bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiovascular risk of metabolically healthy obesity in two european populations: Prevention potential from a metabolomic study
Authors: Wei Dongmei , González-Marrachelli Vannina , Melgarejo Jesus D , Liao Chia-Te , Hu Angie , Janssens Stefan , Verhamme Peter , Van Aelst Lucas , Vanassche Thomas , Redon Josep , Tellez-Plaza Maria , Martin-Escudero Juan C , Monleon Daniel , Zhang Zhen-Yu
Published: April 2023

Background

A new definition of metabolically healthy obesity (MHO) has recently been proposed to stratify the heterogeneous mortality risk of obesity. Metabolomic profiling provides clues to metabolic alterations beyond clinical definition. We aimed to evaluate the association between MHO and cardiovascular events and assess its metabolomic pattern.

Methods

This prospective study included Europeans from two population-based studies, the FLEMENGHO and the Hortega study. A total of 2339 participants with follow-up were analyzed, including 2218 with metabolomic profiling. Metabolic health was developed from the third National Health and Nutrition Examination Survey and the UK biobank cohorts and defined as systolic blood pressure < 130 mmHg, no antihypertensive drugs, waist-to-hip ratio < 0.95 for women or 1.03 for men, and the absence of diabetes. BMI categories included normal weight, overweight, and obesity (BMI < 25, 25–30, ≥ 30 kg/m2). Participants were classified into six subgroups according to BMI category and metabolic healthy status. Outcomes were fatal and nonfatal composited cardiovascular events.

Results

Of 2339 participants, the mean age was 51 years, 1161 (49.6%) were women, 434 (18.6%) had obesity, 117 (5.0%) were classified as MHO, and both cohorts had similar characteristics. Over a median of 9.2-year (3.7–13.0) follow-up, 245 cardiovascular events occurred. Compared to those with metabolically healthy normal weight, individuals with metabolic unhealthy status had a higher risk of cardiovascular events, regardless of BMI category (adjusted HR: 3.30 [95% CI: 1.73–6.28] for normal weight, 2.50 [95% CI: 1.34–4.66] for overweight, and 3.42 [95% CI: 1.81–6.44] for obesity), whereas those with MHO were not at increased risk of cardiovascular events (HR: 1.11 [95% CI: 0.36–3.45]). Factor analysis identified a metabolomic factor mainly associated with glucose regulation, which was associated with cardiovascular events (HR: 1.22 [95% CI: 1.10–1.36]). Individuals with MHO tended to present a higher metabolomic factor score than those with metabolically healthy normal weight (0.175 vs. -0.057, P = 0.019), and the score was comparable to metabolically unhealthy obesity (0.175 vs. -0.080, P = 0.91).

Conclusions

Individuals with MHO may not present higher short-term cardiovascular risk but tend to have a metabolomic pattern associated with higher cardiovascular risk, emphasizing a need for early intervention.
Transcriptomics and metabolomics analysis of L-phenylalanine overproduction in Escherichia coli
Authors: Sun Wei , Ding Dongqin , Bai Danyang , Lin Yang , Zhu Yaru , Zhang Cuiying , Zhang Dawei
Published: April 2023

Background

Highly efficient production of L-phenylalanine (L-Phe) in E. coli has been achieved by multiple rounds of random mutagenesis and modification of key genes of the shikimate (SHIK) and L-Phe branch pathways. In this study, we performed transcriptomic (16, 24 and 48 h) and metabolomic analyses (8, 16, 24, 32,40, and 48 h) based on time sequences in an engineered E. coli strain producing L-Phe, aiming to reveal the overall changes of metabolic activities during the fermentation process.

Results

The largest biomass increase rate and the highest production rate were seen at 16 h and 24 h of fermentation, respectively reaching 5.9 h−1 and 2.76 g/L/h, while the maximal L-Phe titer of 60 g/L was accumulated after 48 h of fermentation. The DEGs and metabolites involved in the EMP, PP, TCA, SHIIK and L-Phe-branch pathways showed significant differences at different stages of fermentation. Specifically, the significant upregulation of genes encoding rate-limiting enzymes (aroD and yidB) and key genes (aroF, pheA and aspC) pushed more carbon flux toward the L-Phe synthesis. The RIA changes of a number of important metabolites (DAHP, DHS, DHQ, Glu and PPN) enabled the adequate supply of precursors for high-yield L-Phe production. In addition, other genes related to Glc transport and phosphate metabolism increased the absorption of Glc and contributed to rerouting the carbon flux into the L-Phe-branch.

Conclusions

Transcriptomic and metabolomic analyses of an L-Phe overproducing strain of E. coli confirmed that precursor supply was not a major limiting factor in this strain, whereas the rational distribution of metabolic fluxes was achieved by redistributing the carbon flux (for example, the expression intensity of the genes tyrB, aspC, aroL and aroF/G/H or the activity of these enzymes is increased to some extent), which is the optimal strategy for enhancing L-Phe production.
Asymptomatic Plasmodium falciparum carriage and clinical disease: a 5-year community-based longitudinal study in The Gambia
Authors: Ahmad Abdullahi , Mohammed Nuredin Ibrahim , Joof Fatou , Affara Muna , Jawara Musa , Abubakar Ismaela , Okebe Joseph , Ceesay Serign , Hamid-Adiamoh Majidah , Bradley John , Amambua-Ngwa Alfred , Nwakanma Davis , D’Alessandro Umberto
Published: April 2023

Background

Carriers of persistent asymptomatic Plasmodium falciparum infections constitute an infectious reservoir that maintains malaria transmission. Understanding the extent of carriage and characteristics of carriers specific to endemic areas could guide use of interventions to reduce infectious reservoir.

