bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical utility of multiplex PCR in the detection of pathogens from sterile body fluids
Authors: Cox Christina R. , Weghorn Kristin N. , Ruger Katie , Powers-Fletcher Margaret V. , Powell Eleanor A. , Mortensen Joel E. 
Published: March 2024

ABSTRACT

Rapid identification of pathogens in normally sterile body fluid (NSBF) is essential for appropriate patient management, specifically antimicrobial therapy. Limited sensitivity and increased time to detection of traditional culture prompted us to evaluate additional testing to contribute to the diagnosis of infection. The purpose of this study was to evaluate the GenMark Dx ePlex Blood Culture Identification (BCID) Panels on positive body fluids inoculated into blood culture bottles for the detection of microorganisms. A total of 88 positive body fluids from blood culture bottles were analyzed using a Gram-Positive, Gram-Negative, and/or Fungal pathogen BCID Panel based on the Gram stain result. Each result was compared to routine culture performed from the positive bottle. When using culture as a reference standard, we found the ePlex multiplex panel performed with a positive percent agreement of 96.5% and a negative percent agreement of 99.8%. The use of multiplex PCR may be a useful supplement to routine culture for NSBF in blood culture bottles.

IMPORTANCE
The identification of pathogens in normally sterile body fluid (NSBF) is performed using routine culture, the current gold standard. Limitations of this method include sensitivity and increased turnaround times which could potentially delay vital patient care, especially antimicrobial therapy. Adaptations of NSBF in blood culture bottles prompted us to consider the utility of additional methods to bridge the gap in diagnostic challenges for these life-threatening infections. Multiplex molecular panels have been manufactured for use with multiple specimen types including blood, cerebral spinal fluid, stool, and respiratory. Therefore, the purpose of this study was to evaluate the off-label use of ePlex Blood Culture Identification Panels on positive body fluids grown in blood culture bottles for the detection of microorganisms for research purposes.
The integration of
Coxiella burnetii
PCR testing in serum into the diagnostic algorithm of suspected acute Q fever in an endemic setting
Authors: Ghanem-Zoubi Nesrin , Mustafa-Hellou Mona , Zahran Maram , Gazit Liat , Shalaginov Raya , Dabaja-Younis Halima , Szwarcwort Moran 
Published: March 2024

ABSTRACT

Serum polymerase chain reaction (PCR) for the detection of
Coxiella burnetii
DNA has been suggested for rapid Q fever diagnosis. We evaluated the role of PCR testing in serum in the diagnosis of acute Q fever in an endemic setting. We examined patients suspected of acute Q fever tested for
C. burnetii
-specific serum real-time PCR in a tertiary hospital between January 2019 toand December 2022. In the first half, PCR orders were consultation-based by infectious diseases specialists, while in the second half, they were guided by serology, positive IgM2, and negative IgG1 and IgG2, indicating early acute infection. Logistic regression analyzed independent predictors for positive PCR. PCR positivity rates were calculated using various clinical criteria in the diagnostic algorithm. Out of 272 patients, 13 (4.8%) tested positive and 130 exhibited serologically suspected early infection. Presentation during April–July and aspartate aminotransferase (AST) > 3× upper normal limit (UNL) were independently associated with positive PCR with an odds ratio (OR) = 15.03 [95% confidence interval (CI), 1.58–142.46],
P
= 0.018 and OR = 55.44 [95% CI, 6.16–498.69],
P
< 0.001, respectively. PCR positivity rate was 8.5% in serologically suspected early infection vs 1.4% in other serology, yielding OR = 6.4 [95% CI, 1.4–29.7],
P
= 0.009. Adding AST > 3× UNL increased OR to 49.5 [95% CI, 5.9–408.7],
P ≤
0.001 reducing required PCR tests for a single acute Q fever case from 11.8 to 3. Elevated AST in serologically suspected early Q fever is proposed to be used in a diagnostic stewardship algorithm integrating PCR in serum in an endemic setting.

