bluuebunny/crossref_metadata_2025_split huggingface dataset:
Real-world performance and safety of Halova®ovules in reducing the vaginal symptoms associated with vulvovaginal atrophy and postmenopausal sexual dysfunction
Authors: Iliescu Dominic-Gabriel , Petrita Ramona , Teodorescu Cristina , Olaru Raluca Alexandra , Alexa Andreea Anda , Petre Izabella 
Published: May 2023

AbstractDecreasing sex hormones levels during the postmenopausal period results in tissue atrophy and physiological changes, such as thinning of the vaginal epithelium, prolapse, and decreased pelvic floor strength and control. Sexual dysfunction associated with vaginal dryness has frequently been reported in postmenopausal women. The present study was designed as an observational, multicenter, real-world clinical investigation to evaluate the performance and safety of the medical device Halova®ovules in reducing vaginal symptoms associated with vulvovaginal atrophy and sexual dysfunction. A total of 249 female participants were treated with Halova®ovules, both in monotherapy and in combination with concomitant medication. The primary objective of this study was to evaluate the tolerability of Halova®ovules in the management of symptoms associated with perimenopause or genitourinary syndrome of menopause. The evolution of clinical manifestations such as vaginal dryness, dysuria, dyspareunia, and endometrial thickness in patients with the aforementioned conditions was defined as a secondary objective. Halova®ovules were rated with “excellent” clinical performance by 92.74% of the study participants as a standalone treatment and 95.71% of the study participants when used in association. Sexual dysfunction-related parameters, such as vaginal dryness and dyspareunia, were reduced by similar percentages in each arm. No adverse reactions related to treatment with Halova®have been reported. Halova®may be a therapeutic alternative for patients with controversial local estrogenic treatment. The study and its details are registered withNCT05654610.
Gastric Alimetry®improves patient phenotyping in gastroduodenal disorders compared to gastric emptying scintigraphy alone
Authors: Wang William Jiaen , Foong Daphne , Calder Stefan , Schamberg Gabriel , Varghese Chris , Tack Jan , Xu William , Daker Charlotte , Carson Daniel , Waite Stephen , Hayes Thomas , Du Peng , Abell Thomas L. , Parkman Henry P. , Huang I-Hsuan , Fernandes Vivian , Andrews Christopher N. , Gharibans Armen A. , Ho Vincent , O’Grady Greg 
Published: May 2023

AbstractObjectivesGastric emptying testing (GET) assesses gastric motility, however is non-specific and insensitive for neuromuscular disorders. Gastric Alimetry® (GA) is a new medical device combining non-invasive gastric electrophysiological mapping and validated symptom profiling. This study assessed patient-specific phenotyping using GA compared to GET.MethodsPatients with chronic gastroduodenal symptoms underwent simultaneous GET and GA, comprising a 30-minute baseline,99mTC-labelled egg meal, and 4-hour postprandial recording. Results were referenced to normative ranges. Symptoms were profiled in the validated GA App and phenotyped using rule-based criteria based on their relationships to the meal and gastric activity: i) sensorimotor; ii) continuous; and iii) other.Results75 patients were assessed; 77% female. Motility abnormality detection rates were:GET22.7% (14 delayed, 3 rapid);GA spectral analysis33.3% (14 low rhythm stability / low amplitude; 5 high amplitude; 6 abnormal frequency);combined yield42.7%. In patients with normal spectral analysis,GA symptom phenotypesincluded: sensorimotor 17% (where symptoms strongly paired with gastric amplitude; median r=0.61); continuous 30%; other 53%. GA phenotypes showed superior correlations with GCSI, PAGI-SYM, and anxiety scales, whereas Rome IV Criteria did not correlate with psychometric scores (p>0.05).Delayed emptying was not predictive of specific GA phenotypes.ConclusionsGA improves patient phenotyping in chronic gastroduodenal disorders in the presence and absence of motility abnormalities with improved correlation with symptoms and psychometrics compared to gastric emptying status and Rome IV criteria. These findings have implications for the diagnostic profiling and personalized management of gastroduodenal disorders.Study Highlights1) WHAT IS KNOWNChronic gastroduodenal symptoms are common, costly and greatly impact on quality of lifeThere is a poor correlation between gastric emptying testing (GET) and symptomsGastric Alimetry® is a new medical device combining non-invasive gastric electrophysiological mapping and validated symptom profiling2) WHAT IS NEW HEREGastric Alimetry generates a 1.5x higher yield for motility abnormalities than GETWith symptom profiling, Gastric Alimetry identified 2.7x more specific patient categories than GETGastric Alimetry improves clinical phenotyping, with improved correlation with symptoms and psychometrics compared to GET
Statistical haemoglobin thresholds to define anaemia across the lifecycle
Authors: Braat Sabine , Fielding Katherine , Han Jiru , Jackson Victoria E. , Zaloumis Sophie , Xu Jessica Xu Hui , Moir-Meyer Gemma , Blaauwendraad Sophia M. , Jaddoe Vincent W.V. , Gaillard Romy , Parkin Patricia C. , Borkhoff Cornelia M. , Keown-Stoneman Charles D.G. , Birken Catherine S. , Maguire Jonathon L. ,   Genes & Health Research Team, Bahlo Melanie , Davidson Eliza , Pasricha Sant-Rayn 
Published: May 2023