Methods

In eastern Gambia, an all-age cohort from four villages was followed up from 2012 to 2016. Each year, cross-sectional surveys were conducted at the end of the malaria transmission season (January) and just before the start of the next one (June) to determine asymptomatic P. falciparum carriage. Passive case detection was conducted during each transmission season (August to January) to determine incidence of clinical malaria. Association between carriage at the end of the season and at start of the next one and the risk factors for this were assessed. Effect of carriage before start of the season on risk of clinical malaria during the season was also examined.

Results

A total of 1403 individuals—1154 from a semi-urban village and 249 from three rural villages were enrolled; median age was 12 years (interquartile range [IQR] 6, 30) and 12 years (IQR 7, 27) respectively. In adjusted analysis, asymptomatic P. falciparum carriage at the end of a transmission season and carriage just before start of the next one were strongly associated (adjusted odds ratio [aOR] = 19.99; 95% CI 12.57–31.77, p < 0.001). The odds of persistent carriage (i.e. infected both in January and in June) were higher in rural villages (aOR = 13.0; 95% CI 6.33–26.88, p < 0.001) and in children aged 5–15 years (aOR = 5.03; 95% CI 2.47–10.23, p =  < 0.001). In the rural villages, carriage before start of the season was associated with a lower risk of clinical malaria during the season (incidence risk ratio [IRR] 0.48, 95% CI 0.27–0.81, p = 0.007).

Conclusions

Asymptomatic P. falciparum carriage at the end of a transmission season strongly predicted carriage just before start of the next one. Interventions that clear persistent asymptomatic infections when targeted at the subpopulation with high risk of carriage may reduce the infectious reservoir responsible for launching seasonal transmission.
To what extent has the Iranian Health Transformation Plan addressed inequality in healthcare financing in Iran?
Authors: Moeeni Maryam , Nosratnejad Shirin , Rostampour Manizhe , Ponnet Koen
Published: April 2023

Background

One of the major goals of health systems is providing a financing strategy without inequality; this has a significant impact on people’s access to healthcare. The present study aimed to investigate the inequality in households’ financial contribution (HFC) to health expenditure both before and after the implementation of the Iranian Health Transformation Plan (HTP) in 2014.

Methods

This study is a secondary analysis of two waves of a national survey conducted in Iran. The data were collected from the Households Income and Expenditure Survey in 2013 and 2015. The research sample included 76,195 Iranian households. The inequality in households’ financial contributions to the health system was assessed using the Gini coefficient, and the concentration index (CI). In addition, by using econometric modeling, the relationship between the implementation of the HTP and inequality in HFC was studied. The households’ financial contribution included healthcare and health insurance prepayments.

Results

The Gini coefficient values were 0.67 and 0.65 in 2013 and 2015, respectively, indicating a medium degree of inequality in HFC in both years. The CI values were 0.54 and 0.56 in 2013 and 2015, respectively, suggesting that inequalities in HFC were in favor of higher income quintiles in the years before and after the implementation of the HTP. Regression analysis showed that households with a female head, with an unemployed head, or with a head having income without a job were contributing more to financing health expenditure. The presence of a household member over the age of 65 was associated with a higher level of HFC. The implementation of the HTP had a negative relationship with the HFC.

Conclusion

The HTP, aiming to address inequality in the financing system, did not achieve the intended goal as expected. The implementation of the HTP neglected certain factors at the household level, such as the presence of family members older than the age of 65, a female household head, and unemployment. This resulted in a failure to reduce the inequality of the HFC. We suggest that, in the future, policymakers take into account factors at the household level to reduce inequality in the HFC.
Uncovering COVID-19 infection determinants in Portugal: towards an evidence-based spatial susceptibility index to support epidemiological containment policies
Authors: Alves André , da Costa Nuno Marques , Morgado Paulo , da Costa Eduarda Marques
Published: April 2023

Background

COVID-19 caused the largest pandemic of the twenty-first century forcing the adoption of containment policies all over the world. Many studies on COVID-19 health determinants have been conducted, mainly using multivariate methods and geographic information systems (GIS), but few attempted to demonstrate how knowing social, economic, mobility, behavioural, and other spatial determinants and their effects can help to contain the disease. For example, in mainland Portugal, non-pharmacological interventions (NPI) were primarily dependent on epidemiological indicators and ignored the spatial variation of susceptibility to infection.

Methods

We present a data-driven GIS-multicriteria analysis to derive a spatial-based susceptibility index to COVID-19 infection in Portugal. The cumulative incidence over 14 days was used in a stepwise multiple linear regression as the target variable along potential determinants at the municipal scale. To infer the existence of thresholds in the relationships between determinants and incidence the most relevant factors were examined using a bivariate Bayesian change point analysis. The susceptibility index was mapped based on these thresholds using a weighted linear combination.

Results

Regression results support that COVID-19 spread in mainland Portugal had strong associations with factors related to socio-territorial specificities, namely sociodemographic, economic and mobility. Change point analysis revealed evidence of nonlinearity, and the susceptibility classes reflect spatial dependency. The spatial index of susceptibility to infection explains with accuracy previous and posterior infections. Assessing the NPI levels in relation to the susceptibility map points towards a disagreement between the severity of restrictions and the actual propensity for transmission, highlighting the need for more tailored interventions.

