bluuebunny/crossref_metadata_2025 huggingface dataset:
Comprehensive DNA methylation profiling by MeDIP-NGS identifies potential genes and pathways for epithelial ovarian cancer
Authors: Gautam Priyanka , Gupta Sameer , Sachan Manisha
Published: April 2024

Ovarian cancer, among all gynecologic malignancies, exhibits the highest incidence and mortality rate, primarily because it is often presents with non-specific or no symptoms during its early stages. For the advancement of Ovarian Cancer Diagnosis, it is crucial to identify the potential molecular signatures that could significantly differentiate between healthy and ovarian cancerous tissues and can be used further as a diagnostic biomarker for detecting ovarian cancer. In this study, we investigated the genome-wide methylation patterns in ovarian cancer patients using Methylated DNA Immunoprecipitation (MeDIP-Seq) followed by NGS. Identified differentially methylated regions (DMRs) were further validated by targeted bisulfite sequencing for CpG site-specific methylation profiles. Furthermore, expression validation of six genes by Quantitative Reverse Transcriptase-PCR was also performed. Out of total 120 differentially methylated genes (DMGs), 68 genes were hypermethylated, and 52 were hypomethylated in their promoter region. After analysis, we identified the top 6 hub genes, namely POLR3B, PLXND1, GIGYF2, STK4, BMP2 and CRKL. Interestingly we observed Non-CpG site methylation in the case of POLR3B and CRKL which was statistically significant in discriminating ovarian cancer samples from normal controls. The most significant pathways identified were focal adhesion, the MAPK signaling pathway, and the Ras signaling pathway. Expression analysis of hypermethylated genes was correlated with the downregulation of the genes. POLR3B and GIGYF2 turned out to be the novel genes associated with the carcinogenesis of EOC. Our study demonstrated that methylation profiling through MeDIP-sequencing has effectively identified six potential hub genes and pathways that might exacerbate our understanding of underlying molecular mechanisms of ovarian carcinogenesis.
Mortality rates in Norwegian HEMS—a retrospective analysis from Central Norway
Authors: Wekre Stian Lande , Uleberg Oddvar , Næss Lars Eide , Haugland Helge
Published: April 2024

Background

Helicopter Emergency Medical Services (HEMS) provide rapid and specialized care to critically ill or injured patients. Norwegian HEMS in Central Norway serves an important role in pre-hospital emergency medical care. To grade the severity of patients, HEMS uses the National Advisory Committee for Aeronautics’ (NACA) severity score. The objective of this study was to describe the short- and long term mortality overall and in each NACA-group for patients transported by HEMS Trondheim using linkage of HEMS and hospital data.

Methods

The study used a retrospective cohort design, aligning with the STROBE recommendations. Patient data from Trondheim HEMS between 01.01.2017 and 31.12.2019 was linked to mortality data from a hospital database and analyzed. Kaplan Meier plots and cumulative mortality rates were calculated for each NACA group at day one, day 30, and one year and three years after the incident.

Results

Trondheim HEMS responded to 2224 alarms in the included time period, with 1431 patients meeting inclusion criteria for the study. Overall mortality rates at respective time points were 10.1% at day one, 13.4% at 30 days, 18.5% at one year, and 22.3% at three years. The one-year cumulative mortality rates for each NACA group were as follows: 0% for NACA 1 and 2, 2.9% for NACA 3, 10.1% for NACA 4, 24.7% for NACA 5 and 49.5% for NACA 6. Statistical analysis with a global log-rank test indicated a significant difference in survival outcomes among the groups (p < 2⋅10− 16).

Conclusion

Among patients transported by Trondheim HEMS, we observed an incremental rise in mortality rates with increasing NACA scores. The study further suggests that a one-year follow-up may be sufficient for future investigations into HEMS outcomes.
Characterizing glucokinase variant mechanisms using a multiplexed abundance assay
Authors: Gersing Sarah , Schulze Thea K. , Cagiada Matteo , Stein Amelie , Roth Frederick P. , Lindorff-Larsen Kresten , Hartmann-Petersen Rasmus
Published: April 2024

Background

Amino acid substitutions can perturb protein activity in multiple ways. Understanding their mechanistic basis may pinpoint how residues contribute to protein function. Here, we characterize the mechanisms underlying variant effects in human glucokinase (GCK) variants, building on our previous comprehensive study on GCK variant activity.

Results

Using a yeast growth-based assay, we score the abundance of 95% of GCK missense and nonsense variants. When combining the abundance scores with our previously determined activity scores, we find that 43% of hypoactive variants also decrease cellular protein abundance. The low-abundance variants are enriched in the large domain, while residues in the small domain are tolerant to mutations with respect to abundance. Instead, many variants in the small domain perturb GCK conformational dynamics which are essential for appropriate activity.

Conclusions

In this study, we identify residues important for GCK metabolic stability and conformational dynamics. These residues could be targeted to modulate GCK activity, and thereby affect glucose homeostasis.
National genomic epidemiology investigation revealed the spread of carbapenem-resistant Escherichia coli in healthy populations and the impact on public health
Authors: Li Yan , Zhang Yanyan , Sun Xinran , Wu Yuchen , Yan Zelin , Ju Xiaoyang , Huang Yonglu , Zhou Hongwei , Wang Zhiqiang , Wang Shaolin , Zhang Rong , Li Ruichao
Published: April 2024

Background

Carbapenem-resistant Escherichia coli (CREC) has been considered as WHO priority pathogens, causing a great public health concern globally. While CREC from patients has been thoroughly investigated, the prevalence and underlying risks of CREC in healthy populations have been overlooked. Systematic research on the prevalence of CREC in healthy individuals was conducted here. We aimed to characterize CREC collected from healthy populations in China between 2020 and 2022 and to compare the genomes of CREC isolates isolated from healthy individuals and clinical patients.