AbstractDetection of anaemia is critical for clinical medicine and public health. Current WHO values that define anaemia are statistical thresholds (5thcentile) set over 50 years ago, and are presently <110g/L in children 6-59 months, <115g/L in children 5-11 years, <110g/L in pregnant women, <120g/L in children 12-14 years of age, <120g/L in non-pregnant women, and <130g/L in men. Haemoglobin is sensitive to iron and other nutrient deficiencies, medical illness and inflammation, and is impacted by genetic conditions; thus, careful exclusion of these conditions is crucial to obtain a healthy reference population. We identified data sources from which sufficient clinical and laboratory information was available to determine an apparently healthy reference sample. Individuals were excluded if they had any clinical or biochemical evidence of a condition that may diminish haemoglobin concentration. Discrete 5thcentiles were estimated along with two-sided 90% confidence intervals and estimates combined using a fixed-effect approach. Estimates for the 5thcentile of the healthy reference population in children were similar between sexes. Thresholds in children 6-23 months were 104.4g/L [90% CI 103.5, 105.3]; in children 24-59 months were 110.2g/L [109.5, 110.9]; and in children 5-11 years were 114.1g/L [113.2, 115.0]. Thresholds diverged by sex in adolescents and adults. In females and males 12-17 years, thresholds were 122.2g/L [121.3, 123.1] and 128.2 [126.4, 130.0], respectively. In adults 18-65 years, thresholds were 119.7g/L [119.1, 120.3] in non-pregnant females and 134.9g/L [134.2, 135.6] in males. Limited analyses indicated 5thcentiles in first-trimester pregnancy of 110.3g/L [109.5, 111.0] and 105.9g/L [104.0, 107.7] in the second trimester. All thresholds were robust to variations in definitions and analysis models. Using multiple datasets comprising Asian, African, and European ancestries, we did not identify novel high prevalence genetic variants that influence haemoglobin concentration, other than variants in genes known to cause important clinical disease, suggesting non-clinical genetic factors do not influence the 5thcentile between ancestries. Our results directly inform WHO guideline development and provide a platform for global harmonisation of laboratory, clinical and public health haemoglobin thresholds.
Long-term optical imaging of the spinal cord in awake, behaving animals
Authors: Ahanonu Biafra , Crowther Andrew , Kania Artur , Casillas Mariela Rosa , Basbaum Allan 
Published: May 2023

ABSTRACTAdvances in optical imaging approaches and fluorescent biosensors have enabled an understanding of the spatiotemporal and long-term neural dynamics in the brain of awake animals. However, methodological difficulties and the persistence of post-laminectomy fibrosis have greatly limited similar advances in the spinal cord. To overcome these technical obstacles, we combinedin vivoapplication of fluoropolymer membranes that inhibit fibrosis; a redesigned, cost-effective implantable spinal imaging chamber; and improved motion correction methods that together permit imaging of the spinal cord in awake, behaving mice, for months to over a year. We also demonstrate a robust ability to monitor axons, identify a spinal cord somatotopic map, conduct Ca2+imaging of neural dynamics in behaving animals responding to pain-provoking stimuli, and observe persistent microglial changes after nerve injury. The ability to couple neural activity and behavior at the spinal cord level will drive insights not previously possible at a key location for somatosensory transmission to the brain.
The adiponectin analogue ALY688-SR attenuates diaphragm fibrosis, atrophy and mitochondrial stress in a mouse model of Duchenne muscular dystrophy
Authors: Bellissimo Catherine A. , Gandhi Shivam , Castellani Laura N. , Murugathasan Mayoorey , Delfinis Luca J. , Thuhan Arshdeep , Garibotti Madison C. , Seo Yeji , Rebalka Irena A. , Sweeney Gary , Hawke Thomas J. , Abdul-Sater Ali A. , Perry Christopher G.R. 
Published: May 2023

