bluuebunny/crossref_metadata_2025 huggingface dataset:
An inducible Cd79b mutation confers ibrutinib sensitivity in mouse models of Myd88-driven diffuse large B-cell lymphoma
Authors: Flümann Ruth , Hansen Julia , Meinel Jörn , Pfeiffer Pauline , Goldfarb Wittkopf Hannah , Lütz Anna , Wirtz Jessica , Möllmann Michael , Zhou Tanja , Tabatabai Areya , Lohmann Tim , Jauch Maximilian , Beleggia Filippo , Pelzer Benedikt , Ullrich Fabian , Höfmann Svenja , Arora Aastha , Persigehl Thorsten , Büttner Reinhard , von Tresckow Bastian , Klein Sebastian , Jachimowicz Ron D. , Reinhardt Hans Christian , Knittel Gero
Published: December 2023

Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive lymphoma and constitutes a highly heterogenous disease. Recent comprehensive genomic profiling revealed the identity of numerous molecularly defined DLBCL subtypes, including a cluster which is characterized by recurrent aberrations in MYD88, CD79B, and BCL2, as well as various lesions promoting a block in plasma cell differentiation, including PRDM1, TBL1XR1, and SPIB. Here, we generated a series of autochthonous mouse models to mimic this DLBCL cluster and specifically focused on the impact of Cd79b mutations in this setting. We show that canonical Cd79b immunoreceptor tyrosine-based activation motif (ITAM) mutations do not accelerate Myd88- and BCL2-driven lymphomagenesis. Cd79b-mutant murine DLBCL were enriched for IgM surface expression, reminiscent of their human counterparts. Moreover, Cd79b-mutant lymphomas displayed a robust formation of cytoplasmic signaling complexes involving MYD88, CD79B, MALT1, and BTK. These complexes were disrupted upon pharmacological BTK inhibition. The BTK inhibitor–mediated disruption of these signaling complexes translated into a selective ibrutinib sensitivity of lymphomas harboring combined Cd79b and Myd88 mutations. Altogether, this in-depth cross-species comparison provides a framework for the development of molecularly targeted therapeutic intervention strategies in DLBCL.
Current use of CAR T cells to treat multiple myeloma
Authors: Firestone Ross S. , Mailankody Sham
Published: December 2023

Anti–B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapies currently approved by the US Food and Drug Administration (FDA) have dramatically improved clinical outcomes for patients with heavily pretreated multiple myeloma who have disease refractory to conventional proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies. However, despite this progress, multiple myeloma remains an incurable hematologic malignancy. In this review, we discuss practical considerations for currently FDA approved CAR T-cell therapies, including newer data evaluating those agents in earlier lines of therapy. We also discuss considerations for patients following relapse from anti-BCMA CAR T-cell therapy, which currently represents an unmet clinical need.
Managing side effects: guidance for use of immunotherapies in multiple myeloma
Authors: Liang Emily C. , Sidana Surbhi
Published: December 2023

Chimeric antigen receptor T-cell therapy and bispecific T-cell recruiting antibodies have transformed the treatment landscape for relapsed/refractory multiple myeloma, with B-cell maturation antigen being the most common target and other targets in clinical development. However, these therapies are associated with unique and severe toxicities, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), delayed neurotoxicity, cytopenias, and infection. In addition, immune effector cell-associated hemophagocytic lymphohistiocytosis (HLH)–like syndrome (IEC-HS), which exhibits overlap between CRS and HLH, can be challenging to diagnose and treat. In this review, we provide an overview of toxicities associated with novel immunotherapies for treatment of multiple myeloma and describe management recommendations. The pathophysiology and risk factors behind these toxicities are not yet comprehensively understood. Based on consensus recommendations, treatment for CRS consists of tocilizumab and steroids, while treatment for ICANS includes steroids and anakinra in severe cases. Management of cytopenias and infection is similar to post–hematopoietic cell transplantation principles with antimicrobial prophylaxis, growth factor support, immunoglobulin replacement, and vaccinations. In contrast, effective treatments for delayed neurotoxicity and IEC-HS are lacking, although steroids and anakinra are commonly used. Management of all these toxicities should include a broad differential and multidisciplinary collaboration with infectious diseases, neurology, and/or critical care providers.
Novel therapies upon failure of HMA plus venetoclax
Authors: Chan Onyee , Walker Alison R.
Published: December 2023

The efficacy and tolerability of the combination of hypomethylating agents with venetoclax (HMA-VEN) in patients with newly diagnosed acute myeloid leukemia has been a practice-changing milestone in the field. However, treatment failure and relapse remain major barriers to prolonged survival. TP53 mutation is a predictor of primary induction failure and portends especially poor outcomes. Prelinical data suggest that VEN resistance stems from these genetic changes, which lead to increases in antiapoptotic proteins such as MCL-1 and BCLXL. For patients who discontinue HMA-VEN for reasons other than disease progression, such as post allotransplantation, infection, and personal preference, rechallenge with HMA-VEN at the time of relapse may be considered. For those who progress on HMA-VEN, clinical trials with novel agents or rational drug combinations are preferred if available. If no trial option is available, fit patients may benefit from intensive chemotherapy. Emerging therapies aim to overcome venetoclax resistance, target interactions that promote leukemogenesis, and harness the immune system to irradicate leukemic blasts and stem cells.
East Asian analogues for early Alpine orogenesis
Authors: Milsom John
Published: December 2023

