bluuebunny/crossref_metadata_2025 huggingface dataset:
Protocol for a prospective, multicentre, cross-sectional cohort study to assess personal light exposure
Authors: Guidolin Carolina , Aerts Sam , Agbeshie Gabriel Kwaku , Akuffo Kwadwo Owusu , Aydin Sema Nur , Baeza-Moyano David , Bolte John , Broszio Kai , Cantarero-García Guadalupe , Didikoglu Altug , González-Lezcano Roberto Alonso , Joosten-Ma Hongli , Melero-Tur Sofía , Tengelin Maria Nilsson , Pérez Gutiérrez María Concepción , Stefani Oliver , Svensson Ingemar , Udovičić Ljiljana , Zauner Johannes , Spitschan Manuel
Published: November 2024

Light profoundly impacts many aspects of human physiology and behaviour, including the synchronization of the circadian clock, the production of melatonin, and cognition. These effects of light, termed the non-visual effects of light, have been primarily investigated in laboratory settings, where light intensity, spectrum and timing can be carefully controlled to draw associations with physiological outcomes of interest. Recently, the increasing availability of wearable light loggers has opened the possibility of studying personal light exposure in free-living conditions where people engage in activities of daily living, yielding findings associating aspects of light exposure and health outcomes, supporting the importance of adequate light exposure at appropriate times for human health. However, comprehensive protocols capturing environmental (e.g., geographical location, season, climate, photoperiod) and individual factors (e.g., culture, personal habits, behaviour, commute type, profession) contributing to the measured light exposure are currently lacking. Here, we present a protocol that combines smartphone-based experience sampling (experience sampling implementing Karolinska Sleepiness Scale, KSS ratings) and high-quality light exposure data collection at three body sites (near-corneal plane between the two eyes mounted on spectacle, neck-worn pendant/badge, and wrist-worn watch-like design) to capture daily factors related to individuals’ light exposure. We will implement the protocol in an international multi-centre study to investigate the environmental and socio-cultural factors influencing light exposure patterns in Germany, Ghana, Netherlands, Spain, Sweden, and Turkey (minimum n = 15, target n = 30 per site, minimum n = 90, target n = 180 across all sites). With the resulting dataset, lifestyle and context-specific factors that contribute to healthy light exposure will be identified. This information is essential in designing effective public health interventions.
Pulmonary lymphangiomatosis: insights into an ultra-rare disease
Authors: Polke M. , Polke N. , Piel S. , Brunnemer E. , Wälscher J. , Buschulte K. , Warth A. , Heussel C. P. , Eichinger M. , Frankenstein L. , Eichhorn M. , Miliauskas S. , Herth F. J. F. , Kreuter M.
Published: November 2024

Background

Pulmonary lymphangiomatosis (PL) is an ultrarare disease characterized by diffuse infiltration of the lung, pleura and/or mediastinum by abnormal lymphatic proliferation. Consented diagnostic or treatment approaches are not established. We therefore aimed to collect data on diagnostics and treatments in a cohort of patients with PL from a tertiary center for rare lung diseases.

Methods

Clinical, radiological and outcome data from PL patients were collected retrospectively.

Results

12 patients were diagnosed between 1996 and 2022 in our center. PL was diagnosed more commonly in female (58%), never smokers (75%) and younger patients (mean age 42 years). Main clinical symptoms comprised haem- and chyloptysis (58%) and dyspnea on exertion (83%). Pulmonary function was mostly restrictive (mean VC 59%) with impaired DLCO (mean 65%). Radiological assessment mainly showed mediastinal involvement (83%), and pleural effusion (67%), pleural thickening (67%) and bronchial wall thickening (67%) while interstitial changes were rare. Diagnosis was confirmed by surgical or transbronchial cryobiopsy. 8 patients were treated with sirolimus, 3 of these combined with a surgical intervention and in one case surgical intervention was necessary 9 months after initiation of sirolimus. Clinical and radiological improvement was demonstrated for all patients treated with sirolimus. 1 patient received a lung transplant due disease progression. Survival rates were 90% after a mean follow up of at least 3 months.

Conclusion

This case series illustrates the variability of the clinical presentation of PL. Among our patients, those treated with sirolimus showed significant clinical, functional and radiological improvement. However, further investigation is needed to understand the pathogenesis of lymphangiomatosis in order to establish therapeutic approaches.
Urinary DNA-methylation and protein biomarkers identify urothelial carcinoma among other genitourinary diseases and cancer-free individuals
Authors: Lang Kerstin , Köhler Christina U. , Wichert Katharina , Deix Thomas , Bartsch Georg , Sommer Gudrun , Lübke Christiane , Roghmann Florian , Reike Moritz J. , Krentel Harald , Engellandt Katja , Schiermeier Sven , Menke Valentin , Noldus Joachim , Behrens Thomas , Brüning Thomas , Käfferlein Heiko U.
Published: November 2024

Background

For more than 80 years, cystoscopy has been the gold standard for identification of urothelial carcinoma (UCa). Because of many factors, such as pain of the patients during this procedure or the costs involved, non-invasive detection of UCa remains a challenge. Herein, we verify our previously identified urinary biomarkers C-X-C Motif Chemokine Ligand 16 (CXCL16) and transforming growth-factor beta induced protein (TGFBI) on the protein level as well as the CpG sites ALOX5, TRPS1 and an intergenic region on Chromosome 16 on DNA methylation level in an independent cross-sectional study.

