bluuebunny/crossref_metadata_2025 huggingface dataset:
Cuproptosis-related lncRNA predict prognosis and immune response of lung adenocarcinoma
Authors: Wang Fangwei , Lin Hongsheng , Su Qisheng , Li Chaoqian
Published: September 2022

Background

Lung adenocarcinoma (LUAD) accounts for 50% of lung cancers, with high mortality and poor prognosis. Long non-coding RNA (lncRNA) plays a vital role in the progression of tumors. Cuproptosis is a newly discovered form of cell death that is highly investigated. Therefore, in the present study, we aimed to investigate the role of cuproptosis-related lncRNA signature in clinical prognosis prediction and immunotherapy and the relationship with drug sensitivity.

Material and methods

Genomic and clinical data were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, and cuproptosis-related genes were obtained from cuproptosis-related studies. The prognostic signature was constructed by co-expression analysis and Cox regression analysis. Patients were divided into high and low risk groups, and then, a further series of model validations were carried out to assess the prognostic value of the signature. Subsequently, lncRNAs were analyzed for gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes Enrichment (KEGG), immune-related functions, and tumor mutation burden (TMB). Finally, we used tumor immune dysfunction and exclusion (TIDE) algorithms on immune escape and immunotherapy of cuproptosis-related lncRNAs, thereby identifying its sensitivity toward potential drugs for LUAD.

Results

A total of 16 cuproptosis-related lncRNAs were obtained, and a prognostic signature was developed. We found that high-risk patients had worse overall survival (OS) and progression-free survival (PFS) and higher mortality. Independent prognostic analyses, ROC, C-index, and nomogram showed that the cuproptosis-related lncRNAs can accurately predict the prognosis of patients. The nomogram and heatmap showed a distinct distribution of the high- and low-risk cuproptosis-related lncRNAs. Enrichment analysis showed that the biological functions of lncRNAs are associated with tumor development. We also found that immune-related functions, such as antiviral activity, were suppressed in high-risk patients who had mutations in oncogenes. OS was poorer in patients with high TMB. TIDE algorithms showed that high-risk patients have a greater potential for immune escape and less effective immunotherapy.

Conclusion

To conclude, the 16 cuproptosis-related lncRNAs can accurately predict the prognosis of patients with LUAD and may provide new insights into clinical applications and immunotherapy.
Evaluation of at-home serum anti-Müllerian hormone testing: a head-to-head comparison study
Authors: Silliman Erin , Chung Esther H. , Fitzpatrick Elizabeth , Jolin Julie A. , Brown Michelle , Hotaling James , Styer Aaron K. , Karmon Anatte E.
Published: September 2022

Background

For optimal fertility testing, serum anti-Müllerian hormone levels are used in combination with other testing to provide reliable ovarian reserve evaluations. The use of the ADx 100 card is widely commercially available for at-home reproductive hormone testing, but data demonstrating that its results are reproducible outside of a clinical setting are limited, as well as comparisons of its performance with other newer blood collection techniques. This study aimed to evaluate the concordance of serum AMH levels found via standard venipuncture and self-administered blood collection using the TAP II device (TAP) and ADx card in women of reproductive age.

Methods

This was a prospective, head-to-head-to-head within-person crossover comparison trial that included 41 women of reproductive age (20–39 years). It was hypothesized that the TAP device would be superior to the ADx card both in terms of agreement with venipuncture reference standard and patient experience. Each subject had their blood drawn using the three modalities (TAP, ADx, and venipuncture). We evaluated the concordance of AMH assays from samples obtained via the TAP device and ADx card with the gold standard being venipuncture. Two-sided 95% CIs were generated for each method to compare relative performance across all three modes. Patient preference for the TAP device versus the ADx card was based on self-reported pain and Net Promoter Score (NPS).

Results

The TAP device was superior to the ADx card on all outcome measures. TAP R-squared with venipuncture was 0.99 (95% CI 0.99, > 0.99), significantly higher than the ADx card, which had an R-squared of 0.87 (95% CI 0.80, 0.94) under most favorable treatment. TAP sensitivity and specificity were both 100% (no clinical disagreement with venipuncture), versus 100 and 88%, respectively, for the ADx card. Average pain reported by users of the TAP device was significantly lower than the ADx card (0.75 versus 2.73, p < 0.01) and the NPS was significantly higher than the ADx card (+ 72 versus − 48, p < 0.01).

Conclusions

The TAP was non-inferior to venipuncture and superior to the ADx card with respect to correlation and false positives. Moreover, the TAP was superior to both alternatives on patient experience.

Trial registration

NCT04784325 (Mar 5, 2021).
Effect of TSH on oocyte maturation of PCOS patients with normal thyroid function in IVF
Authors: Xu Shaoyuan , Zhang Ying , Qiang Cancan , Zhang Changjun
Published: September 2022

Background

The serum TSH level of PCOS patients was higher than that of the general female population. For patients with thyroid dysfunction, the abnormal TSH level is negatively related to the outcomes of assisted reproductive technology, but for PCOS patients with normal thyroid function, the effect of TSH level on outcomes of in vitro fertilization has not been reported. In this study, PCOS patients with normal thyroid function were included in this study to evaluate the effect of TSH on the outcomes of IVF-ET.