The Alpine orogeny is a consequence of the collision of Africa with Eurasia, which eliminated the Western Tethys Ocean. Processes similar to those that would have taken place early in that collision can today be seen operating in the islands of the Indo-Pacific gateway between Southeast Asia and Australia and have the potential to offer insights into the beginnings of orogenesis in the Alps. Studies of the gateway area emphasise the importance of the impact on subduction zones of topography on the downgoing plate, and of the effects of flows in the asthenosphere on lithosphere tectonics.
SingleScan: a comprehensive resource for single-cell sequencing data processing and mining
Authors: Wang Kun , Zhang Xiao , Cheng Hansen , Ma Wenhao , Bao Guangchao , Dong Liting , Gou Yixiong , Yang Jian , Cai Haoyang
Published: December 2023

Single-cell sequencing has shed light on previously inaccessible biological questions from different fields of research, including organism development, immune function, and disease progression. The number of single-cell-based studies increased dramatically over the past decade. Several new methods and tools have been continuously developed, making it extremely tricky to navigate this research landscape and develop an up-to-date workflow to analyze single-cell sequencing data, particularly for researchers seeking to enter this field without computational experience. Moreover, choosing appropriate tools and optimal parameters to meet the demands of researchers represents a major challenge in processing single-cell sequencing data. However, a specific resource for easy access to detailed information on single-cell sequencing methods and data processing pipelines is still lacking. In the present study, an online resource called SingleScan was developed to curate all up-to-date single-cell transcriptome/genome analyzing tools and pipelines. All the available tools were categorized according to their main tasks, and several typical workflows for single-cell data analysis were summarized. In addition, spatial transcriptomics, which is a breakthrough molecular analysis method that enables researchers to measure all gene activity in tissue samples and map the site of activity, was included along with a portion of single-cell and spatial analysis solutions. For each processing step, the available tools and specific parameters used in published articles are provided and how these parameters affect the results is shown in the resource. All information used in the resource was manually extracted from related literature. An interactive website was designed for data retrieval, visualization, and download. By analyzing the included tools and literature, users can gain insights into the trends of single-cell studies and easily grasp the specific usage of a specific tool. SingleScan will facilitate the analysis of single-cell sequencing data and promote the development of new tools to meet the growing and diverse needs of the research community. The SingleScan database is publicly accessible via the website at http://cailab.labshare.cn/SingleScan.
Comparative genomic analysis of clinical Enterococcus faecalis distinguishes strains isolated from the bladder
Authors: Hochstedler-Kramer Baylie R. , Ene Adriana , Putonti Catherine , Wolfe Alan J.
Published: December 2023

Background

Enterococcus faecalis is the most commonly isolated enterococcal species in clinical infection. This bacterium is notorious for its ability to share genetic content within and outside of its species. With this increased proficiency for horizontal gene transfer, tremendous genomic diversity within this species has been identified. Many researchers have hypothesized E. faecalis exhibits niche adaptation to establish infections or colonize various parts of the human body. Here, we hypothesize that E. faecalis strains isolated from the human bladder will carry unique genomic content compared to clinical strains isolated from other sources.

Results

This analysis includes comparison of 111 E. faecalis genomes isolated from bladder, urogenital, blood, and fecal samples. Phylogenomic comparison shows no association between isolation source and lineage; however, accessory genome comparison differentiates blood and bladder genomes. Further gene enrichment analysis identifies gene functions, virulence factors, antibiotic resistance genes, and plasmid-associated genes that are enriched or rare in bladder genomes compared to urogenital, blood, and fecal genomes. Using these findings as training data and 682 publicly available genomes as test data, machine learning classifiers successfully distinguished between bladder and non-bladder strains with high accuracy. Genes identified as important for this differentiation were often related to transposable elements and phage, including 3 prophage species found almost exclusively in bladder and urogenital genomes.

Conclusions

E. faecalis strains isolated from the bladder contain unique genomic content when compared to strains isolated from other body sites. This genomic diversity is most likely due to horizontal gene transfer, as evidenced by lack of phylogenomic clustering and enrichment of transposable elements and prophages. Investigation into how these enriched genes influence host-microbe interactions may elucidate gene functions required for successful bladder colonization and disease establishment.
Chronic gastritis may predict risk of cerebral small vessel disease
Authors: Wei Cunsheng , Tan Chang , Zhang Xuemei , Shen Xin , Xu Zongliang , Li Junrong , Xu Gelin
Published: December 2023

Background and purpose

Chronic gastritis, especially that caused by helicobacter pylori (HP) infection, has been associated with increased risk of ischemic stroke. But the relationship between chronic gastritis and cerebral small vessel disease (CSVD) remains largely undetermined. This study aimed to determine the potential predictors for CSVD, with chronic gastritis and its proxies as alternatives.

Method

Patients aged 18 years or older with indications for electronic gastroscopy were enrolled. Presence of CSVD was evaluated with brain magnetic resonance imaging (MRI) results. Degree of CSVD was scored according to established criteria. Logistic regression analysis was used for identifying possible risk factors for CSVD.

