bluuebunny/crossref_metadata_2025_split huggingface dataset:
Methylation of the 4q35 D4Z4 repeat defines disease status in facioscapulohumeral muscular dystrophy
Authors: Erdmann Hannes , Scharf Florentine , Gehling Stefanie , Benet-Pagès Anna , Jakubiczka Sibylle , Becker Kerstin , Seipelt Maria , Kleefeld Felix , Knop Karl Christian , Prott Eva-Christina , Hiebeler Miriam , Montagnese Federica , Gläser Dieter , Vorgerd Matthias , Hagenacker Tim , Walter Maggie C , Reilich Peter , Neuhann Teresa , Zenker Martin , Holinski-Feder Elke , Schoser Benedikt , Abicht Angela 
Published: September 2022

Abstract
Genetic diagnosis of facioscapulohumeral muscular dystrophy (FSHD) remains a challenge in clinical practice as it cannot be detected by standard sequencing methods despite being the third most common muscular dystrophy. The conventional diagnostic strategy addresses the known genetic parameters of FSHD: the required presence of a permissive haplotype, a size reduction of the D4Z4 repeat of chromosome 4q35 (defining FSHD1) or a pathogenic variant in an epigenetic suppressor gene (consistent with FSHD2). Incomplete penetrance and epistatic effects of the underlying genetic parameters as well as epigenetic parameters (D4Z4 methylation) pose challenges to diagnostic accuracy and hinder prediction of clinical severity.
In order to circumvent the known limitations of conventional diagnostics and to complement genetic parameters with epigenetic ones, we developed and validated a multistage diagnostic workflow that consists of a haplotype analysis and a high-throughput methylation profile analysis (FSHD-MPA). FSHD-MPA determines the average global methylation level of the D4Z4 repeat array as well as the regional methylation of the most distal repeat unit by combining bisulphite conversion with next-generation sequencing and a bioinformatics pipeline and uses these as diagnostic parameters. We applied the diagnostic workflow to a cohort of 148 patients and compared the epigenetic parameters based on FSHD-MPA to genetic parameters of conventional genetic testing. In addition, we studied the correlation of repeat length and methylation level within the most distal repeat unit with age-corrected clinical severity and age at disease onset in FSHD patients. The results of our study show that FSHD-MPA is a powerful tool to accurately determine the epigenetic parameters of FSHD, allowing discrimination between FSHD patients and healthy individuals, while simultaneously distinguishing FSHD1 and FSHD2. The strong correlation between methylation level and clinical severity indicates that the methylation level determined by FSHD-MPA accounts for differences in disease severity among individuals with similar genetic parameters. Thus, our findings further confirm that epigenetic parameters rather than genetic parameters represent FSHD disease status and may serve as a valuable biomarker for disease status.
Longitudinal grey matter and metabolic contributions to cognitive changes in amyotrophic lateral sclerosis
Authors: Hinault Thomas , Segobin Shailendra , Benbrika Soumia , Carluer Laurence , Doidy Franck , Eustache Francis , Viader Fausto , Desgranges Béatrice 
Published: September 2022

Abstract
Amyotrophic lateral sclerosis is characterized by rapidly evolving cognitive and brain impairments. While previous work revealed structural and functional alterations associated with cognitive decline in patients suffering from amyotrophic lateral sclerosis, the relationships between anatomo-functional changes and both disease’s progression and the evolution of cognitive performance remain largely unexplored. Here, we took advantage of repeated multi-modal acquisitions in patients with amyotrophic lateral sclerosis over 1 year to assess the longitudinal sequence of grey matter atrophy, glucose metabolism and cognitive changes. Results revealed metabolic and structural changes over frontal, thalamic and temporal regions. Both cortical hypermetabolism and hypometabolism (right temporal gyrus and right angular gyrus, respectively) were associated with cognitive performance and thalamic hypometabolism during the follow-up testing session. Furthermore, the inferior frontal gyrus atrophy mediated the relation between early hypometabolism in this region and the subsequent decline of the theory of mind abilities. Marked volume loss was associated with larger hypometabolism and impaired cognitive performance. To our knowledge, this is the first study to longitudinally examine both grey matter volume and metabolic alteration patterns in patients with amyotrophic lateral sclerosis, over a mean follow-up time of 1 year. We identify how changes of the inferior frontal gyrus critically underly later cognitive performance, shedding new light on its high prognostic significance for amyotrophic lateral sclerosis-related changes. These results have important implications for our understanding of structural and functional changes associated with amyotrophic lateral sclerosis and how they underly cognitive impairments.
Looking into the IL-1 of the storm: are inflammasomes the link between immunothrombosis and hyperinflammation in cytokine storm syndromes?
Authors: Gleeson Tara A , Nordling Erik , Kaiser Christina , Lawrence Catherine B , Brough David , Green Jack P , Allan Stuart M 
Published: September 2022

