bluuebunny/crossref_metadata_2025_split huggingface dataset:
P05 Identifying novel drug targets of the ESKAPE pathogen Pseudomonas aeruginosa
Authors: Scott Ben , Wilkinson Barrie 
Published: January 2024

Abstract
The Gram-negative ESKAPE pathogen Pseudomonas aeruginosa is currently listed top of the priority one pathogens by the WHO that require urgent research and development of new antimicrobials. Currently, microbiologists and clinicians face an ever-growing challenge in treating MDR bacterial infections, for this, and other pathogens, using conventional antibiotics. With a limited number of antibiotics currently in clinical trials and a general stagnation in the discovery of promising antimicrobials, new drug targets are desperately needed, and recent investigations include targeting bacterial virulence factors. Targeting bacterial virulence factors should reduce the pathogenesis of an organism, slow its infection progression and prevent vital virulence processes such as biofilm formation as well as potentially increasing a strain’s susceptibility to antibiotics. However, given the incredible diversity of bacteria, virulence mechanisms vary massively, meaning that identifying a broad-spectrum virulence target presents a major challenge. This important point has brought researchers to a fascinating group of enzymes that are ubiquitous in nature, and possess a plethora of biological roles, including acting as virulence factors. The macrophage infectivity potentiators (Mips) belong to the ubiquitous FK506 binding protein (FKBPs) family of peptidyl-prolyl cis/trans isomerases (PPIases). FKBPs are found in all bacteria serving as general house-keeping proteins involved in protein folding and chaperoning. However, a small subset has been identified as virulence proteins. Mips have been characterized in several Gram-negative pathogens including Legionella pneumophila and Burkholderia pseudomallei and were shown to be essential for invasion of macrophages, both in vitro and in murine-infection models, and for other virulence determinants. Pseudomonas aeruginosa also possess three Mip virulence factors, PaMip1, PaMip2 and PaMip3, which are required for the full virulence of P. aeruginosa in in vivo and ex vivo models. Virulence can be addressed in a pharmacological manner using bacterial natural products.
P07 Antimicrobial stewardship in Ireland 2009–22: a scoping review
Authors: Barry Fiona , Smiddy Maura , Fitzgerald Tony , O’Reilly Eilis J , Murphy Olive 
Published: January 2024

Abstract

Objectives
The aim of this scoping review is to examine the current literature to evaluate progress related to the implementation of the Strategy for the Control of Antimicrobial Resistance in Ireland (SARI) Hospital Antimicrobial Stewardship (AMS) Working Group guidance (2009) on antimicrobial stewardship in hospitals in Ireland.

Methods
Systematic searches were carried out on four electronic databases (PubMed, CINAHL, Embase, Web of Science) and five targeted websites for grey literature sources. Titles and abstracts were screened independently by two reviewers. The remaining full-text publications were reviewed by all authors. Studies were mapped into at least one of four categories defined by recommendation headings from the SARI Hospital Antimicrobial Stewardship Working Group guidance: (A) structure and organization of AMS; (B) roles and responsibilities for prescribers; (C) antimicrobial stewardship interventions; (D) recommendations for non-acute residential healthcare institutions.

Results
The search yielded 545 peer reviewed papers for screening of which 35 were included and 327 grey reports of which 26 were included. Most articles were mapped to (C) antimicrobial stewardship interventions, with the least number mapped to (A) structure and organization of AMS. The most consistent findings in (C) were numerous implementation challenges requiring commitment by hospital leadership to provide human and financial resources, need for improved diagnostic capacity, and educational pathways for prescribers, pharmacists, nurses and patients. The findings in (A) included inadequate staffing across hospitals to implement stewardship programmes (regardless of hospital acuity) and investment required for information and communication technology resources to further support AMS and infection prevention and control.