Methods

We present a nationwide investigation of CREC isolates among healthy populations in China, employing robust molecular and genomic analyses. Antimicrobial susceptibility testing, whole-genome sequencing, and bioinformatics were utilized to analyze a cohort of CREC isolates (n = 113) obtained from fecal samples of 5 064 healthy individuals. Representative plasmids were extracted for third-generation nanopore sequencing. We previously collected 113 non-duplicate CREC isolates (59 in 2018, 54 in 2020) collected from ICU patients in 15 provinces and municipalities in China, and these clinical isolates were used to compare with the isolates in this study. Furthermore, we employ comparative genomics approaches to elucidate molecular variations and potential correlations between clinical and non-clinical CREC isolates.

Results

A total of 147 CREC isolates were identified from 5 064 samples collected across 11 provinces in China. These isolates were classified into 64 known sequence types (STs), but no dominant STs were observed. In total, seven carbapenemase genes were detected with blaNDM-5 (n = 116) being the most prevalent one. Genetic environments and plasmid backbones of blaNDM were conserved in CREC isolated from healthy individuals. Furthermore, we compared clinical and healthy human-originated CRECs, revealing noteworthy distinctions in 23 resistance genes, including blaNDM-1, blaNDM-5, and blaKPC (χ2 test, p < 0.05). Clinical isolates contained more virulence factors associated with iron uptake, adhesion, and invasion than those obtained from healthy individuals. Notably, CREC isolates generally found healthy people are detected in hospitalized patients.

Conclusions

Our findings underscore the significance of healthy populations-derived CRECs as a crucial reservoir of antibiotic resistance genes (ARGs). This highlights the need for ongoing monitoring of CREC isolates in healthy populations to accurately assess the potential risks posed by clinical CREC isolates.
Monoallelic KRAS (G13C) mutation triggers dysregulated expansion in induced pluripotent stem cell-derived hematopoietic progenitor cells
Authors: Lin Huan-Ting , Takagi Masatoshi , Kubara Kenji , Yamazaki Kazuto , Michikawa Fumiko , Okumura Takashi , Naruto Takuya , Morio Tomohiro , Miyazaki Koji , Taniguchi Hideki , Otsu Makoto
Published: April 2024

Background

Although oncogenic RAS mutants are thought to exert mutagenic effects upon blood cells, it remains uncertain how a single oncogenic RAS impacts non-transformed multipotent hematopoietic stem or progenitor cells (HPCs). Such potential pre-malignant status may characterize HPCs in patients with RAS-associated autoimmune lymphoproliferative syndrome-like disease (RALD). This study sought to elucidate the biological and molecular alterations in human HPCs carrying monoallelic mutant KRAS (G13C) with no other oncogene mutations.

Methods

We utilized induced pluripotent stem cells (iPSCs) derived from two unrelated RALD patients. Isogenic HPC pairs harboring either wild-type KRAS or monoallelic KRAS (G13C) alone obtained following differentiation enabled reliable comparative analyses. The compound screening was conducted with an established platform using KRAS (G13C) iPSCs and differentiated HPCs.

Results

Cell culture assays revealed that monoallelic KRAS (G13C) impacted both myeloid differentiation and expansion characteristics of iPSC-derived HPCs. Comprehensive RNA-sequencing analysis depicted close clustering of HPC samples within the isogenic group, warranting that comparative studies should be performed within the same genetic background. When compared with no stimulation, iPSC-derived KRAS (G13C)-HPCs showed marked similarity with the wild-type isogenic control in transcriptomic profiles. After stimulation with cytokines, however, KRAS (G13C)-HPCs exhibited obvious aberrant cell-cycle and apoptosis responses, compatible with "dysregulated expansion," demonstrated by molecular and biological assessment. Increased BCL-xL expression was identified amongst other molecular changes unique to mutant HPCs. With screening platforms established for therapeutic intervention, we observed selective activity against KRAS (G13C)-HPC expansion in several candidate compounds, most notably in a MEK- and a BCL-2/BCL-xL-inhibitor. These two compounds demonstrated selective inhibitory effects on KRAS (G13C)-HPCs even with primary patient samples when combined.