IMPORTANCE

Our study suggests in a diagnostic stewardship approach the integration of molecular testing (Coxiella burnetii targeted PCR) for the diagnosis of acute Q fever in a reliable time in the endemic setting. Integrating PCR detecting
Coxiella burnetii
in serum in routine testing of suspected early acute Q fever based on serology result increased the PCR positivity rate significantly. Adding increased transaminases optimizes PCR utility which is highly requested particularly in endemic areas.
Anaerostipes hadrus
, a butyrate-producing bacterium capable of metabolizing 5-fluorouracil
Authors: Liu Danping , Xie Li-Sheng , Lian Shitao , Li Kexin , Yang Yun , Wang Wen-Zhao , Hu Songnian , Liu Shuang-Jiang , Liu Chang , He Zilong 
Published: March 2024

ABSTRACT

Anaerostipes hadrus
(
A. hadrus
) is a dominant species in the human gut microbiota and considered a beneficial bacterium for producing probiotic butyrate. However, recent studies have suggested that
A. hadrus
may negatively affect the host through synthesizing fatty acid and metabolizing the anticancer drug 5-fluorouracil, indicating that the impact of
A. hadrus
is complex and unclear. Therefore, comprehensive genomic studies on
A. hadrus
need to be performed. We integrated 527 high-quality public
A. hadrus
genomes and five distinct metagenomic cohorts. We analyzed these data using the approaches of comparative genomics, metagenomics, and protein structure prediction. We also performed validations with culture-based
in vitro
assays. We constructed the first large-scale pan-genome of
A. hadrus
(
n
= 527) and identified 5-fluorouracil metabolism genes as ubiquitous in
A. hadrus
genomes as butyrate-producing genes. Metagenomic analysis revealed the wide and stable distribution of
A. hadrus
in healthy individuals, patients with inflammatory bowel disease, and patients with colorectal cancer, with healthy individuals carrying more
A. hadrus
. The predicted high-quality protein structure indicated that
A. hadrus
might metabolize 5-fluorouracil by producing bacterial dihydropyrimidine dehydrogenase (encoded by the
preTA
operon). Through
in vitro
assays, we validated the short-chain fatty acid production and 5-fluorouracil metabolism abilities of
A. hadrus
. We observed for the first time that
A. hadrus
can convert 5-fluorouracil to α-fluoro-β-ureidopropionic acid, which may result from the combined action of the
preTA
operon and adjacent
hydA
(encoding bacterial dihydropyrimidinase). Our results offer novel understandings of
A. hadrus
, exceptionally functional features, and potential applications.

IMPORTANCE

This work provides new insights into the evolutionary relationships, functional characteristics, prevalence, and potential applications of
Anaerostipes hadrus
.
Multifactorial genetic control and magnesium levels govern the production of a
Streptomyces
antibiotic with unusual cell density dependence
Authors: ­ Hindra , Elliot Marie A. 
Published: March 2024

ABSTRACT

Streptomyces
bacteria are renowned both for their antibiotic production capabilities and for their cryptic metabolic potential. Their metabolic repertoire is subject to stringent genetic control, with many of the associated biosynthetic gene clusters being repressed by the conserved nucleoid-associated protein Lsr2. In an effort to stimulate new antibiotic production in wild
Streptomyces
isolates, we leveraged the activity of an Lsr2 knockdown construct and successfully enhanced antibiotic production in the wild
Streptomyces
isolate WAC07094. We determined that this new activity stemmed from increased levels of the angucycline-like family member saquayamycin. Saquayamycin has both antibiotic and anti-cancer activities, and intriguingly, beyond Lsr2-mediated repression, we found saquayamycin production was also suppressed at high density on solid or in liquid growth media; its levels were greatest in low-density cultures. This density-dependent control was exerted at the level of the cluster-situated regulatory gene
sqnR
and was mediated in part through the activity of the PhoRP two-component regulatory system, where deleting
phoRP
led to both constitutive antibiotic production and
sqnR
expression. This suggests that PhoP functions to repress the expression of
sqnR
at high cell density. We further discovered that magnesium supplementation could alleviate this density dependence, although its action was independent of PhoP. Finally, we revealed that the nitrogen-responsive regulators GlnR and AfsQ1 could relieve the repression exerted by Lsr2 and PhoP. Intriguingly, we found that this low density-dependent production of saquayamycin was not unique to WAC07094; saquayamycin production by another wild isolate also exhibited low-density activation, suggesting that this spatial control may serve an important ecological function in their native environments.

