bluuebunny/crossref_metadata_2025 huggingface dataset:
A molnupiravir-associated mutational signature in global SARS-CoV-2 genomes
Authors: Sanderson Theo , Hisner Ryan , Donovan-Banfield I’ah , Hartman Hassan , Løchen Alessandra , Peacock Thomas P. , Ruis Christopher
Published: January 2023

Molnupiravir, an antiviral medication that has been widely used against SARS-CoV-2, acts by inducing mutations in the virus genome during replication. Most random mutations are likely to be deleterious to the virus, and many will be lethal, and so molnupiravir-induced elevated mutation rates reduce viral load2,3. However, if some patients treated with molnupiravir do not fully clear SARS-CoV-2 infections, there could be the potential for onward transmission of molnupiravir-mutated viruses. Here we show that SARS-CoV-2 sequencing databases contain extensive evidence of molnupiravir mutagenesis. Using a systematic approach, we find that a specific class of long phylogenetic branches, distinguished by a high proportion of G-to-A and C-to-T mutations, appear almost exclusively in sequences from 2022, after the introduction of molnupiravir treatment, and in countries and age-groups with widespread usage of the drug. We identify a mutational spectrum, with preferred nucleotide contexts, from viruses in patients known to have been treated with molnupiravir and show that its signature matches that seen in these long branches, in some cases with onwards transmission of molnupiravir-derived lineages. Finally, we analyse treatment records to confirm a direct association between these high G-to-A branches and the use of molnupiravir.
HAPSTR1 localizes HUWE1 to the nucleus to limit stress signaling pathways
Authors: Monda Julie K , Ge Xuezhen , Hunkeler Moritz , Donovan Katherine A , Ma Michelle W , Jin Cyrus Y , Leonard Marilyn , Fischer Eric S , Bennett Eric J
Published: January 2023

HUWE1 is a large, enigmatic HECT domain ubiquitin ligase implicated in the regulation of diverse pathways including DNA repair, apoptosis, and differentiation. How HUWE1 engages its structurally diverse substrates and how HUWE1 activity is regulated are unknown. Using unbiased quantitative proteomics, we identify C16orf72/HAPSTR1 as a dedicated HUWE1 substrate despite HUWE1 targeting substrates in a largely cell type-specific manner. The established physical and genetic interactions between HUWE1 and C16orf72/HAPSTR1 suggest that HAPSTR1 positively regulates HUWE1 function. Here, we show that HAPSTR1 is both a HUWE1 substrate and is required for HUWE1 nuclear localization to facilitate HUWE1 nuclear substrate targeting. HUWE1 or HAPSTR1 loss of function triggers a broad transcriptional stress response. We show that nuclear HUWE1 is both critical for modulating stress signaling pathways, which include p53 and NF-κB-mediated signaling and required for cell proliferation. Combined, our results define a role for HAPSTR1 in gating critical nuclear HUWE1 functions.
The Glucocorticoid Receptor is Required for Efficient Aldosterone-Induced Transcription by the Mineralocorticoid Receptor
Authors: Johnson Thomas A. , Fettweis Gregory , Wagh Kaustubh , Almeida-Prieto Brian , Krishnamurthy Manan , Upadhyaya Arpita , Hager Gordon L. , Alvarez de la Rosa Diego
Published: January 2023

The glucocorticoid and mineralocorticoid receptors (GR and MR, respectively) have distinct, yet overlapping physiological and pathophysiological functions. There are indications that both receptors interact functionally and physically, but the precise role of this interdependence is poorly understood. Here, we analyzed the impact of GR co-expression on MR genome-wide chromatin binding and transcriptional responses to aldosterone and glucocorticoids, both physiological ligands of this receptor. Our data show that GR co-expression alters MR genome-wide binding to consensus DNA sequences in a locus-and ligand-specific way. MR binding to consensus DNA sequences is affected by GR. Transcriptional responses of MR in the absence of GR are weak and show poor correlation with chromatin binding. In contrast, co-expression of GR potentiates MR-mediated transcription, particularly in response to aldosterone. Finally, single-molecule tracking of MR suggests that the presence of GR contributes to productive binding of MR/aldosterone complexes to chromatin. Together, our data indicate that co-expression of GR potentiates aldosterone-mediated MR transcriptional activity, even in the absence of glucocorticoids.
An evaluation of the effectiveness of a therapeutic program for children with global developmental delay
Authors: Al-Yamani Abyan Ismail , Sulaiman Nabil Ali , Al-Ansari Ahmed Malalla
Published: January 2023

Purpose

Global developmental delay (GDD) is highly prevalent among patients at child psychiatry clinics. However, preschool day treatment centers are currently scarce. As such, this study aimed to evaluate a program that was designed for children with GDD in order to improve their global skills and prepare them to join the school system.

Design/methodology/approach

This study utilized an observation retrospective design with a comparative group sample and included all children aged between 3 and 6 years who participated in the program for at least one academic year (experimental group). Their GDD diagnoses were based on the DSM-5 criteria (Diagnostic and Statistical Manual of Mental Disorders). Children with similar diagnoses who were on the waiting list constituted the control group. Pre- and post-scoring of the Children’s Global Assessment Scale (CGAS) were conducted by the children’s teacher and blinded investigator for the experimental group, while the children’s mothers conducted the post-CGAS scoring for the control group.