Methods

We collected N = 1119 urines from individuals coming to urological and gynecological check-ups, follow-up care or patients suspicious for UCa or already diagnosed for different urologic or gynecologic cancer entities. We performed methylation analysis of various CpG sites with DNA isolated from urine sediment and quantified the concentration of the protein markers CXCL16 and TGFBI in the corresponding urine supernatant using ELISA. We tested for patient-group differences with two-sided Wilcoxon rank sum tests and examined the performance with receiver operating characteristic curves. For verification, we analyzed the marker performance with previously set cutoff-values and marker combinations with established and experimental algorithms (with logical OR-conjunction, iterative threshold-based biomarker and score combining algorithm “PanelomiX”).

Results

Evaluation confirmed that our previously identified protein and DNA methylation biomarkers can distinguish UCa from frequent urological and gynecological cancers. CXCL16 and TGFBI discriminated UCa cases with a sensitivity of 31% and 56% and a specificity of 94% and 85%, respectively. Combining methylation markers resulted in UCa detection in men with a sensitivity of 54% and a specificity of 94%. Extending analysis by combining all methylation and protein markers (up to five markers in total) yielded a convincingly high specificity of 97% at a sensitivity of 72% for the identification of UCa patients within a heterogeneous collective of cancer-free individuals and patients suffering from urological or gynecological cancers.

Conclusion

Combining various biomarkers at protein and DNA level demonstrates a new option of non-invasive UCa diagnosis in urine, and thus might help to reduce the number of unnecessary cystoscopies, especially in patients without a history of UCa.
Strategies and interventions for achieving cardiovascular disease risk factor control in low- and middle-income countries: a review of the literature
Authors: Asamoah Kofi Tekyi , Dei-Asamoa Richard , Akumiah Florence Koryo , Ekpata Legbel Armor
Published: November 2024

Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality globally, with increasing rates in low- and low-middle-income countries (LMICs), particularly sub-Saharan Africa (SSA). These occur due to exposure to various risk factors, such as tobacco smoking, physical inactivity, hypertension, and diabetes. There are unique features in LMICs that contribute to the risk factor profile and quality of care offered in these countries. These include cultural influences on diet (carbohydrate-dense diet, use of salt-based spices and preservatives), the lack of dedicated spaces for physical activity, and perceptions of desirable body sizes. The attendant complications affect individuals, families and the community at large. Furthermore, there is a dearth of research to inform change at both the individual and policy level in LMICs. Lifestyle modification is the cornerstone of risk factor control and requires engaging relevant stakeholders in healthcare to enforce sustainable behaviour change among individuals. This includes measures from the individual level to national leadership and requires multisectoral collaboration to ensure sustainability. Such methods include building health worker capacity through a task shifting approach, strengthening the health worker-patient relationship, employing digital/technological applications, and engaging families and communities to serve as accountability partners in the management of CVD and related risk factors. There is a need for increased contextually relevant research output to inform contemporary methods to improve CVD and risk factor control in LMICs.
α-mannosidosis diagnosis in Brazilian patients with MPS-like symptoms
Authors: Marins Maryana , Curiati Marco Antonio , Gomes Caio Perez , Martin Renan Paulo , Nicolicht-Amorim Priscila , Yamamoto Joyce Umbelino da Silva , D’Almeida Vânia , Martins Ana Maria , Pesquero João Bosco
Published: November 2024

Background

α-mannosidosis is an inborn error of metabolism caused by the deficiency of the lysosomal enzyme α-mannosidase, which is encoded by the MAN2B1 gene and inherited in an autosomal recessive manner. The impairment of affected individuals is multisystemic and very similar to the observed in some mucopolysaccharidosis (MPS) patients. The aim of this study was to search for α-mannosidosis cases in individuals with clinical suspicion of MPS without a confirmed diagnosis. Biochemical and molecular analysis were standardized by our group for this study. Two hundred and fifty samples from patients with clinical suspicion of MPS, but with inconclusive MPS biochemical and/or molecular analysis, were screened for α-mannosidase activity. Subsequently the MAN2B1 gene was sequenced in samples from 53 patients by the Sanger method.

Results

The measurement of enzymatic activity detected fifty-three samples with abnormal results, suggesting α-mannosidosis. Molecular analysis confirmed three affected families, which presented the nonsense variant p.Ser899Ter. This variant generates a premature stop codon in exon 22, resulting in a truncated protein with no residual enzymatic activity.

Conclusion

In conclusion, this work brings data for the beginning of a genetic characterization of α-mannosidosis in the Brazilian population. It also shows that α-mannosidosis cases may be underdiagnosed due to the clinical similarity to MPS and the lack of information about this ultra-rare disease. Based on our data, we strongly recommend to all screening centers to consider α-mannosidosis testing together with screening for MPS as a tool for diagnosis to MPS-like phenotype individuals, since the phenotype similarity between these diseases poses a significant challenge for clinicians worldwide and often leads to the failure of the correct clinical diagnosis and treatment.
Conjoint analysis of methylation, transcriptomic, and proteomic profiles in pemphigus vulgaris
Authors: Luo Xiaojia , Ouyang Jianting , Jiang Fuqiong , Zhang Yaozhong , Wang Yuan , Wu Yongzhuo , Hu Lingyu
Published: November 2024

Background

The underlying pathogenesis of pemphigus vulgaris, an autoimmune skin disorder, remains incompletely understood. An integrative analysis comprising DNA methylation, mRNA expression, and proteomic data in patients with pemphigus vulgaris was conducted to identify potential pathogenic contributors and explore the molecular mechanisms involved in its pathogenesis.