Conclusions

This article argues that NPI to contain COVID-19 spread should consider the spatial variation of the susceptibility to infection. The findings highlight the importance of customising interventions to specific geographical contexts due to the uneven distribution of COVID-19 infection determinants. The methodology has the potential for replication at other geographical scales and regions to better understand the role of health determinants in explaining spatiotemporal patterns of diseases and promoting evidence-based public health policies.
Efficacy of CU06-1004 via regulation of inflammation and endothelial permeability in LPS-induced acute lung injury
Authors: Kim Yeomyeong , Bae Cho-Rong , Kim Dongyeop , Kim Hyejeong , Lee Sunghye , Zhang Haiying , Noh Minyoung , Kim Young-Myeong , Mochizuki Naoki , Kwon Young-Guen
Published: April 2023

Background

Acute lung injury (ALI) is a life-threatening condition that fundamentally results from inflammation and edema in the lung. There are no effective treatments available for clinical use. Previously, we found that as a leakage blocker CU06-1004 prevents endothelial barrier disruption and enhances endothelial cell survival under inflammatory conditions. In this study, we aimed to elucidate the effect of CU06-1004 in terms of prevention of inflammation and endothelial dysfunction in an ALI mouse model.

Methods

An ALI model was established that included intraperitoneal administration of LPS. Following LPS administration, survival rates and lung wet/dry ratios were assessed. Histological analysis was performed using hematoxylin and eosin staining. Scanning electron microscopy was used to examine alveolar and capillary morphology. Cytokines such as IL-1β, IL-6, and TNF-α were analyzed using an ELISA assay of bronchoalveolar lavage fluid (BALF) and serum. Neutrophil infiltration was observed in BALF using Wright-Giemsa staining, and myeloperoxidase (MPO) activity was assessed. Pulmonary vascular leakage was confirmed using Evans-blue dye, and the expression of junctional proteins was evaluated using immunofluorescent staining. Expression of adhesion molecules was observed using immunofluorescence staining. NF-κB activation was determined using immunohistochemistry and western blot analysis.

Results

Survival rates and pulmonary edema were ameliorated with CU06-1004 treatment. Administration of CU06-1004 normalized histopathological changes induced by LPS, and alveolar-capillary wall thickening was reduced. Compared with the LPS-challenged group, after CU06-1004 treatment, the infiltration of immune cells was decreased in the BALF, and MPO activity in lung tissue was reduced. Similarly, in the CU06-1004 treatment group, pro-inflammatory cytokines were significantly inhibited in both BALF and serum. Evans-blue leakage was reduced, and the expression of junctional proteins was recovered in the CU06-1004 group. Adhesion molecules were downregulated and NF-κB activation was inhibited after CU06-1004 treatment.

Conclusions

These results suggested that CU06-1004 had a therapeutic effect against LPS-induced ALI via alleviation of the inflammatory response and protection of vascular integrity.
Cost-utility of vitamin D supplementation to prevent acute respiratory infections in children
Authors: Buendía Jefferson Antonio , Patiño Diana Guerrero
Published: April 2023

Introduction

Increasing evidence has demonstrated the effectiveness and safety of vitamin D supplementation to prevent acute respiratory infections in children. More economic evaluations incorporating the new evidence and in the pediatric population are needed to know the efficiency of this treatment. This study aimed to determine the cost-utility of vitamin D supplementation to prevent acute respiratory infections in pediatric patients.

Methods

A decision tree model was used to estimate the cost and quality-adjusted life-years (QALYs) of vitamin D supplementation in healthy school children between 1 and 16 years. Multiple sensitivity analyses were conducted. Cost-effectiveness was evaluated at a willingness-to-pay (WTP) value of $19,000.

Results

The base-case analysis showed that vitamin D supplementation was associated with lower costs and higher QALYs than strategy without this supplementation. The QALYs per person estimated in the model for those treatments were 0,99 with vitamin D supplementation and 0,98 without vitamin D supplementation. The total costs per person were US$ 1354 for vitamin D supplementation and US$ 1948 without vitamin D supplementation. This position of absolute dominance of vitamin D supplementation makes it unnecessary to estimate the incremental cost-effectiveness ratio.

Conclusion

In conclusion, our study shows that Vitamin D supplementation is a cost-effective strategy to prevent ARI in pediatric patients, from a societal perspective.
N,N-Dimethyl-3β-hydroxycholenamide attenuates neuronal death and retinal inflammation in retinal ischemia/reperfusion injury by inhibiting Ninjurin 1
Authors: Shi Yunhong , Liu Yidan , Wu Caiqing , Liu Xiuxing , Hu Wenfei , Yang Zhenlan , Li Zhidong , Li Yangyang , Deng Caibin , Wei Kun , Gu Chenyang , Chen Xuhao , Su Wenru , Zhuo Yehong
Published: April 2023

Background

Retinal ischemia–reperfusion (RIR) injury refers to an obstruction in the retinal blood supply followed by reperfusion. Although the molecular mechanism underlying the ischemic pathological cascade is not fully understood, neuroinflammation plays a crucial part in the mortality of retinal ganglion cells.

Methods

Single-cell RNA sequencing (scRNA-seq), molecular docking, and transfection assay were used to explore the effectiveness and pathogenesis of N,N-dimethyl-3β-hydroxycholenamide (DMHCA)-treated mice with RIR injury and DMHCA-treated microglia after oxygen and glucose deprivation/reoxygenation (OGD/R).