Summary
Inflammasomes and the interleukin (IL)-1 family of cytokines are key mediators of both inflammation and immunothrombosis. Inflammasomes are responsible for the release of the pro-inflammatory cytokines IL-1β and IL-18, as well as releasing tissue factor (TF), a pivotal initiator of the extrinsic coagulation cascade. Uncontrolled production of inflammatory cytokines results in what is known as a “cytokine storm” leading to hyperinflammatory disease. Cytokine storms can complicate a variety of diseases and results in hypercytokinemia, coagulopathies, tissue damage, multiorgan failure, and death. Patients presenting with cytokine storm syndromes have a high mortality rate, driven in part by disseminated intravascular coagulation (DIC). While our knowledge on the factors propagating cytokine storms is increasing, how cytokine storm influences DIC remains unknown, and therefore treatments for diseases, where these aspects are a key feature are limited, with most targeting specific cytokines. Currently, no therapies target the immunothrombosis aspect of hyperinflammatory syndromes. Here we discuss how targeting the inflammasome and pyroptosis may be a novel therapeutic strategy for the treatment of hyperinflammation and its associated pathologies.
Safety and efficacy of very low LDL-cholesterol intensive lowering: a meta-analysis and meta-regression of randomized trials
Authors: Patti Giuseppe , Spinoni Enrico Guido , Grisafi Leonardo , Mehran Roxana , Mennuni Marco 
Published: September 2022

Abstract

Aims
We performed a study-level meta-analysis to provide more robust evidence on safety of very low LDL-cholesterol (LDL-C) levels.

Background
Concerns on the safety of LDL-C values achieved with potent lipid-lowering therapies have been raised.

Methods and results
We searched randomized trials reporting clinical outcomes with intensive lipid-lowering treatments leading to very low (&lt;40 mg/dL) LDL-C levels vs. a control group with higher LDL-C levels. Only studies with follow-up duration ≥ 3 months were considered. Primary endpoint was the incidence of various safety measures. A total of 10 randomized trials were overall included, with 38 427 patients being in the very low LDL-C group vs. 70 668 in the control group. Median follow-up duration was 28.8 months. The incidence of all safety outcomes was similar in the two groups: non-cardiovascular death: OR 1.13, 95% CI 0.87–1.45; P = 0.36; any adverse events: OR 1.00, 0.90–1.11, P = 0.94; adverse events leading to drug discontinuation: OR 1.00, 0.87–1.15, P = 0.99; cancer: OR 1.02, 0.95–1.10, P = 0.57; haemorrhagic stroke OR 0.89, 0.66–1.20, P = 0.44; new-onset diabetes: OR 1.16, 0.91–1.47, P = 0.23; neurocognitive disorders: OR 0.97, 0.91–1.04, P = 0.41; haepatobiliary disorders: OR 0.99, 0.83–1.18, P = 0.93; muscle disorders: OR 0.94, 0.77–1.13, P = 0.49; cataract: OR 1.28, 0.78–2.10, P = 0.34. The rates of major adverse cardiovascular events were significantly lower in the very low LDL-C group: OR 0.82, 0.72–0.94, P = 0.005.

Conclusion
This meta-analysis indicates that very low LDL-C levels on intensive lipid-lowering treatments are not associated with any adverse event and maintain a persistent reduction of cardiovascular events.
Complex genetics cause and constrain fungal persistence in different parts of the mammalian body
Authors: Mullis Martin N , Ghione Caleb , Lough-Stevens Michael , Goldstein Ilan , Matsui Takeshi , Levy Sasha F , Dean Matthew D , Ehrenreich Ian M 
Published: September 2022