Results

The analysis revealed differentially methylated regions (DMRs) in the promoter, exon, intron, and downstream regions in the peripheral blood DNA of patients with pemphigus vulgaris. Associations between methylation levels and both transcriptomic and proteomic profiles revealed that differentially expressed genes between patients with pemphigus vulgaris and healthy controls were primarily linked to biological functions such as platelet activation and coagulation, cellular adhesion, and immunoglobulin binding. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis highlighted notable pathway abnormalities, including those related to platelet activation, focal adhesions, tight junctions, and infectious inflammatory responses. Notably, genes such as FGA (fibrinogen alpha chain), VWF (von Willebrand factor), and ACTG1 (actin gamma 1) were dysregulated, with a prominent role in platelet activation.

Conclusion

The dysregulation of genes such as FGA, VWF, and ACTG1 suggests that alterations in their transcription and expression may contribute to the pathogenesis of pemphigus vulgaris.
Human VCP mutant ALS/FTD microglia display immune and lysosomal phenotypes independently of GPNMB
Authors: Clarke Benjamin E. , Ziff Oliver J. , Tyzack Giulia , Petrić Howe Marija , Wang Yiran , Klein Pierre , Smith Claudia A. , Hall Cameron A. , Helmy Adel , Howell Michael , Kelly Gavin , Patani Rickie
Published: November 2024

Background

Microglia play crucial roles in maintaining neuronal homeostasis but have been implicated in contributing to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, the role of microglia in ALS/FTD remains incompletely understood.

Methods

Here, we generated highly enriched cultures of VCP mutant microglia derived from human induced pluripotent stem cells (hiPSCs) to investigate their cell autonomous and non-cell autonomous roles in ALS pathogenesis. We used RNA-sequencing, proteomics and functional assays to study hiPSC derived VCP mutant microglia and their effects on hiPSC derived motor neurons and astrocytes.

Results

Transcriptomic, proteomic and functional analyses revealed immune and lysosomal dysfunction in VCP mutant microglia. Stimulating healthy microglia with the inflammatory inducer lipopolysaccharide (LPS) showed partial overlap with VCP mutant microglia in their reactive transformation. LPS-stimulated VCP mutant microglia displayed differential activation of inflammatory pathways compared with LPS-stimulated healthy microglia. Conserved gene expression changes were identified between VCP mutant microglia, SOD1 mutant mice microglia, and postmortem ALS spinal cord microglial signatures, including increased expression of the transmembrane glycoprotein GPNMB. While knockdown of GPNMB affected inflammatory and phagocytosis processes in microglia, this was not sufficient to ameliorate cell autonomous phenotypes in VCP mutant microglia. Secreted factors from VCP mutant microglia were sufficient to activate the JAK-STAT pathway in hiPSC derived motor neurons and astrocytes.

Conclusions

VCP mutant microglia undergo cell autonomous reactive transformation involving immune and lysosomal dysfunction that partially recapitulate key phenotypes of microglia from other ALS models and post mortem tissue. These phenotypes occur independently of GPNMB. Additionally, VCP mutant microglia elicit non cell autonomous responses in motor neurons and astrocytes involving the JAK-STAT pathway.
Selective metabolic regulations by p53 mutant variants in pancreatic cancer
Authors: Caporali Sabrina , Butera Alessio , Ruzza Alessia , Zampieri Carlotta , Bantula’ Marina , Scharsich Sandra , Ückert Anna-Katerina , Celardo Ivana , Kouzel Ian U. , Leanza Luigi , Gruber Andreas , Montero Joan , D’Alessandro Angelo , Brunner Thomas , Leist Marcel , Amelio Ivano
Published: November 2024

Background

Approximately half of all human cancers harbour mutations in the p53 gene, leading to the generation of neomorphic p53 mutant proteins. These mutants can exert gain-of-function (GOF) effects, potentially promoting tumour progression. However, the clinical significance of p53 GOF mutations, as well as the selectivity of individual variants, remains controversial and unclear.

Methods

To elucidate the metabolic regulations and molecular underpinnings associated with the specific p53R270H and p53R172H mutant variants (the mouse equivalents of human p53R273H and p53R175H, respectively), we employed a comprehensive approach. This included integrating global metabolomic analysis with epigenomic and transcriptomic profiling in mouse pancreatic cancer cells. Additionally, we assessed metabolic parameters such as oxygen consumption rate and conducted analyses of proliferation and cell–cell competition to validate the biological impact of metabolic changes on pancreatic ductal adenocarcinoma (PDAC) phenotype. Our findings were further corroborated through analysis of clinical datasets from human cancer cohorts.