Conclusions

Our findings indicate that a monoallelic oncogenic KRAS can confer dysregulated expansion characteristics to non-transformed HPCs, which may constitute a pathological condition in RALD hematopoiesis. The use of iPSC-based screening platforms will lead to discovering treatments that enable selective inhibition of RAS-mutated HPC clones.
Classification of substances by health hazard using deep neural networks and molecular electron densities
Authors: Singh Satnam , Zeh Gina , Freiherr Jessica , Bauer Thilo , Türkmen Isik , Grasskamp Andreas T.
Published: April 2024

In this paper we present a method that allows leveraging 3D electron density information to train a deep neural network pipeline to segment regions of high, medium and low electronegativity and classify substances as health hazardous or non-hazardous. We show that this can be used for use-cases such as cosmetics and food products. For this purpose, we first generate 3D electron density cubes using semiempirical molecular calculations for a custom European Chemicals Agency (ECHA) subset consisting of substances labelled as hazardous and non-hazardous for cosmetic usage. Together with their 3-class electronegativity maps we train a modified 3D-UNet with electron density cubes to segment reactive sites in molecules and classify substances with an accuracy of 78.1%. We perform the same process on a custom food dataset (CompFood) consisting of hazardous and non-hazardous substances compiled from European Food Safety Authority (EFSA) OpenFoodTox, Food and Drug Administration (FDA) Generally Recognized as Safe (GRAS) and FooDB datasets to achieve a classification accuracy of 64.1%. Our results show that 3D electron densities and particularly masked electron densities, calculated by taking a product of original electron densities and regions of high and low electronegativity can be used to classify molecules for different use-cases and thus serve not only to guide safe-by-design product development but also aid in regulatory decisions.

Scientific contribution

We aim to contribute to the diverse 3D molecular representations used for training machine learning algorithms by showing that a deep learning network can be trained on 3D electron density representation of molecules. This approach has previously not been used to train machine learning models and it allows utilization of the true spatial domain of the molecule for prediction of properties such as their suitability for usage in cosmetics and food products and in future, to other molecular properties. The data and code used for training is accessible at https://github.com/s-singh-ivv/eDen-Substances.
Protocol for a systematic review and meta-analysis of the prevalence of mental illness among nursing home residents
Authors: Holt Jared , Bhar Sunil , Schofield Penelope , Koder Deborah , Owen Patrick , Seitz Dallas , Bhowmik Jahar
Published: April 2024

Background

There is a high prevalence of mental illness in nursing home residents compared to older adults living in the community. This was highlighted in the most recent comprehensive systematic review on the topic, published in 2010. In the context of a rapidly aging population and increased numbers of older adults requiring residential care, this study aims to provide a contemporary account of the prevalence of mental illness among nursing home residents.

Methods

This protocol was prepared in line with the PRISMA-P 2015 Statement. Systematic searches will be undertaken across six electronic databases: PubMed, Embase, Web of Science, PsycNET, CINAHL, and Abstracts in Social Gerontology. Peer-reviewed studies published from 2009 onwards which report the prevalence of mental illness within nursing home populations will be included. Database searches will be supplemented by forward and backward citation searching. Titles and abstracts of records will be screened using a semi-automated process. The full text of selected records will be assessed to confirm inclusion criteria are met. Study selection will be recorded in a PRISMA flowchart. A pilot-tested form will be used to extract data from included studies, alongside the JBI Critical Appraisal Checklist for Studies Reporting Prevalence Data. A study characteristics and results table will be prepared to present key details from each included study, supported by a narrative synthesis. Random-effects restricted maximum likelihood meta-analyses will be performed to compute pooled prevalence estimates for mental illnesses represented in the identified studies. Heterogeneity will be assessed using Cochran’s Q and Higgins’ I2 statistics. A Funnel plot and Egger’s test will be used to assess publication bias. The GRADE approach will be used to assess the quality of the body of evidence identified.

Discussion

The study will provide a comprehensive and contemporary account of the prevalence of mental illness among nursing home residents. Meta-analyses will provide robust prevalence estimates across a range of presentations. Key insights will be highlighted, including potential sources of heterogeneity. Implications for residents, researchers, care providers, and policymakers will be noted.

Systematic review registration

PROSPERO: CRD42023456226.
Efficacy and safety of antibiotics for treatment of leptospirosis: a systematic review and network meta-analysis
Authors: Ji Zhenhua , Jian Miaomiao , Su Xuan , Pan Yingyi , Duan Yi , Ma Weijie , Zhong Lei , Yang Jiaru , Song Jieqin , Wu Xinya , Gao Li , Ma Weijiang , Kong Jing , Li Bingxue , Chen Jinjing , Liu Meixiao , Fan Yuxin , Peng Li , Dong Yan , Bao Fukai , Liu Aihua
Published: April 2024

Background

Leptospirosis, an important zoonotic bacterial disease, commonly affects resource-poor populations and results in significant morbidity and mortality worldwide. The value of antibiotics in leptospirosis remains unclear, as evidenced by the conflicting opinions published.

Methods

We conducted a search in the PubMed, Web of Science, and Cochrane Library databases for studies. These studies included clinical trials and retrospective studies that evaluated the efficacy or safety of antibiotics for leptospirosis treatment. The primary outcomes assessed were defervescence time, mortality rate, and hospital stays. Subgroup analyses were performed based on whether there were cases involving children and whether there were cases of severe jaundice. Safety was defined as the prevalence of adverse events associated with the use of antibiotics. p scores were utilized to rank the efficacy of the antibiotics.

Results

There are included 9 randomized controlled trials (RCTs), 1 control trial (CT), and 3 retrospective studies (RS) involving 920 patients and 8 antibiotics. Six antibiotics resulted in significantly shorter defervescence times compared to the control, namely cefotaxime (MD, − 1.88; 95% CI =  − 2.60 to − 1.15), azithromycin (MD, − 1.74; 95% CI =  − 2.52 to − 0.95), doxycycline (MD, − 1.53; 95% CI =  − 2.05 to − 1.00), ceftriaxone (MD, − 1.22; 95% CI =  − 1.89 to − 0.55), penicillin (MD, − 1.22; 95% CI =  − 1.80 to − 0.64), and penicillin or ampicillin (MD, − 0.08; 95% CI =  − 1.01 to − 0.59). The antibiotics were not effective in reducing the mortality and hospital stays. Common adverse reactions to antibiotics included Jarisch–Herxheimer reaction, rash, headache, and digestive reactions (nausea, vomiting, diarrhea, abdominal pain, and others).

