bluuebunny/crossref_metadata_2025 huggingface dataset:
Validation of a simplified HPV genotyping assay designed for cervical screening in low-resource settings
Authors: Desai Kanan T. , Ajenifuja Kayode O. , Adepiti Clement A. , Inturrisi Federica , Dagnall Casey , Hoffman Amanda C. , Egemen Didem , Gage Julia C. , Wentzensen Nicolas , de Sanjose Silvia , Schiffman Mark
Published: December 2024

Human papillomavirus (HPV) genotype predicts cervical cancer risk, and genotyping could help guide the management of HPV positives as part of cervical screening. An isothermal amplification HPV extended genotyping test (ScreenFire HPV RS assay) can assay up to 96 samples/controls in 1 hour plus preparation time. A novel format with pre-aliquoted reagents and an anti-contamination component (Zebra BioDome) could simplify the HPV testing process and reduce the chances of post-amplification contamination. We validated the Zebra BioDome formulation prior to its clinical use. Residual provider-collected cervical samples (
n
= 450) from a population-based study in rural Nigeria were retested with ScreenFire, once using the standard assay version (liquid reagents combined onsite) and twice with Zebra BioDome. HPV results with adequate DNA (
N
= 427) were analyzed channel-by-channel and using the cervical cancer risk-based hierarchy of HPV type channels (HPV16, else 18/45, else 31/33/35/52/58, else 39/51/56/59/68, else high-risk HPV negative) to evaluate Zebra BioDome repeatability and accuracy against the standard version. Zebra BioDome reduced the number of pipetting steps to run the ScreenFire HPV assay. Following amplification, the BioDome material formed a sealant layer above the reaction components. Zebra BioDome had excellent repeatability and agreement with the standard version, both at the channel-specific analysis (positive percent agreement between 88.4% [HPV39/51/56/59/68] and 100% [HPV16]; negative percent agreement between 97.8% [HPV31/33/35/52/58] and 100% [HPV39/51/56/59/68]) and hierarchical analysis (overall agreement 97.2%). The assay version utilizing Zebra BioDome performed similarly to the previously validated standard version of the ScreenFire HPV assay and is now undergoing field evaluation. This solution has the potential to reduce assay preparation time and risk of contamination, providing a simpler, low-cost, near-point-of-care HPV testing and extended genotyping solution for cervical screening in lower-resource settings. The potential application of Zebra BioDome technology to other PCR assays should be considered.

IMPORTANCE

This work validates a novel pre-packed formulation for the ScreenFire human papillomavirus (HPV) assay, which has the potential to simplify the HPV testing process and to reduce the chances of post-amplification contamination, providing a simpler, low-cost, near-point-of-care HPV testing, and extended genotyping solution for cervical screening in resource-limited settings as part of the ultimate public health goal to accelerate cervical cancer prevention. This technology can also have broad applications for other DNA amplification assays beyond HPV.
Delivery determinants of an
Acinetobacter baumannii
type VI secretion system bifunctional peptidoglycan hydrolase
Authors: Bezkorovayna Valeriya , Hayes Brooke K. , Gillett Francesca N. , Wright Amy , Roper David I. , Harper Marina , McGowan Sheena , Boyce John D.
Published: December 2024

Acinetobacter baumannii
is a Gram-negative opportunistic pathogen and is a common cause of nosocomial infections. The increasing development of antibiotic resistance in this organism is a global health concern. The
A. baumannii
clinical isolate AB307-0294 produces a type VI secretion system (T6SS) that delivers three antibacterial effector proteins that give this strain a competitive advantage against other bacteria in polymicrobial environments. Each effector, Tse15, Tde16, and Tae17, is delivered
via
a non-covalent interaction with a specific T6SS VgrG protein (VgrG15, VgrG16, and VgrG17, respectively). Here we define the regions of interaction between Tae17 and its cognate delivery protein VgrG17 and identify that amino acids G1069 and W1075 in VgrG17 are essential for Tae17 delivery
via
the T6SS, the first time such specific delivery determinants of T6SS cargo effectors have been defined. Furthermore, we determine that the Tae17 effector is a multidomain, bifunctional, peptidoglycan-degrading enzyme that has both amidase activity, which targets the sugar-peptide bonds, and lytic transglycosylase activity, which targets the peptidoglycan sugar backbone. Moreover, we show that the Tae17 transglycosylase activity is more important than amidase activity for the killing of
Escherichia coli
. This study provides molecular insight into how the T6SS allows
A. baumannii
strains to gain dominance in polymicrobial communities and thus improve their chances of survival and transmission.

IMPORTANCE

We have shown that the
Acinetobacter baumannii
T6SS effector Tae17 is a modular, bifunctional, peptidoglycan-degrading enzyme that has both lytic transglycosylase and amidase activities. Both activities contribute to the ability to degrade peptidoglycan, but the transglycosylase activity was more important for the killing of
Escherichia coli
. We have defined the specific regions of Tae17 and its cognate delivery protein VgrG17 that are necessary for the non-covalent interactions and, for the first time, identified specific amino acids essential for T6SS cargo effector delivery. This work contributes to our molecular understanding of bacterial competition strategies in polymicrobial environments and may provide a window to design new therapeutic approaches for combating infection by
A. baumannii
.
Transposon-sequencing across multiple
Mycobacterium abscessus
isolates reveals significant functional genomic diversity among strains
Authors: Akusobi Chidiebere , Choudhery Sanjeevani , Benghomari Bouchra S. , Wolf Ian D. , Singhvi Shreya , Ioerger Thomas R. , Rubin Eric J.
Published: December 2024

