bluuebunny/crossref_metadata_2025 huggingface dataset:
Physical Activity Report Card Indicators and the United Nations Sustainable Development Goals: Insights From Global Matrix 4.0
Authors: Silva Diego Augusto Santos , Aubert Salomé , Manyanga Taru , Lee Eun-Young , Salvo Deborah , Tremblay Mark S.
Published: October 2024

Background: The World Health Organization recognizes that physical activity (PA) during childhood is crucial for healthy development, aligning well with the achievement of several United Nations (UN) Sustainable Development Goals (SDGs). This study aimed to explore the associations between 10 key indicators of PA for children and adolescents assessed in the Global Matrix 4.0 project, and the UN SDGs. Methods: Data from 57 countries/jurisdictions of the Global Matrix 4.0 project were used. The UN SDG indicators were sourced from the SDG Transformation Center, which publishes each country’s performance on each of the 17 SDGs. Given the robust evidence supporting plausible links between PA and SDGs 3 (good health and well-being), 9 (industry, innovation, and infrastructure), 11 (sustainable cities and communities), 13 (climate action), and 16 (peace, justice, and strong institutions), these SDGs were investigated. Results: Countries/jurisdictions with good and moderate performance in achieving SDG 3, SDG 9, SDG 11, and SDG 16 had higher grades than countries/jurisdictions with fair performance in achieving these SDGs for the following indicators: Organized Sports and PA, Community and Environment, and Government Investments and Strategies. However, countries/jurisdictions with good performance in achieving SDG 13 had lower grades than countries/jurisdictions with fair performance in achieving SDG 13 for the following indicators: Organized Sports and PA, Community and Environment, and Government Investments and Strategies. Conclusions: Organized Sports and PA, Community and Environment, and Government Investments and Strategies were the indicators that demonstrated differences between countries/jurisdictions with good and poor performance in achieving the SDGs.
Modern Pain Science and Alexander Technique: How Might Alexander Technique Reduce Pain?
Authors: Hodges Mari , Cohen Rajal G. , Cacciatore Timothy W.
Published: October 2024

This article brings together research from the fields of pain science and Alexander Technique (AT) to investigate the mechanisms by which AT helps reduce pain. AT is a cognitive embodiment practice and a method for intentionally altering habitual postural behavior. Studies show that AT helps with various kinds of pain, although the mechanisms of pain reduction are currently not well understood. Advances in pain science may give insight into how this occurs. Modern interventions with efficacy for improving pain and function are consistent with active approaches within kinesiology. They also share similarities with AT and may have common mechanisms such as learning, mind–body engagement, normalization of sensorimotor function, improvement of psychological factors, and self-efficacy, as well as nonspecific treatment effects. AT likely has additional unique mechanisms, including normalization of muscle tone, neuronal excitability, and tissue loading, as well as alterations to body schema, attention redirection, and reduction in overall reactivity.
Context, Climate, and Red Tape: Considerations for Social-Justice Curriculum Development in Kinesiology
Authors: Gaudreault Karen Lux , Shiver Victoria , Vasquez Martin , Fullerton Sean , Sanchez Martinez Luis
Published: October 2024

Curricula grounded in social justice are vital in higher education, including kinesiology programs. The United States has seen continued increases in diversity, with education consistently displaying poor representation of historically marginalized groups. The purpose of this paper is to offer three elements that kinesiology programs should consider when aiming to successfully engage in developing social-justice curricula: context, climate, and “red tape.” We define and describe each element and how it influences our approach to curriculum development and provide specific examples from our work in the University of New Mexico Physical Education Teacher Education program to illustrate practical implementation. We argue that social-justice curriculum development is required to prepare young professionals to enter the field with the knowledge, skills, and dispositions to meet the needs of diverse communities.
Variability of macrolide-resistant profile in
Mycobacterium avium
complex pulmonary disease
Authors: Fukushima Kiyoharu , Matsumoto Yuki , Abe Yuko , Hashimoto Kazuki , Motooka Daisuke , Kitada Seigo , Saito Haruko , Komukai Sho , Fukui Eriko , Niitsu Takayuki , Nabeshima Hiroshi , Nagahama Yasuharu , Yamauchi June , Nitta Tadayoshi , Nii Takuro , Matsuki Takanori , Tsujino Kazuyuki , Miki Keisuke , Shintani Yasushi , Kumanogoh Atsushi , Akira Shizuo , Nakamura Shota , Kida Hiroshi
Published: October 2024

This single-center retrospective study aimed to analyze the variability of macrolide resistance (MR) in 68 patients with
Mycobacterium avium
complex pulmonary disease. Among 25 patients treated without macrolides, 13 (52%) reverted to macrolide-susceptible (MS) profiles. Only one (2%) of 43 patients who continued macrolide treatment showed this change. We compared 30 MR isolates with recent specimens. Among them, seven shifted to MS (five attributed to clonally related strains; two resulting from reinfection or polyclonal infection).
Hybrid paper/PDMS microfluidic device integrated with RNA extraction and recombinase polymerase amplification for detection of norovirus in foods
Authors: Lu Yuxiao , Hua Marti Z. , Luo Yuhang , Lu Xiaonan , Liu Qian
Published: October 2024