Findings

The pre- and post-CGAS scores for the experimental group were 49.5 ± 12.8 and 58.3 ± 12.7 and 47.3 ± 17.3 and 66.6 ± 17.3 for the control group, respectively (p = 0.001). The children in the experimental group scored significantly better than the control group with respect to securing places in integrated, regular classes in the education system (p = 0.001).

Research limitations/implications

This study had certain limitations. First, the number of children in the control group was relatively small. Second, the baseline skill levels of some of the children in the control group may have been lower than those of the children in the experimental group at the beginning of the evaluation; this may explain why they had been put on the waiting list. Third, the information was gathered retrospectively; this is a method that is known to have its own limitations.

Practical implications

The clinical implications of the study are that the early identification and referral of GDD are key elements in the rehabilitation of these children and that early intervention programs are necessary for cases of moderate and severe GDD. Primary care physicians should follow up with GDD patients to ensure that referrals are being appropriately sought (Choo et al., 2019).

Originality/value

The program was effective in both increasing the general functioning skills of the children in the experimental group and preparing them to attend regular, integrated classes. The program should be expanded and made available to more children with GDD.
Fleet management system, perceived service quality and the public health sector performance in Zimbabwe
Authors: Chikazhe Lovemore , Siziba Sibonile , Bhebhe Thomas , Sifile Obert , Nyagadza Brighton
Published: January 2023

Purpose

The purpose of the study is to establish the relationship between public health sector performance (PHSP), fleet management system, perceived service quality (PSQ) and management style (MS).

Design/methodology/approach

A total of 260 managerial employees were randomly selected from 5 major public hospitals in Zimbabwe to participate in this cross-sectional survey.

Findings

Fleet management system was found to positively influence both PSQ and PHSP. The results indicated that PSQ has a positive effect on PHSP. MS was found to moderate the effect of fleet management system on both PSQ and PHSP.

Originality/value

The current study provides fresh insights and validates extant knowledge on PHSP, fleet management and PSQ within the public health sector departments. It extends further knowledge on the public health performance in the Sub-Saharan region, as it shows that dimensions on fleet management have a direct influence on PHSP.
Combining corporate environmental sustainability and customer experience management to build an integrated model for decision-making
Authors: Calza Francesco , Sorrentino Annarita , Tutore Ilaria
Published: January 2023

Purpose

The aim of this work is to provide a theoretical model that can help companies to develop a unique approach to achieve both corporate environmental sustainability (CES) and successful customer experience management (CEM).

Design/methodology/approach

A two-phase study achieved the research aim. The first phase consisted of the analysis of contemporary theoretical contributions with a focus on CES and CEM. In the second phase, taking a qualitative approach, the key dimensions identified in the initial analysis were investigated to explore the dominant perceptions of practitioners and to hone the theoretical categories.

Findings

Five innovative pathways emerged from the study to inform decision-making while maintaining the dual objectives of CES and successful CEM. These pathways are combined to offer a strategic tool for managers and for research advances. This original integrated model also offers six novel theoretical propositions that describe how to shape corporate decisions to achieve environmental sustainability in CEM.

Research limitations/implications

Firms can benefit from an approach that integrates CES and CEM to develop a new mindset for an innovative and valuable decision-making process and to design more captivating experiences for customers. Nevertheless, the efficacy and generalizability of the theoretical framework and propositions require empirical testing.

Originality/value

This paper makes an original contribution to the environmental sustainability and marketing literature by bringing together all elements in these fields of research in a conceptual model. Moreover, this paper proposes theoretical propositions that advance knowledge of the subject and offer ideas for future research and managers.
Co‐design and evaluation of a multidisciplinary teaching resource on mental health recovery involving people with lived experience
Authors: Arblaster Karen , Mackenzie Lynette , Buus Niels , Chen Timothy , Gill Katherine , Gomez Lisa , Hamilton Deborah , Hancock Nicola , McCloughen Andrea , Nicholson Margaret , Quinn Yvette , River Jo , Scanlan Justin Newton , Schneider Carl , Schweizer Richard , Wells Karen
Published: January 2023

Background

Students from a range of health disciplines need to learn from people with lived experience of mental distress and recovery to develop recovery capabilities for mental health practice.

Aims

The aims of this study are to describe the co‐design of a teaching resource, to explore the experience of people with lived experience during the resource development, and to evaluate the outcome of the resource on student recovery capabilities.

Method

Using a sequential mixed method, a project group consisting of six people with lived experience and 10 academics from five health disciplines was convened to co‐develop teaching resources. People with lived experience met independently without researchers on several occasions to decide on the key topics and met with the research team monthly. The teaching resource was used in mental health subjects for two health professional programmes, and the Capabilities for Recovery‐Oriented Practice Questionnaire (CROP‐Q) was used before and after to measure any change in student recovery capabilities. Scores were compared using the Wilcoxon signed rank test. The people with lived experience were also interviewed about their experience of being involved in constructing the teaching resources. Interviews were audiotaped, transcribed, and analysed thematically.

Results

The finished resource consisted of 28 short videos and suggested teaching plans. Occupational therapy and nursing student scores on the CROP‐Q prior to using the educational resource (n = 33) were 68 (median) and post scores (n = 28) were 74 (median), indicating a statistically significant improvement in recovery capability (P = 0.04). Lived experience interview themes were (i) the importance of lived experience in education; (ii) personal benefits of participating; (iii) co‐design experience; and (iv) creating the resource.