Methods

A retrospective cohort study was conducted to analyze the clinical data of 3190 patients who underwent IVF-ET in the Department of Human Reproductive Center of Renmin Hospital Hubei University of Medicine from January 2017 to July 2021, including 594 PCOS patients and 2595 non PCOS patients. The IVF-ET outcomes between the two groups were compared; Multi-factor linear regression analysis was used to analyze the correlation between the related variables and the oocyte maturation of PCOS patients; The ROC curve of the effect of TSH on oocyte maturation in PCOS patients was drawn. The PCOS patients were divided into TSH < 2.98 group (n = 454) and TSH ≥ 2.98 group (n = 141) according to ROC threshold TSH 2.98, and the outcomes were compared.

Results

TSH level in PCOS group was significantly higher than that in non-PCOS group (2.42 ± 0.86 vs 2.00 ± 0.89 UU / ml, P < 0.01), and the oocyte maturation rate and 2PN fertilization rate in PCOS group were lower than those in non-PCOS group (90.9% vs 92.4%, P = 0.02) (84.57% vs 86.77%, P = 0.02). There was no significant difference in cleavage rate and high-quality embryo rate between the two groups (P > 0.05); There was no difference in clinical pregnancy rate, abortion rate, ectopic pregnancy rate and live birth rate between the two groups (P > 0.05).

Multi-factor linear regression analysis showed that TSH was negatively correlated with oocyte maturation in PCOS patients [β = -0.124, P = 0.013,95%CI (-0.027 ~ -0.003)]; The oocyte maturation rate in TSH < 2.98 group was significantly higher than that in TSH ≥ 2.98 group (91.7% vs 88.2%, P = 0.001).

Conclusion

The TSH level of PCOS patients with normal thyroid function is higher than that of normal people, and it is negatively correlated with the oocyte maturation in in-vitro fertilization. The ROC curve showed that when TSH > 2.98uIU/ml, the possibility of immature oocytes was higher (specificity 28.9%, sensitivity 83.0%).
User involvement in ageing and health research: a survey of researchers’ and older adults’ perspectives
Authors: Kylén Maya , Slaug Björn , Jonsson Oskar , Iwarsson Susanne , Schmidt Steven M.
Published: September 2022

Background

User involvement in research has rapidly increased and is often a precondition to obtain research funding. Benefits such as effectiveness and increased relevance of research are described in the literature, but the evidence to support this is weak. Little is known about ageing and health researchers’ experiences and perspectives towards user involvement in research, and their attitudes towards user involvement compared to the attitudes of the users involved are largely unknown. To examine researchers’ experiences and perspectives of user involvement in research on ageing and health, and to compare their attitudes towards user involvement to the attitudes of older adults in the general population.

Methods

A panel study survey was used to elicit responses from researchers in ageing and health as well as from older adults (aged 60 years and older). The researcher sample (N = 64) completed the survey online, while the older adult sample (N = 881) could choose among three different options to complete the survey (online, paper format, telephone). A professional survey company collected the data. Descriptive statistics, exploratory comparisons and descriptive qualitative content analysis were used to analyse the data.

Results

More than half (58%) of the researchers had previous experience of involving different categories of users in a wide range of research activities. The most frequent motivation for involving users was to ensure that the research produced is relevant to the target population. A majority (86%) reported benefits, and more than half (59%) described challenges. Differences in attitudes were found between researchers and older adults in the general population.

Conclusions

Ageing and health researchers involve users in their research to improve quality and ensure relevance, but there is no consensus among them whether users should be involved in publicly funded research. While several challenges were identified, training, institutional support and resources from funders could alleviate many of these. Findings reveal significant differences in attitudes between older adults in the general population and researchers. Further research with comparable larger samples is needed to confirm and understand the possible consequences such controversy might have and how to solve them.

IRRID (International Registered Report Identifier): RR2-10.2196/17759.
National governance of de-implementation of low-value care: a qualitative study in Sweden
Authors: Augustsson Hanna , Casales Morici Belén , Hasson Henna , von Thiele Schwarz Ulrica , Schalling Sara Korlén , Ingvarsson Sara , Wijk Hanna , Roczniewska Marta , Nilsen Per
Published: September 2022

Background

The de-implementation of low-value care (LVC) is important to improving patient and population health, minimizing patient harm and reducing resource waste. However, there is limited knowledge about how the de-implementation of LVC is governed and what challenges might be involved. In this study, we aimed to (1) identify key stakeholders’ activities in relation to de-implementing LVC in Sweden at the national governance level and (2) identify challenges involved in the national governance of the de-implementation of LVC.

Methods

We used a purposeful sampling strategy to identify stakeholders in Sweden having a potential role in governing the de-implementation of LVC at a national level. Twelve informants from nine stakeholder agencies/organizations were recruited using snowball sampling. Semi-structured interviews were conducted, transcribed and analysed using inductive thematic analysis.

Results

Four potential activities for governing the de-implementation of LVC at a national level were identified: recommendations, health technology assessment, control over pharmaceutical products and a national system for knowledge management. Challenges involved included various vested interests that result in the maintenance of LVC and a low overall priority of working with the de-implementation of LVC compared with the implementation of new evidence. Ambiguous evidence made it difficult to clearly determine whether a practice was LVC. Unclear roles, where none of the stakeholders perceived that they had a formal mandate to govern the de-implementation of LVC, further contributed to the challenges involved in governing that de-implementation.