Mycobacterium abscessus (Mab
) is a clinically significant pathogen and a highly genetically diverse species due to its large accessory genome. The functional consequence of this diversity remains unknown mainly because, to date, functional genomic studies in
Mab
have been primarily performed on reference strains. Given the growing public health threat of
Mab
infections, understanding the functional genomic differences among
Mab
clinical isolates can provide more insight into how its genetic diversity influences gene essentiality, clinically relevant phenotypes, and importantly, potential drug targets. To determine the functional genomic diversity among
Mab
strains, we conducted transposon-sequencing (TnSeq) on 21 genetically diverse clinical isolates, including 15
M
.
abscessus
subsp.
abscessus
isolates and 6
M
.
abscessus
subsp.
massiliense
isolates, cataloging all the essential and non-essential genes in each strain. Pan-genome analysis revealed a core set of 3,845 genes and a large accessory genome of 11,507. We identified 259 core essential genes across the 21 clinical isolates and 425 differentially required genes, representing ~10% of the
Mab
core genome. We also identified genes whose requirements were subspecies, lineage, and isolate-specific. Finally, by correlating TnSeq profiles, we identified 19 previously uncharacterized genetic networks in
Mab
. Altogether, we find that
Mab
clinical isolates are not only genetically diverse but functionally diverse as well.

IMPORTANCE

This study investigates the genetic diversity of
Mycobacterium abscessus
(
Mab
), a bacteria known for causing difficult-to-treat infections. Researchers performed transposon-sequencing (TnSeq) on 21 different clinical isolates of
Mab
to identify essential and non-essential genes in each strain. Through this analysis, they identified core genes required for growth across all strains. Interestingly, they also identified genes whose requirement for growth or “essentiality” were subspecies, lineage, and isolate-specific. This study reveals that
Mab’
s genetic diversity translates into significant functional differences among clinical isolates. Insights from this paper lay essential groundwork for future studies exploring the biological and clinical implications of genetic diversity in
Mab
clinical isolates. Understanding this diversity could guide targeted therapies and offer new insights into managing infections caused by
Mab
, a growing public health concern.
Complete genome sequence of
Prevotella spp
. GTC17253 isolated from equine in Japan
Authors: Hayashi Masahiro , Yonetamari Jun , Muto Yoshinori , Niwa Hidekazu , Tanaka Kaori
Published: December 2024

Prevotella
is one of the major clinical anaerobic bacteria belonging to the family
Prevotellaceae
. Herein, we report the complete genome sequence of a clinical isolate of new
Prevotella
species obtained from equine bronchial lavage fluid in Japan. The genome comprised a circular chromosome with a length of 2,948,037 bp.
Metagenome-assembled genomes from irradiated human dental plaque
Authors: Filho Romualdo M. , Mengoni Claudia , Bruno Julia S. , Fregnani Eduardo R. , Segata Nicola , Camargo Anamaria A. , Heidrich Vitor
Published: December 2024

We provide 309 quality-controlled bacterial metagenome-assembled genomes recovered from supragingival plaque metagenomes. Samples were collected from head and neck cancer patients following radiotherapy, so the recovered genomes can be useful to investigate the effects of oral cavity irradiation on oral microbiome members.
Complete genome sequence of
Schlesneria
sp. strain DSM 10557, isolated from the leachate of an industrial compost heap
Authors: Friedrich Ines , Klassen Anna , Poehlein Anja , Hertel Robert , Daniel Rolf
Published: December 2024

We present the complete genome of
Schlesneria
sp. DSM 10557, isolated from compost heap leakage (leachate). The genome consists of a single chromosome (7,067,087 bp) with a GC content of 56.48%. Genome-based phylogenetic analysis revealed that strain DSM 10557 is most closely related to members of the genus
Schlesneria
.
Two complete genome sequences of antimonite-oxidizing bacteria,
Mesorhizobium
sp. strain ANAO-SY3R2 and
Hydrogenophaga
sp. strain ANAO-22, isolated from mine tailing soil
Authors: Yamashita Yoriko , Hamamura Natsuko
Published: December 2024

We report the complete genome sequences of two antimony-oxidizing bacteria,
Mesorhizobium
sp. strain ANAO-SY3R2, comprising one chromosome (4.3 Mbp) and four circular plasmids, and
Hydrogenophaga
sp. strain ANAO-22, comprising one chromosome (5.8 Mbp) and two circular plasmids. These genome information extend our understanding of physiological versatility of antimony-transforming microorganisms.
mRNA-LNP vaccines combined with tPA signal sequence elicit strong protective immunity against
Klebsiella pneumoniae
Authors: Huang Ting , Che Siyou , Lv Zheng , Hao Danrui , Wang Runyu , Yi Qinxuan , Mei Ling , Yuan Yang , Zou Hang , Guo Yidong , Wang Xinrong , Chu Yiwen , Zhao Kelei
Published: December 2024