Conclusion

Co‐design of teaching resources with people with lived experience was pivotal to the success and quality of the final product, and people with lived experience described personal benefits of participating in resource development. More evidence to demonstrate the use of the CROP‐Q in teaching and practice is needed.
ALKBH5 inhibits the SIRT3/ACC1 axis to regulate fatty acid metabolism via an m6A‐IGF2BP1‐dependent manner in cervical squamous cell carcinoma
Authors: Zhen Lan , Pan Wuyuan
Published: January 2023

Cervical cancer (CC) is the most common malignancy of the female reproductive system, among which cervical squamous cell carcinoma (CESC) is the most common type. The demethylase ALKBH5 has been previously revealed to be downregulated in CC tissue. N6 methyladenine (m6A) is the most common modification in eukaryotic RNAs and is involved in modulating tumour progression. Therefore, we attempted to clarify the ALKBH5 role and mechanism underlying CESC progression. In CESC, patient tissue and control tissue m6A levels were measured. Reverse transcription quantitative real‐time polymerase chain reaction, western blotting and immunochemistry were used to measure ALKBH5 levels. A correlation between CESC patient survival and ALKBH5 levels was evaluated. Wound healing, transwell and colony formation assays were used to detect CESC cellular behaviours. Corresponding kits and BODIPY staining were used to detect CESC lipid metabolism. Bioinformatics, immunoprecipitation, RNA pulldown and RNA immunoprecipitation assays as well as half‐life measurements were used to assess the association and mechanism of ALKBH5 with silent mating type information regulation 2 homologue 3 (SIRT3), acetyl‐CoA carboxylase 1 (ACC1) and insulin‐like growth factor 2 mRNA binding protein 1 (IGF2BP1). The m6A demethylase ALKBH5 was depleted in CESC tissue and cells, and a low level of ALKBH5 predicted an unfavourable prognosis in CESC patients. ALKBH5 overexpression suppressed CESC growth and lipid metabolism in vitro and CESC tumour growth in vivo, and ACC1 overexpression rescued these changes. ALKBH5 downregulated ACC1 levels in CESC cells by facilitating SIRT3 methylation to repress ACC1 deacetylation. ALKBH5 destabilized SIRT3 to downregulate SIRT3 levels in CESCs in an m6A‐IGF2BP1‐dependent manner. ALKBH5 demethylates and destabilizes SIRT3 in an m6A‐IGF2BP1‐dependent manner, repressing CESC growth, lipid metabolism and tumorigenesis by downregulating ACC1.
Age‐related deficits in neuronal physiology and cognitive function are recapitulated in young mice overexpressing the L‐type calcium channel, CaV1.3
Authors: Moore Shannon J. , Cazares Victor A. , Temme Stephanie J. , Murphy Geoffrey G.
Published: January 2023

The calcium dysregulation hypothesis of brain aging posits that an age‐related increase in neuronal calcium concentration is responsible for alterations in a variety of cellular processes that ultimately result in learning and memory deficits in aged individuals. We previously generated a novel transgenic mouse line, in which expression of the L‐type voltage‐gated calcium, CaV1.3, is increased by ~50% over wild‐type littermates. Here, we show that, in young mice, this increase is sufficient to drive changes in neuronal physiology and cognitive function similar to those observed in aged animals. Specifically, there is an increase in the magnitude of the postburst afterhyperpolarization, a deficit in spatial learning and memory (assessed by the Morris water maze), a deficit in recognition memory (assessed in novel object recognition), and an overgeneralization of fear to novel contexts (assessed by contextual fear conditioning). While overexpression of CaV1.3 recapitulated these key aspects of brain aging, it did not produce alterations in action potential firing rates, basal synaptic communication, or spine number/density. Taken together, these results suggest that increased expression of CaV1.3 in the aged brain is a crucial factor that acts in concert with age‐related changes in other processes to produce the full complement of structural, functional, and behavioral outcomes that are characteristic of aged animals.
Agroecological transition increases arthropod diversity and decreases herbivore abundance on field margins
Authors: Pérez Roig Camila , González Ezequiel , Videla Martin
Published: January 2023

In peri‐urban areas, many farmers are transitioning from conventional agriculture to agroecological practices to reduce pesticide input and preserving ecosystem services such as natural pest control. Field margins represent a stable habitat for arthropods, but community structure depends on many factors, including management type and vegetation features.

We studied the effects of agroecological transitions and vegetation features on arthropods of horticultural field margins, focusing on three feeding guilds (herbivores, predators and parasitoids). We sampled arthropods using the beat‐sheet method in five conventional fields and five under agroecological transition. We also measured vegetation height, richness, flower abundance and plant cover.

Our results showed that arthropod diversity was higher in agroecological fields whereas herbivore abundance was lower, with a consistent pattern across most taxonomic orders. Vegetation features displayed multiple effects among functional and taxonomic groups. Herbivores did not respond to most vegetation variables whereas predators correlated with several, with similar trends among orders.