Human norovirus (HuNoV) is recognized as the leading causative agent of foodborne outbreaks of epidemic gastroenteritis. Consequently, there is a high demand for developing point-of-care testing for HuNoV. We developed an origami microfluidic device that facilitates rapid detection of murine norovirus 1 (MNV-1), a surrogate for HuNoV, encompassing the entire process from sample preparation to result visualization. This process includes RNA absorption
via
a paper strip, RNA amplification using recombinase polymerase amplification (RPA), and a lateral flow assay for signal readout. The on-chip detection of MNV-1 was completed within 35 min, demonstrating 100% specificity to MNV-1 in our settings. The detection limit of this microfluidic device for MNV-1 was 200 PFU/mL, comparable to the in-tube RPA reaction. It also successfully detected MNV-1 in lettuce and raspberries at concentrations of 170 PFU/g and 230 PFU/g, respectively, without requiring extra concentration steps. This device demonstrates high compatibility with isothermal nucleic acid amplification and holds significant potential for detecting foodborne viruses in agri-food products in remote and resource-limited settings.

IMPORTANCE

HuNoV belongs to the family of Caliciviridae and is a leading cause of acute gastroenteritis that can be transmitted through contaminated foods. HuNoV causes around one out of five cases of acute gastroenteritis that lead to diarrhea and vomiting, placing a substantial burden on the healthcare system worldwide. HuNoV outbreaks can occur when food is contaminated at the source (e.g., wild mussels exposed to polluted water), on farms (e.g., during crop cultivation, harvesting, or livestock handling), during packaging, or at catered events. The research outcomes of this study expand the approaches of HuNoV testing, adding value to the framework for routine testing of food products. This microfluidic device can facilitate the monitoring of HuNoV outbreaks, reduce the economic loss of the agri-food industry, and enhance food safety.
Complete genome sequences of three
Pseudomonas aeruginosa
jumbo bacteriophages discovered in Kenya
Authors: Musila Lillian , Bird Jordan T. , Margulieux Katie R. , Kigen Collins , Mzhavia Nino , Filippov Andrey A. , Nikolich Mikeljon P.
Published: October 2024

The genomes of three
Pseudomonas aeruginosa Phikzvirus
bacteriophages isolated in Kenya are described. The genomes of phages vB_PaePAO1-KEN19, vB_Pae3705-KEN49, and vB_Pae10145-KEN51, respectively, had lengths of 278,921, 280,231, and 280,173 bp, with 36.93%, 36.84%, and 36.86% GC content, containing 419, 417, and 417 coding sequences (including seven tRNAs in each genome).
Antibacterial effectors in
Dictyostelium discoideum
: specific activity against different bacterial species
Authors: Munoz-Ruiz Raphael , Lamrabet Otmane , Jauslin Tania , Guilhen Cyril , Bourbon Alixia , Cosson Pierre
Published: October 2024

Dictyostelium discoideum
is a phagocytic amoeba continuously eating, killing, and digesting bacteria. Previous studies have detected in
D. discoideum
cell extracts a bacteriolytic activity effective against
Klebsiella pneumoniae
bacteria. In this study, we characterized bacteriolytic activities found in
D. discoideum
cell extracts against five different bacteria (
K. pneumoniae
,
Escherichia coli
,
Pseudomonas aeruginosa
,
Staphylococcus aureus
, and
Bacillus subtilis
). We first analyzed the bacteriolytic activity against these five bacteria in parallel over a range of pH values. We then measured the remaining bacteriolytic activity in
D. discoideum kil1
and
modA
knockout mutants. We also performed partial fractionation of
D. discoideum
extracts and assessed activity against different bacteria. Together our results indicate that optimal bacteriolytic activity against different bacteria results from the action of different effectors. Proteomic analysis allowed us to propose a list of potential bacteriolytic effectors.

IMPORTANCE

Many antibacterial effectors have been characterized over the past decades, and their biological importance, mode of action, and specificity are often still under study. Here we characterized
in vitro
bacteriolytic activity in
D. discoideum
extracts against five species of Gram-negative and Gram-positive bacteria. Our results reveal that optimal lysis of different bacteria mobilizes different effectors. Proteomic analysis generated a list of potential bacteriolytic effectors. This work opens the way for future analysis of the role of individual effectors in living
D. discoideum
cells.
Comparison of the mechanism of antimicrobial action of the gold(I) compound auranofin in Gram-positive and Gram-negative bacteria
Authors: Quadros Barsé Laísa , Ulfig Agnes , Varatnitskaya Marharyta , Vázquez-Hernández Melissa , Yoo Jihyun , Imann Astrid M. , Lupilov Natalie , Fischer Marina , Becker Katja , Bandow Julia E. , Leichert Lars I.
Published: October 2024