Conclusions
There has been progress on AMS over the last 20 years and implementation remains a significant challenge. Clear identification of AMS programme management, use of data, education and communication need to be considered for the success of future implementation in all healthcare settings.
P14 Study of Prescribing patterns and Effectiveness of Ceftolozane/Tazobactam Real-world Analysis (SPECTRA): results from a multinational, multicentre observational study
Authors: Soriano Alejandro , Puzniak Laura , Paterson David L , Thalhalmmer Florian , Kluge Stefan , Viale Pierluigi , Watanabe Alexandre H , Obi Engels N , Kaul Sunny 
Published: January 2024

Abstract

Background
Ceftolozane/tazobactam (C/T) has demonstrated efficacy to treat complicated intra-abdominal infections (cIAI), complicated urinary tract infections (cUTI) and hospital acquired bacterial and ventilator-associated bacterial pneumonia. However, physicians, providers, and other stakeholders including payers want broader real-world evidence to inform clinical decisions and optimize healthcare resource use.

Methods
SPECTRA is a multinational, multicentre, retrospective, inpatient, observational study of patients treated with C/T in Australia, Austria, Germany, Italy, Mexico, Spain and the UK. Adult inpatients treated with ≥48 h of C/T were included. Demographics, clinical characteristics, treatment management patterns, and outcomes were analysed.

Results
There were 687 patients from 38 participating hospitals in 7 countries. The average age was 57.6 years (SD ±17.3), and most were male (456, 66.4%). The majority had at least one comorbidity (563, 82.0%), with the most common being heart disease (208, 30.3%), immunocompromised state (207, 30.1%) and chronic pulmonary disease (195, 28.4%). The most common indications were pneumonia (204, 29.7%), sepsis (147, 21.4%) and cIAI (106, 15.4%); 162 (23.6%) had multiple sites of infection and 245 (35.7%) were polymicrobial infections. Median C/T treatment was 12.0 days (IQR 11.0). Half of the patients were admitted to the ICU (343, 49.9%), 43.4% of which was related to the infection. Clinical success was 66.1%. All-cause in-hospital mortality was 22.0% with 8.7% being infection related. The 30 day all-cause readmission was 9.8% and 4.7% were infection related.

Conclusions
C/T was used to treat infections among critically ill patients and for multi-source, polymicrobial infections. Despite the complexity of the patients in this real-world analysis, most C/T patients had beneficial outcomes that are similar to results of controlled clinical trials.
P20 Clinical metagenomics from cell-free DNA: overview and lessons learned from 4 years as a clinical metagenomics provider
Authors: Klaften Matthias , Neder Ulrike , Becher Johannes , Holzem Rafael , Clanzett Sebastian , Mazzitelli Sonia , Hennig René , Gil-Farina Irene , Unsleber Sandra , Grumaz Silke 
Published: January 2024

Abstract

Background
Clinical metagenomics emerges more and more from academic research to clinical practice. Here, we share an overview of the field of clinical metagenomics on cell-free DNA found in the blood of patients with severe infections and share a few learning points regarding the implementation as a routine lab service and CE-IVD marked software running in the cloud.

Methods
We use next-generation sequencing of cell-free DNA to digitally determine relevant pathogens from patients with systemic infections in blood and other bodily fluids using our CE-IVD marked DISQVER diagnostic platform. Until now we have collected microbial data from several thousand samples within 4 years of routine service.

Results
The set up of the DISQVER test is within the regulatory framework of CE-IVD marking of software as a service (SaaS) and ISO 13485 accreditation. This brings practical implications on database quality, software lock-in/development/testing, change and risk management, technical documentation, requiring substantial resources. Also the wetlab process runs within tightly defined and controlled QM boundaries, pre-set by extensive analytical validations. We clinically validated our test for pathogen identification from blood within 8 clinical trials for intensive care medicine, haematology and coinfection in COVID-19, showing 2- to 3-fold higher identification rates for pathogens in comparison to standard of care blood culture. Furthermore, several case reports/ case series from different clinical backgrounds, frequently with difficult to diagnose pathogens, have been published. From the analysis of our routine processes with several thousand samples, we could show that the turn-around time of our mNGS process is very fast and can detect more species than blood culture. In particular, the relatively high proportion of fungi and dsDNA viruses indicates superiority of the method compared with the standard diagnostic pathway.