We conclude that agroecological transitions and field margins with high vegetation richness and floral resources influence arthropod communities with potential benefits regarding pest regulation. These practices might be more effective if considered alongside other methods that enhance biodiversity and if they are consistent at a landscape scale.
Targeting Ara h 2 with human‐derived monoclonal antibodies prevents peanut‐induced anaphylaxis in mice
Authors: Paolucci Marta , Wuillemin Natascha , Homère Valentine , Bieli Dimitri , Köhli Alice , Ballmer‐Weber Barbara , Waeckerle‐Men Ying , Pengo Niccolò , Kündig Thomas M. , Sonati Tiziana , Johansen Pål
Published: January 2023

Background

Peanut allergy is a type‐I hypersensitivity immune reaction mediated by the binding of peanut allergens to IgE‐FcεRI complexes on mast cells and basophils and by their subsequent cellular degranulation. Of all major peanut allergens, Ara h 2 is considered the most anaphylactic. With few options but allergen avoidance, effective treatment of allergic patients is needed. Passive immunotherapy (herein called PIT) based on prophylactic administration of peanut‐specific monoclonal antibodies (mAbs) may present a promising treatment option for this under‐served disease.

Method

Fully human recombinant anti‐peanut IgG mAbs were tested in mice sensitized to peanut allergen extract. Allergic mice received intravenous immunotherapy with anti‐peanut Ara h 2‐specific IgG1 or IgG4 mAbs cocktails, and were then challenged by a systemic injection of high‐dose peanut allergen extract. The protection from allergic anaphylaxis was measured by monitoring the core body temperature.

Results

PIT with peanut‐specific mAbs was associated with a significant and dose‐dependent reduction of anaphylactic reactions in peanut‐sensitized mice challenged with peanut allergen extract. Complete protection was observed at doses approximately 0.3–0.6 mg mAbs. Mixtures of mAbs were more effective than single mAbs, and effective treatment could be obtained with mAbs of both IgG1 and IgG4 subclasses. The therapeutic effect of anti‐Ara h 2 mAbs was based on allergen neutralization and independent of the Fcγ receptor and mast‐cell inhibition.

Conclusion

This is the first report that shows that human‐derived anti‐peanut mAbs can prevent allergic anaphylaxis in mice. The study demonstrates that neutralizing allergenic epitopes on Ara h 2 by mAbs may represent a promising treatment option in peanut‐allergy.
The lure of an unavailable world: The shifting stakes of contemporary critique
Authors: Pugh Jonathan
Published: January 2023

The lure of an unavailable world is becoming increasingly prominent in Geography and related disciplines. The concern is that much research today remains affirmational—still grasping and instrumentalising being and relation—and that, whilst no doubt modified in such developments as the relational and ontological turns, this nevertheless continues the legacies of the modern episteme in new ways. Indeed, there is a marked momentum, across the social sciences and humanities, from cultural geography to computer and Black studies, to read the reduction of the world to available ontic and ontological cuts and distinctions as a form of violence. In response, tropes of the non‐relational, non‐ontological, the negative, nothingness, the void, absence and the abyss, for examples—what could be called ‘unavailable geographies’—are of growing appeal and interest. This paper, foregrounding the importance of tracking how the material forces of history are read as enabling for the emergence of any new problem space, provides a distinctive pathway into this sense of a critical shift in Western critique. By way of an illustrative example, it focuses upon how the proliferation of logistics (broadly framed here as the logic of obtaining the world by way of cuts and distinctions, from metric culture, to identity politics, to the grasping of ontology and relation) is increasingly understood to open up the power of an undifferentiating reality; one which expands and deepens the unavailable world as a problem space for critique. Thus, whilst geographers, like many others, are currently critiquing dominant approaches for being too affirmational, the key argument of this paper is that we should also be taking one step back, asking why now, and through what broader forces of history, the lure of an unavailable world today?
Autonomy to a fault: The confluence of organ donation, euthanasia, and the dead donor rule
Authors: Rubin Jonah
Published: January 2023

Five countries now permit organ donation after euthanasia, on the basis of respecting donor autonomy. Some now openly consider performing euthanasia itself via organ extraction to better preserve organ viability, albeit in violation of the dead donor rule. Proponents argue that respect for patient autonomy requires this option; the dead donor rule is inapplicable since it fulfills donors’ wishes. Other ethical arguments, not addressed herein, explore issues including dying at home, impact on clinicians, and societal faith in donation enterprise, but these concerns are not insurmountable. This paper instead solely critiques proponents’ oversimplified understanding of autonomy with an autonomy‐based argument against any linkage of organ donation and euthanasia, regardless of its timing. Respect for patient autonomy does not unilaterally require fulfilling patients' every  wish. Moreover, the very possibility of organ donation with euthanasia limits donor autonomy qualitatively and quantitatively substantially more than by offering it. In fact, organ donation after euthanasia violates the purpose of the dead donor rule, even if not its technicalities.
Why and how do parents decide to adopt? A study on motivations and the decision‐making process in becoming an adoptive family
Authors: Soares Joana , Ralha Sara , Fonseca Sílvia Monteiro , Prego Joana , Barbosa‐Ducharne Maria A.
Published: January 2023