Results

Of the 1191 enrolled patients, 757 (63.6%) were identified as with, and 434 (36.4%) as without CSVD. Multivariate analysis indicated that patients with chronic atrophic gastritis had an increased risk for CSVD than those without (adjusted odds ratio = 1.58; 95% CI, 1.08–2.32; P < 0.05).

Conclusions

Chronic atrophic gastritis is associated with the presence of CSVD. We should routinely screen the presence of CSVD for patients with chronic atrophic gastritis.
The reliability and suitability of strength assessments in frail and pre-frail older adults: recommendations for strength testing in older populations
Authors: Swales Bridgitte , Ryde Gemma C. , Fletcher Iain , Whittaker Anna C.
Published: December 2023

Background

Lifelong strength is fundamental to physical function, health, and quality of life. Reliable appropriate strength assessment measures for older adults play an important role in effective evaluation of baseline ability and exercise prescription to counter disease and disuse. This study aimed to investigate the within-session reliability of maximal isometric knee extension and flexion, hip abduction and adduction, and handgrip strength measures in frail and pre-frail older adults.

Method

The study was conducted at a residential care home in Birmingham, UK. All care home residents aged ≥ 65 years; pre-frail or frail according to the Fried Frailty phenotype criteria; able to speak and read English; not currently involved in any other clinical trial; without severe sensory impairments; and with a predicted life expectancy greater than the trial length were eligible. Maximal isometric lower limb testing was performed using specialised resistance training equipment and a portable measurement device, and grip strength was assessed using a portable dynamometer. All eligible participants attended a single testing session and performed three trials per measure. Peak force measures were obtained for analysis. Within-session reliability for each measure was calculated from repeated-measures analysis of variance, intraclass correlation coefficients (ICC), and coefficients of variation (CV) with 95% confidence intervals.

Results

Eleven frail and eleven pre-frail older adults participated in the study. Within-session absolute and relative measures were found to be reliable with the highest overall repeatability indicated between trial 2 and trial 3 for knee extension, hip abduction, and handgrip (CV ≤ 4.65%, ICC ≥ 0.96) with variation evident across all measures, except knee extension, from trial 1 to 2.

Conclusions

Overall, maximal isometric strength in frail and pre-frail older adults with no previous testing experience can be measured with good to high reliability within their first testing session. An initial two familiarisation trials followed by two measurement trials is recommended to achieve the highest level of overall repeatability.

Trial registration

The trial was registered with ClinicalTrials.gov: NCT03141879 on 05/05/2017.
Verification of a comprehensive framework for mobility using data from the Canadian Longitudinal Study on Aging: a structural equation modeling analysis
Authors: Webber Sandra C. , Liu Yixiu , Jiang Depeng , Ripat Jacquie , Nowicki Scott , Tate Robert , Barclay Ruth
Published: December 2023

Background

Mobility within and between life spaces is fundamental for health and well-being. Our objective was to verify a comprehensive framework for mobility.

Methods

This was a cross-sectional study. We used structural equation modeling to estimate associations between latent factors with data from the Canadian Longitudinal Study on Aging for participants 65–85 years of age (65+, n = 11,667) and for adults with osteoarthritis (OA) aged 45–85 (n = 5,560). Latent factors included life space mobility, and physical, psychosocial, environmental, financial, and cognitive elements. Personal variables (age, sex, education) were covariates.

Results

The models demonstrated good fit (65+: CFI = 0.90, RMSEA (90% CI) = 0.025 (0.024, 0.026); OA: CFI = 0.90, RMSEA (90% CI) = 0.032 (0.031, 0.033)). In both models, better psychosocial and physical health, and being less afraid to walk after dark (observed environmental variable) were associated with greater life space mobility. Greater financial status was associated with better psychosocial and physical health. Higher education was related to better cognition and finances. Older age was associated with lower financial status, cognition, and physical health. Cognitive health was positively associated with greater mobility only in the 65 + model. Models generated were equivalent for males and females.

Conclusions

Associations between determinants described in the mobility framework were verified with adults 65–85 years of age and in an OA group when all factors were considered together using SEM. These results have implications for clinicians and researchers in terms of important outcomes when assessing life space mobility; findings support interdisciplinary analyses that include evaluation of cognition, depression, anxiety, environmental factors, and community engagement, as well as physical and financial health. Public policies that influence older adults and their abilities to access communities beyond their homes need to reflect the complexity of factors that influence life space mobility at both individual and societal levels.
Rural parents’ adherence to infant feeding guidelines to prevent allergy: a cross sectional study in New South Wales
Authors: Rossi Gianni , Cesca Jessica , Fong Charmie , Wallace Andrew , DComm Peter Simmons , Osuagwu Uchechukwu Levi , Bailey Jannine , Dutton Tegan , De Alwis Adambarage Chandima
Published: December 2023

Background

Responding to international research showing that early introduction of common food allergens can reduce the chance of developing allergies, in 2016 the Australasian Society of Clinical Immunology and Allergy (ASCIA) revised allergen introduction guidelines, recommending earlier introduction of allergens to infants in their first year. Australia has high food allergy rates, and limited understanding of adherence to allergen introduction guidelines, especially in rural areas. This project explored rural parent adherence to ASCIA guidelines.