Results

DMHCA could suppress inflammatory gene expression and attenuate neuronal lesions, restoring the retinal structure in vivo. Using scRNA-seq on the retina of DMHCA-treated mice, we provided novel insights into RIR immunity and demonstrated nerve injury-induced protein 1 (Ninjurin1/Ninj 1) as a promising treatment target for RIR. Moreover, the expression of Ninj1, which was increased in RIR injury and OGD/R-treated microglia, was downregulated in the DMHCA-treated group. DMHCA suppressed the activation of the nuclear factor kappa B (NF-κB) pathways induced by OGD/R, which was undermined by the NF-κB pathway agonist betulinic acid. Overexpressed Ninj1 reversed the anti-inflammatory and anti-apoptotic function of DMHCA. Molecular docking indicated that for Ninj1, DMHCA had a low binding energy of − 6.6 kcal/mol, suggesting highly stable binding.

Conclusion

Ninj1 may play a pivotal role in microglia-mediated inflammation, while DMHCA could be a potential treatment strategy against RIR injury.
Cross-cultural adaptation, validity and reliability of the Persian translation of the Western Ontario Shoulder Instability Index (WOSI)
Authors: Kheradmand Ehsan , Rahimi Seyed Mohsen , Nakhaei Amroodi Morteza , Nejati Parisa , Griffin Sharon
Published: April 2023

Purpose

The Western Ontario Shoulder Instability Index (WOSI) is the most commonly used patient-reported outcome measure to record the quality of life in patients with shoulder instability. The current study aimed to translate the WOSI into the Persian language and evaluate its psychometric properties.

Methods

The translation procedure of the WOSI was performed according to a standard guideline. A total of 52 patients were included in the study and responded to the Persian WOSI, Oxford shoulder score (OSS), Oxford shoulder instability score (OSIS), and disabilities of arm, shoulder and hand (DASH). A sub-group of 41 patients responded for the second time to the Persian WOSI after an interval of 1–2 weeks. The internal consistency, test–retest reliability using intraclass correlation coefficient (ICC), measurement error, minimal detectable change (MDC), and floor and ceiling effect were analyzed. The hypothesis testing method was used to assess construct validity by calculating Pearson correlation coefficient between WOSI and DASH, OSS, and OSIS.

Results

Cronbach's alpha value was 0.93, showing strong internal consistency. Test–retest reliability was good to excellent (ICC = 0.90). There was no floor and ceiling effect. The standard error of measurement and MDC were 8.30% and 23.03%, respectively. Regarding construct validity, 83.3% of the results agreed with hypotheses. High correlations were observed between WOSI and DASH, OSS and OSIS (0.746, 0.759 and 0.643, respectively) indicating excellent validity for the Persian WOSI.

Conclusion

The current study results demonstrated that the Persian WOSI is a valid and reliable instrument and can be used in the clinic and research for Persian-speaking patients with shoulder instability.
Daurisoline attenuates H2O2-induced chondrocyte autophagy by activating the PI3K/Akt/mTOR signaling pathway
Authors: Zhang Yang , Liu Wenguang , Liu Zhonghao , Liu Yi
Published: April 2023

Background

Osteoarthritis (OA) is a chronic degenerative joint disease characterized by cartilage degeneration and intra-articular inflammation. Daurisoline (DAS) is an isoquinoline alkaloid isolated from Rhizoma Menispermi, whose antitumor and anti-inflammatory pharmacological effects have been demonstrated, but the effects of DAS on OA have rarely been researched. In this study, we aimed to explore the potential role of DAS in OA and its partial mechanism.

Materials and methods

The cytotoxicity of H2O2 and DAS toward chondrocytes was detected by the Cell Counting Kit-8 assay. Safranin O staining was used to detect chondrocyte phenotype changes. Cell apoptosis was measured by both flow cytometry and quantitative analysis of the protein levels of the apoptosis-related factors Bax, Bcl-2 and cleaved caspase-3 by western blot. Western blotting and immunofluorescence were used to assess the expression of the autophagy-related proteins LC3, Beclin-1 and p62. In addition, key signal pathway targets and matrix-degrading indicators were measured by western blot.

Results

Our results indicated that H2O2 induced human chondrocyte apoptosis and activated autophagy in a dose-dependent manner. DAS treatment dose-dependently reversed the expression of apoptosis-related proteins (Bax, Bcl-2 and cleaved caspase3) and the apoptosis rate induced by H2O2. Western blot and immunofluorescence analyses showed that DAS decreased the H2O2-induced upregulation of the autophagy marker Beclin-1 and the LC3 II/LC3 I ratio and upregulated the p62 protein level. Mechanistically, DAS inhibited autophagy through the activation of the classical PI3K/AKT/mTOR signaling pathway and protected chondrocytes from apoptosis. In addition, DAS alleviated the H2O2-induced degradation of type II collagen and the high expression of matrix metalloproteinase 3 (MMP3) and MMP13.

Conclusion

Our research demonstrated that DAS alleviated chondrocyte autophagy caused by H2O2 through activation of the PI3K/AKT/mTOR signaling pathway and protected chondrocytes from apoptosis and matrix degradation. In conclusion, these findings suggest that DAS may serve as a promising therapeutic strategy for OA.
Social media use of adolescents who died by suicide: lessons from a psychological autopsy study
Authors: Balt Elias , Mérelle Saskia , Robinson Jo , Popma Arne , Creemers Daan , van den Brand Isa , van Bergen Diana , Rasing Sanne , Mulder Wico , Gilissen Renske
Published: April 2023

Background

while there are many benefits for young people to use social media, adverse effects such as cyberbullying, online challenges, social comparison and imitation may provoke and aggravate suicidal thoughts and behaviors. The influence of social media on mental health and suicidal thoughts and behaviours has been amply studied, but there is little empirical evidence for its potential role in adolescent suicides. The current study aimed to inform digital suicide prevention strategies by examining the meaning of social media in the lives of young suicide victims and elucidating the harmful and supportive effects of social media use on their wellbeing and distress.