AbstractFibrosis is associated with respiratory and limb muscle atrophy in Duchenne muscular dystrophy (DMD). Current standard of care partially delays the progression of this myopathy but there remains an unmet need to develop additional therapies. Adiponectin receptor agonism has emerged as a possible therapeutic target to lower inflammation and improve metabolism inmdxmouse models of DMD but the degree to which fibrosis and atrophy are prevented remain unknown. Here, we demonstrate that the recently developed slow-release peptidomimetic adiponectin analogue ALY688-SR prevents fibrosis and fibre type-specific atrophy in diaphragm of D2.mdxmice treated from days 7-28 of age. ALY688-SR also lowered IL-6mRNA but increased IL-6 and TGF-β protein contents in diaphragm, suggesting dynamic inflammatory remodeling. ALY688-SR alleviated mitochondrial redox stress by decreasing complex I-stimulated H2O2emission. Treatment also loweredin vitrodiaphragm force production in diaphragm suggesting a complex relationship between adiponectin receptor activity, muscle remodeling and force generating properties during the very early stages of disease progression in D2.mdxmice. In tibialis anterior, the modest fibrosis at this young age was not altered by treatment, and atrophy was not apparent at this young age. These results demonstrate that short-term treatment of ALY688-SR partially prevents fibrosis and atrophy in the more disease-apparent diaphragm of young D2.mdxmice in relation to lower mitochondrial redox stress. These results provide a foundation for the exploration of slow-release adiponectin-based therapies to prevent fibrosis and atrophy in Duchenne muscular dystrophy.
Prudent burrow-site selection in a landscape of fear
Authors: Torsekar Viraj R. , Lajmi Aparna , Hawlena Dror 
Published: May 2023

AbstractPrey should select safer breeding sites over riskier sites of otherwise similar habitats. This preference, however, may differ between conspecifics of different competitive abilities if the costs of intraspecific competition overpower the benefits of breeding in a safer site. Our goal was to test this hypothesis by exploring the burrow-site selection of different-sized desert isopods (Hemilepistus reaumuri) near and away from a scorpion burrow. We found that larger females are more likely to occupy burrows than smaller females, regardless of whether these burrows were close or away from scorpion burrows. We also found that larger females stayed longer in safer burrows and that smaller females tended to stay longer in riskier sites even in the absence of direct competition, implying a prudent burrow-site selection. We found no association between male size and the tendency to occupy or to spend time in a burrow, regardless of whether these burrows were close or away from scorpion burrows. Our work highlights the need to consider intraspecific competition when exploring how predators regulate prey behavior.
The Structural Role of N170 in Substrate-assisted Deacylation in KPC-2 β-Lactamase
Authors: Parwana Diksha , Gu Jing , Chen Shuang , Bethel Christopher R. , Marshall Emma , Hujer Andrea M. , Bonomo Robert A. , Haider Shozeb 
Published: May 2023