Abstract
Determining how genetic polymorphisms enable certain fungi to persist in mammalian hosts can improve understanding of opportunistic fungal pathogenesis, a source of substantial human morbidity and mortality. We examined the genetic basis of fungal persistence in mice using a cross between a clinical isolate and the lab reference strain of the budding yeast Saccharomyces cerevisiae. Employing chromosomally encoded DNA barcodes, we tracked the relative abundances of 822 genotyped, haploid segregants in multiple organs over time and performed linkage mapping of their persistence in hosts. Detected loci showed a mix of general and antagonistically pleiotropic effects across organs. General loci showed similar effects across all organs, while antagonistically pleiotropic loci showed contrasting effects in the brain vs the kidneys, liver, and spleen. Persistence in an organ required both generally beneficial alleles and organ-appropriate pleiotropic alleles. This genetic architecture resulted in many segregants persisting in the brain or in nonbrain organs, but few segregants persisting in all organs. These results show complex combinations of genetic polymorphisms collectively cause and constrain fungal persistence in different parts of the mammalian body.
Crystal structure and sugar-binding ability of the C-terminal domain of N-acetylglucosaminyltransferase IV establish a new carbohydrate-binding module family
Authors: Oka Nozomi , Mori Sota , Ikegaya Marina , Park Enoch Y , Miyazaki Takatsugu 
Published: September 2022

Abstract
N-glycans are modified by glycosyltransferases in the endoplasmic reticulum and Golgi apparatus. N-acetylglucosaminyltransferase IV (GnT-IV) is a Golgi-localized glycosyltransferase that synthesizes complex-type N-glycans in vertebrates. This enzyme attaches N-acetylglucosamine (GlcNAc) to the α-1,3-linked mannose branch of the N-glycan core structure via a β-1,4 linkage. Deficiency of this enzyme is known to cause abnormal cellular functions, making it a vital enzyme for living organisms. However, there has been no report on its 3-dimensional structure to date. Here, we demonstrated that the C-terminal regions (named CBML) of human GnT-IVa and Bombyx mori ortholog have the ability to bind β-N-acetylglucosamine. In addition, we determined the crystal structures of human CBML, B. mori CBML, and its complex with β-GlcNAc at 1.97, 1.47, and 1.15 Å resolutions, respectively, and showed that they adopt a β-sandwich fold, similar to carbohydrate-binding module family 32 (CBM32) proteins. The regions homologous to CBML (≥24% identity) were found in GnT-IV isozymes, GnT-IVb, and GnT-IVc (known as GnT-VI), and the structure of B. mori CBML in complex with β-GlcNAc indicated that the GlcNAc-binding residues were highly conserved among these isozymes. These residues are also conserved with the GlcNAc-binding CBM32 domain of β-N-acetylhexosaminidase NagH from Clostridium perfringens despite the low sequence identity (&lt;20%). Taken together with the phylogenetic analysis, these findings indicate that these CBMLs may be novel CBM family proteins with GlcNAc-binding ability.
Active and healthy ageing in urban environments: laying the groundwork for solution-building through citizen science
Authors: Wood Grace E R , Pykett Jessica , Stathi Afroditi 
Published: September 2022

Summary
Urban age-friendly initiatives strive to promote active and healthy ageing by addressing urban influences that impact individuals as they age. Collaborative community partnerships with multi-level stakeholders are crucial for fostering age-friendly initiatives that can transform urban community health. Employing a citizen social science (CSS) approach, this study aimed to engage older adults and stakeholders in Birmingham, UK, to (i) identify key urban barriers and facilitators to active and healthy ageing, and (ii) facilitate collaboration and knowledge production to lay the groundwork for a citizen science project. Older adults (n = 16; mean age = 72(7.5 SD); 11 female) and community stakeholders (n = 11; 7 female) were engaged in six online group discussions, with audio recordings transcribed and thematically analysed to present key urban barrier and facilitator themes. Ageism, winter, technology and safety were barriers identified by both groups. Outdoor spaces and infrastructure, transportation, community facilities, and Covid-19 pandemic were identified as barriers and/or facilitators. Older adults identified the ageing process as a barrier and diversity of the city, health and mobility and technology as facilitators. For stakeholders, barriers were deprivation and poverty, gender differences, and ethnicity, whereas age-inclusive activities were a facilitator. Organic and active opportunities for older adults and stakeholders to connect, co-produce knowledge on urban environments and share resources presented foundations of solution-building and future collaboration. CSS effectively facilitated a range of stakeholders across local urban spaces to collaborate and co-produce ideas and solutions for enhancing local urban environments to promote active and healthy ageing.
Reconfiguring the biomedical dominance of pain: time for alternative perspectives from health promotion?
Authors: Johnson Mark I , Bonacaro Antonio , Georgiadis Emmanouil , Woodall James 
Published: September 2022

