bluuebunny/crossref_metadata_2025 huggingface dataset:
Klotho reduces the risk of osteoporosis in postmenopausal women: a cross-sectional study of the National Health and Nutrition Examination Survey (NHANES)
Authors: Jiang Jialin , Liu Qinyu , Mao Yaqian , Wang Nengyin , Lin Wei , Li Liantao , Liang Jixing , Chen Gang , Huang Huibin , Wen Junping
Published: July 2023

Background

Osteoporosis (OP) is one of the diseases that endanger the health of the elderly population. Klotho protein is a hormone with anti-aging effects. A few studies have discussed the relationship between Klotho and OP. However, there is still a lack of research on larger populations. This study aims to evaluate the association between OP and Klotho in American postmenopausal women.

Methods

This is a retrospective study. We searched the National Health and Nutrition Examination Survey (NHANES) database and collected data of 3 survey cycles, finally involving 871 postmenopausal women over 50 years old in the present study. All participants took dual-energy X-ray absorptiometry examination and serum Klotho testing at the time of investigation. After adjusting the possible confounding variables, a multivariate regression model was employed to estimate the relationship between OP and Klotho proteins. Besides, the P for trend and restricted cubic spline (RCS) were applied to examine the threshold effect and calculate the inflection point.

Results

Factors influencing the occurrence of OP included age, ethnicity, body mass index and Klotho levels. Multivariate regression analysis indicated that the serum Klotho concentration was lower in OP patients than that in participants without OP (OR[log2Klotho] = 0.568, P = 0.027). The C-index of the prediction model built was 0.765, indicating good prediction performance. After adjusting the above-mentioned four variables, P values for trend showed significant differences between groups. RCSs revealed that when the Klotho concentration reached 824.09 pg/ml, the risk of OP decreased drastically.

Conclusion

Based on the analysis of the data collected from the NHANES database, we propose a correlation between Klotho and postmenopausal OP. A higher serum Klotho level is related to a lower incidence of OP. The findings of the present study can provide guidance for research on diagnosis and risk assessment of OP.
Effect evaluation of a tele-neurologic intervention in primary care in a rural area in Germany—the NeTKoH study protocol of a stepped-wedge cluster randomized trial
Authors: Wainwright Kerstin , Mayer Imke , Oliveira Gonçalves Ana S. , Schulz Ricarda S. , Kiel Simone , Chenot Jean-François , Flöel Agnes , von Podewils Felix , Angermaier Anselm , Kurth Tobias ,   the NeTKoH Consortium
Published: July 2023

Background

Neurological disorders account for a large and increasing proportion of the global burden of disease. Therefore, it is important to strengthen the management of neurologic care, particularly in rural areas. The use of tele-neurology in primary care in rural areas is internationally considered to have the potential to increase access to health care services and improve the quality of care in these underserved areas. NeTKoH aims to address the existing knowledge gap regarding the effects of a tele-neurologic intervention in primary care under real-world conditions in a rural area in Germany.

Methods

NeTKoH is a cluster-randomized controlled trial with a stepped-wedge design involving 33 outpatient general practitioner’s (GP) offices (clusters) in a rural area in Northeast Germany. During 11 predetermined steps, all clusters are randomized before they cross over into groups from the control to the intervention arm. The targeted sample size is 1,089 patients with neurologic symptoms that are continuously being recruited. In the intervention arm, tele-neurologic consultations will be provided via a face-to-face video conferencing system with a neurologic expert at a university hospital. The control arm will receive usual care. The primary outcome is the proportion of neurologic problems being solved at the GP’s office. Secondary outcomes will comprise hospital stays and days, time until neurologic specialist appointments and diagnostics, patients’ health status and quality of life, outpatient and inpatient referrals.

A concurrent observational study, together with a process, implementation, and health economic evaluation, will also be conducted.

Discussion

Using a stepped-wedge cluster design in a real-life situation can help with logistic challenges and enhance the motivation of the participating GPs, as all, at some point, will be in the intervention phase. With the additional implementation evaluation pertaining to external validity, an observational study, and a health economic evaluation, NeTKoH will be able to provide an extensive evaluation for health policy decision-makers regarding the uptake into standard care.

Trial registration

German Clinical Trials Register (DRKS00024492). Date registered: September 28, 2021. Date and protocol version: June 2023, version 1.
CD44 regulates Epac1-mediated β-adrenergic-receptor-induced Ca2+-handling abnormalities: implication in cardiac arrhythmias
Authors: Chan Yi-Hsin , Tsai Feng-Chun , Chang Gwo-Jyh , Lai Ying-Ju , Chang Shang-Hung , Chen Wei-Jan , Yeh Yung-Hsin
Published: July 2023

Background

Sustained, chronic activation of β-adrenergic receptor (β-AR) signaling leads to cardiac arrhythmias, with exchange proteins directly activated by cAMP (Epac1 and Epac2) as key mediators. This study aimed to evaluate whether CD44, a transmembrane receptor mediating various cellular responses, participates in Epac-dependent arrhythmias.

Methods

The heart tissue from CD44 knockout (CD44−/−) mice, cultured HL-1 myocytes and the tissue of human ventricle were used for western blot, co-immunoprecipitaiton and confocal studies. Line-scanning confocal imaging was used for the study of cellular Ca2+ sparks on myocytes. Optical mapping and intra-cardiac pacing were applied for arrhythmia studies on mice’s hearts.