While highly effective at killing Gram-positive bacteria, auranofin lacks significant activity against Gram-negative species for reasons that largely remain unclear. Here, we aimed to elucidate the molecular mechanisms underlying the low susceptibility of the Gram-negative model organism
Escherichia coli
to auranofin when compared to the Gram-positive model organism
Bacillus subtilis
. The proteome response of
E. coli
exposed to auranofin suggests a combination of inactivation of thiol-containing enzymes and the induction of systemic oxidative stress. Susceptibility tests in
E. coli
mutants lacking proteins upregulated upon auranofin treatment suggested that none of them are directly involved in
E. coli
’s high tolerance to auranofin.
E. coli
cells lacking the efflux pump component TolC were more sensitive to auranofin treatment, but not to an extent that would fully explain the observed difference in susceptibility of Gram-positive and Gram-negative organisms. We thus tested whether
E. coli
’s thioredoxin reductase (TrxB) is inherently less sensitive to auranofin than TrxB from
B. subtilis
, which was not the case. However,
E. coli
strains lacking the low-molecular-weight thiol glutathione, but not glutathione reductase, showed a high susceptibility to auranofin. Bacterial cells expressing the genetically encoded redox probe roGFP2 allowed us to observe the oxidation of cellular protein thiols
in situ
. Based on our findings, we hypothesize that auranofin leads to a global disturbance in the cellular thiol redox homeostasis in bacteria, but Gram-negative bacteria are inherently more resistant due to the presence of drug export systems and high cellular concentrations of glutathione.

IMPORTANCE

Auranofin is an FDA-approved drug for the treatment of rheumatoid arthritis. However, it has also high antibacterial activity, in particular against Gram-positive organisms. In the current antibiotics crisis, this would make it an ideal candidate for drug repurposing. However, its much lower activity against Gram-negative organisms prevents its broad-spectrum application. Here we show that, on the level of the presumed target, there is no difference in susceptibility between Gram-negative and Gram-positive species: thioredoxin reductases from both
Escherichia coli
and
Bacillus subtilis
are equally inhibited by auranofin. In both species, auranofin treatment leads to oxidative protein modification on a systemic level, as monitored by proteomics and the genetically encoded redox probe roGFP2. The single largest contributor to
E. coli
’s relative resistance to auranofin seems to be the low-molecular-weight thiol glutathione, which is absent in
B. subtilis
and other Gram-positive species.
Genomic characterization and clinical evaluation of prosthetic joint infections caused by
Cutibacterium acnes
Authors: Liew-Littorin C. , Davidsson S. , Nilsdotter-Augustinsson Å. , Hellmark B. , Brüggemann H. , Söderquist B.
Published: October 2024

Cutibacterium acnes
is a major skin commensal that may act as an opportunistic pathogen. It is difficult to interpret findings of
C. acnes
in tissue cultures obtained during arthroplasty revision surgery, since they may represent true infection or contamination. This study investigated whether
C. acnes
obtained from prosthetic joint infections (PJIs) were related and shared common genomic traits that might correlate with clinical courses and patient outcomes.
C. acnes
isolates from revision surgery of patients with PJIs of the hip, shoulder, and knee were characterized using molecular methods to determine the sequence type (ST) and the presence of possible virulence determinants (Christie–Atkins–Munch-Peterson factors, dermatan sulfate-binding adhesion 1, hyaluronidase lyase, and linear plasmid). A standardized review of the patients’ medical charts was performed. The study included 37 patients with
C. acnes
culture-positive tissue samples where multiple isolates of
C. acnes
belonged to the same ST. Most of the isolates belonged to phylotype IA
1
. Phylogenetic analysis of virulence determinants revealed no shared pattern among PJI isolates. Seven patients had a polymicrobial infection. Exchange revision was performed in 70% of the patients, and >50% of all patients received antibiotic treatment for ≥3 months. Failure was noted in seven patients. No specific ST or any identifiable unique feature among virulence determinants were found among
C. acnes
isolated from PJIs of hips and shoulders. The majority of patients had low inflammatory markers and were treated successfully, even polymicrobial infections. However, failure was more common among shoulder infections compared with hip infections.

IMPORTANCE

Prosthetic joint infection (PJI) is a rare complication after arthroplasty surgery. The infection seldom resolves without a combination of both surgical and antibiotic treatment and can cause significant suffering among affected patients.
Cutibacterium acnes
is a common skin bacterium that is most often found in shoulder PJIs but can also infect other prostheses. In this study, we conducted a review of patients with previously verified PJIs involving
C. acnes
in hip or shoulder prostheses, along with a genomic analysis of the bacteria causing the infections. The majority of patients had successful outcomes. We did not identify any specific phylogenetic lineage or specific molecular signature of virulence factors among these PJI-associated
C. acnes
isolates that seemed to be associated with increased potential to cause infection among this species. This indicates that
C. acnes
isolated from PJIs originates from the patients’ own skin microbiome and is inoculated during the arthroplasty surgery.
Characterization of
Pseudomonas aeruginosa
from subjects with diffuse panbronchiolitis
Authors: Met Charles M. , Hofstaedter Casey E. , O'Keefe Ian P. , Yang Hyojik , Moustafa Dina A. , Sherman Matthew E. , Doi Yohei , Rasko David A. , Sweet Charles R. , Goldberg Joanna B. , Ernst Robert K.
Published: October 2024

