bluuebunny/crossref_metadata_2025 huggingface dataset:
LncRNA MALAT1-Targeting Antisense Oligonucleotide Ameliorates the AngII-Induced Vascular Smooth Muscle Cell Proliferation and Migration Through Nrf2/GPX4 Antioxidant Pathway
Authors: Liao Zili , Ni Zhonghan , Cao Jun , Liao Jin , Zhu Hengqing , Zhong Xiutong , Cao Gang , Huang Ling , Li Xiaoyue , Jiang Guojun , Pei Fang
Published: December 2023

The high level of oxidative stress induced by angiotensin II (AngII) is the main pathophysiological process that promotes the proliferation and migration of vascular smooth muscle cells (VSMCs) and induces vascular remodeling. LncRNA metastasis-related lung adenocarcinoma transcript 1 (MALAT1) has been determined to play an important role in the modulation of oxidative stress and the development of cardiovascular diseases. Nevertheless, the function and underlying mechanism of MALAT1 in restenosis induced by hypertensive angioplasty remain unclear. AngII increased the expression of MALAT1 in VSMCs. We found that antisense oligonucleotide lncRNA MALAT1 (ASO-MALAT1) could inhibit AngII-induced reactive oxygen species production and VSMCs proliferation and migration by inducing the expression of glutathione peroxidase 4 (GPX4), which can be reversed by siRNA-GPX4. GPX4 overexpression can inhibit the proliferation and migration of VSMCs induced by AngII. In addition, we found that the process by which MALAT1 knockdown induces GPX4 expression involves nuclear factor erythrocyte 2–related factor 2 (Nrf2). Overexpression of Nrf2 can increase the expression of GPX4, and downregulation of GPX4 by ML385 (Nrf2 inhibitor) blocked the protective effect of ASO-MALAT1 on AngII-induced proliferation and migration of VSMCs. Ferrostatin-1 (Fer-1, ip 5 mg/kg per day for 2 weeks), a GPX4 agonist, significantly inhibited neointimal formation in spontaneously hypertensive rat by the inhibition of oxidative stress. In conclusion, these data imply that ASO-MALAT1 suppresses the AngII-induced oxidative stress, proliferation, and migration of VSMCs by activating Nrf2/GPX4 antioxidant signaling. GPX4 may be a potential target for the therapeutic intervention of hypertensive vascular restenosis.
Chronic obstructive pulmonary disease and cardiovascular disease: mechanistic links and implications for practice
Authors: Maeda Tetsuro , Dransfield Mark T.
Published: December 2023

Purpose of review

Chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD) are both significant burdens on the healthcare system and often coexist. Mechanistic links between the two conditions and their clinical impact are increasingly understood.

Recent findings

Recent studies demonstrate multiple mechanisms by which the pathobiology of COPD may have negative effects on the cardiovascular system. These include extrapulmonary consequences of the COPD inflammatory state, cardiac autonomic dysfunction, which has been recently implicated in worsening respiratory symptoms and exacerbation risk, and mechanical effects of lung hyperinflation on left ventricular diastolic function.

Clinical studies have consistently shown a high prevalence of CVD in COPD patients and worsened outcomes (and vice versa). Exacerbations of COPD have also been demonstrated to dramatically increase the risk of cardiovascular events. While some safety concerns exist, medications for COPD and cardiovascular disease should be used in accordance with respective guidelines. However, real-world data show suboptimal management for patients with COPD and CVD.

COPD and cardiovascular disease have complicated interrelationships. Further mechanistic studies may lead to defining better targets for interventions. Education for medical professionals and implementation of novel screening protocols should be encouraged to fill in the gaps in clinical care for these patients.
Bempedoic acid: new evidence and recommendations on use
Authors: Paponja Kristina , Pećin Ivan , Reiner Željko , Banach Maciej
Published: December 2023

Purposes of review

Cardiovascular diseases (CVDs) are the leading cause of mortality and morbidity worldwide. Recognizing the importance of dyslipidemia treatment in the prevention of cardiovascular events has become a part of standard clinical practice. Desired values of LDL cholesterol (LDL-C) have become lower and lower in the last few decades, as evidenced by the most recent guidelines. Therefore, efforts to lower LDL cholesterol concentrations with conventional therapies and combinations of lipid-lowering therapy may not be successful in a high proportion of patients.

Recent findings

Bempedoic acid is a novel agent, first in-class ATP Citrate Lyase (ACL) inhibitor, which targets biosynthesis of the cholesterol in the liver. Considering the results of phase 3 studies, it has been approved for sole use for dyslipidemia treatment for patients who are statin-intolerant or in combination with statin-ezetimibe for those suffering from familial hypercholesterolemia or ASCVD and unable to reach targeted LDL-C values.