AbstractThe amino acid substitutions inKlebsiella pneumoniaecarbapenemase 2 (KPC-2) that have arisen in the clinic are observed to lead to the development of resistance to ceftazidime-avibactam, a preferred treatment for KPC bearing Gram-negative bacteria. Specific substitutions in the omega loop (R164-D179) results in changes in the structure and function of the enzyme, leading to alterations in substrate specificity, decreased stability, and more recently observed, increased resistance to ceftazidime/avibactam. Using accelerated rare-event sampling well-tempered metadynamics simulations, we explored in detail the structural role of R164 and D179 variants that are described to confer ceftazidime/avibactam resistance. The buried conformation of D179 substitutions produce a pronounced structural disorder in the omega loop - more than R164 mutants, where the crystallographic omega loop structure remains mostly intact. Our findings also reveal that the conformation of N170 plays an underappreciated role impacting drug binding and restricting deacylation. The results further support the hypothesis that KPC-2 D179 variants employ substrate-assisted catalysis for ceftazidime hydrolysis, involving the ring amine of the aminothiazole group to promote deacylation and catalytic turnover. Moreover, the shift in the WT conformation of N170 contributes to reduced deacylation and altered spectrum of enzymatic activity.
Causal evidence that herpes zoster vaccination prevents a proportion of dementia cases
Authors: Eyting Markus , Xie Min , Heß Simon , Heß Simon , Geldsetzer Pascal 
Published: May 2023

AbstractThe root causes of dementia are still largely unclear, and the medical community lacks highly effective preventive and therapeutic pharmaceutical agents for dementia despite large investments into their development. There is growing interest in the question if infectious agents play a role in the development of dementia, with herpesviruses attracting particular attention. To provide causal as opposed to merely correlational evidence on this question, we take advantage of the fact that in Wales eligibility for the herpes zoster vaccine (Zostavax) for shingles prevention was determined based on an individual’s exact date of birth. Those born before September 2 1933 were ineligible and remained ineligible for life, while those born on or after September 2 1933 were eligible to receive the vaccine. By using country-wide data on all vaccinations received, primary and secondary care encounters, death certificates, and patients’ date of birth in weeks, we first show that the percentage of adults who received the vaccine increased from 0.01% among patients who were merely one week too old to be eligible, to 47.2% among those who were just one week younger. Apart from this large difference in the probability of ever receiving the herpes zoster vaccine, there is no plausible reason why those born just one week prior to September 2 1933 should differ systematically from those born one week later. We demonstrate this empirically by showing that there were no systematic differences (e.g., in pre-existing conditions or uptake of other preventive interventions) between adults across the date-of-birth eligibility cutoff, and that there were no other interventions that used the exact same date-of-birth eligibility cutoff as was used for the herpes zoster vaccine program. This unique natural randomization, thus, allows for robust causal, rather than correlational, effect estimation. We first replicate the vaccine’s known effect from clinical trials of reducing the occurrence of shingles. We then show that receiving the herpes zoster vaccine reduced the probability of a new dementia diagnosis over a follow-up period of seven years by 3.5 percentage points (95% CI: 0.6 – 7.1, p=0.019), corresponding to a 19.9% relative reduction in the occurrence of dementia. Besides preventing shingles and dementia, the herpes zoster vaccine had no effects on any other common causes of morbidity and mortality. In exploratory analyses, we find that the protective effects from the vaccine for dementia are far stronger among women than men. Randomized trials are needed to determine the optimal population groups and time interval for administration of the herpes zoster vaccine to prevent or delay dementia, as well as to quantify the magnitude of the causal effect when more precise measures of cognition are used. Our findings strongly suggest an important role of the varicella zoster virus in the etiology of dementia.
Pathformer: a biological pathway informed Transformer integrating multi-omics data for disease diagnosis and prognosis
Authors: Liu Xiaofan , Tao Yuhuan , Cai Zilin , Bao Pengfei , Ma Hongli , Li Kexing , Li Mengtao , Zhu Yunping , Lu Zhi John 
Published: May 2023