Results

In mice, isoproterenol, a β-AR agonist, upregulated CD44 and Epac1 and increased the association between CD44 and Epac1. Isoproterenol upregulated the expression of phospho-CaMKII (p-CaMKII), phospho-ryanodine receptor (p-RyR), and phospho-phospholamban (p-PLN) in mice and cultured myocytes; these effects were attenuated in CD44−/− mice compared with wild-type controls. In vitro, isoproterenol, 8-CPT-cAMP (an Epac agonist), and osteopontin (a ligand of CD44) significantly upregulated the expression of p-CaMKII, p-RyR, and p-PLN; this effect was attenuated by CD44 small interfering RNA (siRNA). In myocytes, resting Ca2+ sparks were induced by isoproterenol and overexpressed CD44, which were prevented by inhibiting CD44. Ex vivo optical mapping and in vivo intra-cardiac pacing studies showed isoproterenol-induced triggered events and arrhythmias in ventricles were prevented in CD44−/− mice. The inducibility of ventricular arrhythmias (VAs) was attenuated in CD44−/− HF mice compared with wild-type HF controls. In patients, CD44 were upregulated, and the association between CD44 and Epac1 were increased in ventricles with reduced contractility.

Conclusion

CD44 regulates β-AR- and Epac1-mediated Ca2+-handling abnormalities and VAs. Inhibition of CD44 is effective in reducing VAs in HF, which is potentially a novel therapeutic target for preventing the arrhythmias and sudden cardiac death in patients with diseased hearts.
Overexpression of POLA2 in hepatocellular carcinoma is involved in immune infiltration and predicts a poor prognosis
Authors: Liu Long , Wang Qi , Wu Linjun , Zhang Lele , Huang Yuxi , Yang Haihua , guo Le , Fang Zheping , Wang Xuequan
Published: July 2023

Background

Hepatocellular carcinoma (HCC) is the second malignancy worldwide. POLA2 initiates DNA replication, regulates cell cycle and gene repair that promote tumorigenesis and disease progression. However, the prognostic and biological function roles of POLA2 in HCC had not been conclusively determined.

Methods

The expression levels and prognosis role of POLA1 and POLA2 in HCC were analyzed based on TCGA-LIHC database and recruited 24 HCC patients. Gene mutations were analyzed using “maftools” package. POLA2 and immune cells correlations were analyzed by TIMER. POLA2 co-expressed genes functional enrichment were evaluated using Metascape. The mRNA and protein level of POLA2 was detected in HCC cells and tissues. Cell migration, invasion, proliferation, cell cycle and HCC cell lines derived xenograft model were performed to investigate POLA2 biological function.

Results

POLA2 was significantly high expressed in HCC than in normal liver tissue in both TCGA-LIHC and our collected HCC samples. In validation cohort, POLA2 significantly related to tumor differentiation, tumor size and Ki-67 (p < 0.05). In TCGA-LIHC cohort, overexpression of POLA2 predicted a low OS and associated with different clinical stages. Multivariate Cox regression showed overexpression of POLA2 effectively distinguished the prognosis at different T, N, M, stages and grades of HCC. POLA2 expression correlated with mutation burden, immune cells infiltration and immune-associated genes expression of HCC. Functional enrichment revealed that POLA2 co-expressed genes were linked to cellular activity, plasma membrane protein complex and leukocyte activity, immune response-regulated cell surface receptor signaling pathway, and immune response-regulated signaling pathway. Moreover, POLA2 was also positively co-expressed with some immune checkpoints (CD274, CTL-4, HAVCR2, PDCD1, PDCD1LG2, TIGIT, and LAG3) (p < 0.001). Gene knockdown revealed that POLA2 promoted proliferation, migration, invasion, and cell cycle of SMMC-7721 and HepG2. The HCC xenograft tumor model also demonstrated remarkably tumor size inhibition, tumor proliferation inhibtion and tumor necrosis promotion when POLA2 knockdown.

Conclusions

POLA2 influenced immune microenvironment and tumor progression of HCC indicated that it might be a potential molecular marker for prognostic evaluation or a therapeutic target for HCC.
Aging modifies endometrial dendritic cell function and unconventional double negative T cells in the human genital mucosa
Authors: Parthasarathy Siddharth , Shen Zheng , Carrillo-Salinas Francisco J. , Iyer Vidya , Vogell Alison , Illanes Diego , Wira Charles R. , Rodriguez-Garcia Marta
Published: July 2023

Background

Immune function in the genital mucosa balances reproduction with protection against pathogens. As women age, genital infections, and gynecological cancer risk increase, however, the mechanisms that regulate cell-mediated immune protection in the female genital tract and how they change with aging remain poorly understood. Unconventional double negative (DN) T cells (TCRαβ + CD4-CD8-) are thought to play important roles in reproduction in mice but have yet to be characterized in the human female genital tract. Using genital tissues from women (27–77 years old), here we investigated the impact of aging on the induction, distribution, and function of DN T cells throughout the female genital tract.