Conclusions

Findings recommend that leptospirosis patients be treated with antibiotics, which significantly reduced the leptospirosis defervescence time. Cephalosporins, doxycycline, and penicillin are suggested, and azithromycin may be a suitable alternative for drug-resistant cases.

Systematic review registration

PROSPERO CRD42022354938.
Novel results for separate families of fuzzy-dominated mappings satisfying advanced locally contractions in b-multiplicative metric spaces with applications
Authors: Rasham Tahair , Qadir Romana , Hasan Fady , Agarwal R. P. , Shatanawi Wasfi
Published: April 2024

The objective of this research is to present new fixed point theorems for two separate families of fuzzy-dominated mappings. These mappings must satisfy a unique locally contraction in a complete b-multiplicative metric space. Also, we have obtained novel results for families of fuzzy-dominated mappings on a closed ball that meet the requirements of a generalized locally contraction. This research introduces new and challenging fixed-point problems for families of ordered fuzzy-dominated mappings in ordered complete b-multiplicative metric spaces. Moreover, we demonstrate a new concept for families of fuzzy graph-dominated mappings on a closed ball in these spaces. Additionally, we present novel findings for graphic contraction endowed with graphic structure. These findings are groundbreaking and provide a strong foundation for future research in this field. To demonstrate the uniqueness of our novel findings, we provide evidence of their applicability in obtaining the common solution of integral and fractional differential equations. Our findings have resulted in modifications to several contemporary and classical results in the research literature. This provides further evidence of the originality and impact of our work.
Dynamical behaviors of a stochastic SIRV epidemic model with the Ornstein–Uhlenbeck process
Authors: Shang Jiaxin , Li Wenhe
Published: April 2024

Vaccination is an important tool in disease control to suppress disease, and vaccine-influenced diseases no longer conform to the general pattern of transmission. In this paper, by assuming that the infection rate is affected by the Ornstein–Uhlenbeck process, we obtained a stochastic SIRV model. First, we prove the existence and uniqueness of the global positive solution. Sufficient conditions for the extinction and persistence of the disease are then obtained. Next, by creating an appropriate Lyapunov function, the existence of the stationary distribution for the model is proved. Further, the explicit expression for the probability density function of the model around the quasi-equilibrium point is obtained. Finally, the analytical outcomes are examined by numerical simulations.
FiTMuSiC: leveraging structural and (co)evolutionary data for protein fitness prediction
Authors: Tsishyn Matsvei , Cia Gabriel , Hermans Pauline , Kwasigroch Jean , Rooman Marianne , Pucci Fabrizio
Published: April 2024

Systematically predicting the effects of mutations on protein fitness is essential for the understanding of genetic diseases. Indeed, predictions complement experimental efforts in analyzing how variants lead to dysfunctional proteins that in turn can cause diseases. Here we present our new fitness predictor, FiTMuSiC, which leverages structural, evolutionary and coevolutionary information. We show that FiTMuSiC predicts fitness with high accuracy despite the simplicity of its underlying model: it was among the top predictors on the hydroxymethylbilane synthase (HMBS) target of the sixth round of the Critical Assessment of Genome Interpretation challenge (CAGI6) and performs as well as much more complex deep learning models such as AlphaMissense. To further demonstrate FiTMuSiC’s robustness, we compared its predictions with in vitro activity data on HMBS, variant fitness data on human glucokinase (GCK), and variant deleteriousness data on HMBS and GCK. These analyses further confirm FiTMuSiC’s qualities and accuracy, which compare favorably with those of other predictors. Additionally, FiTMuSiC returns two scores that separately describe the functional and structural effects of the variant, thus providing mechanistic insight into why the variant leads to fitness loss or gain. We also provide an easy-to-use webserver at https://babylone.ulb.ac.be/FiTMuSiC, which is freely available for academic use and does not require any bioinformatics expertise, which simplifies the accessibility of our tool for the entire scientific community.
Quantitative analysis methods for evaluating colour on architectural heritage: survey of colour restoration and perception of the Wen Yuan Ge in the Forbidden City
Authors: Shao Jie , Li Luke , Jiang Yutong , Liu Xin , Yang Hong
Published: April 2024

Three methods can be used to evaluate the colour used on architectural heritage: manual evaluation, instrumental measurement, and process restoration. Optical instruments that can obtain relatively accurate chromaticity data are ideal. As architectural heritage sites age, their colour fluctuates. Researchers must screen colour data and analyse the features based on experience with colour perception. This study combines quantitative colour analysis and a scaled perception survey to analyse the Wen Yuan Ge in the Forbidden City and provide a new reference for researching and designing colour in architectural heritage.
Performance assessment of activated carbon thermally modified with iron in the desulfurization of biogas in a static batch system supported by headspace gas chromatography
Authors: Montaño Mayerlin Edith Acuña , Effting Luciane , Guedes Carmen Luisa Barbosa , Arizaga Gregorio Guadalupe Carbajal , Giona Renata Mello , Cordeiro Patricia Hissae Yassue , Tarley César Ricardo Teixeira , Bail Alesandro
Published: April 2024