Methods

This was a mixed method cross sectional study using an online survey including multiple-choice and qualitative short answer responses. The sample were 336 women from two rural health districts in New South Wales. All were aged 18 or over, and either pregnant or had delivered a baby since July 2018. Descriptive statistics were used to measure behavioural alignment with the recommended guidelines, thematic analysis was used to analyse attitudes and explanations.

Results

In 84.3% of children, feeding adhered to all four guidelines studied, including no elimination of allergens during pregnancy (98%), age of introduction of solids (97.7%), continuation of breast milk/cow’s milk formula during introduction of solids (95%), and age of introduction of allergens (92.9%). Adherence was not significantly correlated with the education (X2 = 17.9, P = .056), prior history of allergy [neither mother (X2 = 0.945,P = .623) nor previous children (X2 = 0.401,P = .818)], or primary care received during pregnancy. More than 90% of participants agreed or strongly agreed that the guidelines are realistic, trustworthy, and important for the health of their child. However, thematic analysis revealed that parents’ perceptions of a child’s individual progress, and medical conditions or other circumstances, such as challenges with breastfeeding, will often take precedence over adherence to specific guideline recommendations.

Conclusions

High rates of adherence with ASCIA guidelines found here are comparable with findings from metropolitan studies and encouraging for future population health. Participant comments on the guidelines imply to rural policymakers that there are multiple influences on parent decisions about infant feeding, often including parents’ own intuition and experiences. Further studies to improve understanding of the role of information, carers, and other influences on parent decision-making concerning feeding attitudes and behaviours will be necessary to optimise adherence in rural areas.
The new clinical classification of metastatic spinal malignancies serves as a vital reference for surgical management: a retrospective case-control study
Authors: Bai Junjun , Li Jian , Lv Jia , Yang Wangzhe , Wang Yushan , Feng Yi , Lv Zhi
Published: December 2023

Background

It is commonly accepted that surgical treatment is an essential component of the comprehensive management of metastatic spinal malignancies. However, up until now, the clinical classification of metastatic spinal malignancies has not been well-structured.

Methods

After IRB approval, 86 patients with metastatic spinal malignancies were adopted. According to the vascular distribution, stability of vertebrae, and degree of nerve compression, metastatic spinal malignancies can be classified into five types. Tumors classified as type I typically appear in the vertebral body. Type II tumors are those that develop in the transverse processes, superior and inferior articular processes, and spinal pedicles. Type III denotes malignancies that are present in the spinous process and vertebral plate. Types IVa and IVb are included in type IV. Type IVa combines type I and type II, whereas type IVb combines type II and type III. Type V tumors are those of types I, II, and III that co-occur and spread in different directions into the spinal canal. 20 of included 86 patients who did not receive segmental arterial embolization were set as the non-embolization group. The embolization group included 24 patients who received segmental arterial embolization on both sides of the diseased vertebrae. 42 patients were included in the offending embolization group after receiving responsible arterial embolization. A surgical intervention was performed within 24 h following an embolization. Surgical intervention with the purpose of removing as much of the tumor as possible and providing an effective reconstruction of the spinal column.

Results

In comparison with the non-embolization group and embolization group, the offending embolization group presented unique advantages in terms of bleeding volume (p<0.001), operation time (p<0.001), and local recurrence rate within 12 months (p=0.006).

Conclusion

By significantly reducing surgical trauma and local recurrence rate (12 months), responsible arterial vascular embolization procedures together with associated surgical protocols developed on the basis of the clinical classification of metastatic spinal malignancies, are worthy of clinical dissemination.
Visualization of airborne droplets generated with dental handpieces and verification of the efficacy of high-volume evacuators: an in vitro study
Authors: Kim Min Jung , Kuroda Mana , Kobayashi Yoshikazu , Yamamoto Takahisa , Aizawa Takako , Satoh Koji
Published: December 2023

Background

The COVID-19 pandemic led to concerns about the potential airborne transmission of the virus during dental procedures, but evidence of actual transmission in clinical settings was lacking. This study aimed to observe the behavior of dental sprays generated from dental rotary handpieces and to evaluate the effectiveness of high-volume evacuators (HVEs) using laser light sheets and water-sensitive papers.

Methods

A dental manikin and jaw model were mounted in a dental treatment unit. Mock cutting procedures were performed on an artificial tooth on the maxillary left central incisor using an air turbine, a contra-angle electric micromotor (EM), and a 1:5 speed-up contra-angle EM (×5EM). Intraoral vacuum and extraoral vacuum (EOV) were used to verify the effectiveness of the HVEs. The dynamics and dispersal range of the dental sprays were visualized using a laser light sheet. In addition, environmental surface pollution was monitored three-dimensionally using water-sensitive papers.

Results

Although the HVEs were effective in both the tests, the use of EOV alone increased vertical dispersal and pollution.