IMPORTANCE

Streptomyces
specialized metabolic gene clusters are subject to complex regulation, and their products are frequently not observed under standard laboratory growth conditions. For the wild
Streptomyces
isolate WAC07094, production of the angucycline-family compound saquayamycin is subject to a unique constellation of control factors. Notably, it is produced primarily at low cell density, in contrast to the high cell density production typical of most antibiotics. This unusual density dependence is conserved in other saquayamycin producers and is driven by the pathway-specific regulator SqnR, whose expression is influenced by both nutritional and genetic elements. Collectively, this work provides new insights into an intricate regulatory system governing antibiotic production and indicates there may be benefits to including low-density cultures in antibiotic screening platforms.
Semaglutide treatment for children with obesity: an observational study
Authors: van Boxel Elizabeth-Jane , Rahman Saqib , Lai Karen , Boulos Nabil , Davis Nikki 
Published: March 2024

ObjectiveTo assess efficacy and tolerability of semaglutide as a weight loss treatment for children living with comorbid obesity.DesignRetrospective observational study of the first 50 children from a weight management service treated with semaglutide for at least 6 months.SettingA tertiary paediatric multidisciplinary weight management clinic in a UK hospital.PatientsAged 10–18 years old with a body mass index (BMI) SD score (SDS) >2 with a weight-related comorbidity (including insulin resistance (defined as homeostatic model assessment for insulin resistance >4), type 2 diabetes, metabolic-associated fatty liver disease, obstructive sleep apnoea or hypertension).InterventionsOnce-weekly injectable semaglutide titrated over 8 weeks to a final dose of 1 mg in addition to dietary and lifestyle advice.Main outcome measuresPrimary outcome measures were change in weight, BMI SDS and percentage body weight. Secondary outcomes were side effects and cessation of treatment.ResultsAfter 6 months of treatment, statistically significant decreases in BMI SDS (0.32±0.27, p<0.001) and body weight (7.03±7.50 kg, p<0.001) were seen. Mean percentage total weight loss was 6.4±6.3% (p<0.001). For the 14 patients for whom 12-month data were available, statistically significant decreases were seen in mean BMI SDS (0.54±0.52, p<0.001). Mean body weight decreased by 9.7±10.8 kg (p<0.001). Percentage total weight loss at 12 months was 8.9±10.0% (p<0.001). Mild gastrointestinal side effects were common. One patient developed gallstones. Five patients discontinued treatment due to side effects.ConclusionSemaglutide appears to be a safe and effective weight loss adjunct when used in a multidisciplinary weight management clinic.
Association between corneal hysteresis and glaucoma in a Japanese population: the Hisayama Study
Authors: Fujiwara Kohta , Ueda Emi , Hata Jun , Nakano Satoko , Hashimoto Sawako , Nakamura Shun , Murakami Yusuke , Kubota Toshiaki , Yoshitomi Takeshi , Ninomiya Toshiharu , Sonoda Koh-Hei 
Published: March 2024

AimsTo investigate the association between corneal hysteresis and the presence of glaucoma and its subtypes in a general Japanese population.MethodsWe analysed the data of 2338 Japanese community-dwellers aged ≥40 years (1059 men, 1279 women) who underwent an eye examination in 2018 as part of the population-based, cross-sectional Hisayama Study. Participants were divided into quartile levels of corneal hysteresis, which had been measured with an ocular response analyzer. Glaucoma was defined based on the International Society of Geographical and Epidemiological Ophthalmology criteria. We conducted a logistic regression analysis to determine the ORs and their 95% CIs for the presence of outcomes according to the corneal hysteresis quartiles.ResultsGlaucoma was diagnosed in 154 participants: primary open-angle glaucoma (POAG), n=115; primary angle-closure glaucoma, n=17; exfoliation glaucoma, n=21 and secondary glaucoma without exfoliation glaucoma, n=1. After adjustment for confounders, the OR for prevalent glaucoma was significantly increased in the participants in the first corneal-hysteresis quartile compared with those in the fourth quartile (OR: 1.80; 95% CI: 1.03 to 3.17). Regarding glaucoma subtypes, the first-quartile participants had significantly greater likelihoods of the presence of POAG (OR: 1.63; 95% CI: 1.02 to 2.61) and exfoliation glaucoma (OR: 6.49; 95% CI: 1.44 to 29.30) compared with those in the third and fourth quartiles after adjustment for potential confounders.ConclusionsThese results demonstrated a significant inverse association between corneal hysteresis and the likelihood of glaucoma, suggesting that the measurement of corneal hysteresis would provide useful information for elucidating the aetiology of glaucoma.
What works for whom, how and why in mental health education for undergraduate health profession students? A realist synthesis protocol
Authors: McCormack Zoe , Kerr Aisling , Simpson Andrew , Keating Dolores , Strawbridge Judith 
Published: March 2024