Conclusions

Various activities were performed to govern the de-implementation of LVC at a national level in Sweden; however, these were limited and had a lower priority relative to the implementation of new methods. Challenges involved relate to unfavourable change incentives, ambiguous evidence, and unclear roles to govern the de-implementation of LVC. Addressing these challenges could make the national-level governance of de-implementation more systematic and thereby help create favourable conditions for reducing LVC in healthcare.
The mechanisms and prediction of non-structural carbohydrates accretion and depletion after mechanical wounding in slash pine (Pinus elliottii) using near-infrared reflectance spectroscopy
Authors: Li Yanjie , Sun Honggang , de Paula Protásio Thiago , Hein Paulo Ricardo Gherardi , Du Baoguo
Published: September 2022

Background

The allocation of non-structural carbohydrates (NSCs) plays a critical role in the physiology and metabolism of tree growth and survival defense. However, little is known about the allocation of NSC after continuous mechanical wounding of pine by resin tapping during tree growth.

Results

Here, we examine the NSC allocation in plant tissues after 3 year lasting resin tapping, and also investigate the use of near-infrared reflectance (NIR) spectroscopy to quantify the NSC, starch and free sugar (e.g., sucrose, glucose, and fructose) concentrations in different plant tissues of slash pine. Spectral measurements on pine needle, branch, trunk phloem, and root were obtained before starch and free sugar concentrations were measured in the laboratory. The variation of NSC, starch and free sugars in different plant tissues after resin tapping was analyzed. Partial least squares regression was applied to calibrate prediction models, models were simulated 100 times for model performance and error estimation. More NSC, starch and free sugars were stored in winter than summer both in tapped and control trees. The position of resin tapping significantly influenced the NSCs allocation in plant tissues: more NSCs were transformed into free sugars for defensive resin synthesis close to the tapping wound rather than induced distal systemic responses. Models for predicting NSC and free sugars of plant tissues showed promising results for the whole tree for fructose (R2CV = 0.72), glucose (R2CV = 0.67), NSCs (R2CV = 0.66) and starch (R2CV = 0.58) estimates based on NIR models. Models for individual plant tissues also showed reasonable predictive ability: the best model for NSCs and starch prediction was found in root. The significance multivariate correlation algorithm for variable selection significantly reduced the number of variables. Important variables were identified, including features at 1021–1290 nm, 1480, 1748, 1941, 2020, 2123 and 2355 nm, which are highly related to NSC, starch, fructose, glucose and sucrose.

Conclusions

NIR spectroscopy provided a rapid and cost-effective method to monitor NSC, starch and free sugar concentrations after continuous resin tapping. It can be used for studying the trade-off between growth and production of defensive metabolites.
A randomized controlled trial in schools aimed at exploring mechanisms of change of a multifaceted implementation strategy for promoting mental health at the workplace
Authors: Kwak Lydia , Toropova Anna , Powell Byron J. , Lengnick-Hall Rebecca , Jensen Irene , Bergström Gunnar , Elinder Liselotte Schäfer , Stigmar Kjerstin , Wåhlin Charlotte , Björklund Christina
Published: September 2022

Background

This study will explore implementation mechanisms through which a single implementation strategy and a multifaceted implementation strategy operate to affect the implementation outcome, which is fidelity to the Guideline For The Prevention of Mental Ill Health within schools. The guideline gives recommendations on how workplaces can prevent mental ill health among their personnel by managing social and organizational risks factors in the work environment. Schools are chosen as the setting for the study due to the high prevalence of mental ill health among teachers and other personnel working in schools. The study builds on our previous research, in which we compared the effectiveness of the two strategies on fidelity to the guideline. Small improvements in guideline adherence were observed for the majority of the indicators in the multifaceted strategy group. This study will focus on exploring the underlying mechanisms of change through which the implementation strategies may operate to affect the implementation outcome.

Methods

We will conduct a cluster-randomized-controlled trial among public schools (n=55 schools) in Sweden. Schools are randomized (1:1 ratio) to receive a multifaceted strategy (implementation teams, educational meeting, ongoing training, Plan-Do-Study-Act cycles) or a single strategy (implementation teams, educational meeting). The implementation outcome is fidelity to the guideline. Hypothesized mediators originate from the COM-B model. A mixed-method design will be employed, entailing a qualitative study of implementation process embedded within the cluster-randomized controlled trail examining implementation mechanisms. The methods will be used in a complementary manner to get a full understanding of the implementation mechanisms.

Discussion

This implementation study will provide valuable knowledge on how implementation strategies work (or fail) to affect implementation outcomes. The knowledge gained will aid the selection of effective implementation strategies that fit specific determinants, which is a priority for the field. Despite recent initiatives to advance the understanding of implementation mechanisms, studies testing these mechanisms are still uncommon.

Trial registration

ClinicalTrials.org dr.nr 2020-01214.
Inhibition of lncRNA NEAT1 induces dysfunction of fibroblast-like synoviocytes in rheumatoid arthritis via miRNA-338-3p-mediated regulation of glutamine metabolism
Authors: Zhang Mei , Lu Ning , Li Hong-Jun , Guo Xiao-Yun , Lu Lu , Guo Ying
Published: September 2022

Background

Rheumatoid arthritis (RA) is a systemic chronic autoimmune disease; cellular glutamine metabolism in fibroblast-like synoviocytes (FLSs) of RA was known to be essential for RA pathogenesis and progression. NEAT1, a long non-coding RNA, functions as an oncogene in diverse cancers. The exact roles and molecular mechanisms of NEAT1 in fibroblast-like synoviocytes (FLSs) of RA patients are unknown.