Klebsiella pneumoniae
is a prominent Gram-negative and encapsulated opportunistic pathogen that causes a multitude of infections such as severe respiratory and healthcare-associated infections. Despite the widespread anti-microbial resistance and the high mortality rate, currently, no clinically vaccine is approved for battling
K. pneumoniae
. To date, messenger RNA (mRNA) vaccine is one of the most advancing technologies and are extensively investigated for viral infection, while infrequently applied for prevention of bacterial infections. In the present study, we aim to construct a new mRNA vaccine encoding YidR or combining with a tissue plasminogen activator signal sequence for preventing
K. pneumoniae
infection. Adaptive immunity was determined in mRNA vaccines-immunized mice and the protective effects of mRNA vaccines were evaluated in
K. pneumoniae
infected models. The results showed that lipid nanoparticle (LNP)-YidR-mRNA vaccine was produced with good morphology, high the encapsulation efficiency, and the specific antigen was highly expressed in cells
in vitro
. In addition, immunization with either LNP-YidR or LNP-YidR-SP elicited a Th1-biased immune response, reduced bacterial load, and provided broad protection in the lung infection models. Importantly, the LNP-YidR-SP mRNA vaccine induced strong adaptive humoral and cellular immunity and increased the survivability of mice compared to the other groups. Our findings serve as a focal point for developing a potential mRNA vaccine against
K. pneumoniae
, indicating the potential of mRNA vaccines for improving next-generation bacterial vaccine.

IMPORTANCE

K. pneumoniae
is a notorious and clinical bacterium that is evolving in community-acquired and nosocomial settings. This opportunistic pathogen causes severe infectious diseases, including urinary tract infection and pneumonia, and causes a concerning global public burden. Despite efforts having been created to develop different types of
K. pneumoniae
vaccines, there is no licensed vaccine for preventing
K. pneumoniae
infection. Therefore, to develop an effective tactic is essential to combat
K. pneumoniae
-caused diseases. This study provides a novel vaccine strategy against
K. pneumoniae
and a potent platform to elicit high levels of humoral and cell-meditated immunity.
Clinical and microbiological analyses of colistin-resistant strains among carbapenem-resistant
Enterobacter cloacae
complex clinical isolates
Authors: Yang Jinyoung , Baek Jin Yang , Ko Jae-Hoon , Huh Kyungmin , Cho Sun Young , Chung Doo Ryeon , Peck Kyong Ran , Huh Hee Jae , Ko Kwan Soo , Kang Cheol-In
Published: December 2024

Carbapenem-resistant
Enterobacter cloacae
complex (CR-ECC), which is rapidly increasing as the cause of nosocomial infections, has limited treatment options. The aim of this study is to investigate the microbiological and clinical traits and molecular epidemiology of isolates of CR-ECC and provide guidance for antibiotic selection in clinical practice. Clinical CR-ECC isolates (ertapenem MIC ≥ 2 mg/L) were collected from 2021 to 2022. Species identification was performed using
hsp60
gene analysis, and antibiotic susceptibility tests were conducted by broth microdilution. The clinical characteristics of patients with CR-ECC isolates were retrospectively analyzed. Among the 108 CR-ECC isolates, 25 (23.2%) were non-susceptible to colistin, with colistin susceptibility being higher in
Enterobacter hormaechei
compared to non-
E
.
hormaechei
isolates (
P
< 0.0001). Of the 108 CR-ECC isolates, 9 (8.3%) produced carbapenemases, and only 6 of the 22 colistin-resistant CR-ECC isolates (27.3%) harbored the
mcr
gene. A total of 73 sequence types (STs), including 28 newly identified STs, were detected, demonstrating significant clonal diversity. The most common ST was ST74, known for its high prevalence and association with carbapenem resistance, with 77.8% identified as
E. hormaechei
subsp.
hoffmannii. E. hormaechei
was more common in the colistin-susceptible group than in the non-susceptible group (88.0% vs 37.5%,
P
< 0.0001), and
E. hormaechei
was the only protective factor for colistin resistance (HR 0.089, CI 0.030–0.261,
P
< 0.001). Although colistin resistance of CR-ECC is high, colistin could be administered safely to
E. hormaechei
. It is imperative to maintain ongoing surveillance and to further research on CR-ECC.

IMPORTANCE

Although new antibiotics are being developed, there are still limited options for treating carbapenem-resistant
Enterobacter cloacae
complex (CR-ECC) in regions where their use is restricted. The resistance level to one of these options, colistin, was investigated using bacteria isolated from clinical samples. In clinical practice, colistin is frequently administered empirically without susceptibility testing. However, this study suggests that colistin can be safely administered to certain species such as
Enterobacter hormaechei
within the CR-ECC.
How does gut microbiota affect the vaginitis axis? The mediating role of plasma metabolites
Authors: Li Mo , Zhang Qianyu , Wu Tong , Ma Lanfang , Hu Dianxing , Yuan Zixuan , Wang Shixuan , Luo Aiyue , Zhang Jinjin
Published: December 2024

Vaginitis is the most common problem afflicting women of childbearing age. However, the underlying etiological factors remain poorly understood, leading to recurrent vaginitis and constraining clinical management. Here, we explored whether the gut microbiota influences the risk of vaginitis by performing a two-sample Mendelian randomization analysis using the largest genome-wide association studies to date. Four gut taxa in genus levels were identified related to vaginitis:
Candidatus Soleaferrea
(inverse-variance weighted [IVW] odds ratio [OR] = 2.20,
P
= 0.026),
Dialister
(IVW OR = 2.62,
P
= 0.029),
Lachnospiraceae UCG-008
(IVW OR = 0.41,
P
= 0.0067), and
Ruminiclostridium 5
(IVW OR = 0.080,
P
= 1.42 × 10
−5
). We further explored the mediation effect of the plasma metabolites by two-step Mendelian randomization (MR) and multivariable MR. The findings indicated that 3-phosphoglycerate and lysophosphatidylcholine antagonistically act against the two identified risk factors (
Candidatus Soleaferrea
and
Dialister
, respectively) of vaginitis, thus appearing to confer protective effects against vaginitis. On the contrary, the elevation of arachidonate/pyruvate ratio and reduction in palmitate/myristate ratio mediated the protective effects of
Lachnospiraceae UCG-008
against vaginitis. These findings support a potential causal role for gut microbiota in the development of vaginitis, thereby providing potential strategies for its prevention and intervention.

