Pritchardlist7023

rug action can help address common challenges in NE clinical trials and allow for faster selection and validation of promising therapies for more extensive investigation.BACKGROUND Necrotizing enterocolitis (NEC) develops through exaggerated toll-like receptor 4 (TLR4) signaling in the intestinal epithelium. Breast milk is rich in non-digestible oligosaccharides and prevents NEC through unclear mechanisms. We now hypothesize that the human milk oligosaccharides 2'-fucosyllactose (2'-FL) and 6'-sialyllactose (6'-SL) can reduce NEC through inhibition of TLR4 signaling. METHODS NEC was induced in newborn mice and premature piglets and infant formula was supplemented with 2'-FL, 6'-SL, or lactose. Intestinal tissue was obtained at surgical resection. HMO inhibition of TLR4 was assessed in IEC-6 enterocytes, mice, and human tissue explants and via in silico modeling. RESULTS Supplementation of infant formula with either 2'-FL and/or 6'-SL, but not the parent sugar lactose, reduced NEC in mice and piglets via reduced apoptosis, inflammation, weight loss, and histological appearance. Mechanistically, both 2'-FL and 6'-SL, but not lactose, reduced TLR4-mediated nuclear factor kappa lNEC in mice and piglets. 2'-FL and 6'-SL but not lactose inhibited TLR4 signaling in cultured enterocytes, in enteroids derived from mouse intestine, and in human intestinal explants obtained at the time of surgical resection for patients with NEC. In seeking the mechanisms involved, 2'-FL and 6'-SL but not lactose were found to directly bind to TLR4, explaining the inhibition and protection against NEC. These findings may impact clinical practice by suggesting that administration of HMOs could serve as a preventive strategy for premature infants at risk for NEC development.Neisseria gonorrhoeae represents an urgent public health threat due to the rapid emergence of resistance to current antibiotics and the limited number of anti-gonococcal agents currently in clinical trials. This study utilized a drug repositioning strategy to investigate FDA-approved gold-containing drugs against N. gonorrhoeae. Auranofin, sodium aurothiomalate and aurothioglucose inhibited 48 clinical isolates of N. gonorrhoeae including multidrug-resistant strains at a concentration as low as 0.03 µg/mL. A time-kill assay revealed that auranofin exhibited rapid bactericidal activity against N. gonorrhoeae. Moreover, both sodium aurothiomalate and aurothioglucose did not inhibit growth of vaginal protective commensal lactobacilli. Auranofin, in combination with azithromycin, ceftriaxone, cefixime or tetracycline showed an additive effect against four N. gonorrhoeae strains, suggesting the possibility of using auranofin in dual therapy. Moreover, auranofin reduced the burden of intracellular N. gonorrhoeae by over 99% outperforming the drug of choice ceftriaxone. Auranofin was found superior to ceftriaxone in reducing the secretion of the pro-inflammatory cytokine IL-8 by endocervical cells infected with N. gonorrhoeae. Furthermore, auranofin exhibited a prolonged post-antibiotic effect over 10 h, as well as inability to generate resistant mutants. PF-543 clinical trial Overall, the current study suggests that repurposing gold-containing drugs, like auranofin, for treatment of gonorrhea warrants further investigation.An amendment to this paper has been published and can be accessed via a link at the top of the paper.Little is known about the potential population-level impact of HIV pre-exposure prophylaxis (PrEP) use among cisgender male sex workers (MSWs), a high-risk subset of cisgender men who have sex with men (MSM). Using an agent-based model, we simulated HIV transmission among cisgender MSM in Rhode Island to determine the impacts of PrEP implementation where cisgender MSWs were equally ("standard expansion") or five times as likely ("focused expansion") to initiate PrEP compared to other cisgender MSM. Without PrEP, the model predicted 920 new HIV infections over a decade, or an average incidence of 0.39 per 100 person-years. In a focused expansion scenario where 15% of at-risk cisgender MSM used PrEP, the total number of new HIV infections was reduced by 58.1% at a cost of $57,180 per quality-adjusted life-year (QALY) gained. Focused expansion of PrEP use among cisgender MSWs may be an efficient and cost-effective strategy for reducing HIV incidence in the broader population of cisgender MSM.During recent years, a new disease of Siberian fir (A. sibirica) emerged in Central Siberia, exhibiting symptoms of stem/branch deformation, cambium necrosis, and dieback of branches and twigs, the causal agent remaining unknown. The aim was to identify agent of the disease and to investigate its pathogenicity to A. sibirica and Norway spruce (Picea abies). Symptomatic tissues of fir were subjected to pure culture isolation of anticipated pathogen(s). Obtained isolates were subjected to molecular identification, phylogenetic analyses, and pathogenicity tests with A. sibirica saplings, and seeds and seedlings of A. sibirica and P. abies. The study demonstrated that, (i) most commonly isolated fungus from canker wounds of A. sibirica exhibited Acremonium-like anamorphs; (ii) phylogeny demonstrated that investigated fungi belong to genus Corinectria, but are genetically well separated from other worldwide known Corinectria spp.; (iii) one species of isolated fungi has the capacity to cause the disease and kill A. sibirica saplings and seedlings, but also seedlings of P. abies. Guidelines for future research were defined in order to generate needed information on species description, its origin and ecology, and estimation of potential risks upon the eventual invasion of the pathogen to new geographic areas, in particular of Europe.The United Kingdom has a long history of many good dental periodicals. The reputation of its scientific publication is a major mark of any professional organisation. Without doubt the British Dental Journal (BDJ) is very highly regarded throughout the worldwide scientific and clinical community, frequently appearing in important citation indices. This does not happen by chance. It needs an enthusiastic, skilled team led by a gifted editor. Stephen Hancocks has reached his fifteenth year as editor-in-chief of the BDJ, following in the footsteps of illustrious predecessors. Part 1 examines who they were and when they held the reins of the journal in the early days. Part 2 looks at the post-war editors.