Conclusions

The use of various types of HVEs to reduce the exposure of operators and assistants to dental sprays when using dental rotary cutting instruments is beneficial. The study findings will be helpful in the event of a future pandemic caused by an emerging or re-emerging infectious disease.
Clinical efficacy of Yukgunja-tang combined with a proton pump inhibitor for refractory gastroesophageal reflux disease: study protocol for randomized, double-blind, double-dummy clinical trial
Authors: Ha Na-Yeon , Kim Jung-Wook , Kim Jinsung
Published: December 2023

Background

Yukgunja-tang (YGJ) is an herbal prescription used to treat the symptoms of gastroesophageal reflux disease (GERD). Although many preclinical and clinical studies on YGJ have been conducted on GERD, there is a lack of evidence from blinded studies to exclude placebo effects. Therefore, this protocol proposes a clinical trial that is single-centered, randomized, double-blinded, double-dummy to objectively evaluate the efficacy and safety of co-administered YGJ and rabeprazole (RPZ) in patients with GERD previously treated with proton pump inhibitors (PPIs) and still experiencing symptoms.

Methods

A total of 86 participants with refractory GERD (rGERD) will be randomized in a 1:1 ratio to the treatment [YGJ and RPZ (10 mg/d)] and control groups [double-dose RPZ (20 mg/d)] for 4 weeks of treatment (weeks 0–4) followed by 4 weeks of follow-up (weeks 4–8). The Frequency Scale for the Symptoms of GERD will be analyzed for the primary endpoint. Reflux Disease Questionnaire, Reflux Symptom Score, GERD-Health Related Quality of Life, Overall Treatment Evaluation, Spleen Qi Deficiency Questionnaire, Damum Questionnaire, and dyspepsia Visual Analogue Scale will be used to evaluate treatment effects on GERD related symptoms and quality of life and to compare treatment effects by subgroups. Safety tests will be analyzed by investigating adverse events.

Discussion

This clinical trial will be the first rigorous double-blind, double-dummy, placebo-controlled study to precisely evaluate the efficacy and safety of the combination of YGJ and PPIs in the treatment of rGERD. The results of this study will provide a reliable clinical basis for selecting botanical drug treatments for patients with rGERD.

Trial registration

Clinical Research Information Service (registration number: KCT0008600, July 13, 2023, https://cris.nih.go.kr).
A phenomenological exploration of the feedback experience of medical students after summative exam failure
Authors: Jay Robert , Hagan Pamela , Madan Christopher , Patel Rakesh
Published: December 2023

Background

Preventing medical students entering cycles of underperformance following assessment is a priority due to the consequences for the student, faculty, and wider society. The benefits from feedback may be inadequately accessed by students in difficulty due to the emotional response evoked by examination failure. This study aims to explore medical students’ experiences of receiving feedback after summative assessment failure and investigate the role of emotions on motivation for learning after underperformance, to better support remediation and preparation for future assessments.

Methods

This study used interpretative phenomenological analysis (IPA) to explore the experiences of four medical students who failed summative assessments. Additionally, a content analysis was conducted using Linguistic Inquiry and Word Count (LIWC) to investigate the characteristics and use of language to describe their emotional response.

Results

Anger, fear, anxiety, and sadness were emotions frequently experienced after examination failure. These emotions led to feelings of mistrust of the medical school and subsequent distrust in the university’s assessment processes, impacting on the desire to engage with feedback. There was dissonance between the students' perceptions of what feedback should provide and what benefit feedback provided after summative assessments. The linguistic inquiry further confirmed an initial (and sometimes long lived) negative affective state after experiencing failure, and a barrier to engagement with remediation when not effectively managed.

Conclusions

A range of emotions, directed at themselves and the medical school are experienced by students following exam failure. These emotions lead to a range of negative feelings and responses that affect how students make sense of and move on from the failure experience. There is a need for educators to better understand and support students to manage, reflect and contextualise their emotional responses, minimise external attribution and to enable focus on remediation and learning.
Strategies to improve the magnetic resonance imaging experience for autistic individuals: a cross-sectional study exploring parents and carers’ experiences
Authors: Stogiannos Nikolaos , Pavlopoulou Georgia , Papadopoulos Chris , Walsh Gemma , Potts Ben , Moqbel Sarah , Gkaravella Antigoni , McNulty Jonathan , Simcock Clare , Gaigg Sebastian , Bowler Dermot , Marais Keith , Cleaver Karen , Lloyd Jane Harvey , dos Reis Cláudia Sá , Malamateniou Christina
Published: December 2023

Background

Autistic individuals encounter numerous barriers in accessing healthcare, including communication difficulties, sensory sensitivities, and a lack of appropriate adjustments. These issues are particularly acute during MRI scans, which involve confined spaces, loud noises, and the necessity to remain still. There remains no unified approach to preparing autistic individuals for MRI procedures.

Methods

A cross-sectional online survey was conducted with parents and carers of autistic individuals in the UK to explore their experiences, barriers, and recommendations concerning MRI scans. The survey collected demographic information and experiential accounts of previous MRI procedures. Quantitative data were analysed descriptively, while key themes were identified within the qualitative data through inductive thematic analysis.

Results

Sixteen parents/carers participated. The majority reported difficulties with communication, inadequate pre-scan preparation, and insufficient adjustments during MRI scans for their autistic children. Key barriers included an overwhelming sensory environment, radiographers’ limited understanding of autism, and anxiety stemming from uncertainties about the procedure. Recommended improvements encompassed accessible communication, pre-visit familiarisation, noise-reduction and sensory adaptations, staff training on autism, and greater flexibility to meet individual needs.