Bempedoic acid has proven beneficial for further reduction of LDL cholesterol for targeted groups of patients. It is not only efficient but also a well tolerated, affordable, and available agent whose place in lipid-lowering management is yet to be fully understood with new data collected from ongoing clinical research. In this review we suggest the place of bempedoic acid in lipid-lowering management.
Ovarian Mesonephric-like Adenocarcinoma Recurring With a Rhabdomyosarcoma Component: A Case Report
Authors: Yamamoto Akiko , Nagai Takeshi , Sukeda Aoi , Kajiwara Manami , Fukunaga Masaharu , Sasaki Toru , Kinoshita Yuta , Hayashi Motoshige , Hayashi Shigehiro , Ono Masataka , Futagami Masayuki , Nishi Hirotaka
Published: December 2023

Mesonephric-like adenocarcinoma (MLA) has recently been described as a tumor of the endometrium or ovaries, which, morphologically and immunohistochemically, resembles mesonephric adenocarcinoma arising mostly in the uterine cervix. Herein, we report, to our knowledge, the first case of ovarian MLA that developed into an extremely rapidly growing recurrent mesonephric-like carcinosarcoma, as confirmed by a genomic profiling test. A 51-year-old woman underwent chemotherapy with complete debulking surgery for ovarian carcinoma. Pathologically, the patient was diagnosed with stage IVB ovarian MLA. Subsequent to 15 months of complete remission, an enhanced computed tomography scan revealed a solid tumor of 10 cm diameter in the abdominal cavity. Secondary surgery was terminated with a 2 cm2 tumor biopsy specimen collection considering perioperative complications. Histologically, the tumor consisted of short spindle cells, and immunohistochemical staining revealed a rhabdomyosarcomatous profile without an epithelial component. Despite treatment for the sarcoma, she died 3 months after the detection of the tumor. The genomic profiling of the primary ovarian carcinoma and secondary resected tumor biopsy specimens revealed an identical KRAS mutation in both. Therefore, we concluded that the ovarian MLA recurred with a rhabdomyosarcoma component.
Left ventricular assist device-associated driveline infections as a specific form of complicated skin and soft tissue infection/acute bacterial skin and skin structure infection – issues and therapeutic options
Authors: Eckmann Christian , Sunderkötter Cord , Becker Karsten , Grabein Béatrice , Hagel Stefan , Hanses Frank , Wichmann Dominic , Thalhammer Florian
Published: December 2023

Purpose of review

This review comments on the current guidelines for the treatment of wound infections under definition of acute bacterial skin and skin structure infections (ABSSSI). However, wound infections around a catheter, such as driveline infections of a left ventricular assist device (LVAD) are not specifically listed under this definition in any of the existing guidelines.

Recent findings

Definitions and classification of LVAD infections may vary across countries, and the existing guidelines and recommendations may not be equally interpreted among physicians, making it unclear if these infections can be considered as ABSSSI. Consequently, the use of certain antibiotics that are approved for ABSSSI may be considered as ‘off-label’ for LVAD infections, leading to rejection of reimbursement applications in some countries, affecting treatment strategies, and hence, patients’ outcomes. However, we believe driveline exit site infections related to LVAD can be included within the ABSSSI definition.

We argue that driveline infections meet the criteria for ABSSSI which would enlarge the ‘on-label’ antibiotic armamentarium for treating these severe infections, thereby improving the patients’ quality of life.
Fibrous Dysplasia With Atypical Bilateral Upper Extremity Pattern
Authors: Chang Amy , Franssen Nathan , Sahakyan Karine
Published: December 2023

Fibrous dysplasia (FD) typically presents unilaterally in the lower limbs, or in the skull, mandible, or pelvis. Bilateral presentation is rarely reported. Most cases are diagnosed in the teens with 75% of patients diagnosed before the age of 30 years. In this case, a 63-year-old woman with suspected diagnosis of malignancy was referred to 99mTc-MDP scan and found to have polyostotic FD in bilateral upper extremities. Nuclear medicine can play an important role in diagnosing FD cases with atypical presentation and help risk stratification for more aggressive transformation.
22q13.33 duplication involving SHANK3 gene: a boy and his mother with “persistent” language and speech sound disorder
Authors: Granocchio Elisa , Pollina Eleonora , De Salvatore Marinella , Scopelliti Maria R. , Tanzi Giorgia , Sciacca Francesca L. , D’Arrigo Stefano , Ciaccio Claudia
Published: December 2023

Patients carrying 22q13.33 duplication present variable neurodevelopmental phenotype. Among these, patients with genetic alteration disrupting SHANK3 gene are very rare and they also present neurodevelopmental disorder such as autism spectrum disorder and intellectual disability. The real incidence is unknown because mild and variable phenotype could cause reduction in diagnosed cases. We describe the first case of 22q13.33 microduplication disrupting SHANK3 gene, inherited from mother to son, that presents a “persistent” language and speech sound disorder as main symptom without intellectual disability and autism spectrum disorder. More clinical reports with accurate phenotype description are needed to better define the profile of carriers of this genetic alteration.
Assessment of microbial contamination in laser materials processing laboratories used for prototyping of biomedical devices
Authors: Somorin Yinka M. , O'Connor Gerard M.
Published: December 2023

Microbial contamination of medical devices during pilot production can be a significant barrier as the laboratory environment is a source of contamination. There is limited information on microbial contaminants in laser laboratories and environments involved in the pilot production of medical devices. This study aimed to determine the bioburden and microbial contaminants present in three laser laboratories – an ISO class 7 clean room, a pilot line facility and a standard laser laboratory. Microbiological air sampling was by passive air sampling using settle plates and the identity of isolates was confirmed by DNA sequencing. Particulate matter was analysed using a portable optical particle counter. Twenty bacterial and 16 fungal genera were isolated, with the genera

Staphylococcus

and

Micrococcus

being predominant. Most isolates are associated with skin, mouth, or upper respiratory tract. There was no significant correlation between microbial count and PM2.5 concentration in the three laboratories. There were low levels but diverse microbial population in the laser-processing environments. Pathogenic bacteria such as

Acinetobacter baumannii

and Candida parapsilosis were isolated in those environments. These results provide data that will be useful for developing a contamination control plan for controlling microbial contamination and facilitating advanced manufacturing of laser-based pilot production of medical devices.
Pharmacological characterization of seven human histamine H3receptor isoforms
Authors: Gao Meichun , Dekker Mabel E. , Leurs Rob , Vischer Henry F.
Published: December 2023

The histamine H3receptor (H3R) regulates as a presynaptic G protein-coupled receptor the release of histamine and other neurotransmitters in the brain, and is consequently a potential therapeutic target for neuronal disorders. The human H3R encodes for seven splice variants that vary in the length of intracellular loop 3 and/or the C-terminal tail but are all able to induce heterotrimeric Giprotein signaling. The last two decades H3R drug discovery and lead optimization has been exclusively focused on the 445 amino acids-long reference isoform H3R-445.