IntroductionIt has been shown that mental health education can support positive attitudes of health profession students towards people with mental health challenges, which supports them to provide optimal healthcare to this group. There are many different approaches to designing and delivering mental health education to health profession students. Each has their own advantages and disadvantages, and often mental health education programmes incorporate a multimodal approach in order to reap the benefits of a variety of teaching and learning approaches. The aim of this study is to understand the current landscape of teaching and learning approaches to mental health education for undergraduate health profession students. We will examine the features of successful outcomes for health profession students for:Learning environment.Knowledge development and retention.Confidence.Motivation.Preparedness for professional practice.MethodsFor this, a realist synthesis has been chosen in order to review the literature. Realist synthesis lends itself to the review of complex interventions such as mental health education for undergraduate health profession curricula because it seeks to uncover the range of different mechanisms and context configurations that produce different outcomes. Health profession education and education practice, in general, is complex. A patient and public involvement (PPI) group is involved throughout this study and includes undergraduate health profession students, and members of the St John of Gods Hospital Consumers and Carers Council who are involved at every stage of the research. This study will engage with a stakeholder group who will support the refining of the programme theory.Ethics and disseminationEthical approval has been sought and approved by Royal College of Surgeons, Ireland Ethical Committee (REC number: 212622783). We will aim to write up and publish the full synthesis as a journal article. We will also discuss ways of dissemination outside of academia with our PPI group.
High response rate with extended dosing of cemiplimab in advanced cutaneous squamous cell carcinoma
Authors: Rischin Danny , Hughes Brett G M , Basset-Séguin Nicole , Schadendorf Dirk , Bowyer Samantha , Trabelsi Messai Sabiha , Meier Friedegund , Eigentler Thomas K , Casado Echarren Victoria , Stein Brian , Beylot-Barry Marie , Dalac Sophie , Dréno Brigitte , Migden Michael R , Hauschild Axel , Schmults Chrysalyne D , Lim Annette M , Yoo Suk-Young , Paccaly Anne J , Papachristos Apostolos , Nguyen Jenny-Hoa , Okoye Emmanuel , Seebach Frank , Booth Jocelyn , Lowy Israel , Fury Matthew G , Guminski Alexander 
Published: March 2024

BackgroundCemiplimab (Libtayo®), a human monoclonal immunoglobulin G4 antibody to the programmed cell death-1 receptor, is approved for the treatment of patients with advanced cutaneous squamous cell carcinoma (CSCC), who are not candidates for curative surgery or curative radiation, using an every-3-weeks (Q3W) dosing interval. Pharmacokinetic modeling indicated that Ctroughof extended intravenous dosing of 600 mg every 4 weeks (Q4W) would be comparable to the approved intravenous dosage of 350 mg Q3W. We examined the efficacy, pharmacokinetics, and safety of cemiplimab dosed Q4W.MethodsIn this open-label, phase II trial (ClinicalTrials.gov identifierNCT02760498), the cohort of patients ≥18 years old with advanced CSCC received cemiplimab 600 mg intravenously Q4W for up to 48 weeks. Tumor measurements were recorded every 8 weeks. The primary endpoint was objective response rate by independent central review.ResultsSixty-three patients with advanced CSCC were treated with cemiplimab. The median duration of follow-up was 22.4 months (range: 1.0–39.8). An objective response was observed in 39 patients (62%; 95% CI: 48.8% to 73.9%), with 22% of patients (n=14) achieving complete response and 40% (n=25) achieving partial response. The most common treatment-emergent adverse events were diarrhea, pruritus, and fatigue.ConclusionsExtended dosing of cemiplimab 600 mg intravenously Q4W exhibited substantial antitumor activity, rapid and durable responses, and an acceptable safety profile in patients with advanced CSCC. These results confirm that cemiplimab is a highly active therapy for advanced CSCC. Additional data would help ascertain the benefit−risk profile for the 600 mg intravenous dosing regimen compared with the approved regimen.
Mefloquine enhances the efficacy of anti-PD-1 immunotherapy via IFN-γ-STAT1-IRF1-LPCAT3-induced ferroptosis in tumors
Authors: Tao Qian , Liu Nian , Wu Jie , Chen Jing , Chen Xiang , Peng Cong 
Published: March 2024