IMPORTANCE

Vaginitis is the most common problem afflicting women of childbearing age. However, the underlying etiological factors remain poorly understood, leading to recurrent vaginitis and constraining clinical management. Besides, the human gut and vagina are important organs that are both colonized by thousands of microorganisms impacting human physiology and health. Whether there is an interplay between the microecosystems is intriguing and unclear. This study evaluated the potential causal relationship between the gut microbiota and vaginitis and suggested that specific types of gut microbiota may be the potential risk or protective factors of vaginitis mediated or suppressed by certain plasma metabolites. These findings provide treatment insights for vaginitis.
Cadmium isotope constraints on primary productivity and environmental perturbations across the Late Ordovician mass extinction
Authors: Zhao He , Poulton Simon W. , Wang Xiangdong , Sun Jun , Huang Yuangeng , Hao Fang
Published: December 2024

The Late Ordovician mass extinction (LOME) constitutes the second largest of the “Big Five” extinctions of the Phanerozoic. The LOME comprised two extinction pulses associated with sea level changes linked to the Hirnantian glaciation. Although climate change has been implicated as a potential driver of the mass extinction, uncertainty remains as to its precise impact relative to the concurrent development of ocean anoxia. Here, we investigate the behavior of the oceanic cadmium (Cd) cycle, as a key element involved in a number of biological processes, across the LOME and into the Early Silurian. Our focus is on the Wangjiawan section in South China, which is the Global Stratotype Section and Point section marking the base of the Hirnantian Stage. We combine authigenic Cd isotope analyses (δ114Cdauth) with total organic carbon concentrations and isotopes, and major and trace element systematics, to determine the evolution of marine productivity across the LOME and to provide insight into the mass extinction and relationships between climatic and environmental change. Our δ114Cdauth data display a gradually decreasing trend from the late Katian to the Katian‒Hirnantian boundary, suggesting enhanced biological assimilation of isotopically light Cd followed by export to the sediments. This interpretation is supported by an increase in organic carbon isotope (δ13Corg) compositions, as well as a progressive decrease in P/Al ratios and increase in Corg/P ratios in the early part of the late Katian. A slight increase in Cd isotope values in the early Hirnantian was likely caused by drawdown of light Cd (as CdS) in euxinic shallower seawater settings. During glacial melting in the late Hirnantian, organic carbon burial declined, consistent with lower Cd/Al, Zn/Al, and Ni/Al ratios. However, δ114Cdauth values remain low across this interval, possibly due to an increase in the supply of isotopically light Cd from enhanced weathering and rising sea levels, as supported by elevated Al contents and chemical index of alteration (CIA) values. Elevated δ114Cdauth values subsequently occurred in the Early Silurian (Rhuddanian), alongside a decline in CIA and Al values, suggesting that the Cd sink was gradually balanced by a decline in the weathering input of Cd and lower rates of primary productivity. Our data provide new insight into the Cd cycle through the Late Ordovician to Early Silurian, and suggest that elevated marine productivity drove enhanced burial of organic matter, which likely contributed to CO2 drawdown and the initiation of the Hirnantian glaciation.
Effects of head direction during prone position on postoperative delirium in elderly patients undergoing thoracolumbar spine surgery: a study protocol for a randomised controlled trial
Authors: Zhu Jixiang , Chen Yongzhuang , Chen Yangyang , Ma Hong , Liu Fengyun , Chen Qian , Wang Fang , Chen Xuetai , Xue Zhouya , Ni Kun , Li Feng , Qian Bin
Published: December 2024

Introduction

Prone positioning with head rotation can influence cerebral haemodynamics, potentially affecting cerebral perfusion and oxygenation. Elderly patients with impaired brain perfusion and oxygenation are at an increased risk of developing postoperative delirium (POD). Despite this, few studies have explored whether head orientation during prone positioning contributes to POD in older adults, an aspect often overlooked by clinicians. This study aimed to evaluate the impact of head orientation during prone positioning on the incidence of POD in elderly patients undergoing thoracolumbar spine surgery.

Methods and analysis

This study is a single-centre, randomised, single-blind trial, with the assessors blinded to the intraoperative head position. Eligible participants are patients aged ≥65 years undergoing elective thoracolumbar spine surgery. A total of 500 patients will be randomly assigned to either the prone position with the head centred, or the prone position with the head deviated. The primary outcome is the incidence of POD, measured using the 3 min Diagnostic Interview for Confusion Assessment Method (3D-CAM) until postoperative day 5. Secondary outcomes include the severity of POD assessed by the Memorial Delirium Assessment Scale (MDAS), postoperative cognitive impairment evaluated using the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA), intraoperative regional cerebral oxygen saturation (rSO2), changes in vertebrobasilar artery and middle cerebral artery haemodynamics, and plasma levels of calcium channel-binding protein S100 subunit beta (S100B) and neuron-specific enolase (NSE).

Ethics and dissemination

Ethical approval was obtained from Yancheng No. 1 People’s Hospital Ethics Examination Committee (2023-K-120–01). The findings will be disseminated through presentations at annual conferences and publications in scientific journals.