A static batch arrangement composed of anti-leak vials coupled to gas chromatography is proposed as a complementary system for performance assessment of biogas desulfurization by adsorption. For testing, a modified commercial activated carbon produced by controlled thermal treatment in the presence of iron(III) species improved biogas desulfurization. The adsorbents showed a superior hydrogen sulfide removal compared to ordinary one. Pseudo-first-order, pseudo-second-order, and Bangham’s kinetic models were used to fit experimental data. All studied samples followed pseudo-first-order model, indicating the predominance of physisorption, and Bangham’s model, confirming that the micropores structure played an important role for gases diffusion and adsorbent capacity. Additionally, the materials were characterized by N2 adsorption–desorption, X-ray diffraction, infrared spectroscopy, scanning electron microscopy and energy-dispersive spectroscopy. The thermal treatment associated with iron impregnation caused significant modifications in the surface of the materials, and the iron species showed two main benefits: an expressive increase in the specific area and the formation of specific adsorption sites for hydrogen sulfide removal. The results reinforce the advantages of iron-modified adsorbents in relation to their non-modified counterparts. The analytical methodology based on the confinement of multiple gases contributes to improving the understanding of the hydrogen sulfide adsorption process using pressure swing adsorption technology.

Graphical Abstract
Direct and accurate miRNA detection based on CRISPR/Cas13a-triggered exonuclease-iii-assisted colorimetric assay
Authors: Li Yunxiao , Wang Qiuxia , Wang Yali
Published: April 2024

The abnormally expressed microRNAs (miRNAs) serve as crucial indicators for disease diagnosis and are strongly associated with the progression of various diseases. The quantification of miRNAs is highly significant for the clinical diagnosis and treatment of various types of cancers. This study utilizes the CRISPR/Cas13a system, which combines CRISPR RNA (crRNA) and CRISPR-associated Cas13a, to recognize the miRNA directly and specifically, thus activating the trans-cleavage activity of Cas13a. By integrating the CRISPR-Cas13a system with an exonuclease-iii (Exo-iii)-assisted chain cleavage of silver ions (Ag+)-aptamer and an Ag+ -based color reaction, a method for the detection of miRNA that is specific and sensitive is developed. This approach demonstrated exceptional sensitivity in detecting miRNA, with a low detection limit of 5.12 fM. Moreover, the suggested method was effectively utilized to precisely measure the amount of miRNA in intricate biological samples, demonstrating its practical applicability. Furthermore, due to its elevated sensitivity and simple probe design and fluorophore labeling, the suggested colorimetric technique holds great potential for use in clinical diagnostics.
The Night-Time Sleep and Autonomic Activity of Male and Female Professional Road Cyclists Competing in the Tour de France and Tour de France Femmes
Authors: Sargent Charli , Jasinski Summer , Capodilupo Emily R. , Powers Jeremy , Miller Dean J. , Roach Gregory D.
Published: April 2024

Background

Sleep is a critical component of recovery, but it can be disrupted following prolonged endurance exercise. The objective of this study was to examine the capacity of male and female professional cyclists to recover between daily race stages while competing in the 2022 Tour de France and the 2022 Tour de France Femmes, respectively. The 17 participating cyclists (8 males from a single team and 9 females from two teams) wore a fitness tracker (WHOOP 4.0) to capture recovery metrics related to night-time sleep and autonomic activity for the entirety of the events and for 7 days of baseline before the events. The primary analyses tested for a main effect of ‘stage classification’—i.e., rest, flat, hilly, mountain or time trial for males and flat, hilly or mountain for females—on the various recovery metrics.

Results

During baseline, total sleep time was 7.2 ± 0.3 h for male cyclists (mean ± 95% confidence interval) and 7.7 ± 0.3 h for female cyclists, sleep efficiency was 87.0 ± 4.4% for males and 88.8 ± 2.6% for females, resting HR was 41.8 ± 4.5 beats·min−1 for males and 45.8 ± 4.9 beats·min−1 for females, and heart rate variability during sleep was 108.5 ± 17.0 ms for males and 119.8 ± 26.4 ms for females. During their respective events, total sleep time was 7.2 ± 0.1 h for males and 7.5 ± 0.3 h for females, sleep efficiency was 86.4 ± 1.2% for males and 89.6 ± 1.2% for females, resting HR was 44.5 ± 1.2 beats·min−1 for males and 50.2 ± 2.0 beats·min−1 for females, and heart rate variability during sleep was 99.1 ± 4.2 ms for males and 114.3 ± 11.2 ms for females. For male cyclists, there was a main effect of ‘stage classification’ on recovery, such that heart rate variability during sleep was lowest after mountain stages. For female cyclists, there was a main effect of ‘stage classification’ on recovery, such that the percentage of light sleep (i.e., lower-quality sleep) was highest after mountain stages.