Conclusions
To bridge the gap between academic research and clinical implementation, many aspects of regulatory, technical and data protection requirements need to be addressed. Within the timeframe of commercial availability DISQVER from cell-free DNA found in the blood of infected patients is increasingly becoming a useful tool for infection diagnostics.
Long-Read DNA and RNA Sequencing to Streamline Clinical Genetic Testing and Reduce Barriers to Comprehensive Genetic Testing
Authors: Damaraju Nikhita , Miller Angela L , Miller Danny E 
Published: January 2024

Abstract

Background
Obtaining a precise molecular diagnosis through clinical genetic testing provides information about disease prognosis or progression, allows accurate counseling about recurrence risk, and empowers individuals to benefit from precision therapies or take part in N-of-1 trials. Unfortunately, more than half of individuals with a suspected Mendelian condition remain undiagnosed after a comprehensive clinical evaluation, and the results of any individual clinical genetic test ordered during a typical evaluation may take weeks or months to return. Furthermore, commonly used technologies, such as short-read sequencing, are limited in the types of disease-causing variation they can identify. New technologies, such as long-read sequencing (LRS), are poised to solve these problems.

Content
Recent technical advances have improved accuracy, increased throughput, and decreased the costs of commercially available LRS technologies. This has resolved many historical concerns about the use of LRS in the clinical environment and opened the door to widespread clinical adoption of LRS. Here, we review LRS technology, how it has been used in the research setting to clarify complex variants or identify disease-causing variation missed by prior clinical testing, and how it may be used clinically in the near future.

Summary
LRS is unique in that, as a single data source, it has the potential to replace nearly every other clinical genetic test offered today. When analyzed in a stepwise fashion, LRS will simplify laboratory processes, reduce barriers to comprehensive genetic testing, increase the rate of genetic diagnoses, and shorten the amount of time required to make a molecular diagnosis.
Aging effects on osteoclast progenitor dynamics affect variability in bone turnover via feedback regulation
Authors: Kim Young Kwan , Kameo Yoshitaka , Tanaka Sakae , Adachi Taiji 
Published: January 2024

Abstract
Bone turnover markers (BTMs) are commonly used in osteoporosis treatment as indicators of cell activities of bone-resorbing osteoclasts and bone-forming osteoblasts. The wide variability in their values due to multiple factors, such as aging and diseases, makes it difficult for physicians to utilize them for clinical decision-making. The progenitors of osteoclasts and osteoblasts are indispensable for a comprehensive interpretation of the variability in BTM values because these upstream progenitors strongly regulate the downstream cell activities of bone turnover. However, understanding the complex interactions among the multiple populations of bone cells is challenging. In this study, we aimed to gain a fundamental understanding of the mechanism by which the progenitor dynamics affect the variability in bone turnover through in silico experiments by exploring the cell dynamics with aging effects on osteoporosis. Negative feedback control driven by the consumptive loss of progenitors prevents rapid bone loss due to excessive bone turnover, and through feedback regulation, aging effects on osteoclast differentiation and osteoclast progenitor proliferation cause variability in the osteoclast and osteoblast activity balance and its temporal transition. By expressing the variability in the bone turnover status, our model describes the individualities of patients based on their clinical backgrounds. Therefore, our model could play a powerful role in assisting tailored treatment and has the potential to resolve the various health problems associated with osteoporosis worldwide.
The Nature and Purpose of Public Dissections in Early Modern London
Authors: Murel Jacob 
Published: January 2024

Abstract
Modern scholarship on the early modern European anatomy theater has long argued that public dissections were theatrical, carnivalesque affairs characterized by viewers’ fascination with the material exposure of the dissected body. This essay builds from the recent work on early modern public dissections to argue against such monolithic presentations of the early modern anatomy. To this end, the essay examines three principal source materials connected with public dissections in early modern London to more specifically argue that public dissections in sixteenth- and seventeenth-century London were solemn events focused on promoting the status of London’s barber-surgeons’ guild, the Royal College of Physicians, and the education and knowledge of their respective members. In this regard, the essay further suggests that there was no single, dominant perception of dissection and anatomy at the time, but that dissection was utilized as a tool for different individual, occupational, and institutional purposes.
Allelic reprogramming of chromatin states in human early embryos
Authors: Yuan Shenli , Gao Lei , Tao Wenrong , Zhan Jianhong , Lu Gang , Zhang Jingye , Zhang Chuanxin , Yi Lizhi , Liu Zhenbo , Hou Zhenzhen , Dai Min , Zhao Han , Chen Zi-Jiang , Liu Jiang , Wu Keliang 
Published: January 2024