Trial registration number

ChiCTR2300078839.
Digital supportive supervision (DiSS) of maternal health, child health and nutrition (MCHN) service delivery in Rajasthan, India: study protocol for impact evaluation and cost-effectiveness analysis
Authors: Sharda Shweta , Kshtriya Pranav , Agrawal Praween Kumar , Singh Prakash , Trakroo Ajay , Joshi Anurag , Agarwal Anil , Goyal Aarti , D'Aquino Luigi , Singh Shubhra , Singh Raghuraj , Prinja Shankar
Published: December 2024

Background

A digital supportive supervision (DiSS) tool was developed and implemented in Rajasthan, India, to enhance the coverage and quality of maternal health, child health and nutrition (MCHN) services. This study aims to assess the impact and cost-effectiveness of DiSS compared to traditional paper-based supportive supervision.

Methods and analysis

A quasi-experimental research design incorporating interrupted time series regression analysis will be employed to evaluate the impact of DiSS. Two districts from the high DiSS intensity group, defined as having at least 25% of the MCHN sessions supervised digitally, will be randomly selected as intervention districts. Two comparator districts will be selected from the low DiSS intensity group (less than 25% of MCHN sessions supervised digitally) after matching with intervention districts based on three indicators—female literacy, proportion of population belonging to scheduled caste or tribe and coverage of four antenatal care visits. District-level monthly data on the number of beneficiaries using MCHN services will be obtained from the state’s routine health management information system. Key informants involved in supervising MCHN sessions will also be interviewed to complement the quantitative findings. A mixed micro-costing methodology, incorporating top-down and bottom-up approaches, for assessing the cost of implementing supervision in either scenario. A decision model will estimate long-term health outcomes, in the form of quality-adjusted life years (QALY), in both the intervention and comparator groups. Cost-effectiveness of DiSS will be assessed by computing the incremental cost per QALY gained in the intervention versus comparator group.

Ethics and dissemination

The study has been approved by the Institute Ethics Committee of the PGIMER, Chandigarh, India (IEC No. IEC-03/2023–2671). The study results will be disseminated at research conferences and published in peer-reviewed journals.
Pathway to care, treatment and disease burden of pulmonary arterial hypertension: a real-world survey of physicians and patients in Latin America
Authors: Orozco-Levi Mauricio , Souza Rogerio , Bluro Ignacio M , Harley Julia , Hernández Oropeza Jose Luis , Lescano Adrian , Meyer Gisela , Pineda Tatiana , Ramirez Alicia , Small Mark , Valencia Angelo , Pulido Tomás
Published: December 2024

Objectives

To investigate clinical characteristics, symptom profile, testing practices, treatment patterns and quality of life (QoL) among patients with pulmonary arterial hypertension (PAH) in Latin America.

Design

Data from the Adelphi Real World PAH Disease Specific Programme, a cross-sectional survey with retrospective data collection.

Setting

University/teaching hospital, regional centres, private practices and government institutions in Argentina, Brazil, Colombia and Mexico.

Participants

246 physicians provided data for 958 patients, of which 533 patients also self-reported data.

Results

Mean (SD) patient age was 53.7 (17) years, 70% of patients were female and 79% were WHO functional class (WHO FC) I–II. Overall, 76% had undergone a right heart catheterisation, ranging from 92% in Argentina to 64% in Brazil (p<0.0001). Only 28% underwent a simplified risk assessment strategy in the past 12 months, ranging from 46% in Argentina to 16% in Brazil. Fatigue and dyspnoea on exertion were reported most commonly by physicians (37% and 53%) and patients (68% and 67%). Patient–physician agreement on symptom reporting was minimal-to-weak (kappa, 0.21–0.42). PAH-specific combination therapy varied across countries (21% Mexico, 30% Brazil, 70% Colombia and 79% Argentina, p<0.0001)). Overall, 73% of patients received a phosphodiesterase type 5 inhibitor; 52% an endothelin receptor antagonist, 15% a prostacyclin pathway agent and 11% a soluble guanylate cyclase stimulator. The mean (SD) EQ-5D (generic instrument to define quality of life)utility ranged from 0.66 (0.20) to 0.70 (0.20) across countries and the mean (SD) EQ-5D Visual Analogue Scale (VAS) was 67.0 (18.10). Lower VAS and utility scores were reported among patients with higher WHO FC (p<0.05).

Conclusions

Patients reported a high burden of PAH in terms of symptoms and QoL, particularly within higher WHO FC. Low usage of risk assessment strategies and PAH-specific combination therapy was seen in Brazil and Mexico. Further research could identify barriers to prescribing optimal treatment.
Effects of intravascular administration of mesenchymal stromal cells derived from Wharton’s Jelly of the umbilical cord on systemic immunomodulation and neuroinflammation after traumatic brain injury (TRAUMACELL): study protocol for a multicentre randomised controlled trial
Authors: Sigaut Stéphanie , Tardivon Coralie , Jacquens Alice , Bottlaender Michel , Gervais Philippe , Habert Marie-Odile , Monsel Antoine , Roquilly Antoine , Boutonnet Mathieu , Galanaud Damien , Cras Audrey , Boucher-Pillet Hélène , Florence Aline-Marie , Cavalier Ines , Menasche Philippe , Degos Vincent , Couffignal Camille
Published: December 2024

Introduction

Traumatic brain injury (TBI) is one of the leading causes of death and disability worldwide. Treatments for TBI patients are limited and none has been shown to provide prolonged and long-term neuroprotective or neurorestorative effects. A growing body of evidence suggests a link between TBI-induced neuro-inflammation and neurodegenerative post-traumatic disorders. Consequently, new therapies triggering immunomodulation and promoting neurological recovery are the subject of major research efforts. We hypothesise that repeated intravenous treatment with mesenchymal stromal cells derived from Wharton’s Jelly of the umbilical cord-derived mesenchymal stromal cells ((WJ-UC-MSC) may be associated with a significant decrease of post-TBI neuroinflammation and improvement of neurological status.