Conclusions

Some aspects of recovery were compromised after the most demanding days of racing, i.e., mountain stages. Overall however, the cyclists obtained a reasonable amount of good-quality sleep while competing in these physiologically demanding endurance events. This study demonstrates that it is now feasible to assess recovery in professional athletes during multiple-day endurance events using validated fitness trackers.
Advancements in alveolar bone grafting and ridge preservation: a narrative review on materials, techniques, and clinical outcomes
Authors: Kim Suyoung , Kim Seong-Gon
Published: April 2024

This narrative review systematically explores the progression of materials and techniques in alveolar ridge preservation (ARP). We commence by delineating the evolution from traditional ARP methods to cutting-edge alternatives, including platelet-rich fibrin, injectable bone repair materials, and hydrogel systems. Critical examination of various studies reveals these innovative approaches not only accelerate bone healing but also significantly improve patient-reported outcomes, such as satisfaction, pain perception, and overall quality of life. Emphasis is placed on the correlation between advanced ARP techniques and enhanced patient comfort and clinical efficacy, underscoring their transformative potential in dental implantology. Highlighting the effectiveness of ARP, the implant survival rate over a span of 5 to 7 years was high, showcasing the reliability and success of these methods. Further, patients expressed high aesthetic satisfaction with the soft tissue outcome, evidenced by an average visual analog scale (VAS) score of 94. This positive aesthetic appraisal is linked to the clinical health of implants, potentially due to the employment of tooth-supported surgical guides. The economic analysis reveals a varied cost range for bone graft substitutes ($46.2 to $140) and socket sealing materials ($12 to $189), with a noteworthy correlation between the investment in barrier membranes and the diminished horizontal and vertical ridge resorption. This suggests that membrane usage significantly contributes to preserving ridge dimensions, offering a cost-effective strategy for enhancing ARP outcomes. In conclusion, this review illuminates the significant advancements in ARP, highlighting the shift towards innovative materials and techniques that not only promise enhanced bone regeneration and reduced healing times but also improve patient satisfaction and aesthetic outcomes. The documented high implant survival rate and the beneficial economic implications of membrane use further validate the effectiveness of contemporary ARP strategies, paving the way for their broader adoption in dental implantology.
The implementation of embedded researchers in policy, public services, and commercial settings: a systematic evidence and gap map
Authors: Kneale Dylan , Stansfield Claire , Goldman Rebecca , Lester Sarah , Edwards Rachael C. , Thomas James
Published: April 2024

Background

Embedding researchers into policy and other settings may enhance research capacity within organisations to enable them to become more research active. We aimed to generate an evidence map on evaluations of embedded researcher interventions to (i) identify where systematic reviews and primary research are needed and (ii) develop conceptual understandings of ‘embedded researchers’. We define ‘embedded researchers’ through a set of principles that incorporate elements such as the aim of activities, the types of relationships and learning involved, and the affiliations and identities adopted.

Methods

We included studies published across all sectors, searching fourteen databases, other web sources and two journals for evaluations published between 1991 and spring 2021. Data were extracted using a coding tool developed for this study. We identified new typologies of embedded researcher interventions through undertaking Latent Class Analysis.

Results

The map describes 229 evaluations spanning a variety of contexts. Our set of principles allowed us to move beyond a narrow focus on embedded researchers in name alone, towards consideration of the wide range of roles, activities, identities, and affiliations related to embedded researchers. We identified 108 different allied terms describing an embedded researcher. Embedded researcher activity spanned a continuum across lines of physical, cultural, institutional, and procedural embeddedness (from weaker to more intense forms of embeddedness) and took a range of forms that bridge or blur boundaries between academia and policy/practice.

Conclusions

We developed a broad map of international embedded researcher activity in a wide range of sectors. The map suggests that embedded researcher interventions occupy a broader suite of models than previously acknowledged and our findings also offer insight on the type and nature of this literature. Given the clear policy interest in this area, a better understanding of the processes involved with becoming embedded within an organisation is needed. Further work is also necessary to address the challenges of evaluating the work of embedded researchers, including consideration for which outcome measures are most appropriate, to better understand their influence.
Genetic Susceptibility, Mendelian Randomization, and Nomogram Model Construction of Gestational Diabetes Mellitus
Authors: Liang Qiulian , Li Ming , Huang Gongchen , Li Ruiqi , Qin Linyuan , Zhong Ping , Xing Xuekun , Yu Xiangyuan
Published: April 2024

Context

Gestational diabetes mellitus (GDM) is a pregnancy-complicated disease that poses a risk to maternal and infant health. However, the etiology of the disease has been not yet elucidated.

Objective

To detect the genetic susceptibility and construct a nomogram model with significantly associated polymorphisms and key clinical indicators for early prediction of GDM.

Methods

Eleven functional single nucleotide polymorphisms (SNPs) screened by genome-wide association study were genotyped in 554 GDM cases and 641 healthy controls. Functional analysis of GDM positively associated SNPs, multivariate mendelian randomization (MVMR), and a GDM early predictive nomogram model construction were performed.

Result

rs1965211, rs3760675, and rs7814359 were significantly associated with genetic susceptibility to GDM after adjusting age and prepregnancy body mass index (pre-BMI). It seems that GDM-associated SNPs have effects on regulating target gene transcription factor binding, posttranscriptional splicing, and translation product structure. Besides, rs3760675 can be expression quantitative trait loci and increase the XAB2 mRNA expression level (P = .047). The MVMR analysis showed that the increase of clinical variables of BMI, hemoglobin A1c (HbA1c), and fasting plasma glucose (FPG) had significant causal effects on GDM (BMI-ORMVMR = 1.52, HbA1c-ORMVMR = 1.32, FPG-ORMVMR = 1.78), P < .05. A nomogram model constructed with pre-BMI, FPG, HbA1c, and genotypes of rs1965211, rs3760675, and rs7814359 showed an area under the receiver operating characteristic curve of 0.824.