Results

We discovered a novel site-specific regulation of dendritic cells (DCs) and unconventional DN T cells in the genital tract that changes with age. Human genital DCs, particularly CD1a + DCs, induced proliferation of DN T cells in a TFGβ dependent manner. Importantly, induction of DN T cell proliferation, as well as specific changes in cytokine production, was enhanced in DCs from older women, indicating subset-specific regulation of DC function with increasing age. In human genital tissues, DN T cells represented a discrete T cell subset with distinct phenotypical and transcriptional profiles compared to CD4 + and CD8 + T cells. Single-cell RNA and oligo-tag antibody sequencing studies revealed that DN T cells represented a heterogeneous population with unique homeostatic, regulatory, cytotoxic, and antiviral functions. DN T cells showed relative to CD4 + and CD8 + T cells, enhanced expression of inhibitory checkpoint molecules and genes related to immune regulatory as well as innate-like anti-viral pathways. Flow cytometry analysis demonstrated that DN T cells express tissue residency markers and intracellular content of cytotoxic molecules. Interestingly, we demonstrate age-dependent and site-dependent redistribution and functional changes of genital DN T cells, with increased cytotoxic potential of endometrial DN T cells, but decreased cytotoxicity in the ectocervix as women age, with implications for reproductive failure and enhanced susceptibility to infections respectively.

Conclusions

Our deep characterization of DN T cell induction and function in the female genital tract provides novel mechanistic avenues to improve reproductive outcomes, protection against infections and gynecological cancers as women age.
A quadruple fluorescence quantitative PCR method for the identification of wild strains of african swine fever and gene-deficient strains
Authors: Zuo Xuezhi , Peng Guorui , Xia Yingju , Xu Lu , Zhao Qizu , Zhu Yuanyuan , Wang Cheng , Liu Yebing , Zhao Junjie , Wang Haidong , Zou Xingqi
Published: July 2023

Background

Originating in Africa, African swine fever (ASF) was introduced to China in 2018. This acute and highly virulent infectious disease affects domestic pigs. The World Organization for Animal Health has listed it as a statutory reportable disease, and China has listed it as a category A infectious disease.

Methods

Primers and probes were designed for four ASFV genes (B646L, EP402R, MGF505-3R, and A137R). The primers/probes were highly conserved compared with the gene sequences of 21 ASFV strains.

Results

After optimization, the calibration curve showed good linearity (R2 > 0.99), the minimum concentration of positive plasmids that could be detected was 50 copies/µL, and the minimum viral load detection limit was 102 HAD50/mL. Furthermore, quadruple quantitative polymerase chain reaction (qPCR) with nucleic acids from three porcine-derived DNA viruses and cDNAs from eight RNA viruses did not show amplification curves, indicating that the method was specific. In addition, 1 × 106, 1 × 105, and 1 × 104 copies/µL of mixed plasmids were used for the quadruple qPCR; the coefficient of variation for triplicate determination between groups was < 2%, indicating the method was reproducible.

Conclusions

The results obtained by testing clinical samples containing detectable EP402R, MGF505-3R, and A137R strains with different combinations of gene deletions were as expected. Therefore, the established quadruple qPCR method was validated for the molecular diagnosis of ASF using gene-deleted ASFV strains.
Temporal dynamics of ecosystem, inherent, and underlying water use efficiencies of forests, grasslands, and croplands and their responses to climate change
Authors: Chen Wei , Liu Shuguang , Zhao Shuqing , Zhu Yu , Feng Shuailong , Wang Zhao , Wu Yiping , Xiao Jingfeng , Yuan Wenping , Yan Wende , Ju Hui , Wang Qinyi
Published: July 2023

Background

Understanding temporal trends and varying responses of water use efficiency (WUE) to environmental changes of diverse ecosystems is key to predicting vegetation growth. WUE dynamics of major ecosystem types (e.g., forest, grassland and cropland) have been studied using various WUE definitions/metrics, but a comparative study on WUE dynamics and their driving forces among different ecosystem types using multiple WUE metrics is lacking. We used eddy covariance measurements for 42 FLUXNET2015 sites (396 site years) from 1997 to 2014, as well as three commonly used WUE metrics (i.e., ecosystem, inherent, and underlying WUE) to investigate the commonalities and differences in WUE trends and driving factors among deciduous broadleaf forests (DBFs), evergreen needleleaf forests (ENFs), grasslands, and croplands.

Results

Our results showed that the temporal trends of WUE were not statistically significant at 73.8% of the forest, grassland and cropland sites, and none of the three WUE metrics exhibited better performance than the others in quantifying WUE. Meanwhile, the trends observed for the three WUE metrics were not significantly different among forest, grassland and cropland ecosystems. In addition, WUE was mainly driven by atmospheric carbon dioxide concentration at sites with significant WUE trends, and by vapor pressure deficit (VPD) at sites without significant trends (except cropland).

Conclusions

Our findings revealed the commonalities and differences in the application of three WUE metrics in disparate ecosystems, and further highlighted the important effect of VPD on WUE change.
Asymmetries of foot strike patterns during running in high-level female and male soccer players
Authors: Siegel Stanislav Dimitri , Mason Joel , Hamacher Daniel , Rahlf Anna Lina , Zech Astrid
Published: July 2023

Backround

Foot strike pattern (FSP) is defined by the way the foot makes initial ground contact and is influenced by intrinsic and extrinsic factors. This study investigated the effect of running speed on asymmetries of FSP.

