus pneumoniae infection is a major public health concern with high morbidity and mortality rates. This study aimed to evaluate the serotype distribution,...
Serotype distribution, antibiotic resistance, multilocus sequence typing, and virulence factors of invasive and non-invasive Streptococcus pneumoniae in Northeast China from 2000 to 2021.
Streptococcus pneumoniae infection is a major public health concern with high morbidity and mortality rates. This study aimed to evaluate the serotype distribution, antimicrobial resistance changes, clonal composition, and virulence factors of S. pneumoniae isolates causing pneumococcal disease in northeast China from 2000 to 2021. A total of 1,454 S. pneumoniae isolates were included, with 568 invasive strains and 886 non-invasive strains. The patients from whom the S. pneumoniae were isolated ranged in age from 26 days to 95 years, with those ≤ 5 years old comprising the largest group (67.19%). 19 F, 19 A, 23 F, 14, and 6B were the most common serotypes, of which 19 A and 19 F were the main serotypes of invasive and non-invasive S. pneumoniae, respectively. CC271 was the most common multilocus sequence type. Serotype 14 had the lowest expression of cbpA, rrgA, and psrP genes, but expression levels of 19 A and 19 F genes were similar. All isolates were sensitive to ertapenem, moxifloxacin, linezolid, and vancomycin but highly resistant to macrolides, tetracyclines, and cotrimoxazole. Simultaneous resistance to erythromycin, clindamycin, tetracyclines, and trimethoprim/sulfamethoxazole was common pattern among multidrug-resistant isolates. Non-invasive S. pneumoniae had higher resistance to β-lactam antibiotics than invasive strains. 19 A and 19 F were the main strains of penicillin-resistant S. pneumoniae. The resistance rate of β-lactam antibiotics decreased from 2017 to 2021 compared to previous periods. Including PCV13 in the national immunization program can reduce the morbidity and mortality rates of pneumococcal disease effectively.
Topics: Streptococcus pneumoniae; Humans; Multilocus Sequence Typing; China; Virulence Factors; Pneumococcal Infections; Serogroup; Child, Preschool; Infant; Middle Aged; Adolescent; Anti-Bacterial Agents; Adult; Child; Aged; Young Adult; Aged, 80 and over; Infant, Newborn; Microbial Sensitivity Tests; Female; Male; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial
PubMed: 38954065
DOI: 10.1007/s00430-024-00797-w -
Clinical Cardiology Jul 2024The DESyne novolimus-eluting coronary stent (NES) is a new-generation drug-eluting stent (DES) that is widely used, but clinical data are rarely reported for this stent.... (Observational Study)
Observational Study Comparative Study
INTRODUCTION
The DESyne novolimus-eluting coronary stent (NES) is a new-generation drug-eluting stent (DES) that is widely used, but clinical data are rarely reported for this stent. We compared the safety and effectiveness of the DESyne NES and the Orsiro bioresorbable polymer sirolimus-eluting stent (SES) in patients undergoing percutaneous coronary intervention (PCI).
METHODS
This was a retrospective, single-center, observational study. Between July 2017 and December 2022, patients who presented with chronic or acute coronary syndrome undergoing PCI with DESyne NES or Orsiro SES were consecutively enrolled in the present study. The primary endpoint, major adverse cardiovascular event (MACE), was a composite of cardiovascular death, target-vessel myocardial infarction, or clinically driven target-lesion revascularization.
RESULTS
A total of 776 patients (age 68.8 ± 12.2; 75.9% male) undergoing PCI were included. Overall, 231 patients with 313 lesions received NES and 545 patients with 846 lesions received SES. During a follow-up duration of 784 ± 522 days, the primary endpoint occurred in 10 patients (4.3%) in the NES group and in 36 patients (6.6%) in the SES group. After multivariate adjustment, the risk of MACE did not significantly differ between groups (NES vs. SES, hazard ratio 0.74, 95% CI, 0.35-1.55, p = 0.425). The event rate of individual components of the primary endpoint was comparable between the two groups.
CONCLUSIONS
Favorable and similar clinical outcomes were observed in patients undergoing PCI with either NES or SES in a medium-term follow-up duration. Future studies with adequately powered clinical endpoints are required for further evaluation.
Topics: Humans; Drug-Eluting Stents; Male; Female; Sirolimus; Retrospective Studies; Aged; Percutaneous Coronary Intervention; Treatment Outcome; Prosthesis Design; Coronary Artery Disease; Time Factors; Follow-Up Studies; Acute Coronary Syndrome; Risk Factors; Middle Aged; Coronary Angiography; Macrolides
PubMed: 38953595
DOI: 10.1002/clc.24317 -
MSystems Jul 2024The erythromycin resistance RNA methyltransferase () confers cross-resistance to all therapeutically important macrolides, lincosamides, and streptogramins (MLS...
UNLABELLED
The erythromycin resistance RNA methyltransferase () confers cross-resistance to all therapeutically important macrolides, lincosamides, and streptogramins (MLS phenotype). The expression of is often induced by the macrolide-mediated ribosome stalling in the upstream co-transcribed leader sequence, thereby triggering a conformational switch of the intergenic RNA hairpins to allow the translational initiation of . We investigated the evolutionary emergence of the upstream regulatory elements and the impact of allelic variation on erm expression and the MLS phenotype. Through systematic profiling of the upstream regulatory sequences across all known operons, we observed that specific subfamilies, such as and , have independently evolved distinct configurations of small upstream ORFs and palindromic repeats. A population-wide genomic analysis of the upstream regions revealed substantial non-random allelic variation at numerous positions. Utilizing machine learning-based classification coupled with RNA structure modeling, we found that many alleles cooperatively influence the stability of alternative RNA hairpin structures formed by the palindromic repeats, which, in turn, affects the inducibility of expression and MLS phenotypes. Subsequent experimental validation of 11 randomly selected variants demonstrated an impressive 91% accuracy in predicting MLS phenotypes. Furthermore, we uncovered a mixed distribution of MLS-sensitive and MLS-resistant loci within the evolutionary tree, indicating repeated and independent evolution of MLS resistance. Taken together, this study not only elucidates the evolutionary processes driving the emergence and development of MLS resistance but also highlights the potential of using non-coding genomic allele data to predict antibiotic resistance phenotypes.
IMPORTANCE
Antibiotic resistance (AR) poses a global health threat as the efficacy of available antibiotics has rapidly eroded due to the widespread transmission of AR genes. Using Erm-dependent MLS resistance as a model, this study highlights the significance of non-coding genomic allelic variations. Through a comprehensive analysis of upstream regulatory elements within the family, we elucidated the evolutionary emergence and development of AR mechanisms. Leveraging population-wide machine learning (ML)-based genomic analysis, we transformed substantial non-random allelic variations into discernible clusters of elements, enabling precise prediction of MLS phenotypes from non-coding regions. These findings offer deeper insight into AR evolution and demonstrate the potential of harnessing non-coding genomic allele data for accurately predicting AR phenotypes.
PubMed: 38953319
DOI: 10.1128/msystems.00430-24 -
EuroIntervention : Journal of EuroPCR... Jul 2024
Topics: Humans; Coronary Artery Disease; Registries; Sirolimus; Treatment Outcome; Angioplasty, Balloon, Coronary; Male; Female; Middle Aged; Aged; Drug-Eluting Stents
PubMed: 38949239
DOI: 10.4244/EIJ-D-23-00966