Results

Our investigation revealed that the p53R270H variant, but not p53R172H, sustains mitochondrial function and energy production while also influencing cellular antioxidant capacity. Conversely, p53R172H, while not affecting mitochondrial metabolism, attenuates the activation of pro-tumorigenic metabolic pathways such as the urea cycle. Thus, the two variants selectively control different metabolic pathways in pancreatic cancer cells. Mechanistically, p53R270H induces alterations in the expression of genes associated with oxidative stress and reduction in mitochondrial respiration. In contrast, p53R172H specifically impacts the expression levels of enzymes involved in the urea metabolism. However, our analysis of cell proliferation and cell competition suggested that the expression of either p53R270H or p53R172H does not influence confer any selective advantage to this cellular model in vitro. Furthermore, assessment of mitochondrial priming indicated that the p53R270H-driven mitochondrial effect does not alter cytochrome c release or the apoptotic propensity of pancreatic cancer cells.

Conclusions

Our study elucidates the mutant-specific impact of p53R270H and p53R172H on metabolism of PDAC cancer cells, highlighting the need to shift from viewing p53 mutant variants as a homogeneous group of entities to a systematic assessment of each specific p53 mutant protein. Moreover, our finding underscores the importance of further exploring the significance of p53 mutant proteins using models that more accurately reflect tumor ecology.
Effects of prebiotics on microbial diversity and abundance in young children with acute malnutrition: study protocol for a multi-centered, double-blinded randomized controlled trial
Authors: Saleem Javeria , Zakar Rubeena , Iqbal Sanaullah , Arshad Muhammad , Shahzad Ruhma , Batool Munazza , Nawaz Muhammad , Butt Muhammad Salman , Fischer Florian
Published: November 2024

Background

The anti-inflammatory and antimicrobial benefits of prebiotics may present an affordable and cost-effective strategy for not only the prevention but also treatment of malnutrition. Therefore, the present trial has been designed with the aim to evaluate the role of prebiotics on the gut microbiome of severe acute malnourished (SAM) children.

Methods

The study is designed as a prospective, double-blinded, triple-armed, multi-centered randomized controlled trial, with 6–59 months old uncomplicated SAM children recruited to the experimental group receiving ready-to-use therapeutic food (RUTF) plus prebiotics and the active comparator group receiving RUTF plus starch for 2 months duration (8 weeks). Healthy children with matching age and gender will be recruited to placebo comparator group and will receive starch as a placebo during the study period. A total of 58 participants will be recruited to each arm with 1:1:1 allocation ratio following a pre-defined inclusion and exclusion criteria. The results of the gut microbiome diversity will serve as the primary outcome, while weight-for-height/length z-score, mid-upper-arm circumference, neurodevelopment assessment, and body mass accumulation will serve as the secondary outcome. Data collection and evaluations will be conducted at baseline and at the end of the trial (week 8), while the safety monitoring will be conducted at every second week. For analysis, the principles of intention-to-treat will be followed.

Conclusions

Conclusively, the results of the present trial would provide useful insights and high-quality data for the treatment and management of SAM children by evaluating the effect of RUTF plus prebiotic on the gut microbiome diversity of children, leading to medical evidence for designing the large-scale studies.

Trial registration

The present trial is registered at ClinicalTrials.gov with identifier No: NCT06155474 and registration date 4 December 2023.
Pharmacophore-based virtual screening, molecular docking, and molecular dynamics investigation for the identification of novel, marine aromatase inhibitors
Authors: Kotb Mohamed A. , Abdelmawgood Islam Ahmed , Ibrahim Ibrahim M.
Published: November 2024

Breast cancer remains a leading cause of mortality among women worldwide. Our current research focuses on identifying effective therapeutic agents by targeting the human aromatase enzyme. Aromatase inhibitors (AIs) have been effective in treating postmenopausal breast cancer but face challenges such as drug resistance and long-term side effects like cognitive decline and osteoporosis. Natural products, especially from marine organisms, are emerging as potential sources for new drug candidates due to their structural diversity and pharmacological properties. This study aims to discover marine natural products capable of inhibiting human aromatase by combining ligand-based and structure-based pharmacophore models for virtual screening against the Comprehensive Marine Natural Products Database. From the initial virtual screening of more than 31,000 compounds, 1,385 marine natural products were identified as possible candidates. Following initial molecular docking analysis, only four compounds managed to pass the criteria this research has introduced to confirm strong binding affinity to aromatase. All four compounds yielded acceptable binding affinities, with CMPND 27987 having the highest −10.1 kcal/mol. All four hits were subjected to molecular dynamics, and CMPND 27987 was further confirmed to be the most stable at the protein’s active site, with an MM-GBSA free binding energy of −27.75 kcal/mol. Our in silico studies indicate that CMPND 27987 interacts effectively within the binding site of the human aromatase, maintaining high affinity and stability. Based on these findings, we propose that CMPND 27987 could hold significant potential for further lead optimization and drug development.
In silico prediction of the action of bromelain on PI3K/Akt signalling pathway to arrest nasopharyngeal cancer oncogenesis by targeting phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha protein
Authors: Shamsuri Alyaa Syafiqah , Sim Edmund Ui -Hang
Published: November 2024

Objective

This research investigates the potential anti-tumour effects of bromelain, an aqueous extract from pineapple stems and fruits, on nasopharyngeal cancer (NPC). While bromelain is known for its medicinal properties in various cancers, its impact on NPC remains unexplored.