Methods

Seventeen female and nineteen male soccer players performed an incremental running test on an instrumented treadmill starting at 2.0 m/s until complete exhaustion. Force plate data were used to categorize foot strikes into rearfoot (RFS) and non-rearfoot strikes. Additionally, peak vertical ground reaction force (peakGRF) and stride time were calculated. The symmetry index (SI) was used to quantify lateral asymmetries between legs.

Results

The SI indicated asymmetries of the rate of RFS (%RFS) of approximately 30% at slow running speed which decreased to 4.4% during faster running speed (p = 0.001). There were minor asymmetries in peakGRF and stride time at each running stage. Running speed influenced %RFS (p < 0.001), peakGRF (p < 0.001) and stride time (p < 0.001). Significant interaction effects between running speed and sex were shown for %RFS (p = 0.033), peakGRF (p < 0.001) and stride time (p = 0.041).

Conclusion

FSP of soccer players are asymmetric at slower running speed, but symmetry increases with increasing speed. Future studies should consider that FSP are non-stationary and influenced by running speed but also differ between legs.
Breathing cessation events that compose the apnea–hypopnea index are distinctively associated with the adverse outcomes in Alzheimer’s disease
Authors: Targa Adriano D. S. , Benítez Iván D. , Moncusí-Moix Anna , Dakterzada Farida , Minguez Olga , Vaca Rafaela , Dalmases Mireia , Sanchez-de-la-Torre Manuel , Barbé Ferran , Piñol-Ripoll Gerard
Published: July 2023

Background

Previous studies challenge the impact of obstructive sleep apnea (OSA) once patients are diagnosed with Alzheimer’s disease (AD). Nevertheless, OSA recognizably disrupts sleep, and relevant associations between sleep, AD pathological markers, and cognition have been demonstrated. We aimed to further explore this, evaluating the associations between each breathing cessation event that compose the apnea–hypopnea index (AHI) and the sleep structure to finally investigate whether this was related to increased levels of AD markers and higher cognitive decline.

Methods

Observational, prospective study, including consecutive patients diagnosed with mild-moderate AD. The participants were submitted to overnight polysomnography followed by a cerebrospinal fluid collection for AD pathological markers levels determination. Neuropsychological assessment was performed at baseline and after 12 months of follow-up.

Results

The cohort was composed of 116 patients (55.2% females) with a median [p25;p75] age of 76.0 [72.0;80.0] years and an AHI of 25.9 [15.1;48.5], which was mainly defined by the presence of hypopneas and obstructive apneas. These were distinctively associated with the sleep structure, with obstructive apneas being related to arousals and sleep lightening and hypopneas being related to an increased number of arousals only. Despite having a lower frequency, mixed and central apneas also presented associations with the sleep structure, particularly increasing the time spent in the lighter sleep stages. In relation to AD pathological markers, obstructive and mixed apneas were related to an augment in neurofilament light levels while hypopneas were associated with a higher phosphorylated-tau/amyloid-beta protein ratio. Hypopneas were the most important event for an increased cognitive decline at the 12-month follow-up.

Conclusions

Our findings highlight the importance of a patient-centered approach, with a comprehensive and detailed analysis of the AHI to effectively predict the different outcomes and tailor the appropriate therapeutic strategies.
Infection prevention and control in the medical imaging environment: a scoping review
Authors: Jimenez Yobelli A. , Lewis Sarah J.
Published: July 2023

Infection prevention and control (IPC) practices are key to preventing and controlling the spread of pathogens in medical imaging departments (MIDs). The objective of this scoping review was to synthesise information about current research in MID regarding IPC and to use the Systems Engineering Initiative for Patient Safety (SEIPS) model to identify the work system factors (‘persons’, ‘organisation’, ‘tools and technology’, ‘tasks’ and ‘environment’) influencing the practice of IPC, in order to better understand challenges and facilitators that affect IPC in MID. Predefined search terms and medical subject headings relating to IPC in the medical imaging setting were used to search 3 databases. A total of 46 publications met the inclusion criteria, which combined, encompassed all five SEIPS domains influencing IPC. The literature supports the interrelated nature of the five SEIPS domains, and influence to one another. Hand hygiene was a major focus of publications. Mechanisms of infection in contrast-enhanced computed tomography were most reported, with human error, lack of education, and issues associated with devices and processes mechanisms found to influence IPC breaches. A systems approach, such as the SEIPS model, is useful for understanding barriers and hence opportunities for improvement of IPC in the medical imaging setting. Future studies should address individuals’ decision-making processes in the medical imaging setting, and a greater focus should be placed into the procedural steps, education and tools used for contrast media administration.

Critical relevance statement

A systems approach, such as the Systems Engineering Initiative for Patient Safety model, is useful for understanding barriers and hence opportunities for improvement of IPC in the medical imaging setting.

Graphical Abstract

Key points

IPC in the medical imaging setting would benefit from a systems approach.

The role of education and monitoring of IPC compliance requires further research.