Methods

data were analyzed from a psychological autopsy study of 35 adolescents who died by suicide in the Netherlands (43% of all adolescents who died by suicide in that year). These were 18 girls and 17 boys. All were under the age of twenty years, with an average of seventeen years. Interpretative Phenomenological Analysis was performed of 55 semi structured interviews with peers and parents of the decedents.

Results

young people benefitted from peer support and recovery stories. However, various themes were discussed relating to the harmful effects of social media, including dependency, triggers and imitation, challenges, cybervictimization and psychological entrapment. The themes of dependency and triggers and imitation were more salient in young females. A group of girls cultivated an online identity around their suicidal thoughts and behaviours. Next-of-kin, particularly parents, faced various challenges to talk to the adolescents about social media use, including technological illiteracy, online anonymity, and the youths’ closedness.

Conclusions

based on the findings, we recommend education to stimulate the digital literacy of parents, health workers and educators, supporting conscientious social media use in young people, and extending the prevention of cyberbullying. We encourage future research to examine how virtual social networks may sustain suicidal thoughts and behaviour, and to further investigate the effectiveness of digital interventions, like moderated peer support and the use of positive role models.
Analysis of serum reproductive hormones and ovarian genes in pubertal female goats
Authors: Zhu Yanyun , Ye Jing , Qin Ping , Yan Xu , Gong Xinbao , Li Xiaoqian , Liu Ya , Li Yunsheng , Yu Tong , Zhang Yunhai , Ling Yinghui , Wang Juhua , Cao Hongguo , Fang Fugui
Published: April 2023

Background

Age at puberty is an important factor affecting goat fertility, with endocrine and genetic factors playing a crucial role in the onset of puberty. To better understand the relationship between endocrine and genetic factors and mechanisms underlying puberty onset in goats, reproductive hormone levels were analyzed by ELISA and ultraperformance liquid chromatography–multiple reaction monitoring–multistage/mass spectrometry and RNA sequencing was performed to analyze ovarian genes.

Results

Serum follicle stimulating hormone, luteinizing hormone, estradiol, 11-deoxycortisol, 11-deoxycorticosterone, corticosterone, cortisone, and cortisol levels were found to be higher but progesterone were lower in pubertal goats as compared to those in prepubertal goats (P < 0.05). A total of 18,139 genes were identified in cDNA libraries, and 75 differentially expressed genes (DEGs) were identified (|log2 fold change|≥ 1, P ≤ 0.05), of which 32 were significantly up- and 43 were down-regulated in pubertal goats. Gene ontology enrichment analyses indicated that DEGs were mainly involved in “metabolic process,” “signaling,” “reproduction,” and “growth.” Further, DEGs were significantly enriched in 91 Kyoto Encyclopedia of Genes and Genomes pathways, including estrogen signaling pathway, steroid hormone biosynthesis, and cAMP signaling pathway. Bioinformatics analysis showed that PRLR and THBS1 were highly expressed in pubertal ovaries, and ZP3, ZP4, and ASTL showed low expression, suggesting their involvement in follicular development and lutealization.

Conclusions

To summarize, serum hormone changes and ovarian DEGs expression were investigated in our study. Further studies are warranted to comprehensively explore the functions of DEGs in goat puberty.
Mechanisms of ovarian aging in women: a review
Authors: Wang Xiangfei , Wang Lingjuan , Xiang Wenpei
Published: April 2023

Ovarian aging is a natural and physiological aging process characterized by loss of quantity and quality of oocyte or follicular pool. As it is generally accepted that women are born with a finite follicle pool that will go through constant decline without renewing, which, together with decreased oocyte quality, makes a severe situation for women who is of advanced age but desperate for a healthy baby. The aim of our review was to investigate mechanisms leading to ovarian aging by discussing both extra- and intra- ovarian factors and to identify genetic characteristics of ovarian aging. The mechanisms were identified as both extra-ovarian alternation of hypothalamic–pituitary-ovarian axis and intra-ovarian alternation of ovary itself, including telomere, mitochondria, oxidative stress, DNA damage, protein homeostasis, aneuploidy, apoptosis and autophagy. Moreover, here we reviewed related Genome-wide association studies (GWAS studies) from 2009 to 2021 and next generation sequencing (NGS) studies of primary ovarian insufficiency (POI) in order to describe genetic characteristics of ovarian aging. It is reasonable to wish more reliable anti-aging interventions for ovarian aging as the exploration of mechanisms and genetics being progressing.
Diagnostic accuracy of clinical examination to identify life- and limb-threatening injuries in trauma patients
Authors: Wohlgemut Jared M. , Marsden Max E. R. , Stoner Rebecca S. , Pisirir Erhan , Kyrimi Evangelia , Grier Gareth , Christian Michael , Hurst Thomas , Marsh William , Tai Nigel R. M. , Perkins Zane B.
Published: April 2023

Background

Timely and accurate identification of life- and limb-threatening injuries (LLTIs) is a fundamental objective of trauma care that directly informs triage and treatment decisions. However, the diagnostic accuracy of clinical examination to detect LLTIs is largely unknown, due to the risk of contamination from in-hospital diagnostics in existing studies. Our aim was to assess the diagnostic accuracy of initial clinical examination for detecting life- and limb-threatening injuries (LLTIs). Secondary aims were to identify factors associated with missed injury and overdiagnosis, and determine the impact of clinician uncertainty on diagnostic accuracy.