Results

Using in silico methods, we studied the predicted interactions between bromelain and key proteins involved in NPC oncogenesis, specifically β-catenin, PIK3CA, mTOR, EGFR, and BCL2. Molecular docking strategies were performed using a myriad of computational tools. A 3D model of bromelain was constructed using SWISS-MODEL, followed by molecular docking simulations performed with ClusPro. The binding affinities of the docked complexes were evaluated using HawkDock, and the interactions were analysed with LigPlot+. The docking scores indicated potential spontaneous interactions, with binding affinities based on being − 103.89 kcal/mol (PIK3CA), -73.16 kcal/mol (EGFR), -71.18 kcal/mol (mTOR), -65.22 kcal/mol (β-catenin), and − 57.48 kcal/mol (BCL2). LigPlot + analysis revealed the presence of hydrogen bonds, hydrophobic interactions, and salt bridges, indicating stable predicted interactions.

Conclusion

Our findings suggest that bromelain can target key proteins involved in NPC oncogenesis, with the strongest affinity towards PIK3CA. This suggests a hypothetical insight into bromelain’s anticancer effects on NPC through the modulation of the PI3K/Akt signaling pathway.
Computerized decision support to optimally funnel patients through the diagnostic pathway for dementia
Authors: van Gils Aniek M. , Tolonen Antti , van Harten Argonde C. , Vigneswaran Sinthujah , Barkhof Frederik , Visser Leonie N. C. , Koikkalainen Juha , Herukka Sanna-Kaisa , Hasselbalch Steen Gregers , Mecocci Patrizia , Remes Anne M. , Soininen Hilkka , Lemstra Afina W. , Teunissen Charlotte E. , Jönsson Linus , Lötjönen Jyrki , van der Flier Wiesje M. , Rhodius-Meester Hanneke F. M.
Published: November 2024

Background

The increasing prevalence of dementia and the introduction of disease-modifying therapies (DMTs) highlight the need for efficient diagnostic pathways in memory clinics. We present a data-driven approach to efficiently guide stepwise diagnostic testing for three clinical scenarios: 1) syndrome diagnosis, 2) etiological diagnosis, and 3) eligibility for DMT.

Methods

We used data from two memory clinic cohorts (ADC, PredictND), including 504 patients with dementia (302 Alzheimer’s disease, 107 frontotemporal dementia, 35 vascular dementia, 60 dementia with Lewy bodies), 191 patients with mild cognitive impairment, and 188 cognitively normal controls (CN). Tests included digital cognitive screening (cCOG), neuropsychological and functional assessment (NP), MRI with automated quantification, and CSF biomarkers. Sequential testing followed a predetermined order, guided by diagnostic certainty. Diagnostic certainty was determined using a clinical decision support system (CDSS) that generates a disease state index (DSI, 0–1), indicating the probability of the syndrome diagnosis or underlying etiology. Diagnosis was confirmed if the DSI exceeded a predefined threshold based on sensitivity/specificity cutoffs relevant to each clinical scenario. Diagnostic accuracy and the need for additional testing were assessed at each step.

Results

Using cCOG as a prescreener for 1) syndrome diagnosis has the potential to accurately reduce the need for extensive NP (42%), resulting in syndrome diagnosis in all patients, with a diagnostic accuracy of 0.71, which was comparable to using NP alone. For 2) etiological diagnosis, stepwise testing resulted in an etiological diagnosis in 80% of patients with a diagnostic accuracy of 0.77, with MRI needed in 77%, and CSF in 37%. When 3) determining DMT eligibility, stepwise testing (100% cCOG, 83% NP, 75% MRI) selected 60% of the patients for confirmatory CSF testing and eventually identified 90% of the potentially eligible patients with AD dementia.

Conclusions

Different diagnostic pathways are accurate and efficient depending on the setting. As such, a data-driven tool holds promise for assisting clinicians in selecting tests of added value across different clinical contexts. This becomes especially important with DMT availability, where the need for more efficient diagnostic pathways is crucial to maintain the accessibility and affordability of dementia diagnoses.
Early reduction in gut microbiota diversity in critically ill patients is associated with mortality
Authors: Wozniak Hannah , Gaïa Nadia , Lazarevic Vladimir , Le Terrier Christophe , Beckmann Tal Sarah , Balzani Eleonora , Urner Martin , Pugin Jérôme , Schrenzel Jacques , Heidegger Claudia-Paula ,   Gut Microbiota working group, Fröhlich Lorin , Negro Tommaso Rochat , Soccorsi Tania , Suh Noémie , Perret Aurélie , Chaabane Chiraz
Published: November 2024

Background

Critical illness is associated with an altered gut microbiota, yet its association with poor outcomes remains unclear. This study evaluates the early gut microbiota diversity changes in intensive care unit patients and its association with mortality. Additionally, it explores fecal pH as a potential biomarker for these changes.

Methods

In this prospective observational cohort study, fecal samples were collected at two time points: S1, the first stool passed upon intensive care unit admission, and S2, the first stool passed at least 24 h after S1. Full-length 16S rRNA gene sequencing was performed for gut microbiota analysis, with α-diversity measured using the Shannon index. Bayesian joint models were used to estimate the association between time-varying changes in gut microbiota diversity and 60-day mortality, as well as the association between daily changes in stool pH and in diversity.