Methods

Expression of NEAT1 and miR-338-3p was measured by qRT-PCR. lncRNA-miRNA and miRNA-mRNA interactions were predicted from starBase and validated by RNA pull-down and luciferase assay. The glutamine metabolism of FLSs was evaluated by glutamine uptake and glutaminase activity. Cell death in FLSs in response to H2O2 was assessed by MTT and Annexin V assays.

Results

NEAT1 was significantly upregulated, and miR-338-3p was significantly downregulated in FLSs from RA patients compared to normal FLSs. Silencing of NEAT1 and overexpression of miR-338-3p suppressed glutamine metabolism in FLSs-RA and promoted H2O2-induced apoptosis. Bioinformatics analysis showed that NEAT1 sponges miR-338-3p to form competing endogenous RNA (ceRNAs), which was verified by RNA pull-down assay and luciferase assay FLSs-RA had an increased rate of glutamine metabolism compared to normal FLSs increased compared to normal FLSs. The results confirmed that GLS (Glutaminase), a key enzyme in glutamine metabolism, is a direct target of miR-338-3p in FLSs-RA. miR-338-3p inhibition of glutamine metabolism was verified by rescue experiments verified. Finally, restoration of miR-338-3p in FLSs-RA expressing NEAT1 overcomes NEAT1-promoted glutamine metabolism and resistance to apoptosis.

Conclusions

This study reveals the essential role and molecular targets of NEAT1-regulated glutamine metabolism and FLSs-RA dysfunction in fibroblast-like synoviocytes of RA and indicates that blocking the molecular pathway via non-coding RNAs may be beneficial for RA patients.
Quality assessment and Q-markers discovery of Tongsaimai tablet by integrating serum pharmacochemistry and network pharmacology for anti-atherosclerosis benefit
Authors: Cheng Yanfen , Xiao Meng , Chen Jiamei , Wang Di , Hu Yichen , Zhang Chenfeng , Wang Tuanjie , Fu Chaomei , Wu Yihan , Zhang Jinming
Published: September 2022

Background

The limited therapeutic outcomes of atherosclerosis (AS) have allowed, traditional Chinese medicine has been well established as an alternative approach in ameliorating AS and associated clinical syndromes. Clinically, Tongsaimai tablet (TSMT), a commercial Chinese patent medicine approved by CFDA, shows an obvious therapeutic effect on AS treatment. However, its effective mechanism and quality control still need thorough and urgent exploration.

Methods

The mice were orally administered with TSMT and their serum was investigated for the absorbed compounds using serum pharmacochemistry via the UPLC-Q-Exactive Orbitrap/MS analysis was employed to investigate these absorbed compounds in serum of mice orally administrated with TSMT. Based on these absorbed prototype compounds in serum derived from TSMT, a component-target-disease network was constructed using network pharmacology strategy, which elucidated the potential bioactive components, effective targets, and molecular mechanisms of TSMT against AS. Further, the screened compounds from the component-target network were utilized as the quality control (QC) markers, determining multi-component content determination and HPLC fingerprint to assess quality of nine batches of TSMT samples.

Results

A total of 164 individual components were identified in TSMT. Among them, 29 prototype compounds were found in serum of mice administrated with TSMT. Based on these candidate prototype components, 34 protein targets and 151 pathways related to AS were predicted, and they might significantly exhibit potential anti-AS mechanisms via synergistic regulations of lipid regulation, shear stress, and anti-inflammation, etc. Five potentially bioactive ingredients in TSMT, including Ferulic acid, Liquiritin, Senkyunolide I, Luteolin and Glycyrrhizic acid in quantity not less than 1.2798, 0.4716, 0.5419, 0.1349, 4.0386 mg/g, respectively, screened from the component-target-pathway network. Thereby, these indicated that these five compounds of TMST which played vital roles in the attenuation of AS could serve as crucial marker compounds for quality control.

Conclusions

Overall, based on the combination of serum pharmacochemistry and network pharmacology, the present study firstly provided a useful strategy to establish a quality assessment approach for TSMT by screening out the potential anti-AS mechanisms and chemical quality markers.

Graphical Abstract
ERN CRANIO patient coverage of craniosynostosis in Europe
Authors: Spivack O. , Gaillard L. ,   ERN CRANIO hospital representatives, Mathijssen Irene M. J. , Delye Hans , Arnaud Eric , Bulstrode Neil , Johnson David , Evans Martin , Parks Chris , Poca Maria A. , Romance Ana , Kölby Lars , Nowinski Daniel , Faggin Roberto , Giussani Carlo , Valentini Laura , Tamburrini Gianpiero , Thomale Ulrich-Wilhelm , Vuola Pia , Faria Cláudia , Di Rocco Federico , Mena-Bernal José Hinojosa , Genitori Lorenzo , Reinert Siegmar
Published: September 2022

Background

Against the backdrop of the European Directive on patients’ rights in cross-border healthcare, 24 European Reference Networks (ERNs) were launched in 2017. ERNs are networks of specialised hospitals working together to support patients with rare and/or complex diseases. ERN CRANIO is the ERN for craniofacial anomalies and ear, nose and throat disorders. The aim of this study was to explore ERN CRANIO’s patient coverage of craniosynostosis.

Methods

ERN CRANIO members and applicants were asked to retrospectively report the number of ‘new craniosynostosis patients’ (isolated and syndromic) seen in 2017. The number of live births per country in 2017 was retrieved from EUROSTAT, the EU’s statistical office. The number of new patients reported per country and the number of live births were used to generate country-specific prevalence figures per 10,000 live births. These figures were compared to expected prevalence ranges for craniosynostosis, and syndromic craniosynostosis specifically, defined by recent European studies. The percentage of syndromic craniosynostosis cases per country was also compared to the expected percentage range.