Methods

Retrospective diagnostic accuracy study of consecutive adult (≥ 16 years) patients examined at the scene of injury by experienced trauma clinicians, and admitted to a Major Trauma Center between 01/01/2019 and 31/12/2020. Diagnoses of LLTIs made on contemporaneous clinical records were compared to hospital coded diagnoses. Diagnostic performance measures were calculated overall, and based on clinician uncertainty. Multivariate logistic regression analyses identified factors affecting missed injury and overdiagnosis.

Results

Among 947 trauma patients, 821 were male (86.7%), median age was 31 years (range 16–89), 569 suffered blunt mechanisms (60.1%), and 522 (55.1%) sustained LLTIs. Overall, clinical examination had a moderate ability to detect LLTIs, which varied by body region: head (sensitivity 69.7%, positive predictive value (PPV) 59.1%), chest (sensitivity 58.7%, PPV 53.3%), abdomen (sensitivity 51.9%, PPV 30.7%), pelvis (sensitivity 23.5%, PPV 50.0%), and long bone fracture (sensitivity 69.9%, PPV 74.3%). Clinical examination poorly detected life-threatening thoracic (sensitivity 48.1%, PPV 13.0%) and abdominal (sensitivity 43.6%, PPV 20.0%) bleeding. Missed injury was more common in patients with polytrauma (OR 1.83, 95% CI 1.62–2.07) or shock (systolic blood pressure OR 0.993, 95% CI 0.988–0.998). Overdiagnosis was more common in shock (OR 0.991, 95% CI 0.986–0.995) or when clinicians were uncertain (OR 6.42, 95% CI 4.63–8.99). Uncertainty improved sensitivity but reduced PPV, impeding diagnostic precision.

Conclusions

Clinical examination performed by experienced trauma clinicians has only a moderate ability to detect LLTIs. Clinicians must appreciate the limitations of clinical examination, and the impact of uncertainty, when making clinical decisions in trauma. This study provides impetus for diagnostic adjuncts and decision support systems in trauma.
Clinical evaluation of molecular surrogate subtypes in patients with ipsilateral multifocal primary breast cancer
Authors: Janeva Slavica , Krabbe Ellen , Parris Toshima Z. , Nasic Salmir , Sundquist Marie , Karlsson Per , Audisio Riccardo A. , Olofsson Bagge Roger , Kovács Anikó
Published: April 2023

Background

When ipsilateral multifocal primary breast cancer (IMBC) is detected, standard routine is to evaluate the largest tumor with immunohistochemistry (IHC). As all foci are not routinely characterized, many patients may not receive optimal adjuvant treatment. Here, we assess the clinical relevance of examining at least two foci present in patients with IMBC.

Methods

Patients diagnosed and treated for IMBC at Sahlgrenska University Hospital (Gothenburg, Sweden) between 2012 and 2017 were screened. In total, 180 patients with ≥ 2 invasive foci (183 specimens) were assessed with IHC and included in this study. Expression of the estrogen (ER) and progesterone (PR) receptors, Ki67, HER2, and tumor grade were used to determine the molecular surrogate subtypes and discordance among the foci was recorded. An additional multidisciplinary team board was then held to re-assess whether treatment recommendations changed due to discordances in molecular surrogate subtype between the different foci.

Results

Discordance in ER, PR, HER2, and Ki67 was found in 2.7%, 19.1%, 7.7%, and 16.9% of invasive foci, respectively. Discordance in the molecular surrogate subtypes was found in 48 of 180 (26.7%) patients, which resulted in therapy changes for 11 patients (6.1%). These patients received additional endocrine therapy (n = 2), chemotherapy (n = 3), and combined chemotherapy and trastuzumab (n = 6).

Conclusion

Taken together, when assessing at least two tumor foci with IHC, regardless of shared morphology or tumor grade between the different foci, 6.1% of patients with IMBC were recommended additional adjuvant treatment. A pathologic assessment using IHC of all foci is therefore recommended to assist in individualized treatment decision making.
Large-scale analysis of de novo mutations identifies risk genes for female infertility characterized by oocyte and early embryo defects
Authors: Li Qun , Zhao Lin , Zeng Yang , Kuang Yanping , Guan Yichun , Chen Biaobang , Xu Shiru , Tang Bin , Wu Ling , Mao Xiaoyan , Sun Xiaoxi , Shi Juanzi , Xu Peng , Diao Feiyang , Xue Songguo , Bao Shihua , Meng Qingxia , Yuan Ping , Wang Wenjun , Ma Ning , Song Di , Xu Bei , Dong Jie , Mu Jian , Zhang Zhihua , Fan Huizhen , Gu Hao , Li Qiaoli , He Lin , Jin Li , Wang Lei , Sang Qing
Published: April 2023

Background

Oocyte maturation arrest and early embryonic arrest are important reproductive phenotypes resulting in female infertility and cause the recurrent failure of assisted reproductive technology (ART). However, the genetic etiologies of these female infertility-related phenotypes are poorly understood. Previous studies have mainly focused on inherited mutations based on large pedigrees or consanguineous patients. However, the role of de novo mutations (DNMs) in these phenotypes remains to be elucidated.