Geographical location is a key variable in IPC research in medical imaging.
A simple scoring system for the prediction of early pregnancy loss developed by following 13,977 infertile patients after in vitro fertilization
Authors: Ouyang Yan , Peng Yangqin , Zhang Senmao , Gong Fei , Li Xihong
Published: July 2023

A retrospective study was conducted to investigate a convenient simple scoring system for the prediction of early pregnancy loss (EPL) based on simple demographics. A total of 13,977 women undergoing transvaginal ultrasound scans on Days 27–29 after in vitro fertilization-embryo transfer (IVF-ET) from June 2016 and December 2017 were included. The first trimester pregnancy outcome was recorded at 12 weeks of gestation. The areas under the curve of this scoring system were 0.884 (95% confidence interval (CI) 0.870–0.899) and 0.890 (95% CI 0.878–0.903) in the training set and test set, respectively. The score totals ranged from -8 to 14 points. A score of 5 points, which offered the highest predictive accuracy (94.01%) and corresponded to a 30% miscarriage risk, was chosen as the cutoff value, with a sensitivity of 62.84%, specificity of 98.79%, positive predictive value (PPV) of 88.87% and negative predictive value (NPV) of 94.54% for the prediction of EPL in the training set. In the test set, a score of 5 points had a sensitivity of 64.69%, specificity of 98.78%, PPV of 89.87% and NPV of 93.62%, and 93.91% of the cases were correctly predicted. Therefore, the simple scoring system using conventionally collected data can be conveniently used to predict EPL after ET. However, considering the limitations, its predictive value needs to be further verified in future clinical practice.
Neotropical bee microbiomes point to a fragmented social core and strong species-level effects
Authors: Kueneman Jordan G. , Bonadies Ernesto , Thomas Devin , Roubik David W. , Wcislo William T.
Published: July 2023

Background

Individuals that band together create new ecological opportunities for microorganisms. In vertical transmission, theory predicts a conserved microbiota within lineages, especially social bees. Bees exhibit solitary to social behavior among and/or within species, while life cycles can be annual or perennial. Bee nests may be used over generations or only once, and foraging ecology varies widely. To assess which traits are associated with bee microbiomes, we analyzed microbial diversity within solitary and social bees of Apidae, Colletidae, and Halictidae, three bee families in Panama’s tropical forests. Our analysis considered the microbiome of adult gut contents replicated through time, localities, and seasons (wet and dry) and included bee morphology and comparison to abdominal (dissected) microbiota. Diversity and distribution of tropical bee microbes (TBM) within the corbiculate bee clade were emphasized.

Results

We found the eusocial corbiculate bees tended to possess a more conserved gut microbiome, attributable to vertical transmission, but microbial composition varied among closely related species. Euglossine bees (or orchid bees), corbiculates with mainly solitary behavior, had more variable gut microbiomes. Their shorter-tongued and highly seasonal species displayed greater diversity, attributable to flower-visiting habits. Surprisingly, many stingless bees, the oldest corbiculate clade, lacked bacterial genera thought to predate eusociality, while several facultatively social, and solitary bee species possessed those bacterial taxa. Indeed, nearly all bee species displayed a range of affinities for single or multiple variants of the “socially associated” bacterial taxa, which unexpectedly demonstrated high sequence variation.

Conclusions

Taken together, these results call into question whether specific bacterial associates facilitate eusocial behavior, or are subsequently adopted, or indicate frequent horizontal transmission between perennial eusocial colonies and other social, facultatively social, and solitary bees.
Pharmacovariome scanning using whole pharmacogene resequencing coupled with deep computational analysis and machine learning for clinical pharmacogenomics
Authors: Tafazoli Alireza , Mikros John , Khaghani Faeze , Alimardani Maliheh , Rafigh Mahboobeh , Hemmati Mahboobeh , Siamoglou Stavroula , Golińska Agnieszka Kitlas , Kamiński Karol A. , Niemira Magdalena , Miltyk Wojciech , Patrinos George P.
Published: July 2023

Background

This pilot study aims to identify and functionally assess pharmacovariants in whole exome sequencing data. While detection of known variants has benefited from pharmacogenomic-dedicated bioinformatics tools before, in this paper we have tested novel deep computational analysis in addition to artificial intelligence as possible approaches for functional analysis of unknown markers within less studied drug-related genes.

Methods

Pharmacovariants from 1800 drug-related genes from 100 WES data files underwent (a) deep computational analysis by eight bioinformatic algorithms (overall containing 23 tools) and (b) random forest (RF) classifier as the machine learning (ML) approach separately. ML model efficiency was calculated by internal and external cross-validation during recursive feature elimination. Protein modelling was also performed for predicted highly damaging variants with lower frequencies. Genotype–phenotype correlations were implemented for top selected variants in terms of highest possibility of being damaging.

Results

Five deleterious pharmacovariants in the RYR1, POLG, ANXA11, CCNH, and CDH23 genes identified in step (a) and subsequent analysis displayed high impact on drug-related phenotypes. Also, the utilization of recursive feature elimination achieved a subset of 175 malfunction pharmacovariants in 135 drug-related genes that were used by the RF model with fivefold internal cross-validation, resulting in an area under the curve of 0.9736842 with an average accuracy of 0.9818 (95% CI: 0.89, 0.99) on predicting whether a carrying individuals will develop adverse drug reactions or not. However, the external cross-validation of the same model indicated a possible false positive result when dealing with a low number of observations, as only 60 important variants in 49 genes were displayed, giving an AUC of 0.5384848 with an average accuracy of 0.9512 (95% CI: 0.83, 0.99).