Results

Based on previous studies, the expected prevalence ranges for craniosynostosis and syndromic craniosynostosis specifically were respectively defined as 4.4–7.2 and 0.9–1.6 patients/10,000 live births. For craniosynostosis (‘total’; isolated + syndromic), 'new patient' data from the UK and Finland generated prevalence figures within the expected range, and those in France, Spain, Italy, Portugal and Germany are lower than expected. However, when including applicant data, the prevalence figures for France, Spain and Italy become in range. Data from the Netherlands and Sweden generated higher prevalence figures than expected. For France, Finland, Italy and Sweden, there is inconsistency between patient coverage of ‘total’ and syndromic patients. For France, Germany, Finland and Italy, the percentage of syndromic craniosynostosis was lower than the expected range.

Conclusion

ERN CRANIO’s coverage of craniosynostosis varies across Europe. Results may be explained by data collection methods, genetic testing policies and/or national healthcare systems. With centre caseload a driving force for quality, additional ERN membership calls may not necessarily ensure sufficient patient coverage for countries with decentralised healthcare systems. Liaison with national health ministries should be encouraged to optimise patient coverage.
Effectiveness of time-limited eye movement desensitization reprocessing therapy for parents of children with a rare life-limiting illness: a randomized clinical trial
Authors: Conijn T. , De Roos C. , Vreugdenhil H. J. I. , Van Dijk-Lokkart E. M. , Wijburg F. A. , Haverman L.
Published: September 2022

Background

Parents of children with a rare progressive life-limiting illness are at risk for parental posttraumatic stress disorder (PTSD). Studies on the treatment of parental PTSD with eye movement and desensitization reprocessing (EMDR) therapy in pediatric practice are lacking. Therefore this study aims to evaluate the feasibility and effectiveness of time-limited EMDR therapy in reducing PTSD symptoms, comorbid psychological symptoms, distress, and parental stress.

Methods

Mono-center randomized clinical trial conducted between February 2020 and April 2021. Fourteen parents (N = 7 mothers,N = 7 fathers) of mucopolysaccharidosis type III patients reporting PTSD symptoms on a (sub)clinical level were assigned to EMDR or a wait-list control condition followed by EMDR. Four sessions of EMDR (each 90 min) divided over two half-days were offered. Measurements were conducted at baseline, post-treatment/post-waitlist, and 3-months post-treatment. The primary outcome was PTSD symptom severity (PTSD Check List for DSM-5). Secondary outcomes included comorbid psychological symptoms (Brief Symptom Inventory), distress (Distress Thermometer for Parents) and parenting stress (Parenting Stress Questionnaire). Between-group comparisons pre-to-post treatment (N = 7 EMDR vs.N = 7 wait-list) and within-group comparisons (EMDR,N = 14) from pre-to-post treatment and from pre-treatment to 3-months follow-up were carried out per intent-to-treat linear mixed model analyses.

Results

Compared to wait-list, EMDR resulted in a significant reduction on total PTSD symptom severity (d = 1.78) and on comorbid psychological symptoms, distress and parenting stress (d = .63–1.83). Within-group comparisons showed a significant effect on all outcomes at post-treatment (d = 1.04–2.21) and at 3-months follow-up (d = .96–2.30) compared to baseline. EMDR was well-tolerated, associated with a low drop-out rate, a high therapy adherence and no adverse events.

Conclusion

Time-limited EMDR reduces PTSD symptoms, psychological comorbidity, distress and parenting stress in parents of children with a rare progressive life-limiting illness. This treatment was feasible for these overburdened parents. Recurrent monitoring of PTSD symptoms, and, if needed, offering this time-limited type of trauma treatment should be introduced in everyday pediatric practice.

Trial registrationNetherlands Trial Register, NL8496. Registered 01-04-2020,https://trialsearch.who.int/Trial2.aspx?TrialID=NL8496.
LRP1 is a neuronal receptor for α-synuclein uptake and spread
Authors: Chen Kai , Martens Yuka A. , Meneses Axel , Ryu Daniel H. , Lu Wenyan , Raulin Ana Caroline , Li Fuyao , Zhao Jing , Chen Yixing , Jin Yunjung , Linares Cynthia , Goodwin Marshall , Li Yonghe , Liu Chia-Chen , Kanekiyo Takahisa , Holtzman David M. , Golde Todd E. , Bu Guojun , Zhao Na
Published: September 2022

Background

The aggregation and spread of α-synuclein (α-Syn) protein and related neuronal toxicity are the key pathological features of Parkinson’s disease (PD) and Lewy body dementia (LBD). Studies have shown that pathological species of α-Syn and tau can spread in a prion-like manner between neurons, although these two proteins have distinct pathological roles and contribute to different neurodegenerative diseases. It is reported that the low-density lipoprotein receptor-related protein 1 (LRP1) regulates the spread of tau proteins; however, the molecular regulatory mechanisms of α-Syn uptake and spread, and whether it is also regulated by LRP1, remain poorly understood.