Diffuse panbronchiolitis (DPB) is a rare, idiopathic inflammatory disease primarily diagnosed in East Asian populations. DPB is characterized by diffuse pulmonary lesions, inflammation of the respiratory bronchioles, and bacterial infections of the airway. Historically, sputum cultures reveal
Pseudomonas aeruginosa
in 22% of DPB patients, increasing to 60% after 4 years from disease onset. Although DPB patients have a known susceptibility to respiratory
P. aeruginosa
infections, as is observed in other chronic lung diseases such as cystic fibrosis (CF), the characterization of DPB
P. aeruginosa
strains is limited. In this study, we characterized 24 strains obtained from a cohort of DPB patients for traits previously associated with virulence, including growth, motility, antibiotic susceptibility, lipopolysaccharide structure, and genomic diversity. Our cohort of DPB
P. aeruginosa
strains exhibits considerable genomic variability when compared with isolates from people with cystic fibrosis chronically colonized with
P. aeruginosa
and acute
P. aeruginosa
infection isolates. Similar to CF, DPB
P. aeruginosa
strains produce a diverse array of modified lipid A structures. Antibiotic susceptibility testing revealed increased resistance to erythromycin, a representative agent of the macrolide antibiotics used to manage DPB patients. Differences in the O-antigen type among
P. aeruginosa
strains collected from these different backgrounds were also observed. Ultimately, the characterization of DPB
P. aeruginosa
strains highlights several unique qualities of
P. aeruginosa
strains collected from chronically diseased airways, underscoring the challenges in treating DPB, CF, and other obstructive respiratory disease patients with
P. aeruginosa
infections.

IMPORTANCE

Diffuse panbronchiolitis (DPB), a chronic lung disease characterized by persistent
P. aeruginosa
infection, serves as an informative comparator to more common chronic lung diseases, such as cystic fibrosis (CF). This study aimed to better address the interplay between
P. aeruginosa
and chronically compromised airway environments through the examination of DPB
P. aeruginosa
strains, as existing literature regarding DPB is limited to case reports, case series, and clinical treatment guidelines. The evaluation of these features in the context of DPB, in tandem with prevailing knowledge of
P. aeruginosa
strains collected from more common chronic lung diseases (e.g., CF), can aid in the development of more effective strategies to combat respiratory
P. aeruginosa
infections in patients with chronic lung diseases.
Transcriptomics identify the triggering of citrate export as the key event caused by manganese deficiency in
Aspergillus niger
Authors: Fekete Erzsébet , Bíró Vivien , Márton Alexandra , Bakondi-Kovács István , Sándor Erzsébet , Kovács Béla , Geoffrion Nicholas , Tsang Adrian , Kubicek Christian P. , Karaffa Levente
Published: October 2024

For over a century, the filamentous Ascomycete fungus
Aspergillus niger
has played a pivotal role in the industrial production of citric acid. A critical fermentation parameter that sustains high-yield citric acid accumulation is the suboptimal concentration of manganese(II) ions in the culture broth at the early stages of the process. However, the requirement for this deficiency has not been investigated on a functional genomics level. In this study, we compared the transcriptome of the citric acid hyper-producer
A. niger
NRRL2270 strain grown under citric acid-producing conditions in 6-L scale bioreactors at Mn
2+
ion-deficient (5 ppb) and Mn
2+
ion-sufficient (100 ppb) conditions at three early time points of cultivation. Of the 11,846 genes in the genome, 963 genes (8.1% of the total) were identified as significantly differentially expressed under these conditions. Disproportionately high number of differentially regulated genes encode predicted extracellular and membrane proteins. The most abundant gene group that was upregulated in Mn
2+
ion deficiency condition encodes enzymes acting on polysaccharides. In contrast, six clusters of genes encoding secondary metabolites showed downregulation under manganese deficiency. Mn
2+
deficiency also triggers upregulation of the
cexA
gene, which encodes the citrate exporter. We provide functional evidence that the upregulation of
cexA
is caused by the intracellular accumulation of citrate or acetyl-CoA and is a major factor in triggering citrate overflow.

IMPORTANCE

Citric acid is produced on industrial scale by batch fermentation of the filamentous fungus
Aspergillus niger
. High-yield citric acid production requires a low (<5 ppb) manganese(II) ion concentration in the culture broth. However, the requirement for this deficiency has not been investigated on a functional genomics level. Here, we compared the transcriptome of a citric acid hyper-producer
A. niger
strain grown under citric acid-producing conditions in 6-L scale bioreactors at Mn
2+
ion-deficient (5 ppb) and Mn
2+
ion-sufficient (100 ppb) conditions at three early time points of cultivation. We observed that Mn
2+
deficiency triggers an upregulation of the citrate exporter gene cexA and provides functional evidence that this event is responsible for citrate overflow. In addition to the industrial relevance, this is the first study that examined the role of Mn
2+
ion deficiency in a heterotrophic eukaryotic cell on a genome-wide scale.
Seismic evidence of an extremely thin crust along a 70 Ma slow-spreading crustal segment in the equatorial Atlantic Ocean
Authors: Dhabaria Nirmit , Singh Satish C.
Published: October 2024