Conclusion

While there are some technologies for functionally assess not-interpreted pharmacovariants, there is still an essential need for the development of tools, methods, and algorithms which are able to provide a functional prediction for every single pharmacovariant in both large-scale datasets and small cohorts. Our approaches may bring new insights for choosing the right computational assessment algorithms out of high throughput DNA sequencing data from small cohorts to be used for personalized drug therapy implementation.
Differential characteristics of bipolar I and II disorders: a retrospective, cross-sectional evaluation of clinical features, illness course, and response to treatment
Authors: Brancati Giulio Emilio , Nunes Abraham , Scott Katie , O’Donovan Claire , Cervantes Pablo , Grof Paul , Alda Martin
Published: July 2023

Background

The distinction between bipolar I and bipolar II disorder and its treatment implications have been a matter of ongoing debate. The aim of this study was to examine differences between patients with bipolar I and II disorders with particular emphasis on the early phases of the disorders.

Methods

808 subjects diagnosed with bipolar I (N = 587) or bipolar II disorder (N = 221) according to DSM-IV criteria were recruited between April 1994 and March 2022 from tertiary-level mood disorder clinics. Sociodemographic and clinical variables concerning psychiatric and medical comorbidities, family history, illness course, suicidal behavior, and response to treatment were compared between the bipolar disorder types.

Results

Bipolar II disorder patients were more frequently women, older, married or widowed. Bipolar II disorder was associated with later “bipolar” presentation, higher age at first (hypo)mania and treatment, less frequent referral after a single episode, and more episodes before lithium treatment. A higher proportion of first-degree relatives of bipolar II patients were affected by major depression and anxiety disorders. The course of bipolar II disorder was typically characterized by depressive onset, early depressive episodes, multiple depressive recurrences, and depressive predominant polarity; less often by (hypo)mania or (hypo)mania-depression cycles at onset or during the early course. The lifetime clinical course was more frequently rated as chronic fluctuating than episodic. More patients with bipolar II disorder had a history of rapid cycling and/or high number of episodes. Mood stabilizers and antipsychotics were prescribed less frequently during the early course of bipolar II disorder, while antidepressants were more common. We found no differences in global functioning, lifetime suicide attempts, family history of suicide, age at onset of mood disorders and depressive episodes, and lithium response.

Conclusions

Differences between bipolar I and II disorders are not limited to the severity of (hypo)manic syndromes but include patterns of clinical course and family history. Caution in the use of potentially mood-destabilizing agents is warranted during the early course of bipolar II disorder.
Neonatal admission after lithium use in pregnant women with bipolar disorders: a retrospective cohort study
Authors: Schonewille Noralie N. , Terpstra Pleun A. , van den Heuvel Maria E. N. , Van Pampus Maria G. , van den Heuvel Odile A. , Broekman Birit F. P.
Published: July 2023

Background

Lithium is the preferred treatment for pregnant women with bipolar disorders (BD), as it is most effective in preventing postpartum relapse. Although it has been prescribed during pregnancy for decades, the safety for neonates and obstetric outcomes are a topic of ongoing scientific debate as previous research has yielded contradicting outcomes. Our study aims to compare (re)admission rates and reasons for admissions in neonates born to women with bipolar disorders (BD) with and without lithium exposure.

Methods

A retrospective observational cohort study was conducted in a Dutch secondary hospital (two locations in Amsterdam). Women with BD who gave birth after a singleton pregnancy between January 2011 and March 2021 and their neonates were included. Outcomes were obtained by medical chart review of mothers and neonates and compared between neonates with and without lithium exposure. The primary outcome was admission to a neonatal ward with monitoring, preterm birth, small for gestational age (SGA), 5-minute Apgar scores, neonatal asphyxia, and readmission ≤ 28 days.

Results

We included 93 women with BD, who gave birth to 117 live-born neonates: 42 (36%) exposed and 75 (64%) non-exposed to lithium. There were no significant differences in neonatal admission with monitoring (16.7 vs. 20.0%, p = 0.844). Additionally, preterm birth (7.1 vs. 5.3%), SGA (0.0 vs. 8.0%), 5-minute Apgar scores (means 9.50 vs. 9.51), neonatal asphyxia (4.8 vs. 2.7%) and readmission (4.8 vs. 5.3%) were comparable. Overall, 18.8% of BD offspring was admitted. Women with BD had high rates of caesarean section (﻿29.1%), gestational diabetes (12.8%) and hypertensive disorders of pregnancy (8.5%).

Conclusions

In a sample of neonates all born to women with BD using various other psychotropic drugs, exposure to lithium was not associated with greater risk of neonatal admission to a ward with monitoring compared to non-exposure to lithium, questioning the necessity for special measures after lithium exposure. However, offspring of women with BD was admitted regularly and women with BD have high obstetric risk which require clinical and scientific attention.
Psychometric evaluation of the depression, anxiety, and stress scale-21 (DASS-21) among Chinese primary and middle school teachers
Authors: Cao Cui-Hong , Liao Xiao-Ling , Jiang Xing-Yong , Li Xu-Dong , Chen I-Hua , Lin Chung-Ying
Published: July 2023

Background

Teachers in high-stress roles face increasing psychological distress such as anxiety and depression, underscoring the need for validated assessment instruments. Given the current absence of a comprehensive, designated, and time-efficient scale capable of evaluating depression, anxiety, and stress among the teacher population, the Depression, Anxiety, and Stress Scale-21 (DASS-21) presents itself as a promising alternative. Despite the widespread application of the DASS-21 for assessing psychological distress across various populations, its validity among teachers, along with questions about its factor structure and its potential property of time equivalence, remain unverified. This study endeavors to address these considerations by investigating the psychometric properties of the DASS-21 specifically within the population of Chinese primary and middle school teachers.