Methods

We established LRP1 knockout (LRP1-KO) human induced pluripotent stem cells (iPSCs) isogenic lines using a CRISPR/Cas9 strategy and generated iPSC-derived neurons (iPSNs) to test the role of LRP1 in α-Syn uptake. We treated the iPSNs with fluorescently labeled α-Syn protein and measured the internalization of α-Syn using flow cytometry. Three forms of α-Syn species were tested: monomers, oligomers, and pre-formed fibrils (PFFs). To examine whether the lysine residues of α-Syn are involved in LRP1-mediated uptake, we capped the amines of lysines on α-Syn with sulfo-NHS acetate and then measured the internalization. We also tested whether the N-terminus of α-Syn is critical for LRP1-mediated internalization. Lastly, we investigated the role of Lrp1 in regulating α-Syn spread with a neuronal Lrp1 conditional knockout (Lrp1-nKO) mouse model. We generated adeno-associated viruses (AAVs) that allowed for distinguishing the α-Syn expression versus spread and injected them into the hippocampus of six-month-old Lrp1-nKO mice and the littermate wild type (WT) controls. The spread of α-Syn was evaluated three months after the injection.

Results

We found that the uptake of both monomeric and oligomeric α-Syn was significantly reduced in iPSNs with LRP1-KO compared with the WT controls. The uptake of α-Syn PFFs was also inhibited in LRP1-KO iPSNs, albeit to a much lesser extent compared to α-Syn monomers and oligomers. The blocking of lysine residues on α-Syn effectively decreased the uptake of α-Syn in iPSNs and the N-terminus of α-Syn was critical for LRP1-mediated α-Syn uptake. Finally, in the Lrp1-nKO mice, the spread of α-Syn was significantly reduced compared with the WT littermates.

Conclusions

We identified LRP1 as a key regulator of α-Syn neuronal uptake, as well as an important mediator of α-Syn spread in the brain. This study provides new knowledge on the physiological and pathological role of LRP1 in α-Syn trafficking and pathology, offering insight for the treatment of synucleinopathies.
Trem2 deletion enhances tau dispersion and pathology through microglia exosomes
Authors: Zhu Bing , Liu Yan , Hwang Spring , Archuleta Kailey , Huang Huijie , Campos Alex , Murad Rabi , Piña-Crespo Juan , Xu Huaxi , Huang Timothy Y.
Published: September 2022

Background

Alzheimer’s disease (AD) is a neurodegenerative disorder that manifests sequential Aβ and tau brain pathology with age-dependent onset. Variants in the microglial immune receptor TREM2 are associated with enhanced risk of onset in sporadic Alzheimer’s disease (AD). While recent studies suggest TREM2 dysfunction can aggravate tau pathology, mechanisms underlying TREM2-dependent modulation of tau pathology remains elusive.

Methods

Here, we characterized differences in progressive tau spreading from the medial entorhinal cortex (MEC) to the hippocampus in wildtype (WT) and Trem2 knockout (KO) mice by injection of AAV-P301L tau into the MEC, and correlated changes in hippocampal tau histopathology with spatial and fear memory. We also compared effects of intraneuronal dispersion between cultured microglia and neurons using a microfluidic dispersion assay, analyzed differences in microglial tau trafficking following uptake, and quantified exosomal tau secretion and pathogenicity from purified WT and Trem2 KO exosomes.

Results

Trem2 deletion in mice (Trem2 KO) can enhance tau spreading from the medial entorhinal cortex (MEC) to the hippocampus, which coincides with impaired synaptic function and memory behavior. Trem2 deletion in microglia enhances intraneuronal dispersion of tau in vitro between neuronal layers cultured in a microfluidic chamber, and the presence of exosome inhibitors can significantly reduce tau in exosomes and extracellular media from tau-loaded microglia. Although microglial Trem2 deletion has no effect on tau uptake, Trem2 deletion enhances distribution to endosomal and cellular pre-exosomal compartments following internalization. Trem2 deletion has little effect on exosome size, however, proteomic analysis indicates that Trem2 deletion can modulate changes in the microglial proteomic landscape with tau and LPS/ATP treatment conditions associated with exosome induction. Furthermore, exosomes from Trem2 KO microglia show elevated tau levels, and feature enhanced tau-seeding capacity in a tau FRET reporter line compared to exosomes from WT microglia.

Conclusion

Together, our results reveal a role for Trem2 in suppressing exosomal tau pathogenicity, and demonstrates that Trem2 deletion can enhance tau trafficking, distribution and seeding through microglial exosomes.

Graphical abstract
Validation and standardization of the Childhood Trauma Screener (CTS) in the general population
Authors: Witt Andreas , Öz Yusuf , Sachser Cedric , Brähler Elmar , Glaesmer Heide , Fegert Jörg M.
Published: September 2022

Background

A valid, quick and widely applicable retrospective screening tool for child maltreatment is of great importance to better adapt interventions and treatments. The Childhood Trauma Screener (CTS), derived from the Childhood Trauma Questionnaire (CTQ), is one such instrument that aims to increase the likelihood of detecting mental and physical disorders that have manifested in adulthood as a result of traumatic experiences and maltreatment in childhood and adolescence. The present study aimed to investigate the psychometric properties of the CTS and generate normative data.

Methods

Data from two representative surveys were combined. Both surveys used identical methods. The CTS, consisting of five items, other self-report instruments, and demographic characteristics were used. Construct validity was examined using confirmatory factor analysis (CFA). A subsample was used to examine convergent validity with the Adverse Childhood Experiences Questionnaire (ACE). Normative data are reported for age groups and gender.

Results

A total of 5039 study participants provided valid responses to the 5-items questionnaire (54.3% female, response rate = 78.9%). CFA showed good fit indices for a 2-factor solution. Convergent validity was generally supported by moderate intercorrelations with the ACE.