BackgroundFerroptosis plays an important role in enhancing the efficacy of anti-programmed cell death 1 (PD-1) immunotherapy; however, the molecular mechanisms by which tumor ferroptosis sensitizes melanoma and lung cancer to anti-PD-1 immunotherapy have not been elucidated.MethodsCytotoxicity assays, colony formation assays, flow cytometry and animal experiments were used to evaluate the effects of mefloquine (Mef) on survival and ferroptosis in melanoma and lung cancer. RNA sequencing, Real-time quantitative PCR (qRT-PCR), western blotting, chromatin immunoprecipitation-qPCR and flow cytometry were used to determine the molecular mechanisms by which Mef regulates lysophosphatidylcholine acyltransferase 3 (LPCAT3). The relationship between LPCAT3 and the efficacy of anti-PD-1 immunotherapy was verified via a clinical database and single-cell RNA sequencing (ScRNA-Seq).ResultsIn this study, we discovered that Mef induces ferroptosis. Furthermore, treatment with Mef in combination with T-cell-derived interferon-γ (IFN-γ) enhanced tumor ferroptosis and sensitized melanoma and lung cancer cells to anti-PD-1 immunotherapy. Mechanistically, Mef upregulated the expression of LPCAT3, a key gene involved in lipid peroxidation, by activating IFN-γ-induced STAT1-IRF1 signaling, and knocking down LPCAT3 impaired the induction of ferroptosis by Mef+IFN-γ. Clinically, analysis of the transcriptome and single-cell sequencing results in patients with melanoma showed that LPCAT3 expression was significantly lower in patients with melanoma than in control individuals, and LPCAT3 expression was positively correlated with the efficacy of anti-PD-1 immunotherapy.ConclusionsIn conclusion, our study demonstrated a novel mechanism by which LPCAT3 is regulated, and demonstrated that Mef is a highly promising new target that can be utilized to enhance the efficacy of anti-PD-1 immunotherapy.
Celastrol ameliorates lupus by promoting apoptosis of autoimmune T cells and preventing autoimmune response in MRL/lpr mice
Authors: Xie Tianhong , Rui Hongliang , Liu Huiqiang , Liu Xin , Liu Xiang , Li Ping 
Published: March 2024

ObjectiveCelastrol is a bioactive constituent extracted fromTripterygium wilfordii(thunder god vine). It has been demonstrated to have a therapeutic effect on experimental disease models for chronic inflammatory and immune disorders. In the present study, we investigated whether and how celastrol exerts a regulatory effect on the autoimmune response in MRL/lpr mice.MethodsWe performed an in vivo study to determine the therapeutic effects of celastrol in MRL/lpr mice and then further investigated the underlying mechanism of celastrol in the regulation of the autoimmune response in MRL/lpr mice.ResultsCelastrol showed a therapeutic effect in MRL/lpr mice by preventing the enlargement of the spleen and lymph nodes, alleviating renal injury, and reducing the levels of ANA and anti-double-stranded DNA antibodies. Furthermore, celastrol suppressed the in vivo inflammatory response in MRL/lpr mice by reducing the serum levels of multiple cytokines, including interleukin (IL)-6, tumour necrosis factor (TNF) and interferon (IFN)-γ, and the production of multiple antibody subsets, including total IgG, IgG1and IgG2b. In vitro, celastrol reduced anti-CD3 antibody stimulation-induced T helper 1 and TNF-producing cells in CD4+ T cells of MRL/lpr mice. In addition, celastrol significantly affected B cell differentiation and prevented the generation of plasma cells from B cells in MRL/lpr mice by reducing the frequency of activated and germinal centre B cells. Celastrol treatment also affected T cell differentiation and significantly reduced central memory T cell frequencies in MRL/lpr mice. Importantly, celastrol treatment specifically promoted apoptosis of CD138+ but not CD138− T cells to suppress autoimmune T cell accumulation in MRL/lpr mice.ConclusionsCelastrol exerted therapeutic effects on lupus by specifically promoting apoptosis of autoimmune T cells and preventing the progression of autoimmune response.