Abstract
The reprogramming of parental epigenomes in human early embryos remains elusive. To what extent the characteristics of parental epigenomes are conserved between humans and mice is currently unknown. Here, we mapped parental haploid epigenomes using human parthenogenetic and androgenetic embryos. Human embryos have a larger portion of genome with parentally specific epigenetic states than mouse embryos. The allelic patterns of epigenetic states for orthologous regions are not conserved between humans and mice. Nevertheless, it is conserved that maternal DNA methylation and paternal H3K27me3 are associated with the repression of two alleles in humans and mice. In addition, for DNA-methylation-dependent imprinting, we report 19 novel imprinted genes and their associated germline differentially methylated regions. Unlike in mice, H3K27me3-dependent imprinting is not observed in human early embryos. Collectively, allele-specific epigenomic reprogramming is different in humans and mice.
First-in-Human Phase I Study of Minnelide in Patients With Advanced Gastrointestinal Cancers: Safety, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity
Authors: Borazanci Erkut , Saluja Ashok , Gockerman Jon , Velagapudi Mohana , Korn Ronald , Von Hoff Daniel , Greeno Ed 
Published: January 2024

Abstract

Background
Minnelide is a water-soluble prodrug of triptolide. Triptolide is an anticancer agent that targets cancer resistance through several mechanisms. Minnelide was evaluated in a phase I study in patients with advanced GI carcinomas to establish the safety, pharmacodynamic, antitumor activity, and recommended phase II dose (RP2D).

Patients and Methods
Patients with refractory GI carcinoma and with measurable disease on CT scan were eligible. The study used a 3 + 3 dose-escalation scheme. Due to neutropenia toxicity, 2 dosing schedules were evaluated to determine the RP2D for future studies. Response was assessed using RECIST 1.1 and Choi criteria. Minnelide and triptolide PK were evaluated. Patients who completed the first 28-day treatment cycle without DLTs continued treatment until disease progression or unacceptable toxicity.

Results
Forty-five patients were enrolled (23 pancreatic cancer, 10 colorectal, and the remaining 9 had other GI tumors); 42 patients received at least one dose of Minnelide. Grade ≥ 3 toxicities occurred in 69% of patients, most common neutropenia (38%). 2 patients with severe cerebellar toxicity who had a 2-fold higher triptolide concentration than other participants. ORR was 4%; the disease control rate (DCR) was 54% (15/28). Choi criteria demonstrated a decrease in average tumor density in 57% (16/28) patients.

Conclusions
This first-in-human, phase I clinical study identified a dose and schedule of Minnelide in patients with refractory GI cancers. The primary toxicity experienced was hematologic. Evidence of efficacy of Minnelide treatment in this group of patients was observed. The DCR ranged from ~2 to 6 months in 14/28 (50%) of evaluable patients. Studies in monotherapy and combination treatments are underway.
Aberrant Lipid Metabolic Signatures in Acute Myeloid Leukemia
Authors: Singh Pooja , Murali Roopak , Shanmugam Sri Gayathri , Thomas Steve , Scott Julius , Warrier Sudha , Arfuso Frank , Dharmarajan Arun , Gandhirajan Rajesh Kumar 
Published: January 2024

Abstract
Leukemogenesis is a complex process that involves multiple stages of mutation in either hematopoietic stem or progenitor cells, leading to cancer development over time. Acute myeloid leukemia (AML) is an aggressive malignancy that affects myeloid cells. The major disease burden is caused by immature blast cells, which are eliminated using conventional chemotherapies. Unfortunately, relapse is a leading cause of death in AML patients, with 30%-80% experiencing it within 2 years of initial treatment. The dominant cause of relapse in leukemia is the presence of therapy-resistant leukemic stem cells (LSCs). These cells express genes related to stemness that are frequently difficult to eradicate and tend to survive standard treatments. Studies have demonstrated that by targeting the metabolic pathways of LSCs, it is possible to improve outcomes and extend the survival of those afflicted by leukemia. The overwhelming evidence suggests that lipid metabolism is reprogrammed in LSCs, leading to an increase in fatty acid uptake and de novo lipogenesis. Genes regulating this process also play a crucial role in therapy evasion. In this concise review, we summarize the lipid metabolism in normal hematopoietic cells, AML blast cells, and AML LSCs. We also compare the lipid metabolic signatures in de novo versus therapy-resistant AML blast and LSCs. We further discuss the metabolic switches, cellular crosstalk, potential targets, and inhibitors of lipid metabolism that could alleviate treatment resistance and relapse.
Can the gut microbiome inform the effects of omega-3 fatty acid supplementation trials on cognition?
Authors: Kerman Bilal E. , Self Wade , Yassine Hussein N. 
Published: January 2024