There are several motives underlying the process of deciding to become an adoptive family. However, research exploring this issue is scarce and essentially focused on infertility as the main motivation. The present mixed‐method study aims to fill in this gap by exploring, retrospectively, the motives to adopt of 126 Portuguese adoptive parents. The Parents' Interview on the Adoption Process was used to identify the motives to adopt and describe the adoption decision‐making process. Seven main motives (biological issues, filling in a void/loneliness, adoption as a life project, expanding the family, philanthropy, contact with the child protection system and parenthood) were identified. These motives can be centred on the self, the child or both simultaneously and are characterized by dynamism, permeability and interconnection. Findings allowed for establishing conceptual considerations on motivations to adopt and recommendations for adoption practice.
DNA methylation signature classification of rare disorders using publicly available methylation data
Authors: Hildonen Mathis , Ferilli Marco , Hjortshøj Tina Duelund , Dunø Morten , Risom Lotte , Bak Mads , Ek Jakob , Møller Rikke S. , Ciolfi Andrea , Tartaglia Marco , Tümer Zeynep
Published: January 2023

Disease‐specific DNA methylation patterns (DNAm signatures) have been established for an increasing number of genetic disorders and represent a valuable tool for classification of genetic variants of uncertain significance (VUS). Sample size and batch effects are critical issues for establishing DNAm signatures, but their impact on the sensitivity and specificity of an already established DNAm signature has not previously been tested. Here, we assessed whether publicly available DNAm data can be employed to generate a binary machine learning classifier for VUS classification, and used variants in KMT2D, the gene associated with Kabuki syndrome, together with an existing DNAm signature as proof‐of‐concept. Using publicly available methylation data for training, a classifier for KMT2D variants was generated, and individuals with molecularly confirmed Kabuki syndrome and unaffected individuals could be correctly classified. The present study documents the clinical utility of a robust DNAm signature even for few affected individuals, and most importantly, underlines the importance of data sharing for improved diagnosis of rare genetic disorders.
Modeling mammal response to fire based on species’ traits
Authors: Pocknee Christopher A. , Legge Sarah M. , McDonald Jane , Fisher Diana O.
Published: January 2023

Fire has shaped ecological communities worldwide for millennia, but impacts of fire on individual species are often poorly understood. We performed a meta‐analysis to predict which traits, habitat, or study variables and fire characteristics affect how mammal species respond to fire. We modeled effect sizes of measures of population abundance or occupancy as a function of various combinations of these traits and variables with phylogenetic least squares regression. Nine of 115 modeled species (7.83%) returned statistically significant effect sizes, suggesting most mammals are resilient to fire. The top‐ranked model predicted a negative impact of fire on species with lower reproductive rates, regardless of fire type (estimate = –0.68), a positive impact of burrowing in prescribed fires (estimate = 1.46) but not wildfires, and a positive impact of average fire return interval for wildfires (estimate = 0.93) but not prescribed fires. If a species’ International Union for Conservation of Nature Red List assessment includes fire as a known or possible threat, the species was predicted to respond negatively to wildfire relative to prescribed fire (estimate = –2.84). These findings provide evidence of experts’ abilities to predict whether fire is a threat to a mammal species and the ability of managers to meet the needs of fire‐threatened species through prescribed fire. Where empirical data are lacking, our methods provide a basis for predicting mammal responses to fire and thus can guide conservation actions or interventions in species or communities.
Reporting guidelines enhance the quality and impact of research in Dental Traumatology
Authors: Nagendrababu Venkateshbabu , Duncan Henry F. , Abbott Paul V. , Dummer Paul M. H.
Published: January 2023

Reporting guidelines assist basic scientists, translational healthcare researchers and clinicians to publish manuscripts of the highest standard by improving the accuracy, transparency and completeness of the publications they submit to journals. This paper provides an overview of reporting guidelines relevant for the specialty of dental traumatology and discusses their application, significance and potential impact. The Preferred Reporting Items for study Designs in Endodontology (PRIDE) suite of reporting guidelines includes a range of study designs that can be used within the broad field of Endodontics but they are also applicable to dental traumatology and other dental disciplines (Preferred Reporting Items for Case reports in Endodontics [PRICE] 2020, Preferred Reporting Items for RAndomized Trials in Endodontics [PRIRATE] 2020; Preferred Reporting Items for Animal Studies in Endodontology [PRIASE] 2021; Preferred Reporting Items for Laboratory studies in Endodontology [PRILE] 2021 and Preferred Reporting items for OBservational studies in Endodontics [PROBE] 2023). The PRIDE guidelines were developed by an extensive network of globally renowned academics, researchers and expert clinicians working within dentistry using an accepted and validated consensus methodology. The aim of the PRIDE guidelines is to improve the overall quality of manuscripts describing case reports, randomized trials, animal research, laboratory studies and observational studies. Although attention to reporting guidelines adds a degree of complexity when writing reports, such guidelines provide a template for authors to develop standardized manuscripts of the highest quality, which will allow colleagues, readers and the wider public to have confidence that their findings are valid and robust. They also provide evidence to editors that manuscripts submitted to journals comply with the highest global standards of reporting within their respective discipline. Endorsement of the PRIDE guidelines by editors will lead to improvements in the reporting quality of manuscripts submitted to their journals.
Non‐ADEM encephalitis in patients with myelin oligodendrocyte glycoprotein antibodies: a systematic review
Authors: Vega Enrique , Arrambide Georgina , Olivé Gemma , Castillo Mireia , Felipe‐Rucián Ana , Tintoré Mar , Montalban Xavier , Espejo Carmen , Sepúlveda María , Armangué Thais , Cobo‐Calvo Alvaro
Published: January 2023

Background and purpose

Non‐(acute disseminated encephalomyelitis) (non‐ADEM) encephalitis and/or fluid attenuated inversion recovery hyperintense lesions in anti‐myelin‐oligodendrocyte‐glycoprotein‐associated encephalitis with seizures (FLAMES) are rarely described in patients with myelin oligodendrocyte glycoprotein (MOG) antibodies (Abs). The aim was (i) to describe the clinical features and disease course of children and adults with non‐ADEM encephalitis and/or FLAMES associated with MOG Abs and (ii) to describe their association with other central nervous system autoantibodies.