Methods and analysis

The TRAUMACELL trial is a prospective, national multicentre, phase III, superiority, double-arm comparative randomised (1:1) double-blinded clinical trial. Among patients aged between 18–50, with a severe TBI defined by a Glasgow score less than 12 (within the first 48 hours) with brain traumatic lesion on CT Scan and needing intracranial pressure monitoring, with no other significant organ trauma (abbreviated injury scale<2) and unresponsive to verbal commands after 5 days of sedation discontinuation, 68 will be randomly allocated to receive either WJ-UC-MSC solution or placebo, with three intravenous injections 1 week apart. The primary outcome is the [18F]-DPA-714 signal intensity in corpus callosum measured by dynamic positron emission tomography (PET)-MRI at 6 months after the last injection, blinded to the randomisation arm, to evaluate the post-traumatic neuro-inflammation.

Ethics and dissemination

The TRAUMACELL trial has been approved by an independent ethics committee (CPP SUD EST II) and French Medicines Agency (2023-504415-33-00) for all study centres. Participant recruitment will be starting in September 2024. Results will be published in international peer-reviewed medical journals.

Trial registration number

NCT06146062, first posted 24 November 2023

Protocol version identifier

TRAUMACELL−V.2.0_20240102
Management of uncomplicated acute appendicitis: a protocol for systematic review and network meta-analysis of randomised-controlled trials
Authors: Wang Xiaoyun , Liu Xueyu , Liu Yi , Long Lixi , Zhang Wei
Published: December 2024

Objectives

While multiple studies have shown the safety and efficacy of non-operative management, appendectomy remains the standard treatment for uncomplicated acute appendicitis (UAA). This study presents a protocol for a meta-analysis comparing antibiotic therapy, endoscopic retrograde appendicitis therapy (ERAT) and appendectomy in patients with UAA.

Methods and analysis

We will conduct a systematic search of several databases, including PubMed, Web of Science, Embase, the China National Knowledge Infrastructure and the Cochrane Library. The search will cover the full range of database records up to September 2024. Eligible studies will include randomised-controlled trials (RCTs) evaluating the efficacy of antibiotic therapy, ERAT and appendectomy for UAA. The primary outcome will be treatment success, while secondary outcomes will include major complications, hospital costs, length of stay and recurrence of appendicitis. Two independent reviewers will select studies, extract data and assess bias risk. A Bayesian approach will be used for the network meta-analysis.

Ethics and dissemination

Ethical approval is not required as the study will use data from published RCTs. The findings will be disseminated through publication in peer-reviewed journals.

PROSPERO registration number

CRD42024554427.
Barriers to medication administration error reporting in a tertiary hospital in Lebanon
Authors: Mehanna Diala , El Gerges Najwa , Chalhoub Marianne , Daou Remy
Published: December 2024

Objective

The aim of this study is to identify the key barriers that prevent medication administration errors (MAEs) from being reported by nurses in Lebanese hospitals.

Methods

A quantitative cross-sectional study was conducted at Hotel-Dieu de France Hospital using a self-administered questionnaire. A total of 275 responses were recorded and analysed using the IBM SPSS software V.23.0.

Results

Our study showed that ‘Fear’ and ‘Administrative response’ present the two main types of barriers to MAE reporting with a frequency of 62.9% and 60.7%, respectively, with more than half of our nurses confirming it (52.7%). The significant administrative barriers are: No positive feedback if medications were given correctly, too much emphasis being placed on MAE and the focus by the nursing administration on the individual rather than looking at the systems as a potential cause of the MAE whereas the significant fear barriers are the chances of suing the nurse if MAE is reported, the fear of adverse consequences of MAE reporting, the blame of nurses if something happens to the patient as a result of the MAE. No significant association was found between the barriers and demographic factors such as age, gender, experience and attending the training and orientation programmes.

Conclusion

The findings highlight the need for targeted strategies to address these types of barriers. Anonymous error reporting, fostering a culture of transparency and adopting a non-punitive reporting system are approaches that can be implemented for optimal performance improvement, enhanced safety and healthcare quality and reduced wasting of the hospitals’ financial resources.
Novel pathways for headache via neurology same day emergency care: admission avoidance, prevention of lumbar punctures and reduced length of stay in hospital
Authors: Bierrum William , Spencer Jonathan Ian , Macarimban Roberto , Shirazi Ayala , Dethabrew Agampodi-Umanda , See Isaiah , Henry Alun Marc , Schlattl Anne , Alim-Marvasti Ali-Jesus , Balaratnam Michelle , Chandratheva Arvind , Baruah Tim , Simister Robert , Haider Salman
Published: December 2024

There are various models for acute neurology services in the UK, with considerable variation in practice. Patients are often admittedunnecessarily for neurology review, leading to delay in diagnosis and treatment. Alternative models, such as the Neurology Same Day Emergency Care service (Neuro-SDEC) at University College London Hospital provide a pathway that can prevent admissions and streamline patient care. Headache is one of the commonest presenting symptoms in acute neurology.