The oceanic crust at slow-spreading ridges is formed by a combination of magmatic and tectonic processes. Seismic tomographic studies, commonly used to determine crustal structures, indicate that mature slow-spreading crust has an average thickness of 6.1 ± 0.9 km, with a lower to upper crustal thickness ratio of 2.3. However, tomographic methods are based on high-frequency approximations and can only provide information about large-scale crustal structures. Using seismic full-waveform inversion applied to ocean bottom seismometer data, we report the presence of nearly uniform and extremely thin crust (4 ± 0.2 km) with a lower to upper crustal thickness ratio of 0.74 along an ~100 km, 70 Ma crustal segment formed at the slow-spreading Mid-Atlantic Ridge in the equatorial Atlantic Ocean. This thin crust is underlain by a Moho transition zone that is 1 ± 0.5 km thick, resulting in a combined crustal and Moho transition zone thickness of 5 ± 0.6 km. The crustal thinning is primarily due to the thinning of the lower crust, suggesting that a significant part of the crust is formed by lava flows and dike intrusions. The presence of an extremely thin crust indicates a decrease in mantle temperature by at least 50 °C, suggesting a vast extent of the upper mantle thermal minimum in the equatorial Atlantic Ocean, and the absence of influence of the mantle from the Siera Leone mantle plume 70 m.y. ago.
Ocean oxygenation and ecological restructuring caused by the late Paleozoic evolution of land plants
Authors: Stacey Jack , Wallace Malcolm W. , Hood Ashleigh v.S. , Shuster Alice M. , Corlett Hilary , Reed Christopher P. , Moynihan Conor
Published: October 2024

The dramatic increase in ocean-atmosphere oxygen levels during the Devonian and Mississippian is increasingly linked to the diversification of land plants, yet the timing and extent of this event remain uncertain. This study uses the redox-sensitive rare earth element cerium (cerium anomaly—Ce/Ce*) to investigate ocean redox conditions during the deposition of globally distributed Paleozoic carbonate strata. Our Paleozoic Ce/Ce* record suggests that Cambrian, Ordovician, and Silurian oceans had relatively low O2 levels (mean Ce/Ce* = 0.86 ± 0.10, 0.91 ± 0.14, and 0.91 ± 0.10 [±1σ], respectively). In contrast, short-lived ocean oxygenation events, possibly related to the diversification of small land plants, likely occurred throughout the Early and Middle Devonian (mean Ce/Ce* = 0.80 ± 0.07 and 0.58 ± 0.14, respectively). “Modern” Ce/Ce* values (<0.36) first occurred during the Late Devonian, suggesting that the main phase of Devonian and Mississippian oceanic oxygenation was related to the evolution of large vascular plants and the first forests. Despite this, the significant variability of Ce/Ce* values during this time suggests that shallow marine settings were susceptible to redox instability, possibly caused by upwelling of anoxic deep waters. This redox instability potentially provides evidence of a mechanism for contemporaneous mass extinction and metazoan reef collapse events. Development of strongly oxic conditions during the Late Devonian may have resulted in the demise of many Paleozoic-type organisms, facilitated the radiation of the modern evolutionary fauna, and established the modern oxygenated ocean-atmosphere system.
Investing in health workers: a retrospective cost analysis of a cohort of return-of-service bursary recipients in Southern Africa
Authors: Mabunda Sikhumbuzo A , Durbach Andrea , Chitha Wezile W , Phiri Hawor , Phalane Mahlane , Nomatshila Sibusiso C , Joshi Rohina , Angell Blake
Published: October 2024

Background

Return-of-service (RoS) schemes are investment strategies that governments use to increase the pool of health professionals through the issuing of bursaries and scholarships to health sciences students in return for service after graduation. Despite using these schemes for many years, Eswatini, South Africa, Botswana and Lesotho have not assessed the costs and return on investment of these schemes. This study aimed to assess the costs and relative rates of contract defaulting in these four Southern African countries.

Methods

A retrospective cohort study was carried out by reviewing databases of RoS beneficiaries for selected health sciences programmes who were funded between 2000 and 2010. Costs of the schemes were assessed by country, degree type and whether bursary holders completed their required service or defaulted on their public service obligations.

Results

Of the 5616 beneficiaries who studied between 1995 and 2019 in the four countries, 1225 (21.8%) beneficiaries from 2/9 South African provinces and Eswatini were presented in the final analysis. Only Eswatini had data on debt recovery or financial repayments. Beneficiaries were mostly medical students and slightly biased towards males. Medical students benefited from 56.7% and 81.3% of the disbursement in Eswatini (~US$2 million) and South Africa (~US$57 million), respectively. Each South African medical student studying in Cuba cost more than five times the rate of medical students who studied in South Africa. Of the total expenditure, 47.7% and 39.3% of the total disbursement is spent on individuals who default the RoS scheme in South Africa and Eswatini, respectively.

Conclusions

RoS schemes in these countries have loss of return on investment due to poor monitoring. The schemes are costly, ineffective and have never been evaluated. There are poor mechanisms for identifying beneficiaries who exit their contracts prematurely and inadequate debt recovery processes.
Predicting mucosal inflammation in IBD patients using patient-reported symptom scores and a faecal calprotectin home test: protocol for a multicentre prospective validation study
Authors: Janssen Laura , van Linschoten Reinier Cornelis Anthonius , West Rachel Louise , Gilissen Lennard P L , Romberg-Camps Mariëlle , Brandts Lloyd , Mujagic Zlatan , Römkens Tessa EH , Pierik M
Published: October 2024

Introduction

Crohn’s disease and ulcerative colitis are chronic inflammatory bowel diseases (IBD) with a relapsing-remitting nature. With adequate non-invasive prediction of mucosal inflammation, endoscopies can be prevented and treatment optimised earlier for better disease control. We aim to validate and recalibrate commonly used patient-reported symptom scores combined with a faecal calprotectin (FC) home test as non-invasive diagnostic tool for remote monitoring of IBD, both in daily practice and in a strict trial setting. Endoscopy will be used as the gold standard.