Methods

This was a systematic review following the PRISMA guidelines. Patients fulfilled criteria for non‐ADEM encephalitis and/or FLAMES, and all were MOG Ab positive.

Results

In total, 83 (79%) patients with non‐ADEM encephalitis (48 also had FLAMES) and 22 (21%) with isolated FLAMES were included. At the first episode, children (n = 45) had more infections (11/45, 24.4%; p = 0.017) and more of the phenotype consisting of non‐ADEM encephalitis (42/45, 93.3%; p = 0.014) than adults (n = 38). Children had more episodes consistent with working memory deficits (25/54, 46.3%; p = 0.014) but fewer psychiatric symptoms (16/54, 29.6%; p = 0.002). Twenty‐eight (40.6%) of 69 patients had N‐methyl‐d‐aspartate receptor (NMDAR) Abs in cerebrospinal fluid (CSF), being more frequent in adults (19/29, 65.5%; p < 0.001). Compared to negatives, positive CSF NMDAR Abs had more relapses (14/20, 70%; p = 0.050), required ventilatory support more frequently (8/34, 23.5%; p = 0.009) and had more psychiatric episodes (28/34, 82%; p < 0.001) or abnormal movements (14/34, 41.2%; p = 0.008). Apart from an older age in FLAMES, positive and negative CSF NMDAR Ab groups shared similar features.

Conclusion

Non‐ADEM encephalitis patients with MOG Abs show specific clinical and radiological features, depending on the age at first episode. The presence of MOG Abs in non‐ADEM encephalitis patients should not rule out to test other autoantibodies, especially concomitant NMDAR Abs in patients with suggestive symptoms such as behavioural or movement alterations.
Temporal trends and outcomes in acute ischaemic stroke patients with a current or historical diagnosis of cancer
Authors: Peng Chi , Yang Fan , Peng Liwei , Zhang Chenxu , Lin Zhen , Chen Chenxin , Gao Huachen , He Jia , Jin Zhichao
Published: January 2023

Background and purpose

The aim was to evaluate the temporal trends, characteristics and in‐hospital outcomes of patients hospitalized with acute ischaemic stroke (AIS) between those with and without current or historical malignancies.

Methods

Adult hospitalizations with a primary diagnosis of AIS were identified from the National Inpatient Sample database 2007–2017. Logistic regression was used to compare the differences in the utilization of AIS interventions and in‐hospital outcomes. For further analysis, subgroup analyses were performed stratified by cancer subtypes.

Results

There were 892,862 hospitalizations due to AIS, of which 108,357 (12.14%) had a concurrent diagnosis of current cancer (3.41%) or historical cancer (8.72%). After adjustment for confounders, patients with current malignancy were more likely to have worse clinical outcomes. The presence of historical cancers was not associated with an increase in poor clinical outcomes. Additionally, AIS patients with current malignancy were less likely to receive intravenous thrombolysis (adjusted odds ratio 0.66, 95% confidence interval 0.63–0.71). Amongst the subgroups of AIS patients treated with intravenous thrombolysis or mechanical thrombectomy, outcomes varied by cancer types. Notably, despite these acute stroke interventions, outcome remains poor in AIS patients with lung cancer.

Conclusions

Although AIS patients with malignancy generally have worse in‐hospital outcomes versus those without, there were considerable variations in these outcomes according to different cancer types and the use of AIS interventions. Finally, treatment of these AIS patients with a current or historical cancer diagnosis should be individualized.
Successful pharmacological intervention at different levels of the complement system in an in vitro complement fixation model for bullous pemphigoid
Authors: Giang Jenny , van Doorn Martijn B. A. , Diercks Gilles F. H. , de Cordoba Santiago Rodriguez , van den Bosch Thierry P. P. , Schreurs Marco W. J. , Poppelaars Felix , Damman Jeffrey
Published: January 2023

Bullous pemphigoid (BP) is characterized by deposition of immunoglobulins and complement along the epidermal basement membrane (BM). In humans, there is a lack of functional studies targeting the complement system (CS). This study investigates activation of all complement pathways in BP skin biopsies. Moreover, pharmacological inhibition at different levels of the CS was investigated using anti‐complement compounds in a complement fixation BP assay. In this retrospective study, 21 frozen biopsies from BP patients were stained by direct immunofluorescence for C1q, MBL, ficolin‐2, C4d, properdin, C3c and C5b‐9. Sera from 10 patients were analysed in a complement fixation assay in the presence of C1 inhibitor, anti‐factor B monoclonal antibody (mAb), anti‐C3 mAb and anti‐C5 mAb and compared with dexamethasone. The two readouts were the quantity of complement deposited along the BM and the release of sC5b‐9 in the supernatant. Our results show classical and alternative complement pathway activation in BP skin biopsies, but could not demonstrate significant lectin pathway activation. In contrast to dexamethasone, complement deposition along the BM could be selectively inhibited by anti‐C1 and anti‐ factor B. More downstream, selective intervention at the level of C3 and C5 could effectively reduce complement deposition along the BM and the release of sC5b‐9 in the supernatant. This study shows that selective intervention in either the classical, alternative or terminal pathway prevented deposition of complement along the BM in an in vitro BP model. The results of our study greatly encourage the clinical development of complement inhibitors for the treatment of BP.
Biomodelling and 3D technologies: A novel technique for subungual glomus tumor evaluation
Authors: Canella Clarissa , Nakamura Robertha , de Almeida Carolina Ávila , Werner Heron
Published: January 2023