Conclusions

There is an urgent need to enhance MRI experiences for autistic individuals. This can be achieved through improved staff knowledge, effective communication strategies, thorough pre-scan preparation, and tailored reasonable adjustments. Co-producing clear MRI guidelines with the autism community could standardise sensitive practices. An individualised approach is crucial for reducing anxiety and facilitating participation. Empowering radiographers through autism-specific education and incorporating insights from autistic individuals and their families could transform MRI experiences and outcomes.
Novel autosomal dominant TMC1 variants linked to hearing loss: insight into protein-lipid interactions
Authors: Cho Sung Ho , Yun Yejin , Lee Dae Hee , Cha Joo Hyun , Lee So Min , Lee Jehyun , Suh Myung Hwan , Lee Jun Ho , Oh Seung-Ha , Park Moo Kyun , Lee Sang-Yeon
Published: December 2023

Background

TMC1, which encodes transmembrane channel-like protein 1, forms the mechanoelectrical transduction (MET) channel in auditory hair cells, necessary for auditory function. TMC1 variants are known to cause autosomal dominant (DFNA36) and autosomal recessive (DFNB7/11) non-syndromic hearing loss, but only a handful of TMC1 variants underlying DFNA36 have been reported, hampering analysis of genotype-phenotype correlations.

Methods

In this study, we retrospectively reviewed 338 probands in an in-house database of genetic hearing loss, evaluating the clinical phenotypes and genotypes of novel TMC1 variants associated with DFNA36. To analyze the structural impact of these variants, we generated two structural models of human TMC1, utilizing the Cryo-EM structure of C. elegans TMC1 as a template and AlphaFold protein structure database. Specifically, the lipid bilayer-embedded protein database was used to construct membrane-embedded models of TMC1. We then examined the effect of TMC1 variants on intramolecular interactions and predicted their potential pathogenicity.

Results

We identified two novel TMC1 variants related to DFNA36 (c.1256T > C:p.Phe419Ser and c.1444T > C:p.Trp482Arg). The affected subjects had bilateral, moderate, late-onset, progressive sensorineural hearing loss with a down-sloping configuration. The Phe419 residue located in the transmembrane domain 4 of TMC1 faces outward towards the channel pore and is in close proximity to the hydrophobic tail of the lipid bilayer. The non-polar-to-polar variant (p.Phe419Ser) alters the hydrophobicity in the membrane, compromising protein-lipid interactions. On the other hand, the Trp482 residue located in the extracellular linker region between transmembrane domains 5 and 6 is anchored to the membrane interfaces via its aromatic rings, mediating several molecular interactions that stabilize the structure of TMC1. This type of aromatic ring-based anchoring is also observed in homologous transmembrane proteins such as OSCA1.2. Conversely, the substitution of Trp with Arg (Trp482Arg) disrupts the cation-π interaction with phospholipids located in the outer leaflet of the phospholipid bilayer, destabilizing protein-lipid interactions. Additionally, Trp482Arg collapses the CH-π interaction between Trp482 and Pro511, possibly reducing the overall stability of the protein. In parallel with the molecular modeling, the two mutants degraded significantly faster compared to the wild-type protein, compromising protein stability.

Conclusions

This results expand the genetic spectrum of disease-causing TMC1 variants related to DFNA36 and provide insight into TMC1 transmembrane protein-lipid interactions.
Isthmin-1 (ISM1), a novel adipokine that reflects abdominal adipose tissue distribution in individuals with obesity
Authors: Lopez-Yus Marta , Casamayor Carmen , Soriano-Godes Juan Jose , Borlan Sofia , Gonzalez-Irazabal Yolanda , Garcia-Sobreviela Maria Pilar , Garcia-Rodriguez Beatriz , del Moral-Bergos Raquel , Calmarza Pilar , Artigas Jose Maria , Lorente-Cebrian Silvia , Bernal-Monterde Vanesa , Sanz-Paris Alejandro , Arbones-Mainar Jose M.
Published: December 2023

Background

The assessment of obesity-related health risks has traditionally relied on the Body Mass Index and waist circumference, but their limitations have propelled the need for a more comprehensive approach. The differentiation between visceral (VIS) and subcutaneous (SC) fat provides a finer-grained understanding of these risks, yet practical assessment methods are lacking. We hypothesized that combining the SC-VIS fat ratio with non-invasive biomarkers could create a valuable tool for obesity-related risk assessment.

Methods and results

A clinical study of 125 individuals with obesity revealed significant differences in abdominal fat distribution measured by CT-scan among genders and distinct models of obesity, including visceral, subcutaneous, and the SC/VIS ratio. Stratification based on these models highlighted various metabolic changes. The SC/VIS ratio emerged as an excellent metric to differentiate metabolic status. Gene expression analysis identified candidate biomarkers, with ISM1 showing promise. Subsequent validation demonstrated a correlation between ISM1 levels in SC and plasma, reinforcing its potential as a non-invasive biomarker for fat distribution. Serum adipokine levels also correlated with the SC/VIS ratio. The Receiver Operating Characteristic analysis revealed ISM1’s efficacy in discriminating individuals with favorable metabolic profiles based on adipose tissue distribution. Correlation analysis also suggested that ISM1 was involved in glucose regulation pathways.