Conclusion

Functional polymorphisms can change women's susceptibility to GDM and the predictive nomogram model based on genetic and environmental factors can effectively distinguish individuals with different GDM risks in early stages of pregnancy.
Regulation of the Function of T Follicular Helper Cells and B Cells in Type 1 Diabetes Mellitus by the OX40/OX40L Axis
Authors: Du Xuan , Zhu Yan , Lu Wen , Fu Nannan , Wang Qin , Shi Bimin
Published: April 2024

Objective/Main Outcome

To study the expression of OX40 on T follicular helper (Tfh) cells and the ligand OX40L on antigen-presenting cells (APCs) in peripheral blood of patients with type 1 diabetes mellitus (T1DM) and the role of OX40 signaling in promoting Tfh cells to assist B-cell differentiation.

Design

Cross-sectional study.

Setting

Endocrinology department of a university hospital.

Participants

Twenty-five patients with T1DM and 35 with newly diagnosed type 2 diabetes mellitus (T2DM) from January 2021 to December 2021 (39 males, 21 females; mean age: 31.0 ± 4.5, range: 19-46 years).

Interventions

None.

Methods

The peripheral blood proportion of CD4+CD25−CD127+CXCR5+PD1+ Tfh cells in patients with T1DM or T2DM and the OX40L expression in CD14+ monocytes and CD19+ B cells were analyzed by flow cytometry. The OX40 signal effect on Tfh-cell function was analyzed by coincubating B cells with Tfh cells under different conditions. Flow cytometry detected the ratio of CD19−CD138+ plasmacytes.

Results

The Tfh cells ratio and intracellular IL-21 expression in peripheral blood was significantly higher in patients with T1DM than with T2DM, and the OX40 expression in peripheral Tfh cells and OX40L expression in APC were significantly higher in T1DM. After adding OX40L protein, the CD19−CD138+-plasmacytes percentage was significantly increased and higher in T1DM. Blocking of anti-OX40L monoclonal antibodies significantly reduced the plasmacytes ratio.

Conclusion

The peripheral Tfh cells proportion increased and the OX40 expression in peripheral Tfh cells was upregulated in patients with T1DM vs patients with T2DM. OX40/OX40L signaling enhanced the Tfh-cell function to assist B-cell differentiation, which may contribute to the pathogenesis of T1DM.
Characterization of 35 Novel NR5A1/SF-1 Variants Identified in Individuals With Atypical Sexual Development: The SF1next Study
Authors: Naamneh Elzenaty Rawda , Martinez de Lapiscina Idoia , Kouri Chrysanthi , Sauter Kay-Sara , Sommer Grit , Castaño Luis , Flück Christa E
Published: April 2024

Context

Steroidogenic factor 1 (NR5A1/SF-1) is a nuclear receptor that regulates sex development, steroidogenesis, and reproduction. Genetic variants in NR5A1/SF-1 are common among differences of sex development (DSD) and associate with a wide range of phenotypes, but their pathogenic mechanisms remain unclear.

Objective

Novel, likely disease-causing NR5A1/SF-1 variants from the SF1next cohort of individuals with DSD were characterized to elucidate their pathogenic effect.

Methods

Different in silico tools were used to predict the impact of novel NR5A1/SF-1 variants on protein function. An extensive literature review was conducted to compare and select the best functional studies for testing the pathogenic effect of the variants in a classic cell culture model. The missense NR5A1/SF-1 variants were tested on the promoter luciferase reporter vector -152CYP11A1_pGL3 in HEK293T cells and assessed for their cytoplasmic/nuclear localization by Western blot.

Results

Thirty-five novel NR5A1/SF-1 variants were identified in the SF1next cohort. Seventeen missense NR5A1/SF-1 variants were functionally tested. Transactivation assays showed reduced activity for 40% of the variants located in the DNA binding domain and variable activity for variants located elsewhere. Translocation assessment revealed 3 variants (3/17) with affected nuclear translocation. No clear genotype-phenotype, structure-function correlation was found.

Conclusion

Genetic analyses and functional assays do not explain the observed wide phenotype of individuals with these novel NR5A1/SF-1 variants. In 9 individuals, additional likely disease-causing variants in other genes were found, strengthening the hypothesis that the broad phenotype of DSD associated with NR5A1/SF-1 variants may be caused by an oligogenic mechanism.
Association of Acylcarnitines With Maternal Cardiometabolic Risk Factors Is Defined by Chain Length: The S-PRESTO Study
Authors: Chen Li , Goh Xue Ping , Bendt Anne K , Tan Karen Mei-Ling , Leow Melvin Khee-Shing , Tan Kok Hian , Chan Jerry Kok Yen , Chan Shiao-Yng , Chong Yap Seng , Gluckman Peter D , Eriksson Johan G , Wenk Markus R , Mir Sartaj Ahmad
Published: April 2024

Context

Due to the essential role of carnitine as an intermediary in amino acid, carbohydrate, and lipid metabolism, a detailed characterization of circulating and urinary carnitine concentrations will aid in elucidating the molecular basis of impaired maternal metabolic flexibility and facilitating timely intervention for expectant mothers.