Subungual glomus tumors often remain undiagnosed for several years with patients seeing an average of 2.5 dermatologists before the diagnosis is confirmed. We describe the use of biomodelling and 3D technologies that allows the detection of tumoral recurrences more easily, as well as providing supplementary information for the radiologist report, such as select anatomical structure analysis, images with 360° rotation and visualization in transparency mode for detailed anatomic analysis.
PKM2 controls the translation of TFE3 to maintain the integrity of the Golgi apparatus for the survival of HeLa and ME‐180 cervical cancer cells
Authors: Taguchi Yuki , Ito Kengo , Kano Fumi
Published: January 2023

The M2 isoform of pyruvate kinase (PKM2) is abundantly expressed in various cancer cells and associated with tumorigenesis, tumour proliferation and tumour progression. However, the role of PKM2 in these oncological processes is not fully understood. In the present study, we depleted PKM2 expression using RNA interference (RNAi), which induced apoptotic cell death and was accompanied by the downregulation of GM130, giantin, and p115 in HeLa and ME‐180 cervical cancer cells. The decreased expression of these proteins caused structural and functional disturbances in the Golgi apparatus, which manifested as the dispersion of the Golgi apparatus and delayed anterograde trafficking from the ER to the Golgi. The transcription factor, TFE3, which functions in the Golgi stress response, was responsible for the expression of GM130, giantin, and p115 that maintained the integrity of the organelle under normal growth conditions. In PKM2‐knockdown cells, the translation of TFE3 was markedly reduced. Knockdown of TFE3 by RNAi resulted in the downregulation of GM130, giantin, and p115, dispersion of the Golgi apparatus, and apoptotic cell death, similar to those observed following PKM2 knockdown. Conversely, the exogenous expression of TFE3 in PKM2 knockdown cells partially mitigated the aforementioned effects. We also demonstrated that PKM2 bound to the 5′ UTR on TFE3 mRNA and promoted translation. This study is the first to identify a new function for PKM2, which activates the basal Golgi stress response to maintain the integrity of the Golgi apparatus through the translation of TFE3 and promote cancer cell survival.
Comparative transcriptomic and metabolomic study reveal that exogenous 24‐epiandrosterone mitigate alkaline stress in broomcorn millet (Panicum miliaceum L.) via regulating photosynthesis and antioxidant capacity
Authors: Ma Qian , Wu Enguo , Wang Honglu , Feng Yu , Zhao Lin , Feng Baili
Published: January 2023

Globally, land alkalinization affecting agricultural development. Considering the increasingly serious effects of alkaline stress on agriculture and environment, phytoremediation may be an efficient way to addressed land alkalinization. Broomcorn millet (Panicum miliaceum L.) is a saline‐alkaline‐tolerant crop and bioenergy crop. However, the molecular mechanism of alkaline response on broomcorn millet remains large gap. To explore the alkaline stress on broomcorn millet and the mitigation of 24‐epicastasterone (BR), the effects of CK (nutrient solution only), CB (nutrient solution + 0.5 mg L−1 BR), AS (alkaline stress), and AB (alkaline stress + 0.5 mg L−1 BR) on TA289 (alkaline‐tolerant) and SA223 (alkaline‐sensitive) were investigated. Alkaline stress enhanced reactive oxygen species and membrane lipid peroxidation. BR boosted antioxidant enzyme activities to reduce oxidative stress. Simultaneously, BR attenuated Na+ toxicity and maintained ion homeostasis. Additionally, BR significantly maintained the physiological structure and photosynthetic properties. Transcriptomic and metabolomic analyses were applied to further evaluate the effect of BR on photosynthetic and antioxidant defense. The results showed that BR significantly reduced the transcriptional responses of photosynthesis and antioxidant defense and promoted the accumulation of effective metabolites such as biliverdin, l‐glutamate, and phosphoric acid. Taken together, BR application can significantly alleviate the damage of alkaline stress to broomcorn millet by altering transcriptional expression and metabolite accumulation and is a simple and effective strategy to alleviate alkaline stress. This study reveals the molecular mechanism of BR to enhance photosynthetic capacity and antioxidant defense of broomcorn millet under alkaline stress, which provides theoretical support for the cultivation of bioenergy crops on alkaline lands and the breeding of alkaline‐tolerant bioenergy varieties.
Ultrafiltration‐induced decrease in relative blood volume is larger in hemodialysis patients with low specific blood volume: Results from a dialysate bolus administration study
Authors: Schmiedecker Michael , Krenn Simon , Waller Maximilian , Paschen Christopher , Mussnig Sebastian , Niknam Janosch , Wabel Peter , Mayer Christopher C. , Hecking Manfred , Schneditz Daniel
Published: January 2023

Introduction

Prescribing the ultrafiltration in hemodialysis patients remains challenging and might benefit from the information on absolute blood volume, estimated by intradialytic dialysate bolus administration. Here, we aimed at determining the relationship between absolute blood volume, normalized for body mass (specific blood volume, Vs), and ultrafiltration‐induced decrease in relative blood volume (∆RBV) as well as clinical parameters including body mass index (BMI).