Conclusions

The results confirm the solid psychometric properties of the CTS as an easy-to-use, ultra-short retrospective measure of child maltreatment. The data can be used to compare sample or individual results with reference data provided.
Somatic copy number alteration and fragmentation analysis in circulating tumor DNA for cancer screening and treatment monitoring in colorectal cancer patients
Authors: Hallermayr Ariane , Wohlfrom Tobias , Steinke-Lange Verena , Benet-Pagès Anna , Scharf Florentine , Heitzer Ellen , Mansmann Ulrich , Haberl Christopher , de Wit Maike , Vogelsang Holger , Rentsch Markus , Holinski-Feder Elke , Pickl Julia M. A.
Published: September 2022

Background

Analysis of circulating free DNA (cfDNA) is a promising tool for personalized management of colorectal cancer (CRC) patients. Untargeted cfDNA analysis using whole-genome sequencing (WGS) does not need a priori knowledge of the patient´s mutation profile.

Methods

Here we established LIquid biopsy Fragmentation, Epigenetic signature and Copy Number Alteration analysis (LIFE-CNA) using WGS with ~ 6× coverage for detection of circulating tumor DNA (ctDNA) in CRC patients as a marker for CRC detection and monitoring.

Results

We describe the analytical validity and a clinical proof-of-concept of LIFE-CNA using a total of 259 plasma samples collected from 50 patients with stage I-IV CRC and 61 healthy controls. To reliably distinguish CRC patients from healthy controls, we determined cutoffs for the detection of ctDNA based on global and regional cfDNA fragmentation patterns, transcriptionally active chromatin sites, and somatic copy number alterations. We further combined global and regional fragmentation pattern into a machine learning (ML) classifier to accurately predict ctDNA for cancer detection. By following individual patients throughout their course of disease, we show that LIFE-CNA enables the reliable prediction of response or resistance to treatment up to 3.5 months before commonly used CEA.

Conclusion

In summary, we developed and validated a sensitive and cost-effective method for untargeted ctDNA detection at diagnosis as well as for treatment monitoring of all CRC patients based on genetic as well as non-genetic tumor-specific cfDNA features. Thus, once sensitivity and specificity have been externally validated, LIFE-CNA has the potential to be implemented into clinical practice. To the best of our knowledge, this is the first study to consider multiple genetic and non-genetic cfDNA features in combination with ML classifiers and to evaluate their potential in both cancer detection and treatment monitoring.

Trial registration DRKS00012890.
Heterogeneity of triple negative breast cancer: Current advances in subtyping and treatment implications
Authors: Asleh Karama , Riaz Nazia , Nielsen Torsten O.
Published: September 2022

As the field of translational ‘omics has progressed, refined classifiers at both genomic and proteomic levels have emerged to decipher the heterogeneity of breast cancer in a clinically-applicable way. The integration of ‘omics knowledge at the DNA, RNA and protein levels is further expanding biologic understanding of breast cancer and opportunities for customized treatment, a particularly pressing need in clinically triple negative tumors. For this group of aggressive breast cancers, work from multiple groups has now validated at least four major biologically and clinically distinct omics-based subtypes. While to date most clinical trial designs have considered triple negative breast cancers as a single group, with an expanding arsenal of targeted therapies applicable to distinct biological pathways, survival benefits may be best realized by designing and analyzing clinical trials in the context of major molecular subtypes. While RNA-based classifiers are the most developed, proteomic classifiers proposed for triple negative breast cancer based on new technologies have the potential to more directly identify the most clinically-relevant biomarkers and therapeutic targets. Phospho-proteomic data further identify targetable signalling pathways in a unique subtype-specific manner. Single cell profiling of the tumor microenvironment represents a promising way to allow a better characterization of the heterogeneity of triple negative breast cancer which could be integrated in a spatially resolved context to build an ecosystem-based patient classification. Multi-omic data further allows in silico analysis of genetic and pharmacologic screens to map therapeutic vulnerabilities in a subtype-specific context. This review describes current knowledge about molecular subtyping of triple negative breast cancer, recent advances in omics-based genomics and proteomics diagnostics addressing the diversity of this disease, key advances made through single cell analysis approaches, and developments in treatments including targeted therapeutics being tested in major clinical trials.
Polymorphisms of the sodium voltage-gated channel, alpha subunit 1 (SCN1A -A3184G) gene among children with non-lesional epilepsy: a case-control study
Authors: Ghazala Esraa , Shahin Doaa A. , Wahba Yahya
Published: September 2022

Background

Mutations in the neuronal sodium voltage-gated channel, alpha subunit 1 (SCN1A) gene have been associated with epilepsy. We investigated the SCN1A-A3184G polymorphism among Egyptian children and adolescents with non-lesional epilepsy.

Methods

A prospective case – control observational study was done in Mansoura University Children’s Hospital, Egypt including 326 children with non-lesional epilepsy (163 antiepileptic drugs (AEDs) resistant cases & 163 AEDs responders) and 163 healthy controls. One step real time polymerase chain reaction (PCR) was used for the molecular analysis. Student’s t-test, and Monto Carlo, chi-square and Mann–Whitney tests were used for the statistical analysis.