Results

Twenty-four of 96 patients overall died during follow-up. Daily Shannon index decreased on average by −0.1 points [95% Credible Intervals (CrI) −0.20 to −0.10]. Every point decrease in Shannon index was associated with a 1.99-fold increase in the hazard of death (95% CrI, 1.04 to 4.51). Time-varying fecal pH levels were not associated with changes in Shannon index.

Conclusions

Gut microbiota diversity decreased over time, associated with increased mortality. Fecal pH is an unreliable marker of gut microbiota change. Future studies on gut microbiota and related biomarkers should focus on the initial days in the intensive care unit to detect and mitigate a decline in gut microbiota diversity.
Prevalence, risk factors and molecular identification of paramphistomid species in sheep from a Spanish endemic area
Authors: García-Dios David , Díaz Pablo , Remesar Susana , Viña Miguel , Martínez-Calabuig Néstor , Saldaña Ana , Díez-Baños Pablo , Panadero Rosario , Morrondo Patrocinio , López Ceferino Manuel
Published: November 2024

Background

Paramphistomids are ruminal trematodes that cause important losses in tropical and subtropical regions. However, their presence in Europe has increased significantly in recent decades. In northwestern Spain, this trend has been confirmed in cattle, but data in sheep are scarce and not updated. Moreover, the paramphistomid species affecting sheep in the area have never been molecularly identified. To evaluate the prevalence of paramphistomid infections in sheep from northwestern Spain, 826 faecal samples from 25 sheep farms were collected and analysed via coproscopic techniques. In addition, the rumens of 85 roe deer from the same area were examined to detect adult paramphistomids. The species present were molecularly identified. Multivariate analyses for identifying the risk factors affecting the prevalence and egg shedding of rumen flukes were also performed.

Results

Overall, 14% of the animals and 44% of the flocks were positive; the mean egg count was 20.5 eggs per gram of faeces. In contrast, no adult paramphistomids were found in roe deer. Older sheep, those from farms located in the central climatic area, without water throughs available on pastures and using their own manure to fertilize, were considered significantly more susceptible to infection with paramphistomids. With respect to egg shedding, animals from 37 to 72 months of age, farms under semiextensive management, and those coinfected with Fasciola hepatica presented significantly greater egg counts. Molecular identification revealed 100% similarity with Calicophoron daubneyi sequences from other European and Mediterranean countries.

Conclusions

The present study confirms the increase in the prevalence of paramphistomid infections in sheep in the area with high dissemination of the parasite, as previously reported in cattle, and represents the first molecular identification of C. daubneyi in sheep from Spain. Our results demonstrate that special attention should be given to adult animals since they are the main carriers and are responsible for environmental contamination. In addition, detecting risk areas and applying effective control management measures such as the installation of watering points on pastures seems essential for limiting infections in livestock, especially in sheep, since they are susceptible to developing clinical paramphistomidosis at any time in their lives. The absence of adult flukes in roe deer suggests that they represent less suitable hosts for this trematode than cattle and sheep, although more robust studies monitoring the situation in sympatric areas with domestic ruminants are needed.
Modelling the impact of past and future land-use changes on land cover degradation at territorial level in Eastern DR Congo
Authors: Nacishali Nteranya Jean , Kiplagat Andrew , Ucakuwun Elias K. , Nzabandora Chantal Kabonyi
Published: November 2024

Land use and land cover (LULC) changes are recognized as drivers of environmental changes at the local, regional, and global levels. Detecting these changes is essential in developing land management plans and strategies. More particularly, the LULC changes constitute one of the sub-indicators used for setting the baseline for land degradation neutrality (LDN) planning and assessing the progress toward the sustainable development goal 15.3. This study aims to determine the implication of LULC dynamics on land cover degradation in Eastern DR Congo. This region has been subjected to uncontrolled LULC changes over the last three decades but the impact of these changes on land degradation has not been assessed yet at the territorial level. To fill this gap, the territory of Kalehe has been used as a case study to monitor the LULC changes during the 1987–2020 period based on the classification of Landsat images, to forecast the future LULC for the 2030–2070 period through the hybrid Markov-Support Vector Machine modeling, to determine the extent of land cover degradation associated with these changes and to assess the impact of biophysical and socio-economic factors on the occurrence of land cover degradation using the binary logistic regression model. The results reveal that the overall trends of LULC changes during the 1987–2020 period are the increasing of built-up area, shrubland, and cropland at the expense of forestland, wetland, and grassland. This situation is expected to continue in the future and contribute to the degradation of land cover within the study area. Under the current situation of LULC changes, 34.17% of the land has been subjected to potential degradation. Furthermore, under the business-as-usual scenario 28.28%, 27.28%, and 33.65% of the land will be degraded by 2030, 2050, and 2070 respectively. This land cover degradation is more likely to occur in the proximity of roads, localities, highly populated areas, mining concessions, and high-altitudinal zones. Since the current land use system is unsustainable, there is a necessity to implement sustainable land management strategies that take into account the biophysical and socio-economic specificities of this region to reverse the problem of land cover degradation.
The role of fluids in earthquake swarms in northeastern Noto Peninsula, central Japan: insights from source mechanisms
Authors: Takano Sayaka , Hiramatsu Yoshihiro , Yukutake Yohei
Published: November 2024