Objective

To investigate the association of maternal plasma and urinary free carnitine and acylcarnitines with cardiometabolic risk factors.

Methods

Liquid chromatography tandem mass spectrometry–based quantification of free carnitine and acylcarnitines (C2-C18) was performed on 765 plasma and 702 urine samples collected at preconception, 26 to 28 weeks’ pregnancy, and 3 months postpartum in the Singapore PREconception Study of long-Term maternal and child Outcomes (S-PRESTO) cohort study.

Results

Plasma concentrations of free carnitine and acylcarnitines decreased coupled with increased renal clearance in pregnancy compared with preconception and postpartum. Renal clearance of carnitine increased with an increase in prepregnancy body mass index (ppBMI) and gestational weight gain. Plasma short-chain acylcarnitines were positively associated with ppBMI, irrespective of the physiological state, while medium- and long-chain acylcarnitines were negatively associated with ppBMI at preconception and postpartum but showed a positive association in pregnancy. Similarly, plasma short-chain acylcarnitines were positively associated with Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) whereas medium- and long-chain acylcarnitines were negatively associated with HOMA-IR at preconception and in pregnancy. Mothers who developed gestational diabetes mellitus during pregnancy had ∼10% higher plasma propionylcarnitine concentration and ∼18% higher urine tiglylcarnitine concentration than mothers with normal glucose metabolism at preconception.

Conclusion

This study provides the metabolic and physiological basis of maternal carnitine homeostasis, which can be used in assessment of maternal cardiometabolic health at preconception to improve pregnancy outcomes.
Clinicopathological and Molecular Profile of Sellar Neurocytoma
Authors: Liu Yulou , Guo Jing , Cheng Jianhua , Fang Qiuyue , Wang Dawei , Xie Weiyan , Li Chuzhong
Published: April 2024

Objective

To investigate the clinical features, imaging characteristics, and molecular profile of sellar neurocytoma (SN).

Methods

Clinical, imaging, and pathological features of 11 cases of SN were retrospectively analyzed. Electron microscopy was performed in 5 cases. Molecular features were detected in tumor tissue by RNA sequencing, quantitative polymerase chain reaction, and immunohistochemistry.

Results

The clinical features of SN patients showed a high incidence of hyponatremia (73%, 8/11), and the tumors tended to invade the lateral side of the saddle area from preoperative imaging analysis. The tumors had positive NeuN, synaptophysin, neurofilament, somatostatin receptor 2 (SSTR2) immunohistochemistry staining. Tumor transcriptomic analysis suggested a new LMCD1-AS1:GRM7-AS1 fusion gene event and increased expression of 10 hypothalamus-secreted hormones in SN. Fifteen differentially expressed genes were verified for quantitative polymerase chain reaction verification. SSTR2 has been verified by immunohistochemistry.

Conclusion

Hyponatremia is the dominant clinical features of SN. Preoperative imaging suggests that growth toward the dorsal region is the imaging feature of SN. SSTR2 expression and LMCD1-AS1:GRM7-AS1 fusion gene event expected to become a new molecular marker for SN. Somatostatin receptor ligand therapy may be a potential therapy for SN.
Dietary n-3 Fatty Acids Intake and All-Cause and Cardiovascular Mortality in Patients With Prediabetes and Diabetes
Authors: Che Jinhang , He Na , Kuang Xue , Zheng Caiyin , Zhou Ruoyu , Zhan Xiaodan , Liu Zengzhang
Published: April 2024

Context

While the association between n-3 polyunsaturated fatty acids (PUFAs) and cardiovascular (CV) events has been thoroughly examined, there is still a scarcity of research regarding their effect on the long-term prognosis in diabetic patients.

Objective

We aimed to explore the effects of n-3 PUFA on all-cause and cardiovascular mortality in patients with pre-diabetes and diabetes.

Method

Herein, a total of 16 539 eligible individuals were enrolled from the National Health and Nutrition Examination Survey (NHANES) 2003 to 2018, and categorized into T1, T2, and T3 based on the tertiles of n-3 PUFA. The Cox proportional risk regression models, Kaplan-Meier curve, and subgroup analysis were conducted to evaluate the association between n-3 PUFA and mortality. Restricted cubic spline (RCS) curves graphically demonstrated the dose-response relationship. Additionally, weighted quantile sum (WQS) models were adopted to measure the mixed and individual effects of n-3 PUFA on mortality.

Results

Following a median follow-up period of 8.42 years, 3010 individuals died, with 989 deaths attributed to CV diseases. Significantly lower risk of all-cause (T2: 0.81 [0.71-0.92], T3: 0.77 [0.64-0.94]) and CV (T2: 0.75 [0.61-0.93]) mortality was observed after adjusting for multivariables compared to the reference (T1). Meanwhile, the RCS curve revealed a negative nonlinear association between n-3 PUFA and mortality. None of the interactions in any subgroup analysis were statistically significant except for BMI (P for interaction = .049). Finally, the WQS analysis demonstrated alpha-linolenic acid (ALA) and docosapentaenoic acid (DPA) as the main contributors to n-3 PUFAs’ benefits against mortality.

Conclusion

Increased dietary intake of n-3 PUFAs, particularly ALA and DPA, was associated with a reduced risk of all-cause and CV mortality among Americans with prediabetes and diabetes.