In this study, we pharmacologically characterized for the first time all seven H3R isoforms by determining their binding affinities for reference histamine H3receptor agonists and inverse agonists. The H3R-453, H3R-415, and H3R-413 isoforms display similar binding affinities for all ligands as the H3R-445. However, increased agonist binding affinities were observed for the three shorter isoforms H3R-329, H3R-365, and H3R-373, whereas inverse agonists such as the approved anti-narcolepsy drug pitolisant (Wakix®) displayed significantly decreased binding affinities for the latter two isoforms. This opposite change in binding affinity of agonist versus inverse agonists on H3R-365 and H3R-373 is associated with their higher constitutive activity in a cAMP biosensor assay as compared to the other 5 isoforms. The observed differences in pharmacology between longer and shorter H3R isoforms should be considered in future drug discovery programs.
The evidence supporting AHA guidelines on adult cardiopulmonary resuscitation (CPR)
Authors: Junedahl Emma , Lundgren Peter , Andersson Erik , Gupta Vibha , Råmunddal Truls , Rawshani Aidin , Riva Gabriel , Arnetorp Ida , Hessulf Fredrik , Herlitz Johan , Djärv Therese , Rawshani Araz
Published: December 2023

Background

Guidelines for the management of cardiac arrest play a crucial role in guiding clinical decisions and care. We examined the strength and quality of evidence underlying these recommendations in order to elucidate strengths and gaps in knowledge.

Methods

Using the 2020 American Heart Association (AHA) Guidelines for Adult CPR, we subdivided all recommendations into advanced life support (ALS), basic life support (BLS), and recovery after cardiac arrest, as well as a more granular categorization by topic (i.e. the intervention or evaluation recommended). The Class of Recommendation (COR) and Level of Evidence (LOE) for each were reviewed.

Results

We noted 254 recommendations, of which 181 were ALS, 69 were BLS, and 4 were recovery after resuscitation. In total, only 2 (0.8%) had the most robust evidence (LOE A), while 23% were at LOE B-NR(Non-Randomized), 15% at LOE B-R (Randomized), 50% at LOE C-LD (Limited Data), and 12% relied on expert opinion LOE C-EO (Expert Opinion). Despite the strength of ALS recommendations (Class 1, 2a, or 2b), none had LOE A. In BLS, no recommendations were supported by LOE A. For BLS, 74% of recommendations had LOE C (C-LD or C-EO). The evidence for specific BLS topics, such as airway management, was notably low. Among ALS topics, neurological prognostication had relatively stronger evidence. Overall, 26.1% of BLS recommendations had LOE A or B, versus 43.1% for ALS recommendations.

Conclusions

There is a strong discrepancy between the strength of recommendation and the underlying evidence in cardiac arrest guidelines. The findings underscore a pressing need for more rigorous research, particularly randomized trials.
Bridge-like lipid transfer protein family member 2 suppresses ciliogenesis
Authors: Parolek Jan , Burd Christopher G.
Published: December 2023

Bridge-like lipid transfer protein family member 2 (BLTP2) is an evolutionary conserved protein with unknown function(s). The absence of BLTP2 inDrosophila melanogasterresults in impaired cellular secretion and larval death, while in mice (Mus musculus), it causes preweaning lethality. Structural predictions propose that BLTP2 belongs to the repeating β-groove domain-containing (also called the VPS13) protein family, forming a long tube with a hydrophobic core, suggesting that it operates as a lipid transfer protein (LTP). We establishBLTP2as a negative regulator of ciliogenesis in RPE-1 cells based on a strong genetic interaction withWDR44, a gene that also suppresses ciliogenesis. Like WDR44, BLTP2 localizes to membrane contact sites involving the endoplasmic reticulum and the tubular endosome network in HeLa cells and that BLTP2 depletion enhanced ciliogenesis by serum-fed RPE-1 cells, a condition where ciliogenesis is normally suppressed. This study establishes human BLTP2 as a putative lipid transfer protein acting between tubular endosomes and ER that regulates primary cilium biogenesis.

Significance statement

We show the involvement of an ER-localized bridge-like lipid transfer protein, BLTP2, in ciliogenesis and establish that BLTP2 is enriched at organelle-organelle membrane contact sites involving the endoplasmic reticulum (ER) and the tubular endosome network (TEN). These results implicate, for the first time, the involvement of bulk lipid transfer between the ER and TEN in regulating ciliogenesis.
Development and clinical validation of molecular subgrouping in medulloblastoma by targeted methylation sequencing
Authors: Srivastava Shreya , Bhaisora Kamlesh , Polavarapu Naveen Kumar , Pal Lily , Singh Shalini , Rai Neha , Lingaiah Raghavendra
Published: December 2023

Background

The WHO classification of CNS tumors confers promising prognostic value to the molecular classification of medulloblastoma (MB). Next-generation sequencing (NGS) has been the primary method employed for molecular classification through transcriptomic, genomic, or methylation profiling. However, due to cost and infrastructural needs, particularly in developing countries, we propose a relatively simple, rapid, and economical Sanger sequencing-based targeted methylation sequencing method for MB classification and prognostication.