This study compared the impact of Neuro-SDEC on the care for patients presenting with headache against the standard pathway.

A prospective audit was undertaken from November – December 2023 to evaluate all appropriate patients seen by the Neuro-SDEC service or admitted to the ward. For Neuro-SDEC patients, each case was reviewed to see whether an admission, lumbar puncture or neurology outpatient referral was avoided. For admitted patients, length of inpatient stay, time to neurology review and discharge diagnosis was recorded.

Fifty-one patients were seen by Neuro-SDEC, twenty-five of whom would have been admitted to hospital on the standard pathway. Thirty general neurology outpatient clinic referrals were prevented and 5 patients avoided a lumbar puncture. In 45% of cases, the working diagnosis changed after the patient was seen by the Neuro-SDEC team. There were seven admitted patients not seen by the service with a combined length of stay of 17 bed days. The average wait time for inpatient neurology review was 42 hours. 3 admitted patients underwent a lumbar puncture. 2 patients were referred on to neuro-SDEC to enable an earlier discharge from hospital. Migraine was the most common final diagnosis in both groups.

This study highlights that Neuro-SDEC is effective at reducing hospital admissions, as well as unnecessary tests and referrals to generalneurology outpatients. For admitted patients, the service enabled earlier discharge from hospital and reduced length of stay.
Seasonality in mortality and its impact on life expectancy levels and trends across Europe
Authors: Marinetti Isabella , Jdanov Dmitri A. , Jasilionis Domantas , Nepomuceno Marília , Islam Nazrul , Janssen Fanny
Published: December 2024

Background

Seasonal fluctuations in mortality affect annual life expectancy at birth (e0). Nevertheless, evidence on the impact of seasonal mortality on longevity is very limited and mainly restricted to assessing season-specific mortality levels due to shocks (e.g., heatwaves and influenza epidemics). We investigated the influence of seasonality in mortality on life expectancy levels and temporal trends across 20 European countries during 2000–2019.

Data and methods

We used harmonised weekly population-level mortality data from the Human Mortality Database. Seasonal contributions to life expectancy at birth and age 65, by sex, were estimated using the excess mortality approach and decomposition analysis. Time-series analysis was used to evaluate the impact on long-term mortality trends.

Results

Seasonal mortality had a substantial but stable impact on e0between 2000 and 2019. On average, we found an annual reduction in life expectancy due to seasonal excess mortality of 1.14 years for males and 0.80 years for females. Deaths in the elderly population (65+) were the main driver of this impact: around 70% and 90% of these reductions in life expectancy were attributable to older ages. Excess mortality in winter had the strongest impact on annual life expectancy, especially in Portugal and Bulgaria (around 0.8-year loss on e0).

Conclusions

The study revealed significant cross-country variations in contributions of seasonal mortality. The most pronounced effects were observed in winter months and at older ages. These findings underscore the need for timely and targeted public health interventions to mitigate excess seasonal mortality.
Re-visiting professional ethics in psychotherapy: reflections on the use of talking therapies as a supportive adjunct for myalgic encephalomyelitis/chronic fatigue syndrome and ‘medically unexplained symptoms’
Authors: Hunt Joanne , Blease Charlotte
Published: December 2024

Following years of debate over the effectiveness of cognitive behavioural therapy for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), public health bodies in the UK and beyond have determined that no psychotherapy is clinically proven for this patient group. In the field of ME/CFS and the wider arena of ‘medically unexplained symptoms’ (MUS), patient survey data and qualitative research capturing patient experiences and psychotherapist attitudes suggest that therapeutic practice may sometimes fall short of required ethical standards. This raises questions about how psychotherapists can safely support, as opposed to treat, people with these debilitating conditions. We consider four ethical principles that feature throughout psychotherapists’ codes of practice, those of respect, competence, responsibility and integrity, and discuss examples of good and poor practice in this arena as evinced by recent empirical literature. Following this, we offer a variety of suggestions to help strengthen ethical psychotherapy practice with patients with ME/CFS and other MUS. In terms of practitioner education, we recommend greater emphasis on humility, reflexivity and disability-affirming practices, exploration of personal as well professional ethics, and integration of patient expertise-by-experience, accompanied with the latest evidence, into foundational and ongoing training. In terms of ongoing practice, we suggest consideration of formalised patient-focused feedback systems and greater transparency vis-à-vis patient access to clinical notes. Finally, we underline the importance of elevating patients from mere subjects to co-producers of psychotherapy research.
Risk profiles of common brachial plexus block sites: results from the net-ra registry
Authors: Kubulus Christine , Saadati Maral , Müller-Wirtz Lukas M , Patterson William M , Gottschalk Andre , Schmidt Rene , Volk Thomas
Published: December 2024

Introduction

Regional anesthesia is frequently used for upper limb surgeries and postoperative pain control. Different approaches to brachial plexus blocks are similarly effective but may differ in the frequency and severity of iatrogenesis. We, therefore, examined large-scale registry data to explore the risks of typical complications among different brachial plexus block sites for regional anesthesia.

Methods

26,947 qualifying adult brachial plexus blocks (2007–2022) from the Network for Safety in Regional Anesthesia and Acute Pain Therapy registry were included in a retrospective cohort analysis. Interscalene, supraclavicular, infraclavicular, and axillary approaches were compared for block failure and bloody punctures using generalized estimating equations. For continuous procedures, we analyzed the influence of the approach on catheter failure, neurological disorders, and infections.