Conclusion

The study’s results support the hypothesis that the SC-VIS fat ratio and its derived non-invasive biomarkers can comprehensively assess obesity-related health risks. ISM1 could predict abdominal fat partitioning and be a potential biomarker for evaluating obesity-related health risks.
Relationship between dietary carotenoid intake and sleep duration in American adults: a population-based study
Authors: Deng Ming-Gang , Liu Fang , Wang Kai , Liang Yuehui , Nie Jia-Qi , Liu Jiewei
Published: December 2023

Objective

To investigate the relationship between dietary carotenoid intake and sleep duration.

Methods

Adults enrolled in the National Health and Nutrition Examination Survey (NHANES) 2007–2018 without missing information on dietary carotenoid intake (α-carotene, β-carotene, β-cryptoxanthin, lycopene, and lutein + zeaxanthin), sleep duration, and covariates were included. Participants’ carotenoid consumption was divided into three groups by quartiles and sleep duration was grouped as short (< 7 h/night), optimal (7–8 h/night), and long (> 8 h/night). Multinominal logistic regression was constructed to examine the association between dietary carotenoid intake and sleep duration. Restricted cubic spline (RCS) regression was further utilized to explore their dose-response relationship. The weighted quantile sum (WQS) model was adopted to calculate the mixed and individual effect of 5 carotenoid sub-types on sleep duration.

Results

Multinominal logistic regression presented that people with higher intakes of α-carotene, β-carotene, β-cryptoxanthin, lycopene, and lutein + zeaxanthin were less likely to sleep too short or too long. Consistent with the findings from multinominal logistic regression, the RCS models suggested a reverse U-shaped relationship between sleep duration and carotenoid intakes. The mixed effects were also significant, where β-cryptoxanthin and lutein + zeaxanthin were the top 2 contributors associated with the decreased risks of short sleep duration, while β-carotene, α-carotene, and β-cryptoxanthin were the main factors related to the lower risk of long sleep duration.

Conclusion

Our study revealed that the American adults with optimal sleep duration were associated with more dietary carotenoid intake, in comparison to short or long sleepers.
Nanogels with covalently bound and releasable trehalose for autophagy stimulation in atherosclerosis
Authors: Zhong Yuan , Maruf Ali , Qu Kai , Milewska Małgorzata , Wandzik Ilona , Mou Nianlian , Cao Yu , Wu Wei
Published: December 2023

Atherosclerosis, cholesterol-driven plaque formation in arteries, is a complex multicellular disease which is a leading cause of vascular diseases. During the progression of atherosclerosis, the autophagic function is impaired, resulting in lipid accumulation-mediated foam cell formation. The stimulation of autophagy is crucial for the recovery of cellular recycling process. One of the potential autophagy inducers is trehalose, a naturally occurring non-reducing disaccharide. However, trehalose has poor bioavailability due to its hydrophilic nature which results in poor penetration through cell membranes. To enhance its bioavailability, we developed trehalose-releasing nanogels (TNG) for the treatment of atherosclerosis. The nanogels were fabricated through copolymerization of 6-O-acryloyl-trehalose with the selected acrylamide-type monomers affording a high trehalose conjugation (~ 58%, w/w). TNG showed a relatively small hydrodynamic diameter (dH, 67 nm) and a uniform spherical shape and were characterized by negative ζ potential (-18 mV). Thanks to the trehalose-rich content, TNG demonstrated excellent colloidal stability in biological media containing serum and were non-hemolytic to red blood cells. In vitro study confirmed that TNG could stimulate autophagy in foam cells and enhance lipid efflux and in vivo study in ApoE−/− mice indicated a significant reduction in atherosclerotic plaques, while increasing autophagic markers. In conclusion, TNG hold great promise as a trehalose delivery system to restore impaired autophagy-mediated lipid efflux in atherosclerosis and subsequently reduce atherosclerotic plaques.

Graphical abstract
M-type pyruvate kinase 2 (PKM2) tetramerization alleviates the progression of right ventricle failure by regulating oxidative stress and mitochondrial dynamics
Authors: Guo Lizhe , Wang Lu , Qin Gang , Zhang Junjie , Peng Jin , Li Longyan , Chen Xiang , Wang Dandan , Qiu Jian , Wang E.
Published: December 2023

Background

Right ventricle failure (RVF) is a progressive heart disease that has yet to be fully understood at the molecular level. Elevated M-type pyruvate kinase 2 (PKM2) tetramerization alleviates heart failure, but detailed molecular mechanisms remain unclear.

Objective

We observed changes in PKM2 tetramerization levels during the progression of right heart failure and in vitro cardiomyocyte hypertrophy and explored the causal relationship between altered PKM2 tetramerization and the imbalance of redox homeostasis in cardiomyocytes, as well as its underlying mechanisms. Ultimately, our goal was to propose rational intervention strategies for the treatment of RVF.

Method

We established RVF in Sprague Dawley (SD) rats by intraperitoneal injection of monocrotaline (MCT). The pulmonary artery pressure and right heart function of rats were assessed using transthoracic echocardiography combined with right heart catheterization. TEPP-46 was used both in vivo and in vitro to promote PKM2 tetramerization.