Methods

Eleven epigenetic targets were amplified using optimized primers and bisulfite-converted DNA for Sanger sequencing. Chromas software was used for low-quality data trimming and NCBI’s Needleman Wunsch alignment tool was used for sequence alignment to reference. The developed method was applied to tissues from twelve cases of medulloblastoma.

Results

Successful interpretation of methylation status in ten out of eleven targets was achieved which was sufficient for classification according to the latest WHO classification of Medulloblastoma tumors. Twelve medulloblastoma cases were classified into WNT (n=2), Group 3 (n=5), and Group 4 (n=5).

Conclusion

The developed Sanger sequencing method is a cost-effective, in-house solution that can be used for molecular subgrouping of medulloblastoma. It offers an alternative to NGS, can be done on a case-to-case basis, and does not require high-end infrastructure, sample pooling, or extensive bioinformatics knowledge.

Impact statement

Molecular classification is imperative for determining the prognosis of medulloblastoma and is recommended by WHO. However, NGS proves to be an expensive option in developing countries. This study has come up with an affordable targeted methylation Sanger sequencing method requiring minimal bioinformatic skills, by utilizing epigenetic targets, for prognostication and risk stratification in medulloblastoma patients. The molecular subgroups of all recruited cases were successfully determined according to WHO classification which is crucial information that, when combined with clinical findings, will enable the clinicians to determine effective treatment strategies.
Utility of Cerebrospinal Fluid Protein Levels as a Potential Predictive Biomarker of Disease Severity in HIV-Associated Cryptococcal Meningitis
Authors: Kasibante John , Irfanullah Eesha , Wele Abduljewad , Okafor Elizabeth , Ssebambulidde Kenneth , Okurut Samuel , Kagimu Enock , Gakuru Jane , Rutakingirwa Morris K. , Mugabi Timothy , Nuwagira Edwin , Jjunju Samuel , Mpoza Edward , Tugume Lillian , Nsangi Laura , Musibire Abdu K , Muzoora Conrad , Rhein Joshua , Meya David B. , Boulware David R. , Abassi Mahsa
Published: December 2023

Background

Cerebrospinal fluid (CSF) protein levels exhibit high variability in HIV-associated cryptococcal meningitis from being normal to markedly elevated. However, the clinical implications of CSF protein levels in cryptococcal meningitis remain unclear.

Methods

We analysed data from 890 adults with HIV-associated cryptococcal meningitis randomized into two clinical trials in Uganda between 2015 and 2021. CSF protein was grouped into ≥100 mg/dL (n=249) and <100 mg/dL (n=641). We described baseline clinical variables and mortality by CSF protein levels.

Results

Approximately one-third of individuals had a baseline CSF protein ≥100 mg/dL. Those with CSF protein ≥100 mg/dL were more likely to present with Glasgow coma scale scores <15 (P<0.01), self-reported seizures at baseline (P=0.02), higher CD4 T-cells (p<0.001), and higher CSF white cells (p<0.001). Moreover, those with a baseline CSF protein ≥100 mg/dL also had a lower baseline CSF fungal burden (p<0.001) and a higher percentage of sterile CSF cultures at day 14 (p=0.02). Individuals with CSF protein ≥100 mg/dL demonstrated a more pronounced immune response consisting of upregulation of immune effector molecules pro-inflammatory cytokines, type-1 T-helper cell cytokines, type-3 chemokines, and immune-exhaustion marker (p<0.05). 18-week mortality risk in individuals with a CSF protein <100 mg/dL was 34% higher, (unadjusted Hazard Ratio 1.34; 95% CI, 1.05 to 1.70; p=0.02) than those with ≥100 mg/dL.

Conclusion

In cryptococcal meningitis, individuals with CSF protein ≥100 mg/dL more frequently presented with seizures, altered mental status, immune activation, and favourable fungal outcomes. Baseline CSF protein levels may serve as a surrogate marker of immune activation and prognosis.
Improving dictionary-based named entity recognition with deep learning
Authors: Nastou Katerina , Koutrouli Mikaela , Pyysalo Sampo , Jensen Lars Juhl
Published: December 2023

Motivation

Dictionary-based named entity recognition (NER) allows terms to be detected in a corpus and normalized to biomedical databases and ontologies. However, adaptation to different entity types requires new high-quality dictionaries and associated lists of blocked names for each type. The latter are so far created by identifying cases that cause many false positives through manual inspection of individual names, a process that scales poorly.

Results

In this work we aim to improve block lists by automatically identifying names to block, based on the context in which they appear. By comparing results of three well-established biomedical NER methods, we generated a dataset of over 12.5 million text spans where the methods agree on the boundaries and type of entity tagged. These were used to generate positive and negative examples of contexts for four entity types (genes, diseases, species, chemicals), which were used to train a Transformer-based model (BioBERT) to perform entity type classification. Application of the best model (F1-score=96.7%) allowed us to generate a list of problematic names that should be blocked. Introducing this into our system doubled the size of the previous list of corpus-wide blocked names. Additionally, we generated a document-specific list that allows ambiguous names to be blocked in specific documents. These changes boosted text mining precision by∼5.5% on average, and over 8.5% for chemical and 7.5% for gene names, positively affecting several biological databases utilizing this NER system, like the STRING database, with only a minor drop in recall (0.6%).