Results

To decipher the role of DNMs in ART failure and female infertility with oocyte and embryo defects, we explore the landscape of DNMs in 473 infertile parent–child trios and identify a set of 481 confident DNMs distributed in 474 genes. Gene ontology analysis reveals that the identified genes with DNMs are enriched in signaling pathways associated with female reproductive processes such as meiosis, embryonic development, and reproductive structure development. We perform functional assays on the effects of DNMs in a representative gene Tubulin Alpha 4a (TUBA4A), which shows the most significant enrichment of DNMs in the infertile parent–child trios. DNMs in TUBA4A disrupt the normal assembly of the microtubule network in HeLa cells, and microinjection of DNM TUBA4A cRNAs causes abnormalities in mouse oocyte maturation or embryo development, suggesting the pathogenic role of these DNMs in TUBA4A.

Conclusions

Our findings suggest novel genetic insights that DNMs contribute to female infertility with oocyte and embryo defects. This study also provides potential genetic markers and facilitates the genetic diagnosis of recurrent ART failure and female infertility.
Identification of cell barcodes from long-read single-cell RNA-seq with BLAZE
Authors: You Yupei , Prawer Yair D. J. , De Paoli-Iseppi Ricardo , Hunt Cameron P. J. , Parish Clare L. , Shim Heejung , Clark Michael B.
Published: April 2023

Long-read single-cell RNA sequencing (scRNA-seq) enables the quantification of RNA isoforms in individual cells. However, long-read scRNA-seq using the Oxford Nanopore platform has largely relied upon matched short-read data to identify cell barcodes. We introduce BLAZE, which accurately and efficiently identifies 10x cell barcodes using only nanopore long-read scRNA-seq data. BLAZE outperforms the existing tools and provides an accurate representation of the cells present in long-read scRNA-seq when compared to matched short reads. BLAZE simplifies long-read scRNA-seq while improving the results, is compatible with downstream tools accepting a cell barcode file, and is available at https://github.com/shimlab/BLAZE.
The HAVEN study—hydroxychloroquine in ANCA vasculitis evaluation—a multicentre, randomised, double-blind, placebo-controlled trial: study protocol and statistical analysis plan
Authors: Learoyd Annastazia E. , Arnold Lauren , Reid Fiona , Beckley-Hoelscher Nicholas , Casian Alina , Sangle Shirish , Morton Neil , Nel Louise , Cape Angela , John Susan , Kim Sangmi , Shivapatham Dharshene , Luqmani Raashid , Jayne David , Galloway James , Douiri Abdel , D’Cruz David ,   on behalf of the HAVEN study group
Published: April 2023

Background

Patients with non-severe ANCA-associated vasculitis (AAV) are often prescribed immunosuppressive medications that are associated with severe side effects and a reduced quality of life. There is an unmet need for safer effective treatments for these patients. Hydroxychloroquine is being explored due to its effect in similar autoimmune conditions such as systemic lupus erythematosus.

Methods

Double-blind, placebo-controlled multicentre trial recruiting 76 patients across 20 sites. Participants will be randomised 1:1 to hydroxychloroquine or placebo in addition to standard of care immunosuppressive therapies over the course of 52 weeks. A phase II selection design will be used to determine hdroxychloroquine’s efficacy, using prednisolone dosage and Birmingham Vasculitis Activity Score as a measure of disease activity. Secondary outcomes will explore other elements of AAV progression, including disease flares and time to remission.

Discussion

This trial aims to explore Hydroxychloroquine as a treatment for patients with AAV. If effective, the need for immunosuppressive treatments such as prednisolone could be reduced. Hydroxychloroquine is safer, cheaper and has fewer adverse effects than conventional immunosuppressive treatments. This could improve patient outcomes while saving money for the NHS.

Trial registration

ISRCTN: ISRCTN79334891. Registered 07 June 2021.

EudraCT: 2018-001268-40. Registered 13 September 2019.

Clinicaltrials.gov: NCT04316494. Registered 20 March 2020.
Mitochondrial metabolism of the facultative parasite Chilodonella uncinata (Alveolata, Ciliophora)
Authors: Bu Xia-lian , Zhao Wei-shan , Li Wen-xiang , Zou Hong , Wu Shan-gong , Li Ming , Wang Gui-tang
Published: April 2023

Background

Chilodonella uncinata is an aerobic ciliate capable of switching between being free-living and parasitic on fish fins and gills, causing tissue damage and host mortality. It is widely used as a model organism for genetic studies, but its mitochondrial metabolism has never been studied. Therefore, we aimed to describe the morphological features and metabolic characteristics of its mitochondria.

Methods

Fluorescence staining and transmission electron microscopy (TEM) were used to observe the morphology of mitochondria. Single-cell transcriptome data of C. uncinata were annotated by the Clusters of Orthologous Genes (COG) database. Meanwhile, the metabolic pathways were constructed based on the transcriptomes. The phylogenetic analysis was also made based on the sequenced cytochrome c oxidase subunit 1 (COX1) gene.

Results

Mitochondria were stained red using Mito-tracker Red staining and were stained slightly blue by DAPI dye. The cristae and double membrane structures of the mitochondria were observed by TEM. Besides, many lipid droplets were evenly distributed around the macronucleus. A total of 2594 unigenes were assigned to 23 functional classifications of COG. Mitochondrial metabolic pathways were depicted. The mitochondria contained enzymes for the complete tricarboxylic acid (TCA) cycle, fatty acid metabolism, amino acid metabolism, and cytochrome-based electron transport chain (ETC), but only partial enzymes involved in the iron-sulfur clusters (ISCs).

