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BMC Infectious Diseases Jul 2024Multi-drug or rifamycin-resistant tuberculosis (MDR/RR-TB) is an important public health concern, including in settings with high HIV prevalence. TB drug resistance can... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Multi-drug or rifamycin-resistant tuberculosis (MDR/RR-TB) is an important public health concern, including in settings with high HIV prevalence. TB drug resistance can be directly transmitted or arise through resistance acquisition during first-line TB treatment. Limited evidence suggests that people living with HIV (PLHIV) might have an increased risk of acquired rifamycin-resistance (ARR).
METHODS
To assess HIV as a risk factor for ARR during first-line TB treatment, a systematic review and meta-analysis was conducted. ARR was defined as rifamycin-susceptibility at treatment start with rifamycin-resistance diagnosed during or at the end of treatment, or at recurrence. PubMed/MEDLINE, CINAHL, Cochrane Library, and Google Scholar databases were searched from inception to 23 May 2024 for articles in English; conference abstracts were also searched from 2004 to 2021. The Mantel-Haenszel random-effects model was used to estimate the pooled odds ratio of any association between HIV and ARR among individuals receiving first-line TB treatment.
RESULTS
Ten studies that included data collected between 1990 and 2014 were identified: five from the United States, two from South Africa and one each from Uganda, India and Moldova. A total of 97,564 individuals were included across all studies, with 13,359 (13.7%) PLHIV. Overall, 312 (0.32%) acquired rifamycin-resistance, among whom 115 (36.9%) were PLHIV. The weighted odds of ARR were 4.57 (95% CI, 2.01-10.42) times higher among PLHIV compared to HIV-negative individuals receiving first-line TB treatment.
CONCLUSION
The available data, suggest that PLHIV have an increased ARR risk during first-line TB treatment. Further research is needed to clarify specific risk factors, including advanced HIV disease and TB disease severity. Given the introduction of shorter, 4-month rifamycin-based regimens, there is an urgent need for additional data on ARR, particularly for PLHIV.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO CRD42022327337.
Topics: Humans; HIV Infections; Rifamycins; Antitubercular Agents; Tuberculosis, Multidrug-Resistant; Risk Factors; Mycobacterium tuberculosis; South Africa
PubMed: 38956461
DOI: 10.1186/s12879-024-09514-7 -
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 2024Human norovirus (HuNoV) is an enteric infectious pathogen belonging to the Caliciviridae family that causes occasional epidemics. Circulating alcohol-tolerant viral...
Human norovirus (HuNoV) is an enteric infectious pathogen belonging to the Caliciviridae family that causes occasional epidemics. Circulating alcohol-tolerant viral particles that are readily transmitted via food-borne routes significantly contribute to the global burden of HuNoV-induced gastroenteritis. Moreover, contact with enzymes secreted by other microorganisms in the environment can impact the infectivity of viruses. Hence, understanding the circulation dynamics of Caliciviridae is critical to mitigating epidemics. Accordingly, in this study, we screened whether environmentally abundant secretase components, particularly proteases, affect Caliciviridae infectivity. Results showed that combining Bacillaceae serine proteases with epsilon-poly-L-lysine (EPL) produced by Streptomyces-a natural antimicrobial-elicited anti-Caliciviridae properties, including against the epidemic HuNoV GII.4_Sydney_2012 strain. In vitro and in vivo biochemical and virological analyses revealed that EPL has two unique synergistic viral inactivation functions. First, it maintains an optimal pH to promote viral surface conformational changes to the protease-sensitive structure. Subsequently, it inhibits viral RNA genome release via partial protease digestion at the P2 and S domains in the VP1 capsid. This study provides new insights regarding the high-dimensional environmental interactions between bacteria and Caliciviridae, while promoting the development of protease-based anti-viral disinfectants.
Topics: Streptomyces; Polylysine; Serine Proteases; Bacillaceae; RNA, Viral; Humans; Genome, Viral; Animals; Norovirus; Virus Inactivation; Caliciviridae; Antiviral Agents
PubMed: 38956295
DOI: 10.1038/s41598-024-65963-9 -
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 -
Scientific Reports Jul 2024This retrospective cohort study investigated patients with cytomegalovirus anterior uveitis (CMV AU) and compared treatment outcomes between regional and systemic...