Methods

Cross-sectional (n = 9,030) and longitudinal surveys (n = 1,642) were conducted using a non-probability sampling method. In addition to the DASS-21, the Chinese version of Chinese Teachers’ Job Burnout Questionnaire (CTJBO) was utilized to evaluate the criterion validity of this scale. Three different approaches, namely confirmatory factor analysis, Rasch analysis, and network analysis, were employed to evaluate internal reliability, construct validity, as well as time invariance of the DASS-21.

Results

The DASS-21 demonstrated a high degree of internal consistency (Cronbach’s α > 0.85) as well as excellent convergent validity, despite poor discriminant validity as determined by average variance extracted. Confirmatory factor analysis and network analysis further supported convergent validity. The three-factor structure outperformed one- and two-factor alternatives, establishing time invariance. Rasch analysis at the item level identified six inappropriate items within the anxiety and stress subscales, which were subsequently removed. Network analysis presented a better revised network. Regression analysis with emotional exhaustion as the criterion provided logical and accurate results.

Conclusion

The DASS-21 was found to be a reliable and valid tool for measuring the mental health of teachers over time. To assess the instrument’s psychometric properties, a combination of confirmatory factor analysis, Rasch analysis, and network analysis was utilized, which proved effective and is recommended for evaluating contentious instruments. Based on the results of the study, researchers and healthcare professionals are recommended to use the DASS-21 for assessing teachers’ psychological distress. However, certain items identified in the study may need to be removed to enhance the instrument’s appropriateness for this specific population.
Xylaria species associated with fallen leaves and petioles
Authors: Ju Yu-Ming , Hsieh Huei-Mei
Published: July 2023

Background

Xylaria species growing on fallen leaves and petioles have not been treated systematically. One source of confusion in this group of Xylaria species has stemmed from X. filiformis, which is an ancient name published in 1805 as Sphaeria filiformis and has commonly labeled on specimen packets that contain leaf- and petiole-inhabiting Xylaria species. Here we clarified the identity of X. filiformis and distinguish it from the species that are easily confused with it, notably X. simplicissima, to which most specimens labeled as X. filiformis are referred. Our research also led us to encounter many other leaf- and petiole-inhabiting Xylaria species, prompting a comprehensive study of this group of fungi.

Results

Forty-five foliicolous and caulicolous species of Xylaria were studied, including nine newly described species—X. allima, X. appendiculatoides, X. hispidipes, X. minuscula, X. neblinensis, X. spiculaticlavata, X. vermiformis, X. vittatipiliformis, and X. vittiformis; three unnamed species—X. sp. AR1741, X. sp. GS7461A, and X. sp. GS7461B; X. simplicissima, a name newly combined with Xylaria from Rhizomorpha simplicissima; and X. noduliformis and X. imminuta, which are two new replacement names, respectively, for X. maitlandii var. nuda and X. hypsipoda var. microspora. The 45 taxa can be classified into three groups by stromatal shape and conspicuousness of perithecial mounds on the stromatal surface: (i) the X. filiformis group contains 10 species, (ii) the X. phyllocharis group contains 19 species, and (iii) the X. heloidea group contains 16 species. One of the newly described or unnamed species belongs to the X. filiformis group—X. vermiformis; nine of them belong to the X. phyllocharis group—X. allima, X. appendiculatoides, Xylaria minuscula, X. neblinensis, X. sp. AR1741, X. sp. GS7461B, X. spiculaticlavata, X. vittatipiliformis, and X. vittiformis; and three of them belong to the X. heloidea group—X. hispidipes, X. imminuta, and X. sp. GS7461A.

Conclusion

The 45 species of Xylaria associated with fallen leaves and petioles can be identified by using the dichotomous identification key that we provided herein. It is important to note that most of the studied species are represented by only one or several specimens and many have not been recollected and cultured.
Enormously large tippers observed in southwest China: can realistic 3-D EM modeling reproduce them?
Authors: Xu Shan , Chen Chaojian , Kruglyakov Mikhail , Kuvshinov Alexey , Rigaud Rafael , Hu Xiangyun
Published: July 2023

Vertical magnetic transfer functions (tippers) estimated at a global/continental net of geomagnetic observatories/sites can be used to image the electrical conductivity structure of the Earth’s crust and upper mantle (down to around 200 km). We estimated tippers at 54 geomagnetic observatories across China, aiming eventually to invert them in terms of subsurface three-dimensional (3-D) conductivity distribution. Strikingly, we obtained enormously large tippers at three inland observatories in southwest China. Large tippers are often observed at coastal/island observatories due to high conductivity contrasts between resistive bedrock and conductive seawater. However, tippers at those inland observatories appeared to be a few times larger than coastal/island tippers. As far as we know, such large tippers (reaching value 3) were never reported in any region worldwide. We perform electromagnetic simulations in 3-D conductivity models mimicking the geological setting and demonstrate that enormously large tippers are feasible and can be attributed to a current channeling effect.