Methods and analysis

In this multicentre prospective validation study, adult IBD patients are asked to fill out questionnaires regarding disease activity (Monitor IBD At Home, mobile Health Index, Manitoba IBD Index, IBD control and patient-HBI/patient-Simple Clinical Colitis Activity Index), perform a FC home test and collect a stool sample for routine laboratory FC measurement, before the start of the bowel preparation for the ileocolonoscopy. Endoscopic disease activity will be scored according to the simplified endoscopic score for Crohn’s disease (CD) for CD patients or Ulcerative Colitis Endoscopic Index for Severity and Mayo Endoscopic Subscore for ulcerative colitis patients. The main study outcome is the diagnostic test accuracy of the various patient-reported scores to assess mucosal inflammation in combination with a FC home test.

Ethics and dissemination

This study is approved by the Medical Research Ethics Committee of azM/UM in Maastricht dated 03 March 2021 (METC 20–085) and is monitored by the Clinical Trial Centre Maastricht according to Good Clinical Practice guidelines. Written informed consent will be obtained from all patients. Study results will be published in international peer-reviewed medical journals.

Trial registration number

NCT05886322
Exploring willingness to use adverse drug reaction reporting systems: a multicentre qualitative study in China based on the technology acceptance model and task-technology fit integration approach
Authors: Xia Xudong , Yang Xue , Du Jiayi , Cheng Weigao , Chen Xiaobo , Zhang Wan , Yin Zhao
Published: October 2024

Background

Adverse drug reaction (ADR) reporting systems are critical for monitoring and managing drug safety. However, various factors influence the willingness to use these systems. This study aimed to investigate the willingness to use ADR reporting systems through an integrated model of the Technology Acceptance Model (TAM) and Task-Technology Fit (TTF) theory, conducting a multicentre qualitative study from the user’s perspective.

Methods

This study used qualitative research methods, including in-depth interviews with clinicians, nurses, pharmacists and administrators who reported ADRs through the National Adverse Drug Reaction Monitoring System (NADRMS) and the China Hospital Pharmacovigilance System (CHPS). The interviews were audio-recorded, transcribed verbatim and analysed using QDA Miner software for data management and thematic analysis.

Results

Eighteen healthcare workers from five healthcare organisations participated in the study. They found the ease of use and usefulness of the current NADRMS and CHPS to be acceptable. The essential technical requirements identified included accuracy, standardisation, timeliness and confidentiality. However, challenges such as inaccurate information capture, unstable interfacing with medical record systems, low reporting efficiency and lack of data sharing were highlighted. Overall, front-line healthcare workers exhibited a generally negative attitude towards using NADRMS and CHPS, driven more by necessity than preference. Factors influencing their willingness to use these systems included ease of use, practicality, risk perception and social impact, with varying attitudes and requirements observed between user groups.

Conclusion

This study provides practical recommendations that can be readily implemented to enhance the effectiveness and sustainability of ADR reporting systems. While front-line users in China acknowledged the systems’ ease of use and usefulness, they also noted significant gaps in technological adaptation. They expressed the need for improvements in data openness and sharing, accessibility and system intelligence.
Process evaluation of a cluster randomised implementation trial examining strategies to increase early access to exercise for people with knee osteoarthritis: protocol
Authors: Orsatti Amy , Bowden Jocelyn L , Naylor Justine M , Boland Robert , Pardey Margery , Descallar Joseph , Mills Kathryn
Published: October 2024

Introduction

First steps for knee osteoarthritis (OA) is a cluster randomised implementation trial examining the effect of an educational reminder message included in knee X-ray reports on the proportion of people subsequently referred to exercise professionals for their knee OA. Evaluating the processes supporting the completion of the study and the efficacy of the reminder message is essential to interpreting the outcomes of the study and aiding translation into practice.

Methods and analysis

We will conduct a concurrent process evaluation throughout the current study using a previously published framework for examining cluster randomised trials. This framework divides processes into those occurring at the cluster level and those at the target population level. For the current study, the cluster level is within radiology clinics. The target population is people with newly diagnosed radiologically evident, structural knee OA. A mixed methods design, incorporating survey data, administrative records, field notes and semi-structured interviews with representatives from radiology clinics and people with knee OA, will evaluate these processes. The focus of the evaluation will be recruitment and response processes of the radiology clinics and delivery and response processes for the people with knee OA. We will also describe the context and explore how the nudge theory of behavioural change influences the outcome of the study.

Ethics and dissemination

The study protocol, inclusive of the process evaluation, was approved by Macquarie University Human Research Ethics Committee (#520221190343842). Findings will be disseminated through national and international conferences, national industry stakeholders and patient advocacy groups to reach all levels of healthcare. Staff at radiology clinics and people with knee OA involved in interviews provide written, informed consent to participate in the process evaluation. Specific findings will be incorporated into training modules aimed at radiology clinics and will be developed by our industry partners.

Trial registration

Prospectively registered with the Australian New Zealand Clinical Trials Registry (ACTRN12622001414707p). Registration occurred in December 2022
Segmentation and multiparametric evaluation of corneal whorl-like nerves for in vivo confocal microscopy images in dry eye disease
Authors: Yu Kang , Chen Yupei , Feng Ziqing , Wang Gengyuan , Deng Yuqing , Li Jiaxiong , Ling Lirong , Xu Ruiwen , Xiao Peng , Yuan Jin
Published: October 2024

Objective

To establish an automated corneal nerve analysis system for corneal in vivo confocal microscopy (IVCM) images from both the whorl-like corneal nerves in the inferior whorl (IW) region and the straight ones in the central cornea and to characterise the geometric features of cornea nerves in dry eye disease (DED).