This retrospective cohort study investigated patients with cytomegalovirus anterior uveitis (CMV AU) and compared treatment outcomes between regional and systemic antiviral therapies. Treatment modalities included topical (2% ganciclovir [GCV] eye drops or 0.2% GCV eye gel) and systemic (intravenous GCV or oral valganciclovir) groups. The comparison parameters included response rates, time to response, recurrence rates, time to recurrence, and complications. Forty-four patients (54.5% male) with a mean age of 56 ± 9.87 years were enrolled, with 31 eyes in the topical group and 13 eyes in the systemic group. The median response time was significantly slower in the topical group (63 days [IQR 28-112]) compared to the systemic group (28 days [IQR 24-59]) (p = 0.04). Treatment response rates were 87.1% (27/31) in the topical group and 100% (13/13) in the systemic group (p = 0.30), while recurrence rates were 37% (10/27) and 69.2% (9/13) (p = 0.056), with a median time to recurrence of 483 days [IQR 145-1388] and 392 days [IQR 203.5-1907.5] (p = 0.20), respectively. In conclusion, both topical and systemic GCV treatments demonstrated favorable outcomes for CMV AU. Systemic GCV showed rapid control of intraocular inflammation.
Topics: Humans; Male; Female; Middle Aged; Cytomegalovirus Infections; Uveitis, Anterior; Antiviral Agents; Retrospective Studies; Treatment Outcome; Ganciclovir; Aged; Cytomegalovirus; Adult; Valganciclovir; Recurrence; Ophthalmic Solutions
PubMed: 38956212
DOI: 10.1038/s41598-024-66224-5 -
Scientific Reports Jul 2024Durian (Durio zibethinus L.) fruit pulp is a rich source of γ-glutamylcysteine (γ-EC), a direct precursor to the antioxidant glutathione (GSH). This study elucidated...
Durian (Durio zibethinus L.) fruit pulp is a rich source of γ-glutamylcysteine (γ-EC), a direct precursor to the antioxidant glutathione (GSH). This study elucidated the in vitro neuroprotective potential of unripe durian fruit pulp extract (UDE) against HO-induced neurotoxicity in SH-SY5Y cells and neuroinflammation in lipopolysaccharide (LPS)-stimulated BV-2 cells. Treatments with γ-EC, GSH standards, or UDE exhibited no cytotoxicity in SH-SY5Y and BV-2 cells, except at high concentrations. A 4-h pretreatment with 100 µM γ-EC or UDE containing 100 µM γ-EC significantly increased SH-SY5Y cell viability post HO induction. Moreover, a similar pretreatment reduced LPS-stimulated production of proinflammatory cytokines in BV-2 cells. The neuroprotective effect of UDE is primarily attributed to γ-EC provision and the promotion of GSH synthesis, which in turn elevates intracellular GSH levels and reduces proinflammatory cytokines. This study identifies γ-EC in UDE as a potential neuroprotective biomarker boosting intracellular GSH levels, providing insights into UDE's therapeutic potential.
Topics: Glutathione; Oxidative Stress; Plant Extracts; Neuroprotective Agents; Humans; Fruit; Animals; Inflammation; Lipopolysaccharides; Neuroprotection; Mice; Cell Survival; Hydrogen Peroxide; Antioxidants; Cell Line, Tumor; Cell Line; Cytokines; Dipeptides
PubMed: 38956206
DOI: 10.1038/s41598-024-65219-6 -
Scientific Reports Jul 20242K4L is a rationally designed analog of the short α-helical peptide temporin-1CEc, a natural peptide isolated and purified from the skin secretions of the Chinese brown...
2K4L is a rationally designed analog of the short α-helical peptide temporin-1CEc, a natural peptide isolated and purified from the skin secretions of the Chinese brown frog Rana chensinensis by substituting amino acid residues. 2K4L displayed improved and broad-spectrum antibacterial activity than temporin-1CEc in vitro. Here, the antibacterial and anti-inflammatory activities of 2K4L in macrophages, C. elegans and mice were investigated. The results demonstrated that 2K4L could enter THP-1 cells to kill a multidrug-resistant Acinetobacter baumannii strain (MRAB 0227) and a sensitive A. baumannii strain (AB 22933), as well as reduce proinflammatory responses induced by MRAB 0227 by inhibiting NF-κB signaling pathway. Similarly, 2K4L exhibited strong bactericidal activity against A. baumannii uptake into C. elegans, extending the lifespan and healthspan of the nematodes. Meanwhile, 2K4L alleviated the oxidative stress response by inhibiting the expression of core genes in the p38 MAPK/PMK-1 signaling pathway and downregulating the phosphorylation level of p38, thereby protecting the nematodes from damage by A. baumannii. Finally, in an LPS-induced septic model, 2K4L enhanced the survival of septic mice and decreased the production of proinflammatory cytokines by inhibiting the signaling protein expression of the MAPK and NF-κB signaling pathways and protecting LPS-induced septic mice from a lethal inflammatory response. In conclusion, 2K4L ameliorated LPS-induced inflammation both in vitro and in vivo.