Graphical Abstract
Different photosynthetic responses of haploid and diploid Emiliania huxleyi (Prymnesiophyceae) to high light and ultraviolet radiation
Authors: Ruan Zuoxi , Lu Meifang , Lin Hongmin , Chen Shanwen , Li Ping , Chen Weizhou , Xu Huijuan , Qiu Dajun
Published: July 2023

Solar radiation varies quantitatively and qualitatively while penetrating through the seawater column and thus is one of the most important environmental factors shaping the vertical distribution pattern of phytoplankton. The haploid and diploid life-cycle phases of coccolithophores might have different vertical distribution preferences. Therefore, the two phases respond differently to high solar photosynthetically active radiation (PAR, 400–700 nm) and ultraviolet radiation (UVR, 280–400 nm). To test this, the haploid and diploid Emiliania huxleyi were exposed to oversaturating irradiance. In the presence of PAR alone, the effective quantum yield was reduced by 10% more due to the higher damage rate of photosystem II in haploid cells than in diploid cells. The addition of UVR resulted in further inhibition of the quantum yield for both haploid and diploid cells in the first 25 min, partly because of the increased damage of photosystem II. Intriguingly, this UVR-induced inhibition of the haploid cells completely recovered half an hour later. This recovery was confirmed by the comparable maximum quantum yields, maximum relative electron transport rates and yields of the haploid cells treated with PAR and PAR + UVR. Our data indicated that photosynthesis of the haploid phase was more sensitive to high visible light than the diploid phase but resistant to UVR-induced inhibition, reflecting the ecological niches to which this species adapts.

Graphical Abstract
Innovativeness in tradition: a study on the physical performance of leather scale armors during the Joseon Dynasty
Authors: Park Ga Young , Lee Han Bi , Oh Yuree , Lim Jung Ah , Lee Min Wook
Published: July 2023

During the Joseon Dynasty, light and convenient leather armors were developed to replace metal armors, which were heavy and difficult to manufacture. Leather armors allowed easy movement of the troops and, because arrows were the primary weapons at the time, provided them with protection. The excellent performance of leather armors can be attributed to their materials and manufacturing method. The scales of the leather armor relics are prepared by layering animal skins, attaching them with natural glue, and then coating their outer surface with lacquer. The lacquer extracted from the lacquer (Ott) tree is an excellent material with high strength, waterproofing and antiseptic properties, insect repellency, heat resistance, as well as chemical resistance. The superior performance of the leather scale was reported in old scripts; however, it has not been proven through scientific analysis and testing. Therefore, in this study, the physical and mechanical properties, impact resistance, and anti-stab performance of leather scales manufactured following the traditional method were investigated. The results confirmed the excellent protection, impact resistance, and mechanical properties of the leather specimens glued with fish glue and coated with lacquer compared to those of specimens glued with synthetic glue and uncoated specimens glued with fish glue. This study reveals the excellent properties of fish glue and lacquer, which enable them to be used in various industries.
Activatable fluorescent probes for imaging and diagnosis of rheumatoid arthritis
Authors: Luo Pan , Gao Fu-Qiang , Sun Wei , Li Jun-You , Wang Cheng , Zhang Qing-Yu , Li Zhi-Zhuo , Xu Peng
Published: July 2023

Rheumatoid arthritis (RA) is a systemic autoimmune disease that is primarily manifested as synovitis and polyarticular opacity and typically leads to serious joint damage and irreversible disability, thus adversely affecting locomotion ability and life quality. Consequently, good prognosis heavily relies on the early diagnosis and effective therapeutic monitoring of RA. Activatable fluorescent probes play vital roles in the detection and imaging of biomarkers for disease diagnosis and in vivo imaging. Herein, we review the fluorescent probes developed for the detection and imaging of RA biomarkers, namely reactive oxygen/nitrogen species (hypochlorous acid, peroxynitrite, hydroxyl radical, nitroxyl), pH, and cysteine, and address the related challenges and prospects to inspire the design of novel fluorescent probes and the improvement of their performance in RA studies.
PTPRZ1-METFUsion GENe (ZM-FUGEN) trial: study protocol for a multicentric, randomized, open-label phase II/III trial
Authors: Bao Zhaoshi , Li Shouwei , Wang Liang , Zhang Bisi , Zhang Peilong , Shi Hepeng , Qiu Xiaoguang , Jiang Tao
Published: July 2023

Background

PTPRZ1-MET fusion was reported to associate with glioma progression from low-grade to high-grade glioma, which was a target by a MET inhibitor vebreltinib. However, little is known about the further efficacy of vebreltinib among more glioma patients. This trial aims to evaluate the safety and efficacy of vebreltinib enteric-coated capsules in the treatment of sGBM/IDH mutant glioblastoma patients with the ZM fusion gene.

Methods

This multicentric, randomized, open-label, controlled trial plans to include 19 neurosurgical centers and recruit 84 sGBM or IDH mutant glioblastoma patients with the ZM fusion gene. This trial enrolls sGBM or IDH mutant glioblastoma patients with the inclusion criteria and without the exclusion criteria. It was registered with chinadrugtrials.org.cn (CTR20181664). The primary efficacy endpoint is overall survival (OS). The secondary endpoints are progression-free survival (PFS) and objective response rate (ORR).

Discussion

If proven effective, this targeted multifaceted intervention protocol will be extended for more glioma patients as a protocol to evaluate the safety and efficacy of MET inhibitors.

Trial registration

It was registered with chinadrugtrials.org.cn (CTR20181664).