Availability

All resources are available through Zenodohttps://doi.org/10.5281/zenodo.10800530and GitHubhttps://doi.org/10.5281/zenodo.10289360.
Mechano-chemical Insights in Diabetic Kidney Disease through 3D Pathotypic Model of Mesangium
Authors: Ghosh Biswajoy , Fenton Kristin Andreassen , Agarwal Krishna
Published: December 2023

The mesangium is a crucial microenvironment in the kidney. It consists of mesangial cells and extracellular matrix that lends structural integrity to the glomerulus and aids renal filtration. The mesangial cells function in a delicate balance of matrix mechanics and chemical cues to engage in matrix formation, cell interactions, and cytokine production. Irregularities such as diabetes disturb this delicate balance leading to declining kidney function and kidney failure. While chemical and molecular studies on mesangium during diabetic kidney disease (DKD) are abundant, little is known about how the changing matrix mechanics affect the mesangial function. Here we demonstrate the co-stimulatory effects of chemical cues and matrix properties within the mesangial niche afflicted with DKD. To avail control of both mechanical and chemical parameters typical of DKD, we used photo-cured gelatin methacryloyl hydrogels to emulate mesangium in different disease stages. We simulated soft and stiff matrices to mechanically match mesangium in healthy and long-term DKD with fibrosis conditions. The mechanical properties play a dominant role over chemical factors inα−smooth muscle actin formation. This coincided with a reduction in mesangial cell processes and motility, crucial for cell interactions. The fibrotic matrix also profoundly influences collagen IV expression, potentially resulting in a thickened renal basement membrane around capillaries, reducing renal filtration efficiency. The study implies that the mechano-chemical dual input in late-stage DKD causes an accelerated decline in glomerular function. The finding consolidates viable reasoning for therapeutic challenges in late-stage kidney disease and directs future studies to find the missing pieces in understanding kidney disease through such in-vitro pathotypic models.
Beneficial ‘inefficiencies’ of western ranching: Flood-irrigated hay production sustains wetland systems by mimicking historic hydrologic processes
Authors: Donnelly J. Patrick , Jensco Kelsey , Kimball John S. , Ketchum David , Collins Daniel P. , Naugle David E.
Published: December 2023

Ranching in the American West has long relied on riparian ecosystems to grow grass-hay to feed livestock in winter and during drought. Producers seasonally flood grasslands for hay production using stream diversions and low-tech flood-irrigation on riparian floodplains. Inundation mimics natural processes that sustain riparian vegetation and recharge groundwater. The recent doubling in use of more efficient irrigation approaches, such as center-pivot sprinklers, threatens to accelerate climate change impacts by unintentionally decoupling more inefficient, traditional practices that sustain riparian systems. To address this information gap, we developed an exhaustive spatial inventory of grass-hay production and combined it with monthly surface water distributions modeled from satellite data. Surface water data were classified by wetland hydroperiod and used to estimate the proportion of wetlands supported by grass-hay production in the Intermountain West, USA. Elevation and proportion of grass-hay relative to other irrigated lands were enumerated to examine differences in their positions and abundance within landscapes. Lastly, we overlaid the delineated grass-hay wetlands with LANDFIRE pre-Euro-American Settings layer to quantify the efficacy of flood irrigation in mimicking the conservation of historical riparian processes. Findings suggest that inefficient grass-hay irrigation mirrored the timing of natural hydrology, concentrating ∼93% of flooded grasslands in historical riparian ecosystems, affirming that at large scales, this ranching practice, in part, mimics floodplain processes sustaining wetlands and groundwater recharge. Despite representing only 2.5% of irrigated lands, grass-hay operations supported a majority (58%)of temporary wetlands, a rare and declining habitat for wildlife in the Intermountain West. Tolerance for colder temperatures confined grass-hay production to upper watershed reaches where higher value crops are constrained by growing degree days. This novel understanding of grass-hay agroecology highlights the vital role of working ranches in the resilience and stewardship of riparian systems.
Fully automated histological classification of cell types and tissue regions of celiac disease is feasible and correlates with the Marsh score
Authors: Griffin Michael , Gruver Aaron M. , Shah Chintan , Wani Qasim , Fahy Darren , Khosla Archit , Kirkup Christian , Borders Daniel , Brosnan-Cashman Jacqueline A. , Fulford Angie D. , Credille Kelly M. , Jayson Christina , Najdawi Fedaa , Gottlieb Klaus
Published: December 2023

Aims

Histological assessment is essential for the diagnosis and management of celiac disease. Current scoring systems, including modified Marsh (Marsh–Oberhuber) score, lack inter-pathologist agreement. To address this unmet need, we aimed to develop a fully automated, quantitative approach for histology characterisation of celiac disease.

Methods

Convolutional neural network models were trained using pathologist annotations of haematoxylin and eosin-stained biopsies of celiac disease mucosa and normal duodenum to identify cells, tissue and artifact regions. Human interpretable features were extracted and the strength of their correlation with Marsh scores were calculated using Spearman rank correlations.

Results

Our model accurately identified cells, tissue regions and artifacts, including distinguishing intraepithelial lymphocytes and differentiating villous epithelium from crypt epithelium. Proportional area measurements representing villous atrophy negatively correlated with Marsh scores (r=−0.79), while measurements indicative of crypt hyperplasia and intraepithelial lymphocytosis positively correlated (r=0.71 and r=0.44, respectively). Furthermore, features distinguishing celiac disease from normal colon were identified.