Results

All study participants were matched as regards the age, sex and body weight (p = 0.07, 0.347 and 0.462, respectively). They had the (AA) and (AG) genotypes but not the (GG) variant. No significant differences were found between cases and controls regarding (AG) and (AA) genotypes and A- and G-alleles (p = 0.09 and 0.3, respectively). We did not find significant differences between AEDs responders and resistant cases regarding the studied genotypes and alleles (p = 0.61 and 0.746, respectively). In the resistant group, we observed significant associations between the (AG) genotype and seizure frequency (p = 0.05), the tonic-clonic seizure (p < 0.001), the younger age of first seizure attack (p = 0.03), abnormal electroencephalogram (EEG) (p < 0.001), the positive family history of epilepsy (p = 0.006), topiramate (p = 0.03) and valproic acid (p < 0.001), while the (AA) genotype was associated with carbamazepine (p = 0.03). While in AEDs responders, there were significant associations between the AG genotype and the abnormal EEG activity, levetiracetam and carbamazepine (p = 0.016, 0.028 and 0.02).

Conclusions

The SCN1A-A3184G genotypes and alleles were not associated with the epilepsy risk among Egyptian children. Significant associations were reported between the AG genotype and some predictors of refractory epilepsy.
A genome-wide search of Toll/Interleukin-1 receptor (TIR) domain-containing adapter molecule (TICAM) and their evolutionary divergence from other TIR domain containing proteins
Authors: Verma Shailya , Sowdhamini Ramanathan
Published: September 2022

Toll/Interleukin-1 receptor (TIR) domains are cytoplasmic domain that mediates receptor signalling. These domains are present in proteins like Toll-like receptors (TLR), its signaling adaptors and Interleukins, that form a major part of the immune system. These TIR domain containing signaling adaptors binds to the TLRs and interacts with their TIR domains for downstream signaling. We have examined the evolutionary divergence across the tree of life of two of these TIR domain containing adaptor molecules (TICAM) i.e., TIR domain-containing adapter-inducing interferon-β (TRIF/TICAM1) and TIR domain containing adaptor molecule2 (TRAM/TICAM2), by using computational approaches. We studied their orthologs, domain architecture, conserved motifs, and amino acid variations. Our study also adds a timeframe to infer the duplication of TICAM protein from Leptocardii and later divergence into TICAM1/TRIF and TICAM2/TRAM. More evidence of TRIF proteins was seen, but the absence of conserved co-existing domains such as TRIF-NTD, TIR, and RHIM domains in distant relatives hints on diversification and adaptation to different biological functions. TRAM was lost in Actinopteri and has conserved domain architecture of TIR across species except in Aves. An additional isoform of TRAM, TAG (TRAM adaptor with the GOLD domain), could be identified in species in the Mesozoic era. Finally, the Hypothesis based Likelihood ratio test was applied to look for selection pressure amongst orthologues of TRIF and TRAM to search for positively selected sites. These residues were mostly seen in the non-structural region of the proteins. Overall, this study unravels evolutionary information on the adaptors TRAM and TRIF and how well they had duplicated to perform diverse functions by changes in their domain architecture across lineages.
A personalised intervention programme aimed at improving adherence to oral antidiabetic and/or antihypertensive medication in people with type 2 diabetes mellitus, the INTENSE study: study protocol for a randomised controlled trial
Authors: Langendoen-Gort Marlous , Al-Jabr Hiyam , Hugtenburg Jacqueline G. , Rutters Femke , de Wit Maartje , Bhattacharya Debi , Abu-Hanna Ameen , Farmer Andrew , Elders Petra J. M.
Published: September 2022

Background

Medication non-adherence is a prevalent health problem in people with type 2 diabetes mellitus (T2DM). Interventions have previously been developed to improve medication adherence, but inconsistent outcomes have been reported. A potential explanation for this inconsistency is a ‘one size fits all’ approach, with interventions not tailored to the needs and preferences of individuals. Therefore, the aim of this study is to evaluate the effectiveness of a personalised intervention programme aimed at improving adherence to oral antidiabetic and/or antihypertensive medication in people with T2DM.

Methods

A parallel-group randomised controlled trial will be conducted in 40–50 community pharmacies in the Netherlands and the United Kingdom (UK). A total of 300 participants will be included and followed up for a period of 6 months. Participants will be people with T2DM identified as non-adherent to oral antidiabetic and/or antihypertensive medication, aged 35–75 years and mobile phone users. The intervention group will receive a personalised intervention programme that is based on one or more of the participants’ pre-defined non-adherence profile(s), namely (I) Knowledge and perceptions, (II) Practical problems, (III) Side effects and (IV) Negative mood and beliefs. The intervention comprises of one or more supporting modules, namely (I) Brief messaging, (II) Clinical medication review, (III) Medication schedule, (IV) Reminding messaging, (V) Medication dispensing systems, (VI) Smart messaging, (VII) Referral to general practitioner and (VIII) Unguided web-based Self Help Application for low mood. The control group will receive usual care including access to a publicly available informative diabetes website. The primary study outcome is medication adherence measured with a telephone pill count. Secondary outcomes are systolic blood pressure, HbA1c level, self-reported medication adherence, attitude and beliefs toward medication, satisfaction with diabetes treatment, health status and medical consumption and productivity cost. In addition, a process evaluation will be undertaken to establish the fidelity, reach and the extent to which intervention delivery is normalised in the daily practice of community pharmacy teams.

Discussion

The study can lead to a personalised intervention programme that improves medication adherence in people with T2DM that are non-adherent to oral antidiabetic and/or antihypertensive medication.

Trial registration

Dutch Trial Register, Trial NL8747, registered 02 July, 2020; ISRCTN Registry, ISRCTN36009809, registered 05 February, 2020.