Methods and analysis

An encoder–decoder-based semi-supervised method was proposed for corneal nerve segmentation. This model’s performance was compared with the ground truth provided by experienced clinicians, using Dice similarity coefficient (DSC), mean intersection over union (mIoU), accuracy (Acc), sensitivity (Sen) and specificity (Spe). The corneal nerve total length (CNFL), tortuosity (CNTor), fractal dimension (CNDf) and number of branching points (CNBP) were used for further analysis in an independent DED dataset including 50 patients with DED and 30 healthy controls.

Results

The model achieved 95.72% Acc, 97.88% Spe, 80.61% Sen, 75.26% DSC, 77.57% mIoU and an area under the curve value of 0.98. For clinical evaluation, the CNFL, CNBP and CNDffor whorl-like and straight nerves showed a significant decrease in DED patients compared with healthy controls (p<0.05). Additionally, significantly elevated CNTor was detected in the IW in DED patients (p<0.05). The CNTor for straight corneal nerves, however, showed no significant alteration in DED patients (p>0.05).

Conclusion

The proposed method segments both whorl-like and straight corneal nerves in IVCM images with high accuracy and offered parameters to objectively quantify DED-induced corneal nerve injury. The IW is an effective region to detect alterations of multiple geometric indices in DED patients.
Technology supported High Intensity Training in chronic non-specific low back pain (the Techno-HIT trial): study protocol of a randomised controlled trial
Authors: van Eetvelde Julie Sylvie , Timmermans Annick A A , Coninx Karin , Kempeneers Kristof , Meeus Mira , Marneffe Wim , Meus Timo , Meuwissen Iris , Roussel Nathalie Anne , Stassijns Gaetane , Verbrugghe Jonas
Published: October 2024

Chronic low back pain (CLBP) is one of the most common chronic musculoskeletal disorders worldwide. Guidelines recommend exercise therapy (ET) in CLBP management, but more research is needed to investigate specific ET modalities and their underlying mechanisms. The primary goal of this study is to evaluate the short-term and long-term effectiveness of a time-contingent individualised high-intensity training (HIT) protocol on disability compared with a time-contingent moderate-intensity training (MIT) as used in usual care, in persons with severely disabling CLBP. Additionally, the effectiveness on central effects, the added value of prolonged training at home and technology support, and the cost-effectiveness are evaluated. In this randomised controlled trial, CLBP patients will be randomly divided into three groups of 56 participants. Group 1, ‘TechnoHIT’, receives HIT with technology-support in the home-phase. Group 2, ‘HIT’, receives HIT without technology support. Group 3, ‘MIT’, receives MIT, reflecting training intensity as used in usual care. The primary outcome is patient-reported disability, measured by the Modified Oswestry Disability Index. Secondary outcomes include quantitative sensory testing, psychosocial factors, broad physical fitness, quality of life, cost-effectiveness, adherence and usability of technology. Trial registration numberNCT06491121.
GOG-3097/ENGOT-ov81/GTG-UK/RAMP 301: a phase 3, randomized trial evaluating avutometinib plus defactinib compared with investigator’s choice of treatment in patients with recurrent low grade serous ovarian cancer
Authors: Grisham Rachel , Monk Bradley J , Van Nieuwenhuysen Els , Moore Kathleen Nadine , Fabbro Michel , O’Malley David M , Oaknin Ana , Thaker Premal , Oza Amit M , Colombo Nicoletta , Gershenson David , Aghajanian Carol A , Choi Chel Hun , Lee Yeh Chen , Mirza Mansoor Raza , Coleman Robert L , Cobb Lauren , Harter Philipp , Lustgarten Stephanie , Youssoufian Hagop , Banerjee Susana
Published: October 2024

Background

There are no approved treatments specifically for low grade serous ovarian cancer; current standard of care treatment options are limited in efficacy and tolerability. The combination of avutometinib with defactinib has demonstrated efficacy and a consistent safety profile in two clinical trials in recurrent low grade serous ovarian cancer, and a lower discontinuation rate due to adverse events compared with historical rates for standard of care.

Primary Objective

To compare the progression free survival of the combination of avutometinib with defactinib versus investigator’s choice of treatment in patients with recurrent low grade serous ovarian cancer.

Study Hypothesis

Combination treatment with avutometinib–defactinib will significantly improve progression free survival compared with investigator’s choice of treatment in patients with recurrent low grade serous ovarian cancer.

Trial Design

GOG-3097/ENGOT-ov81/GTG-UK/RAMP 301 is a phase 3, randomized, international, open label study designed to compare avutometinib with defactinib versus investigator’s choice of treatment in patients with recurrent low grade serous ovarian cancer who have progressed on a previous platinum based therapy. On confirmation of disease progression using a blinded independent central review, patients on the investigator’s choice of treatment arm may cross over to the avutometinib–defactinib arm.