Conclusions

Our novel model provides an explainable and fully automated approach for histology characterisation of celiac disease that correlates with modified Marsh scores, facilitating diagnosis, prognosis, clinical trials and treatment response monitoring.

KEY MESSAGES

What is already known on this topic

➢

Prior research has utilised machine learning (ML) techniques to detect celiac disease and evaluate disease severity based on Marsh scores.

➢

However, existing approaches lack the capability to provide fully explainable tissue segmentation and cell classifications across whole slide images in celiac disease histology.

➢

The need for a more comprehensive and interpretable ML-based method for celiac disease diagnosis and characterisation is evident from the limitations of currently available scoring systems as well as inter-pathologist variability.

What this study adds

➢

This study is the first to introduce an explainable ML-based approach that provides comprehensive, objective celiac disease histology characterisation, overcoming inter-observer variability and offering a scalable tool for assessing disease severity and monitoring treatment response.

How this study might affect research, practice or policy

➢

This study’s fully automated and ML-based histological analysis, including the correlation of Marsh scores, has the potential to enable more precise disease severity measurement, risk assessment and clinical trial endpoint evaluation, ultimately improving patient care.
Four years of PrEP use; sexual behaviour and STIs in the AMPrEP demonstration project cohort among men who have sex with men in Amsterdam, the Netherlands
Authors: Van Den Elshout Mark A.M. , Wijstma Eline , Boyd Anders , Jongen Vita , Coyer Liza , Anderson Peter L. , Davidovich Udi , De Vries Henry J.C. , Prins Maria , Schim Van Der Loeff Maarten F. , Hoornenborg Elske
Published: December 2023

Background

An increasing number of countries are currently implementing or scaling-up HIV pre-exposure prophylaxis (PrEP) care. With the introduction of PrEP, there was apprehension about possible risk compensation, particularly on the long term. To inform sexual health counselling and STI screening programmes, we aimed to study sexual behaviour and STI incidence among men who have sex with men (MSM) and transgender women who use long-term daily or event-driven PrEP.

Methods

The Amsterdam PrEP demonstration project (AMPrEP) provided oral daily PrEP and event-driven PrEP to MSM and transgender women in 2015-2020. Participants could choose their PrEP regimen, and could switch at each three-monthly visit. STI testing occurred at and, upon request, in-between 3-monthly study visits. We assessed changes in number of sex partners and condomless anal sex acts over time with casual partners (CAS) using negative binomial regression. We assessed changes in incidence rates (IR) of any STI (i.e., chlamydia, gonorrhoea, or infectious syphilis), individual STIs, and HIV over time using Poisson regression.

Findings

367 participants (365 MSM) commenced PrEP and were followed for a median 3.9 years (IQR=3.4-4.0). The number of sex partners decreased over time (adjusted rate ratio [aRR]=0.89/year, 95%CI=0.86-0.92), while the number of CAS acts with casual partners remained stable (aRR=0.98/year, 95%CI=0.94-1.01). IR of any STI was 87/100 person years (PY) (95%CI=82-93) and did not change over time for both daily PrEP or event-driven PrEP users. However, IRs of chlamydia and gonorrhoea decreased slightly in daily PrEP users. Two daily PrEP users, and no event-driven PrEP users, were diagnosed with HIV during their first year on PrEP.

Conclusion

With no increase in the number of casual sex partners nor of CAS acts, we found no indication of possible risk compensation during the first four years of PrEP use. Although the STI incidence was high, it did not increase over time.

Funding

ZonMw, RIVM, GGD, H-TEAM, Gilead.
SARS-CoV-2 infection risk in COVISHIELD (AstraZeneca-SII) Vaccinated Healthcare Workers in a Tertiary Cancer Care Centre of North-East India
Authors: Sarma Dhruba Jyoti , Das Biki Chandra , Rai Avdhesh Kumar , Sarma Pallavi , Baruah Priyanki , Deka Kamalika Bhandari , Bhattacharyya Mouchumee , Sarma Anupam , Barman Debanjana , Kataki Amal Chandra , Das Sawmik , Barman Rashmisnata
Published: December 2023

COVID-19 vaccination of Healthcare workers and vulnerable groups remain priority in containing the spread of SARS-CoV-2 infection and health complications arising post COVID-19. In India, COVISHIELD is the major part of COVID-19 vaccination drive. post-vaccination SARS-CoV-2 infection risk and its impact on severity as well as mortality need to be assessed in vaccinated population. The study included 350 COVISHIELD vaccinated HCWs in tertiary cancer care centre of North-East India. A total of 16 symptomatic HCWs (4.57%) were confirmed as SARS-CoV-2 positive. Among SARS-CoV-2 positive FV HCWs none were positive within 14 days, 13.33 % within 15 to 30 days, 53.33% within 30 to 45 days, and 33.33% after 45 or more days. None of the SARS-CoV-2 positive HCWs required oxygen support or hospitalisation. We also found that 66.67% FV HCWs (n=10) had Ct values below 20, 20% (n=3) had Ct values in between 20-25 and 13.33% (n=2) had Ct values in between 30 to 35. In North-East India COVISHIELD FV HCWs HCW,SARS-CoV-2 infection and COVID-19 symptoms were mild. Majority of FV HCWs have RT-PCR COVID-19 positive Ct Value was below 20. SARS-CoV-2 infection occurred mostly after 15 days to 45 days or more post vaccination.
Analyses using multiple imputation need to consider missing data in auxiliary variables
Authors: Madley-Dowd Paul , Curnow Elinor , Hughes Rachael A. , Cornish Rosie , Tilling Kate , Heron Jon
Published: December 2023