A prolonged earthquake swarm has persisted since June 2018 in northeastern Noto Peninsula (central Japan), with activity focused into distinct southern, western, northern, and eastern clusters. To explore the role of fluids in the occurrence of this swarm, we analyzed the focal mechanisms of the earthquakes occurring from 1 January 2018 to 30 November 2022 and performed stress tensor inversions. The western, northern, and eastern clusters were dominated by a reverse fault-type mechanism with a horizontal P-axis oriented NW–SE. One of the nodal planes of those mechanisms aligns closely with the precisely relocated hypocenter distribution. The stress fields in these three clusters, as determined by stress tensor inversion, have maximum principal stresses oriented horizontally in the NW–SE direction and minimum principal stresses oriented vertically, aligning with the regional stress field. From these focal mechanisms and this stress field, we derived small misfit angles and large slip tendencies. These findings suggest that, in these three clusters, fluids diffused into faults largely aligned with the regional stress field, resulting in earthquakes with compatible focal mechanisms. Conversely, normal and strike-slip fault-type focal mechanisms, which are unfavorable to the regional stress field, dominated in the southern cluster. The estimated stress fields, deviating from the regional stress field, have maximum principal stresses closer to vertical and minimum principal stress oriented horizontally in the ENE–WSW direction. For earthquakes deeper than 15 km, this local stress field results in relatively larger misfit angles and lower slip tendency than the other clusters. These results suggest that those earthquakes in the southern cluster occurred on misoriented fault planes due to elevated pore fluid pressures. These findings provide strong evidence of the ascent of high-pore-pressure fluids from depth in the southern cluster and their subsequent diffusion into a southeast-dipping fault zone.

Graphical Abstract
Challenging the significance of SUV-based parameters in a large-scale retrospective study on lung lesions
Authors: Pini Cristiano , Kirienko Margarita , Gelardi Fabrizia , Bossi Paola , Rahal Daoud , Toschi Luca , Ninatti Gaia , Rodari Marcello , Marulli Giuseppe , Antunovic Lidija , Chiti Arturo , Voulaz Emanuele , Sollini Martina
Published: November 2024

Background

Although many well-known factors affect the maximum standardized uptake value (SUVmax), it remains the most requested and used parameter, especially among clinicians, despite other parameters, such as the standardized uptake value corrected for lean body mass and the metabolic tumor volume, being proven to be less sensitive to the same factors, more robust, and eventually more informative. This study intends to provide robust evidence regarding the diagnostic and prognostic value of SUVmax in a large cohort of subjects with suspected malignant lung nodules imaged by [18F]FDG PET/CT.

Materials and methods

We performed a retrospective analysis of patients with suspected/confirmed primary lung tumours undergoing [18F]FDG PET/CT. The sample size was 567 patients. Demographics, imaging, surgical, histological, and follow-up data were collected. SUVmax was analysed according to histology, stage, scanner, and outcome. The impact on measured values of different reconstruction protocols was assessed. All potential predictors of patients’ outcome were assessed.

Results

91% cases were primary lung tumours. Lung benign nodules or metastases accounted for 5% and 4% of cases. Most patients presented with adenocarcinoma (70%) and stage I disease (51%); 144 patients relapsed and 55 died. SUVmax failed to effectively differentiate benign lesions from primary tumours or metastases. Stage I patients presented lower SUVmax. SUVmax significantly correlated with patient weight, injected [18F]FDG activity, and lesion size and differed between reconstructions’ protocols. Survival analyses revealed no independent prognostic significance for SUVmax in progression-free after adjusting for other variables. SUVmax correlated with overall survival, disease stage and tumour histotype.

Conclusion

Our study confirms that SUVmax, though widely employed, present relevant limitations in discriminating between benign lesion and lung cancer, in classifying cancer histotypes, and in predicting patient outcomes independently. Known influencing factors significantly impact on numerical values, thus SUV values should be regarded with caution in clinical practice.
Female prediabetic rats are protected from vascular dysfunction: the role of nitroso and sulfide signaling
Authors: Cacanyiova Sona , Berenyiova Andrea , Malinska Hana , Huttl Martina , Markova Irena , Aydemir Basak G. , Garaiova Veronika , Cebova Martina
Published: November 2024

Background

The activity of perivascular adipose tissue (PVAT), a specific deposit of adipose tissue surrounding blood vessels, could contribute to sex differences in vascular tone control, particularly in dyslipidemic disorders; however, the mutual associations remain unclear. This study aimed to evaluate the relationships among sex, PVAT and vascular function in Wistar and hereditary hypertriglyceridemic (HTG) rats. Vasoactive responses of the isolated thoracic aorta with preserved or removed PVAT were compared in adult male and female Wistar and HTG rats, and the roles of nitric oxide (NO), hydrogen sulfide (H2S), cyclooxygenase (COX) and inflammatory signaling in vascular function were monitored in females.