SummaryStrategies to reduce the burden of persistent pain in society are rooted in a biomedical paradigm. These strategies are located downstream, managing persistent pain once it has become a problem. Upstream activities that create social conditions to promote health and well-being are likely to help, yet health promotion discourse and research are lacking in pain literature. In this article, we argue that the subjective nature of pain has not sat comfortably with the objective nature of medical practice. We argue that the dominance of the biomedical paradigm, with a simplistic ‘bottom-up’ model of pain being an inevitable consequence of tissue damage, has been detrimental to the health and well-being of people living with persistent pain. Evidence from neuroscience suggests that bodily pain emerges as a perceptual inference based on a wide variety of contextual inputs to the brain. We argue that this supports community, societal and environmental solutions to facilitate whole-person care. We call for more salutogenic orientations to understand how people living with persistent pain can continue to flourish and function with good health. We suggest a need for ‘upstream’ solutions using community-based approaches to address cultural, environmental, economic and social determinants of health, guided by principles of equity, civil society and social justice. As a starting point, we recommend appraising the ways human society appreciates the aetiology, actions and solutions towards alleviating persistent pain.
Transdisciplinarity in transformative ocean governance research—reflections of early career researchers
Authors: Strand Mia , Ortega-Cisneros Kelly , Niner Holly J , Wahome Michel , Bell James , Currie Jock C , Hamukuaya Hashali , La Bianca Giulia , Lancaster Alana M S N , Maseka Ntemesha , McDonald Lisa , McQuaid Kirsty , Samuel Marly M , Winkler Alexander 
Published: September 2022

AbstractThis paper interrogates the concept of transdisciplinarity, both theoretically and practically, from a perspective of early career researchers (ECRs) in transformative ocean governance research. Aiming to advance research methodologies for future complex sustainability challenges, the paper seeks to illuminate some common uncertainties and challenges surrounding transdisciplinarity from a marine science perspective. Following a literature review on transdisciplinary research, workshops, and a series of surveys, we determine that transdisciplinarity appears to be a concept in search of definition, and that there is a need to explore transdisciplinarity specifically from an ocean research perspective. The paper discusses a number of challenges experienced by ECRs in conducting transdisciplinary research and provides recommendations for both ECRs wishing to undertake more equitable transdisciplinary research and for the UN Decade for Ocean Science to support ECRs in this endeavour (Figure 1). Based on our findings, we interrogate the role of non-academic collaborators in transdisciplinary research and argue that future transdisciplinarity will need to address power imbalances in existing research methods to achieve knowledge co-production, as opposed to knowledge integration.
Complete Singular Collineations and Quadrics
Authors: Casarotti Alex , Corniani Elsa , Massarenti Alex 
Published: September 2022

Abstract
We construct wonderful compactifications of the spaces of linear maps and symmetric linear maps of a given rank as blowups of secant varieties of Segre and Veronese varieties. Furthermore, we investigate their birational geometry and their relations with some spaces of degree two stable maps.
COVID-19 lockdown impact on quality of treatment and outcomes of STEMI and stroke patients in a large tertiary medical center: an observational study
Authors: Galper Alex , Magnezi Racheli , Ekka Zohar Anat , Oberman Bernice , Zimlichman Eyal 
Published: September 2022

Abstract

Background
The coronavirus 2019 (COVID-19) pandemic affected health-care systems worldwide, leading to fewer admissions and raising concerns about the quality of care. The objective of this study was to investigate the early effects of the COVID-19 pandemic on quality of care among stroke and ST-elevation myocardial infarction (STEMI) patients, focusing on clinical outcomes and direct treatment costs.

Method
This retrospective, observational study was based on the 10-week period that included the first wave of the COVID-19 pandemic in Israel (15 February 2020–30 April 2020). Emergency department admissions for stroke and STEMI were compared with parallel periods in 2017–2019, focusing on demographics, risk and severity scores, and the effect of clinical outcomes on hospitalization costs.

Results
The 634 stroke and 186 STEMI cases comprised 16% and 19% fewer admissions, respectively, compared to 2019. No significant changes were detected in demographics, most disease management parameters, readmission and mortality outcomes. The mean door-to-balloon time increased insignificantly by 33%, lowering the health quality indicator (HQI) for treatment in &lt;90 min from 94.7% in 2017–2019 to 83% in 2020 (P = 0.022). Among suspected stroke patients, 97.2% underwent imaging, with 28% longer median time from admission (P = 0.05). Consequently, only 24.3% met the HQI of imaging in &lt;29 min, compared to 45.5% in 2017–2019 (P &lt; 0.01). Increased length of stay and more intensive care unit admissions were the leading causes of 6.5% increased mean cost of STEMI patients’ initial hospitalization, which totaled $29 300 in the COVID-19 period (P = 0.008).