Auxiliary variables are used in multiple imputation (MI) to reduce bias and increase efficiency. These variables may often themselves be incomplete. We explored how missing data in auxiliary variables influenced estimates obtained from MI. We implemented a simulation study with three different missing data mechanisms for the outcome. We then examined the impact of increasing proportions of missing data and different missingness mechanisms for the auxiliary variable on bias of an unadjusted linear regression coefficient and the fraction of missing information. We illustrate our findings with an applied example in the Avon Longitudinal Study of Parents and Children. We found that where complete records analyses were biased, increasing proportions of missing data in auxiliary variables, under any missing data mechanism, reduced the ability of MI including the auxiliary variable to mitigate this bias. Where there was no bias in the complete records analysis, inclusion of a missing not at random auxiliary variable in MI introduced bias of potentially important magnitude (up to 17% of the effect size in our simulation). Careful consideration of the quantity and nature of missing data in auxiliary variables needs to be made when selecting them for use in MI models.
GWAS from Spoken Phenotypic Descriptions: A Proof of Concept from Maize Field Studies
Authors: Yanarella Colleen F. , Fattel Leila , Lawrence-Dill Carolyn J.
Published: December 2023

We present a novel approach to Genome-Wide Association Studies (GWAS) by leveraging unstructured, spoken phenotypic descriptions to identify genomic regions associated with maize traits. Utilizing the Wisconsin Diversity panel, we collected spoken descriptions ofZea maysssp.maystraits, converting these qualitative observations into quantitative data amenable to GWAS analysis. First, we determined that visually striking phenotypes could be detected from unstructrured spoken phenotypic descriptions. Next, we developed two methods to process the same descriptions to derive the trait plant height, a well-characterized phenotypic feature in maize: (1) a semantic similarity metric that assigns a score based on the resemblance of each observation to the concept of ‘tallness,’ and (2) a manual scoring system that categorizes and assigns values to phrases related to plant height. Our analysis successfully corroborated known genomic associations and uncovered novel candidate genes potentially linked to plant height. Some of these genes are associated with gene ontology terms that suggest a plausible involvement in determining plant stature. This proof-of-concept demonstrates the viability of spoken phenotypic descriptions in GWAS and introduces a scalable framework for incorporating unstructured language data into genetic association studies. This methodology has the potential not only to enrich the phenotypic data used in GWAS and to enhance the discovery of genetic elements linked to complex traits, but also to expand the repertoire of phenotype data collection methods available for use in the field environment.
Engineering Planar Gram-Negative Outer Membrane Mimics Using Bacterial Outer Membrane Vesicles
Authors: Singh Aarshi N. , Wu Meishan , Ye Tiffany T. , Brown Angela C. , Wittenberg Nathan J.
Published: December 2023

Antibiotic resistance is a major challenge in modern medicine. The unique double membrane structure of gram-negative bacteria limits the efficacy of many existing antibiotics and adds complexity to antibiotic development by limiting transport of antibiotics to the bacterial cytosol. New methods to mimic this barrier would enable high-throughput studies for antibiotic development. In this study, we introduce an innovative approach to modify outer membrane vesicles (OMVs) fromAggregatibacter actinomycetemcomitans,to generate planar supported lipid bilayer membranes. Our method first involves the incorporation of synthetic lipids into OMVs using a rapid freeze-thaw technique to form outer membrane hybrid vesicles (OM-Hybrids). Subsequently, these OM-Hybrids can spontaneously rupture when in contact with SiO2surfaces to form a planar outer membrane supported bilayer (OM-SB). We assessed the formation of OM-Hybrids using dynamic light scattering and a fluorescence quenching assay. To analyze the formation of OM-SBs from OM-Hybrids we used quartz crystal microbalance with dissipation monitoring (QCM-D) and fluorescence recovery after photobleaching (FRAP). Additionally, we conducted assays to detect surface-associated DNA and proteins on OM-SBs. The interaction of an antimicrobial peptide, polymyxin B, with the OM-SBs was also assessed. These findings emphasize the capability of our platform to produce planar surfaces of bacterial outer membranes, which in turn, could function as a valuable tool for streamlining the development of antibiotics.
Multimodal Mitigations for Cybersickness in Motion Base Simulators
Authors: Weech Séamas , Lamontagne Anouk
Published: December 2023

1.

Background

Virtual reality (VR) technologies that integrate with motion-base simulators (MBS) have the potential to accelerate personnel training and enhance workplace safety. Motion sickness on an MBS is a widespread problem with vast individual differences that are likely related to idiosyncrasies in estimates of head, body, and vehicle motions. When combined with head-mounted VR, we term the emergent symptoms ‘cybersickness’.

Methods

We conducted two experiments that evaluated cybersickness mitigations in an MBS. In Experiment 1 (N = 8), we tested the effectiveness of a light-touch body harness attached to a mobile-elevated work platform (MEWP) simulator during two nauseogenic VR tasks. In Experiment 2 (N = 14, 7 of whom completed Experiment 1), we tested the effectiveness of a dynamic field-of-view (dFOV) modifier that adaptively restricted the FOV for vehicle rotations in the same VR tasks. We gathered subjective sickness data and qualitative evaluations of the mitigations after the fact.