Results

We observed that oxidative stress and mitochondrial disorganization were associated with increased apoptosis in the right ventricular tissue of RVF rats. Quantitative proteomics revealed that PKM2 was upregulated during RVF and negatively correlated with the cardiac function. Facilitating PKM2 tetramerization promoted mitochondrial network formation and alleviated oxidative stress and apoptosis during cardiomyocyte hypertrophy. Moreover, enhancing PKM2 tetramer formation improved cardiac mitochondrial morphology, mitigated oxidative stress and alleviated heart failure.

Conclusion

Disruption of PKM2 tetramerization contributed to RVF by inducing mitochondrial fragmentation, accumulating ROS, and finally promoted the progression of cardiomyocyte apoptosis. Facilitating PKM2 tetramerization holds potential as a promising therapeutic approach for RVF.
Clinical features of acute attacks, chronic symptoms, and long-term complications among patients with acute hepatic porphyria in Japan: a real-world claims database study
Authors: Horie Yutaka , Yasuoka Yuka , Adachi Tomohide
Published: December 2023

Background

Acute hepatic porphyria (AHP) is a family of rare genetic diseases, including acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and delta-aminolevulinic acid dehydratase-deficient porphyria. The objective of this retrospective cohort study was to provide information on the clinical features of AHP in Japan—including acute attacks, chronic symptoms, and long-term complications.

Methods

Patients with AHP between April 2008 and June 2020 were selected from Japan’s Medical Data Vision claims database. Patients with AHP were matched 1:10, by sex and age, to patients without AHP. The outcomes were evaluated overall, for patients age ≥ 55 years, and for the matched population.

Results

A total of 391 patients with AHP were included from the Japanese Medical Data Vision database. During the observation period (April 2008–June 2020), 18.2% (71/391) of patients experienced 1 acute attack and 10.5% (41/391) experienced ≥ 2 attacks. Chronic symptoms with rates ~ 10% or higher in the AHP population compared with the matched population included neurotic, stress-related, and somatoform disorders (21.7% vs. 6.7% [15.0% difference]); sleep disorders (23.0% vs. 9.9% [13.1% difference]); other and unspecified abdominal pain (13.6% vs. 3.7% [9.9% difference]); and nausea and vomiting, excluding chemotherapy-induced emesis (17.9% vs. 8.1% [9.8% difference]). Long-term complications with higher incidence rates in the AHP population compared with the matched population included fibrosis and cirrhosis of liver (15.9% vs. 3.0% [12.9% difference]), polyneuropathies and other disorders of the peripheral nervous system (20.5% vs. 7.9% [12.6% difference]), liver cancer (16.9% vs. 4.7% [12.2% difference]), renal failure (16.4% vs. 4.3% [12.1% difference]), and hypertension (26.1% vs. 18.8% [7.3% difference]). Among AHP patients age ≥ 55 years, the most common long-term complications were hypertension, kidney failure, and liver cancer.

Conclusions

In Japan, patients with AHP experience a high clinical burden in terms of acute attacks, chronic symptoms, and long-term complications. The clinical burden related to chronic symptoms and long-term complications was substantially higher in Japanese patients with AHP compared with a matched population without AHP. Recognizing these signs and symptoms of AHP may aid physicians in making an earlier diagnosis, which may help patients avoid attack triggers, implement disease management, and reduce lifetime disease burden.
Association of preoperative retinal microcirculation and perioperative outcomes in patients undergoing congenital cardiac surgery
Authors: Li Cong , Zhu Zhuoting , Yuan Haiyun , Hu Yijun , Xue Yunlian , Zhong Pingting , Huang Manqing , Ren Yun , Kuang Yu , Zeng Xiaomin , Yu Honghua , Yang Xiaohong
Published: December 2023

Background

Microcirculatory dysfunction is associated with increased morbidity and mortality in cardiac surgery patients. This study aimed to investigate the association between preoperative retinal microcirculation evaluated using optical coherence tomography angiography (OCTA) and perioperative outcomes in patients with congenital heart disease (CHD).

Methods

This prospective, observational study was performed from May 2017 to January 2021. OCTA was used to automatically quantify the vessel density (VD) of the superficial capillary plexus, deep capillary plexus (DCP), and radial peripapillary capillary (RPC) preoperatively. The primary outcome was excessive postoperative bleeding, defined as bleeding volume > 75th percentile for 24-hour postoperative chest tube output. The secondary outcome was composite adverse outcomes, including one or more operative mortalities, early postoperative complications, and prolonged length of stay. The association between retinal VD and outcomes was assessed using Poisson regression.

Results

In total, 173 CHD patients who underwent cardiac surgery were included (mean age, 26 years). Among them, 43 (24.9%) and 46 (26.6%) developed excessive postoperative bleeding and composite adverse outcomes, respectively. A lower VD of DCP (odds ratio [OR], 1.24; 95% confidence interval [CI], 1.08–1.43; P = 0.003) was independently associated with excessive postoperative bleeding, and a lower VD of RPC (OR, 1.97; 95% CI, 1.08–3.57; P = 0.027), and DCP (OR, 2.17; 95% CI, 1.08–4.37; P = 0.029) were independently associated with the postoperative composite adverse outcomes.

Conclusion

Preoperative retinal hypoperfusion was independently associated with an increased risk of perioperative adverse outcomes in patients with CHD, suggesting that retinal microcirculation evaluation could provide valuable information about the outcomes of cardiac surgery, thereby aiding physicians in tailoring individualized treatment.