Conclusion
The initial pandemic period caused a decline in HQIs linked to diagnostic and treatment protocols, without changes in outcomes, but with increased hospitalization costs. Medical information and awareness of life-threatening conditions among patients and caregivers should be increased to enable proper diagnosis and management.
Primary resistance against integrase strand transfer inhibitors in integrase strand transfer inhibitor-naive patients failing first- and second-line ART in Tanzania
Authors: Henerico Shimba , Lyimo Eric , Makubi Abel N , Magesa Daniel , Desderius Bernard , Mueller Andreas , Changalucha John , Kalluvya Samuel E , Van Zyl Gert , Preiser Wolfgang , Mshana Stephen E , Kasang Christa 
Published: September 2022

Abstract

Introduction
Sub-Saharan African countries are introducing integrase strand transfer inhibitors (INSTIs) in their ART programmes as the preferred first-line regimen, and dolutegravir is the INSTI of choice due to its potency, tolerability and high genetic barrier to resistance. Dolutegravir was introduced into the first-line ART regimen in Tanzania in 2019. However, there is a paucity of data on the occurrence of mutations in HIV lineages circulating in Tanzania. This study aimed to determine the prevalence of INSTI primary resistance mutations in Tanzanian patients exposed to ART but not INSTIs.

Methods
Plasma samples from 50 INSTI-naive patients failing first- or second-line ART [median (IQR) age: 40 (21.93–46.41) years; 68% women] were subjected to Sanger sequencing of the HIV integrase gene. Participants had been on ART for a median (IQR) duration of 7.32 (4.73–9.29) years, with 80% and 20% failing first- and second-line ART, respectively.

Results
No major INSTI mutations were found, but 2 (4%) participants had the accessory mutation T97A. Using the REGA HIV-1 subtyping tool, HIV subtype A1 (53.1%) was found to be dominant, followed by subtypes C (30.6%) and D (16.3%).

Conclusions
This study found no current evidence for transmitted resistance against INSTIs among unexposed patients failing ART and supports the scale-up of INSTI-based regimens. However, the presence of accessory mutations calls for the surveillance of INSTI resistance mutations to ensure that the anticipated long-term desired outcomes are achieved.
A post-mortem analysis of tenofovir, lamivudine, efavirenz and fluconazole penetration in female genital tissues
Authors: Wang Fan , Namuju Olivie C , Pastick Katelyn A , Abdusalaamu Kizito , Mishra Usha , Collins Lindsey , Boulware David R , Lukande Robert , Meya David B , Nicol Melanie R 
Published: September 2022

Abstract

Background
Optimal penetration of anti-infectives in the female genital tract (FGT) is paramount in the treatment and prevention of infectious diseases. While exposure of anti-infectives in lower FGT tissues (e.g. cervix, vagina) has been described, little data exist on upper genital tissues (e.g. ovary, uterus).

Methods
Autopsies were performed and post-mortem tissues were collected within 24 h of death for female participants with advanced HIV in Uganda (n = 27). Tenofovir, lamivudine, efavirenz and fluconazole concentrations were measured using LC-MS/MS in plasma, ovarian, uterine, cervical and vaginal tissues. Tissue penetration was calculated as tissue-to-plasma concentration ratios (TPRs).

Results
TPRs of tenofovir, lamivudine and fluconazole were highest in vaginal tissue (medians 1.86, 1.83 and 0.94, respectively), while the TPR of efavirenz was highest in ovarian tissue (median 0.65). With cervix as a reference compartment, vaginal TPRs were significantly higher than cervical for all four drugs; TPRs of efavirenz in uterine and ovarian compartments were also significantly higher than cervical. Most of the post-mortem FGT samples had a TPR of greater than 1 for tenofovir and lamivudine, while less than 50% had a TPR of greater than 1 for both efavirenz and fluconazole.

Conclusions
Penetration of anti-infectives was not homogeneous among the FGT compartments. Approximately 70% of FGT tissues had a TPR of greater than 1 for tenofovir and lamivudine, favouring the prevention of local HIV replication and transmission in the FGT.