Results

We observed a reduced level of sickness in both Experiment 1 and 2 when mitigations were applied. In Experiment 1, the use of a harness led to a mild decrease in total cybersickness of between 3-11%, which was only significant for the nausea dimension. In Experiment 2, the use of dFOV imparted a large benefit to comfort, up to a 45% improvement. Both mitigations primarily improved comfort in a bumpy trench traversal task.

Conclusions

Cybersickness mitigations can help to deliver VR training for longer, and to more users. The type of content undertaken should be considered when employing new mitigations.
VARIABILITY IN THERMAL SENSITIVITY OF ADULT REPRODUCTIVE DIAPAUSE IN THE SPRUCE BEETLE, DENDROCTONUS RUFIPENNIS
Authors: Davenport Marianne E. , Bentz Barbara J. , Hansen E. Matthew , Ragland Gregory J.
Published: December 2023

Diapause induction and termination, which regulate seasonal insect life cycles, can be highly variable within and among populations because these traits are often genetically variable and sensitive to environmental fluctuations. Both types of variation may influence how insect populations respond plastically or evolutionarily to changing climates. In this study we assessed variability in the expression of reproductive diapause in spruce beetles (Dendroctonus rufipennis), a major forest pest whose life cycle timing is regulated by both a prepupal and adult reproductive diapause. Prepupal diapause is facultative and dependent on temperature in the field, whereas previous studies suggest that adult reproductive diapause is effectively obligate. We tested for variability in adult reproductive diapause termination within and between two populations of spruce bark beetle collected from sites in Colorado and Wyoming and reared under warm, summer-like conditions in the laboratory. We also sampled beetles from under tree bark during the fall and spring to estimate how reproductive diapause might terminate naturally in the field. We present evidence that though most beetles induce and do not terminate diapause under constant warm conditions, a small proportion of females from both populations developed mature ovaries and successfully reproduced under warm conditions in the lab. Previous studies have suggested that most beetles require exposure to relatively low temperatures for several weeks to months to terminate diapause in the lab. We found that most female beetles sampled in the field had mature ovaries relatively early in the fall, suggesting that exposure to transiently low temperatures in the field may rapidly terminate adult reproductive diapause. Thus, adult reproductive arrest may primarily act as a block to prevent offspring production prior to winter and appears unnecessary for survival overwinter. Overall, our data do not suggest that major shifts in spruce beetle life cycles as mediated by adult reproductive diapause are immediately imminent with changing climates but, if the variability that we observed is heritable, adult reproductive diapause may have some capacity to evolve in both populations.

** Note **all figures/tables designated with ‘S’ are supplemental figures/tables that will appear only in the supplement in the published version. They are provided here alongside the main figures/tables, in-line in the order that they appear in the text for convenience.
Evaluation of recombination rate of microhaplotypes based on the 1000 Genomes Project family data
Authors: Wei Yifan , Li Xi , Shan Tiantian , Wang Haoyu , Dai Xuan , Zhu Qiang , Wang Yufang , Zhang Ji
Published: December 2023

Microhaplotype, a kind of multi-allelic genetic marker that contains two or more SNPs in the range of hundreds of base pairs, has emerged as an important genetic marker in forensic genetics. However, the recombination within the microhaplotype, which has been neglected in most studies, leads to changes in its alleles during inheritance, producing alleles that are not identical to parental alleles and affecting the likelihood ratio calculation of the MH in forensic DNA analysis involving kinship. We constructed a highly dense and extensive MH set in the human genome based on the expanded 1000 Genomes Project (GRCh38). Using the pedigree data contained in 18 populations and a total of 1204 meioses in the GRCh38 dataset, we scanned and confirmed the recombination events that occurred within the above MH loci, to clarify the relationship between recombination and MH polymorphisms. We investigated the average incidence of MH recombinant alleles and the average recombination rate of genome-wide MHs in the hope of providing a reference for the correction of the likelihood ratio in the MH system of future kinship analysis.
Revisiting Alpha Resting State Dynamics Underlying Hallucinatory Vulnerability: Insights from Hidden Semi-Markov Modeling
Authors: Honcamp H. , Schwartze M. , Amorim M. , Linden D.E.J. , Pinheiro A.P. , Kotz S.A.
Published: December 2023

Resting state (RS) brain activity is inherently non-stationary. Hidden Semi-Markov Models (HsMM) can characterize the continuous RS data as a sequence of recurring and distinct brain states along with their spatio-temporal dynamics. Recent explorations suggest that EEG brain state dynamics in the alpha frequency link to auditory hallucination proneness (HP) in non-clinical individuals. The present study aims to replicate these findings to elucidate robust neural correlates of hallucinatory vulnerability. Specifically, we aimed to investigate the reproducibility of HsMM states across different data sets and within-data set variants as well as the replicability of the association between alpha brain state dynamics and HP. We found that most brain states are reproducible in different data sets, confirming that the HsMM characterized robust and generalizable EEG RS dynamics. Brain state topographies and temporal dynamics of different within-data set variants showed substantial similarities and were robust against reduced data length and number of electrodes. However, the association with HP was not directly reproducible across data sets. These results indicate that the sensitivity of brain state dynamics to capture individual variability in HP may depend on the data recording characteristics and individual variability in RS cognition, such as mind wandering. We suggest that the order in which eyes-open and eyes-closed RS data are acquired directly influences an individual’s attentional state and generation of spontaneous thoughts, and thereby might mediate the link to hallucinatory vulnerability.