Results

The axillary plexus block had the highest risk of block failure (adjusted OR, 2.3; 95% CI 1.02 to 5.1; p=0.04), catheter failure (adjusted OR, 1.4; 95% CI 1.1 to 2.0; p=0.02), and neurological dysfunction (adjusted OR, 3.0; 95% CI 1.5 to 5.9; p=0.002). There was no statistically significant difference among block sites for bloody punctures, while infraclavicular blocks had the highest odds for catheter-related infections.

Discussion

The axillary approach to the brachial plexus had the highest odds for block failure and neurological dysfunction after catheter placement, as well as a significant risk for catheter failure. However, considering that the axillary approach precludes other complications such as pneumothorax, none of the four common approaches to the brachial plexus has a fundamentally superior risk profile.
Mapping axillary sensory cutaneous nerves for enhanced analgesic approaches in axillary surgery: a cadaveric study
Authors: Zurkan Brittany , Wilson Timothy D , Biswas Abhijit
Published: December 2024

Background

Innervation of the breast includes branches of thoracic intercostal nerves, the superficial cervical plexus, the brachial plexus, and the intercostobrachial nerve (ICBN). Commonly used blocks for breast surgery provide incomplete analgesia of the axillary region. This cadaveric study aims to identify and map the axillary sensory cutaneous nerves.

Methods

We conducted nine axillary dissections on cadavers of both sexes with cadavers in supine position and upper limbs abducted. Incisions along the anterolateral thorax and superior clavicle created laterally reflecting skin flaps, allowing visualization of the ICBN and brachial plexus. Photographs were taken during dissections to enabled three-dimensional reconstruction using imaging software 3D Slicer.

Results

In all dissections, an ICBN and a branch of the posterior cord were identified entering axillary subcutaneous tissue. A branch of the medial cord was identified entering axillary tissue in 5/9 (56%) cadavers. The ICBN remained localized to the anterior axillary base but demonstrated various extrathoracic branching patterns. The posterior cord branch arose from the proximal posterior cord before penetrating the axillary base at its posterior margin in all cadavers. When present, the medial cord branch arose from the proximal medial cord before penetrating the axillary base along the midaxillary line.

Conclusion

In addition to the ICBN, two branches of the brachial plexus were identified entering axillary subcutaneous tissue. These branches are not currently considered when providing analgesia for breast surgery and may contribute to pain following surgery that involves axillary dissection.
Induction of interleukin 21 receptor expression via enhanced intracellular metabolism in B cells and its relevance to the disease activity in systemic lupus erythematosus
Authors: Ueno Masanobu , Iwata Shigeru , Yamagata Kaoru , Todoroki Yasuyuki , Sonomoto Koshiro , Nagayasu Atsushi , Miyagawa Ippei , Kubo Satoshi , Miyazaki Yusuke , Miyata Hiroko , Kanda Ryuichiro , Aritomi Takafumi , Nakayamada Shingo , Tanaka Yoshiya
Published: December 2024

Objective

To elucidate the association between the changes in intracellular metabolism in the early stage of B cell activation and systemic lupus erythematosus (SLE) pathogenesis.

Methods

CD19+or CD19+CD27-(naïve) cells from the peripheral blood of healthy controls and lupus patients were cultured under different stimuli. The changes in intracellular metabolism and signalling pathways in these cells were evaluated.

Results

Stimulation with CpG (Toll-like receptor 9 (TLR9) ligand) in vitro induced enhanced interleukin 21 (IL-21) receptor expression in CD19+CD27-cells after 24 hours. The addition of IL-21 to the CpG stimulation enhanced the extracellular acidification rate, which indicates glycolysis, within 30 min. IL-21 receptor (IL-21R) expression induced by CpG stimulation was selectively inhibited by 2-deoxy-D-glucose (hexokinase 2 (HK2) inhibitor) and heptelidic acid (glyceraldehyde 3-phosphate dehydrogenase (GAPDH) inhibitor). RNA immunoprecipitation with anti-GAPDH antibody revealed that CpG stimulation dissociated the binding between IL-21R messenger RNA (mRNA) and GAPDH under no stimulation. HK2 and GAPDH expression were higher in CD19+CD27-cells of lupus patients than in those of healthy controls, and GAPDH expression was correlated with the plasmocyte count and disease activity score.

Conclusion

IL-21R mRNA-GAPDH binding dissociation associated with rapid glycolytic enhancement by the TLR9 ligand in B cells may induce plasmocyte differentiation through IL-21 signals and be involved in exacerbating SLE.
Universal First-Order Quantification Over Automata
Authors: Boigelot Bernard , Fontaine Pascal , Vergain Baptiste
Published: December 2024

Deciding formulas that mix arithmetic and uninterpreted predicates is of practical interest, notably for applications in verification. One approach for obtaining a decision procedure consists in building by structural induction an automaton that recognizes the set of models of the formula under analysis, and then testing whether this automaton accepts a non-empty language. A drawback is that universal quantification is usually handled by a reduction to existential quantification and complementation. For logical formalisms in which models are encoded as infinite words, this hinders the practical use of this method due to the difficulty of complementing infinite-word automata. The contribution of this paper is to introduce an algorithm for directly computing the effect of universal first-order quantifiers on automata recognizing sets of models, for formulas involving natural numbers encoded in unary notation. This paves the way to implementable decision procedures for various arithmetic theories.