Topics: Animals; Caenorhabditis elegans; Mice; Acinetobacter baumannii; Macrophages; Lipopolysaccharides; Shock, Septic; NF-kappa B; Antimicrobial Peptides; Humans; p38 Mitogen-Activated Protein Kinases; Signal Transduction; Inflammation; Anti-Bacterial Agents; Anti-Inflammatory Agents; Oxidative Stress; Mitogen-Activated Protein Kinases; Caenorhabditis elegans Proteins
PubMed: 38956179
DOI: 10.1038/s41598-024-64511-9 -
Scientific Reports Jul 2024Biological agents are getting a noticeable concern as efficient eco-friendly method for nanoparticle fabrication, from which fungi considered promising agents in this...
Biological agents are getting a noticeable concern as efficient eco-friendly method for nanoparticle fabrication, from which fungi considered promising agents in this field. In the current study, two fungal species (Embellisia spp. and Gymnoascus spp.) were isolated from the desert soil in Saudi Arabia and identified using 18S rRNA gene sequencing then used as bio-mediator for the fabrication of silver nanoparticles (AgNPs). Myco-synthesized AgNPs were characterized using UV-visible spectrometry, transmission electron microscopy, Fourier transform infrared spectroscopy and dynamic light scattering techniques. Their antibacterial activity against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Klebsiella pneumoniae were investigated. In atrial to detect their possible antibacterial mechanism, Sodium dodecyl sulfate (SDS-PAGE) and TEM analysis were performed for Klebsiella pneumoniae treated by the myco-synthesized AgNPs. Detected properties of the fabricated materials indicated the ability of both tested fungal strains in successful fabrication of AgNPs having same range of mean size diameters and varied PDI. The efficiency of Embellisia spp. in providing AgNPs with higher antibacterial activity compared to Gymnoascus spp. was reported however, both indicated antibacterial efficacy. Variations in the protein profile of K. pneumoniae after treatments and ultrastructural changes were observed. Current outcomes suggested applying of fungi as direct, simple and sustainable approach in providing efficient AgNPs.
Topics: Silver; Saudi Arabia; Metal Nanoparticles; Soil Microbiology; Microbial Sensitivity Tests; Anti-Bacterial Agents; Desert Climate; Fungi; Klebsiella pneumoniae; Pseudomonas aeruginosa; Anti-Infective Agents
PubMed: 38956076
DOI: 10.1038/s41598-024-63117-5 -
Nature Communications Jul 2024Left unchecked, plant-parasitic nematodes have the potential to devastate crops globally. Highly effective but non-selective nematicides are justifiably being...
Left unchecked, plant-parasitic nematodes have the potential to devastate crops globally. Highly effective but non-selective nematicides are justifiably being phased-out, leaving farmers with limited options for managing nematode infestation. Here, we report our discovery of a 1,3,4-oxadiazole thioether scaffold called Cyprocide that selectively kills nematodes including diverse species of plant-parasitic nematodes. Cyprocide is bioactivated into a lethal reactive electrophilic metabolite by specific nematode cytochrome P450 enzymes. Cyprocide fails to kill organisms beyond nematodes, suggesting that the targeted lethality of this pro-nematicide derives from P450 substrate selectivity. Our findings demonstrate that Cyprocide is a selective nematicidal scaffold with broad-spectrum activity that holds the potential to help safeguard our global food supply.
Topics: Animals; Cytochrome P-450 Enzyme System; Nematoda; Antinematodal Agents; Sulfides
PubMed: 38956039
DOI: 10.1038/s41467-024-49738-4 -
Nature Communications Jul 2024The primary obstacle to curing HIV-1 is a reservoir of CD4+ cells that contain stably integrated provirus. Previous studies characterizing the proviral landscape, which...
The primary obstacle to curing HIV-1 is a reservoir of CD4+ cells that contain stably integrated provirus. Previous studies characterizing the proviral landscape, which have been predominantly conducted in males in the United States and Europe living with HIV-1 subtype B, have revealed that most proviruses that persist during antiretroviral therapy (ART) are defective. In contrast, less is known about proviral landscapes in females with non-B subtypes, which represents the largest group of individuals living with HIV-1. Here, we analyze genomic DNA from resting CD4+ T-cells from 16 female and seven male Ugandans with HIV-1 receiving suppressive ART (n = 23). We perform near-full-length proviral sequencing at limiting dilution to examine the proviral genetic landscape, yielding 607 HIV-1 subtype A1, D, and recombinant proviral sequences (mean 26/person). We observe that intact genomes are relatively rare and clonal expansion occurs in both intact and defective genomes. Our modification of the primers and probes of the Intact Proviral DNA Assay (IPDA), developed for subtype B, rescues intact provirus detection in Ugandan samples for which the original IPDA fails. This work will facilitate research on HIV-1 persistence and cure strategies in Africa, where the burden of HIV-1 is heaviest.
Topics: Humans; HIV-1; Proviruses; HIV Infections; Male; Female; Genome, Viral; CD4-Positive T-Lymphocytes; Adult; DNA, Viral; Uganda; Viral Load; Anti-HIV Agents
PubMed: 38956017
DOI: 10.1038/s41467-024-48985-9