AbstractMulti-omics data provide a comprehensive view of gene regulation at multiple levels, which is helpful in achieving accurate diagnosis of complex diseases like cancer. To integrate various multi-omics data of tissue and liquid biopsies for disease diagnosis and prognosis, we developed a biological pathway informed Transformer, Pathformer. It embeds multi-omics input with a compacted multi-modal vector and a pathway-based sparse neural network. Pathformer also leverages criss-cross attention mechanism to capture the crosstalk between different pathways and modalities. We first benchmarked Pathformer with 18 comparable methods on multiple cancer datasets, where Pathformer outperformed all the other methods, with an average improvement of 6.3%-14.7% in F1 score for cancer survival prediction and 5.1%-12% for cancer stage prediction. Subsequently, for cancer prognosis prediction based on tissue multi-omics data, we used a case study to demonstrate the biological interpretability of Pathformer by identifying key pathways and their biological crosstalk. Then, for cancer early diagnosis based on liquid biopsy data, we used plasma and platelet datasets to demonstrate Pathformer’s potential of clinical applications in cancer screen. Moreover, we revealed deregulation of interesting pathways (e.g., scavenger receptor pathway) and their crosstalk in cancer patients’ blood, providing new candidate targets for cancer microenvironment study.
Endogenous pathology in tauopathy mice progresses via brain networks
Authors: Ramirez Denise M.O. , Whitesell Jennifer D. , Bhagwat Nikhil , Thomas Talitha L. , Ajay Apoorva D. , Nawaby Ariana , Delatour Benoît , Bay Sylvie , LaFaye Pierre , Knox Joseph E. , Harris Julie A. , Meeks Julian P. , Diamond Marc I. 
Published: May 2023

AbstractNeurodegenerative tauopathies are hypothesized to propagate via brain networks. This is uncertain because we have lacked precise network resolution of pathology. We therefore developed whole-brain staining methods with anti-p-tau nanobodies and imaged in 3D PS19 tauopathy mice, which have pan-neuronal expression of full-length human tau containing the P301S mutation. We analyzed patterns of p-tau deposition across established brain networks at multiple ages, testing the relationship between structural connectivity and patterns of progressive pathology. We identified core regions with early tau deposition, and used network propagation modeling to determine the link between tau pathology and connectivity strength. We discovered a bias towards retrograde network-based propagation of tau. This novel approach establishes a fundamental role for brain networks in tau propagation, with implications for human disease.One-Sentence SummaryNovel whole brain imaging of p-tau deposition reveals retrograde-dominant network propagation in a tauopathy mouse model.
Acoustically-Targeted Measurement of Transgene Expression in the Brain
Authors: Seo Joon Pyung , Trippett James S. , Huang Zhimin , Wang Ryan Z. , Lee Sangsin , Szablowski Jerzy O. 
Published: May 2023

ABSTRACTGene expression is a critical component of brain physiology and activity, but monitoring this expression in the living brain represents a significant challenge. Here, we introduce a new paradigm called Recovery of Markers through InSonation (REMIS) for noninvasive measurement of gene expression in the brain with cell-type, spatial, and temporal specificity. Our approach relies on engineered protein markers that are designed to be expressed in neurons and exit into the interstitium. By applying ultrasound to targeted brain regions, these markers are released into the bloodstream, where they can be readily detected using biochemical techniques. REMIS can noninvasively confirm gene delivery and measure endogenous signaling in specific brain sites through a simple insonation and a subsequent blood test. Using REMIS, we successfully measured chemogenetic induction of neuronal activity in ultrasound-tar-geted brain regions. REMIS recovery of markers is reliable and demonstrated improved recovery of markers from the brain into the blood in every tested animal. Overall, our work establishes a noninvasive, spatially-specific means of monitoring gene delivery outcomes and endogenous signaling in mammalian brains, opening up possibilities for brain research and noninvasive monitoring of gene therapies in the brain.
Design of optimal labeling patterns for optical genome mapping via information theory
Authors: Nogin Yevgeni , Bar-Lev Daniella , Hanania Dganit , Detinis Zur Tahir , Ebenstein Yuval , Yaakobi Eitan , Weinberger Nir , Shechtman Yoav 
Published: May 2023

AbstractOptical genome mapping (OGM) is a technique that extracts partial genomic information from optically imaged and linearized DNA fragments containing fluorescently labeled short sequence patterns. This information can be used for various genomic analyses and applications, such as the detection of structural variations and copy-number variations, epigenomic profiling, and microbial species identification. Currently, the choice of labeled patterns is based on the available bio-chemical methods, and is not necessarily optimized for the application. In this work, we develop a model of OGM based on information theory, which enables the design of optimal labeling patterns for specific applications and target organism genomes. We validated the model through experimental OGM on human DNA and simulations on bacterial DNA. Our model predicts up to 10-fold improved accuracy by optimal choice of labeling patterns, which may guide future development of OGM bio-chemical labeling methods and significantly improve its accuracy and yield for applications such as epigenomic profiling and cultivation-free pathogen identification in clinical samples.