Conclusions

Our results showed that C. uncinata possess typical mitochondria. Stored lipid droplets inside mitochondria may be the energy storage of C. uncinata that helps its transmission from a free-living to a parasitic lifestyle. These findings also have improved our knowledge of the mitochondrial metabolism of C. uncinata and increased the volume of molecular data for future studies of this facultative parasite.

Graphical Abstract
Particle bombardment-assisted peptide-mediated gene transfer for highly efficient transient assay
Authors: Kimura Mitsuhiro , Endo Akira , Nagira Yozo , Yoshizumi Takeshi
Published: April 2023

Objective

A centrifugation-assisted peptide-mediated gene transfer (CAPT) method was recently developed as an efficient system for gene delivery into plant cells. However, the gene transfer efficiency of CAPT into plant cells was not entirely satisfactory for detecting transient expression of a transgene driven into mitochondria. Here, we report a new gene delivery system using a method called particle bombardment-assisted peptide-mediated gene transfer (PBPT).

Results

We investigated various parameters of the PBPT method to increase transient gene expression efficiency in Brassica campestris. The optimal conditions for PBPT were a single bombardment with gold particles coated with a DNA‒peptide complex (6 µg of DNA and 2 µg of peptide) at an acceleration pressure of 5 kg/cm2 and a target distance of 12.5 cm. Moreover, bombardment under the optimal conditions successfully transferred the transgene into the cells of other plant species, namely B. juncea and tomato. Thus, we developed a PBPT method for highly efficient delivery of a DNA‒peptide complex into plant mitochondria.
Fluorouracil-induced leukoencephalopathy mimicking neuroleptic malignant syndrome: a case report
Authors: Hemachudha Pasin , Rattanawong Wanakorn , Pongpitakmetha Thanakit , Phuenpathom Warongporn
Published: April 2023

Background

Fluorouracil-induced leukoencephalopathy is a rare complication and has been reported to present as confusion, oculomotor abnormality, ataxia, and parkinsonism; however, there is no previous report of a presentation mimicking neuroleptic malignant syndrome. Acute cerebellar syndrome may occur, which can be explained by the extremely high accumulation of the drug in the cerebellum. However, presentation mimicking neuroleptic malignant syndrome similar to our case has never been reported.

Case presentation

Here, we describe a 68-year-old Thai male presenting with advanced-stage cecal adenocarcinoma, as well as symptoms and signs indicative of neuroleptic malignant syndrome. He received two doses of intravenous metoclopramide 10 mg 6 hours before his symptoms occurred. Magnetic resonance imaging scan revealed signal hyperintensity within the bilateral white matter. Further evaluation showed that his thiamine level was extremely low. Thus, he was diagnosed with fluorouracil-induced leukoencephalopathy mimicking neuroleptic malignant syndrome. The concomitant fluorouracil-induced thiamine deficiency eventually leads to rapid depletion of thiamine and was considered a risk factor for fluorouracil-induced leukoencephalopathy.

Conclusion

Fluorouracil-induced leukoencephalopathy is believed to be caused by insult causing mitochondrial dysfunction. However, the exact mechanism remains unknown, but our finding suggests that thiamine deficiency plays a crucial role in fluorouracil-induced leukoencephalopathy. Diagnosis is usually delayed due to a lack of clinical suspicion and results in significant morbidity requiring unnecessary investigations.
Bilateral Grynfeltt lumbar hernia: a case report
Authors: Aza Matthieu Sumai , Yawi Joël Bosomi , Musumba Jackson Kambale , Muliwavyo Faida Kavugho , Kavuyiro Alpha Muhindo , Mitamo Alexendre Amini , Masumboko Claude Kasereka , Akinja Severain Uwanda
Published: April 2023

Introduction

Lumbar hernias are rare, with only 200–300 published cases listed in the literature. Two areas are described to have weakness points: the inferior lumbar triangle (Jean-Louis Petit triangle) and the superior lumbar triangle (Grynfeltt–Lesshaft triangle). Clinical diagnosis is confirmed by computed tomography and possibly by ultrasound or radiography. The surgeon must refine the clinical detection of this condition, as most patients do not have sufficient means to have a computed tomography scan performed, which remains the gold standard for diagnosis. Despite the different techniques recommended, the open route remains the most affordable in our environment.

Case presentation

This case presents an 84-year-old black congolese patient consulted for bilateral swellings of the lumbar regions. The patient was married and in the farming profession for several years. The patient had no notion of trauma or fever and no notion of vomiting or stopping of materials and gases. The lumbar region presented with swellings that were ovoid, soft, painless, impulsive and expansive on coughing or hyperpressure, and non-pulsatile, measuring 9 × 7 cm in diameter (right) and 6 × 5 cm in diameter (left). Ultrasound performed of the upper costolumbal region revealed two lipomatous masses facing Grynfeltt’s quadrilateral with a 1.5 cm hole on either side. The diagnosis of bilateral Grynfeltt hernia was made, and herniorrhaphy was indicated.

Conclusion

Grynfeltt–Lesshaft hernia is a rare surgical condition caused by congenital or acquired etiology. A lower back pain or a pain point localized on the hernia in addition to a lumbar mass that reduces when lying down suggests the diagnosis of lumbar hernia.