Purpose of review
Most omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation clinical trials report inconsistent or null findings on measures of cognition or Alzheimer's disease (AD) with a relatively large variability in the response to n-3 PUFA supplementation. The purpose of this review is to identify whether the gut microbiome together with the metabolome can provide critical insights to understand this heterogeneity in the response to n-3 PUFA supplementation.

Recent findings
A Western diet with high saturated fat and omega-6 fatty acid content, obesity, and lack of exercise puts strain on the gut microbiome resulting in imbalance, dysbiosis, reduced bacterial diversity, and increased abundance of the pro-inflammatory taxa. A plant-based diet has beneficial effects on the gut microbiota even when deficient in n-3 PUFAs. Human and animal studies show that increased intake of the n-3 PUFAs correlates with increased beneficial intestinal bacteria when compared to a Western diet.

Summary
The composition of the gut microbiota can help define the effects of n-3 PUFA supplementation on the brain and lead to more personalized nutritional interventions.
Tick-borne infections in children in North America
Authors: Taylor-Salmon Emma , Shapiro Eugene D. 
Published: January 2024

Purpose of review
Because both incidence and awareness of tick-borne infections is increasing, review of major infections and recent advances related to their diagnosis and management is important.

Recent findings
A new algorithm, termed modified two-tier testing, for testing for antibodies to Borrelia burgdorferi, the cause of Lyme disease, has been approved and may replace traditional two-tier testing. In addition, doxycycline is now acceptable to use for treatment of and/or prophylaxis for Lyme disease for up to 21 days in children of any age. Borrelia miyamotoi, a bacterium in the relapsing fever type of Borrelia, is the first of this type of Borrelia that is transmitted by hard-bodied ticks such as Ixodes scapularis.

Summary
Awareness of these infections and advances in their diagnosis and treatment is important to assure the best outcomes for affected patients. Table 1 contains a summary of infections discussed.
Investigation of the effects of thymoquinone (TQ) and polyvinylpyrrolidone (PVP) on the motility, viability, and chromatin status of sperm in normozoospermic semen samples
Authors: Khosravi Tayebeh , Vahid Dastjerdi Amir Reza , Eftekhari Sayed Amin , Golshan Iranpour Farhad 
Published: January 2024

Objective:
Adverse effects of polyvinylpyrrolidone (PVP) on sperm membrane and chromatin have been proven in many studies. Among the natural products proposed as an alternative for PVP, thymoquinone (TQ)-a major constituent of Nigella sativa plant- has been suggested as a potential natural spermostasis. Therefore, this study aimed to compare the effects of TQ with PVP for sperms motility, survival, DNA denaturation, and DNA fragmentation in normozoospermic men (men with a normal or healthy sperm profile).

Methods:
An experimental trial was carried out on 30 normozoospermic men of the Andrology Unit of (Shahid Beheshti Hospital, Isfahan, Iran). Each washed semen samples were divided into four fractions and was randomly treated with TQ (50 μg/ml), %5 PVP, and %10 PVP (M/V) which was compared to untreated fraction (control).

Results:
There was a significant difference between the four groups in terms of motility, viability, DNA denaturation, and fragmentation (P <0.05). TQ caused sperm immobility, while 5% PVP and 10% PVP decreased (98 and 99%, respectively) sperm motility compared to control. TQ did not affect sperm viability compared to the control group, but PVP decreased it. Besides, TQ did not affect DNA denaturation and fragmentation, but PVP increased it.

Conclusion:
TQ could be used as an alternative natural spermostasis with less adverse effects rather than PVP which causes more efficient immobilization and isolation of individual sperm cells.