Results

HTG rats were hypertensive, but females less than males. Increased 2-h glycemia was observed in HTG rats regardless of sex; however, HTG females exhibited better glucose utilization than males did. Females, independent of strain, had better preserved endothelial function than males did. PVAT inhibited endothelium-dependent relaxation in all the rats except HTG females. In HTG males, pathologically increased aortic contractility was noted; however, in HTG females, the contractile responses were lower, thus approaching physiological levels despite the pro-contractile action of COX products. In HTG females, NO contributed to endothelial function to a lesser extent than it did in controls, but the presence of PVAT eliminated this difference, which corresponded with increased NO synthase activity. Although increased protein expression of several proinflammatory factors (TNFα, IL-6, iNOS, and NfκB) was confirmed in the aortic and PVAT tissue of HTG females, the protein expression of factors regulating the adhesion and infiltration of monocytes (ICAM-1 and MCP-1) was decreased in PVAT. Moreover, in HTG females, unlike in controls, H2S produced by PVAT did not inhibit endothelial relaxation, and regardless of PVAT, endogenous H2S had beneficial anticontractile effects, which were associated with increased protein expression of H2S-producing enzymes in both aortic and PVAT tissues.

Conclusions

Despite increased inflammation and the pathological impact of cyclooxygenase signaling in female HTG rats, protective vasoactive mechanisms associated with milder hypertension and improved endothelial function and contractility linked to PVAT activity were triggered. Sulfide and nitroso signaling represent important compensatory vasoactive mechanisms against hypertriglyceridemia-associated metabolic disorders and may be promising therapeutic targets in prediabetic females.
Phage-induced disturbance of a marine sponge microbiome
Authors: Steiner Leon X. , Schmittmann Lara , Rahn Tanja , Lachnit Tim , Jahn Martin T. , Hentschel Ute
Published: November 2024

Background

Bacteriophages are known modulators of community composition and activity in environmental and host-associated microbiomes. However, the impact single phages have on bacterial community dynamics under viral predation, the extent and duration of their effect, are not completely understood. In this study, we combine morphological and genomic characterization of a novel marine phage, isolated from the Baltic sponge Halichondria panicea, and report on first attempts of controlled phage-manipulation of natural sponge-associated microbiomes.

Results

We used culture-based and culture-independent (16S rRNA gene amplicon sequencing) methods to investigate bacterial community composition and dynamics in sponge microbiomes with and without the addition of phages. Upon application of a novel Maribacter specialist phage Panino under controlled conditions, we were able to detect community-wide shifts in the microbiome composition and load after 72 h. While bacterial community composition became more dissimilar over time in the presence of phages, species evenness and richness were maintained. Upon phage exposure, we observed the loss of several low-abundance constituent taxa of the resident microbiota, while other originally underrepresented taxa increased. Virulent phages likely induce community-wide disturbances, evident in changes in the total sponge microbial profile by specific elimination of constituent taxa, which leads to an increase in bacterial abundance of opportunistic taxa, such as the genera Vibrio, Pseudoalteromonas, and Photobacterium.

Conclusions

Our findings suggest that sponge microbiome diversity and, by extension, its resilience depend on the maintenance of resident bacterial community members, irrespective of their abundance. Phage-induced disturbances can significantly alter community structure by promoting the growth of opportunistic bacteria like Vibrio and shifting the microbiome to a dysbiotic state. These insights highlight the role of bacteriophages in shaping microbiome dynamics and underscore the potential for phage application in managing bacterial community composition in marine host-associated environments.
Navigating the implementation gap for Trastuzumab's journey from health insurance to patient access: a preliminary study in a hospital in China
Authors: Yang Xingxia , Jia Yufei , Xu Jianhong , Zhou Qin , Long Qian , Yang Yi , Liu Yunguo , Zhu Juanying , Zhang Xiaochen
Published: November 2024

Background

Trastuzumab, a monoclonal antibody for breast cancer, faces global accessibility challenges, primarily due to high costs. This study examines how changes in medical insurance policies and price adjustments influence Trastuzumab utilization in China, focusing on implementation challenges and their impact on drug accessibility and affordability.

Methods

This retrospective study investigated Trastuzumab utilization among HER2-positive breast cancer patients at a tertiary hospital from May 2013 to December 2022 in JX, a prefecture-level city in eastern China. Patients were stratified based on their CerbB2 indicator, because those with a 2 + CerbB2 status require further FISH testing to confirm Trastuzumab eligibility. We analyzed the utilization rates of both FISH test and Trastuzumab using logistic regressions, identifying factors that influence their usage.

Results

766 patients were included. The utilization rate of Trastuzumab among patients with CerbB2 3+ rose from 40.40 to 77.94% in September 2017 following the expansion of insurance coverage, and further increased to 90.41% after a price reduction in 2020. The FISH test was not covered by health insurance, and it was not available in the local hospital until Trastuzumab became available in JX city. For patients with CerbB2 2+, the proportion undergoing the FISH test increased dramatically from 8.89 to 82.08% after the price reduction in 2020. The mere inclusion into basic medical insurance, regardless of insurance types, significantly increased the utilization of Trastuzumab and the FISH test. However, rural patients in JX city are still facing financial burdens with Trastuzumab's out-of-pocket cost accounting for 62.9% of their annual disposable income in 2020.

Conclusions

Our findings indicate that insurance coverage and price reduction significantly increased Trastuzumab utilization. However, failure to improve the accessibility of the FISH test can pose challenges in enhancing the uptake of Trastuzumab among eligible patients. With the expiration of Trastuzumab's patent and the development of affordable biosimilars, there are now greater opportunities to enhance treatment access globally. These insights can inform policy makers of implementation guidance about providing financial support for breast cancer patients in other LMICs.