Major Inclusion/Exclusion Criteria

Patients must have recurrent low grade serous ovarian cancer (KRASmutant or wild-type) and have documented progression (radiographic or clinical) or recurrence of low grade serous ovarian cancer after at least one platinum based chemotherapy regimen. Unlimited additional previous lines of therapy are allowed, including previous MEK/RAF inhibitor. Patients will be excluded if they have co-existing high grade ovarian cancer or had previous treatment with avutometinib, defactinib, or any other FAK inhibitor.

Primary Endpoint

Progression free survival according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, blinded-independent central review.

Sample Size

Approximately 270 patients will be randomized in a 1:1 fashion to either the combination avutometinib with defactinib arm (n~135) or the investigator’s choice of treatment arm (n~135).

Estimated Dates for Completing Accrual and Presenting Results

The estimated primary completion date of RAMP 301 is 2028, and the estimated study completion date is 2031.

Trial Registration

ClinicalTrials.govNCT06072781
NSGS mice humanized with cord blood mononuclear cells show sustained and functional myeloid–lymphoid representation with limited graft-versus-host disease
Authors: Panisello Carla , Aschero Rosario , Martinez-Moreno Alba , Roca Ho Heleia , Falgas Aida , González-Navarro Europa Azucena , Carabelli Julieta , Pradenas Edwards , Lázaro-Díez María , Prado Julia G , Blanco Julià , Carrillo Jorge , Juan Manel , Carcaboso Ángel M , Bueno Clara , Menendez Pablo
Published: October 2024

Humanized immunodeficient mice serve as critical models for investigating the functional interplay between transplanted human cells and a pre-reconstituted human immune system. These models facilitate the study of molecular and cellular pathogenic mechanisms and enable the evaluation of the efficacy and toxicity of immunotherapies, thereby accelerating their preclinical and clinical development. Current strategies rely on inefficient, long-term/delayed hematopoietic reconstitution by CD34+ hematopoietic progenitors or short-term reconstitution with peripheral blood mononuclear cells (PB-MNCs) associated with high rates of graft-versus-host disease (GvHD) and an inefficient representation of immune cell populations. Here, we hypothesized that immunologically naïve cord blood mononuclear cells (CB-MNCs) could serve as a superior alternative, providing long-lasting and functionally effective immune reconstitution. We conducted a comprehensive comparison between the non-obese diabetic (NOD).Cg-Prkdc∧ˆscid-IL2rg∧ˆtm1Wjl/SzJ (NSG) and NSG-Tg(CMV-IL3,CSF2,KITLG)∧ˆ1Eav/MloySzJ (NSGS) immunodeficient mouse models following humanization with either PB-MNCs or CB-MNCs. We assessed the engraftment dynamics of various human immune cells over time and monitored the development of GvHD in both models. For the most promising model, we extensively evaluated immune cell functionalityin vitroandin vivousing sarcoma and leukemia xenografts. Humanizing NSGS mice with CB-MNCs results in a rapid, robust, and sustained representation of a diverse range of functional human lymphoid and myeloid cell populations while minimizing GvHD incidence. In this model, human immune cell populations significantly impair the growth and engraftment of sarcoma and B-cell acute lymphoblastic leukemia cells, with a significant inverse correlation between immune cell levels and tumor growth. This study establishes a fast, efficient, and reliablein vivoplatform for various applications in cancer immunotherapy, particularly for exploring the complex interactions between cancer cells, immune cells, and the tumor microenvironmentin vivo, prior to clinical development.
Methyl-donor supplementation in women with systemic lupus erythematosus with different nutritional status: the protocol for a randomised, double-blind, placebo-controlled trial
Authors: da Mota Jhulia C N L , Carvalho Lucas M , Ribeiro Amanda A , Souza Leticia L , Borba Eduardo F , Roschel Hamilton , Gualano Bruno , Nicoletti Carolina F
Published: October 2024

Introduction

DNA hypomethylation in patients with systemic lupus erythematosus (SLE) has been recently documented in the literature. Low levels of DNA methylation have been observed globally and in genes associated with immune and inflammatory pathways in SLE’s CD4+T lymphocytes. Given that certain micronutrients can either donate methyl groups within one-carbon metabolism pathways or serve as cofactors for enzymes involved in the DNA methylation process, this randomised, double-blind, placebo-controlled trial aims to investigate whether a 3-month supplementation of folic acid and vitamin B
12
will modulate the DNA methylation profile in subcutaneous adipose tissue (primary outcome) of women with SLE and normal weight or excess body weight. As secondary objectives, we will assess gene expression, telomere length and phenotypic characteristics (ie, clinical parameters, body weight and composition, abdominal circumference, food intake and disordered eating attitude, physical activity, lipid profile, serum concentrations of leptin, adiponectin, and cytokines).

Methods and analysis

Patients will be classified according to their nutritional status by body mass index in normal weight or excess body weight. Subsequently, patients in each group will be randomly assigned to either a placebo or an intervention group (folic acid (400 mcg) and vitamin B
12
(2000 mcg) supplementation). Endpoint evaluations will be conducted using both intention-to-treat and per-protocol analyses. This study has the potential to design new personalised nutritional approaches as adjunctive therapy for patients with SLE.

Ethics and dissemination

This study has been reviewed and approved by the Ethical Committee from Clinical Hospital of the School of Medicine of the University of Sao Paulo, Brazil (CAAE.: 47317521.8.0000.0068).

Trial registration number

NCT05097365
(first version).