Methods

This retrospective analysis comprised 77 patients who had their dialysate bolus‐based absolute blood volume extracted routinely with an automated method. Patient‐specific characteristics and ∆RBV were analyzed as a function of Vs, dichotomizing the data above or below a previously proposed threshold of 65 ml/kg for Vs. Statistical methodology comprised descriptive analyses, two‐group comparisons, and correlation analyses.

Findings

Median Vs was 68.6 ml/kg (54.9 ml/kg [Quartile 1], 83.4 ml/kg [Quartile 3]). Relative blood volume decreased by 6.3% (2.6%, 12.2%) over the entire hemodialysis session. Vs correlated inversely with BMI (rs = −0.688, p < 0.001). ∆RBV was 9.8% in the group of patients with Vs <65 ml/kg versus 6.0% in the group of patients with Vs ≥65 ml/kg (p = 0.024). The two groups did not differ significantly regarding their specific ultrafiltration volume, normalized for body mass, which amounted to 34.1 ml/kg and 36.0 ml/kg in both groups, respectively (p = 0.630). ∆RBV correlated inversely with Vs (rs = −0.299, p = 0.008).

Discussion

The present study suggests that patients with higher BMI and lower Vs experience larger blood volume changes, despite similar ultrafiltration requirements. These results underline the clinical plausibility and importance of dialysate bolus‐based absolute blood volume determination in the assessment of target weight, especially in view of a previous study where intradialytic morbid events could be decreased when the target weight was adjusted, based on Vs.
Perceived severity of Visual Snow Syndrome is associated with visual allodynia
Authors: Thompson Amy Claire , Goodbourn Patrick T. , Forte Jason D.
Published: January 2023

Objective

To investigate whether sensory sensitivity is associated with the perceived severity of Visual Snow Syndrome (VSS) symptoms.

Background

Visual Snow (VS) is a perceptual anomaly which manifests as flashing pinpricks of light throughout the visual field. VSS has an estimated population prevalence of 2.2% and is thought to be at least moderately debilitating for all who experience it. However, some people who meet the criteria for VSS have no awareness of it. This may be because they have lower sensory sensitivity, allowing them to ignore their visual phenomena.

Method

Our study used a cross‐sectional design. We recruited two distinct samples of people with VSS: a sample of people with confirmed VSS; and a sample of people who met the criteria for the condition but had no prior knowledge of it (latent VSS). The latter group was recruited and screened for symptoms via an online crowd‐sourcing platform. In total, 100 participants with VSS (49 with confirmed VSS, 51 with latent VSS) completed the Visual Snow Handicap Index and three measures of sensory hypersensitivity.

Results

The 100 participants (52 female, 47 male, 1 non‐binary) had a mean age of 35.1 years (SD = 12.2). Leiden Visual Sensitivity Scale scores were associated with both the perceived severity of VSS, β = 0.35, p = 0.003, and the number of VSS symptoms endorsed, β = 0.45, p < 0.001. On average, participants with VSS experienced elevated sensory hypersensitivity across all measures. Furthermore, longer duration of VSS was associated with lower perceived severity, F(1, 98) = 11.37, p = 0.001, R2 = 0.103.

Conclusions

Our results suggest that sensory hypersensitivity may be prevalent in people with VSS and indicate that visual allodynia is associated with increased severity of VSS. Additionally, our findings indicate that inclusion of cases of latent VSS in future research may be important for researchers to develop a more complete understanding of the perceptual experiences of people with VSS.
Visual temporal discrimination is impaired in patients with migraine without aura
Authors: Başarı Ahmet , Boran Hürrem Evren , Vuralli Doga , Cengiz Bülent , Bolay Hayrunnisa
Published: January 2023

Background and Objective

Dysfunctional sensory processing is described in migraine. This study aimed to evaluate visual perception in patients with migraine without aura using the visual temporal discrimination (VTD) test.

Methods

A total of 45 participants were enrolled in this prospective exploratory study. In all, 15 patients had migraine without aura and 15 healthy volunteers were analyzed in the study. The VTD threshold (VTDT) was measured using light‐emitting diode lights to perceive two separate visual stimuli as clearly distinct. VTD was tested during the attack and the interictal period. The disease duration, attack side, visual analog scale for pain, accompanying symptoms, and allodynia were recorded during the attack.

Results

The VTDT of each visual field in both attack (mean [SD] 102.3 [38.4] ms for the right visual field and 106.3 [52.2] ms for the left) and the interictal periods (mean [SD] 75.2 [27.9] ms for the right and 78.2 [27.9] ms for the left) were significantly higher than in the control group (mean [SD] 45.3 [9.9] ms for the right and 48.2 [11.9] ms for the left) (p < 0.001, p < 0.001, p = 0.003, p < 0.001, respectively). The ipsilateral threshold during the attack was significantly prolonged compared to the interictal period (mean [SD] 143.8 [53.8] vs. 78 [19.6] ms, p = 0.025) and the contralateral threshold during the attack (mean [SD] 143.8 [53.8] vs. 71.9 [14.1] ms, p = 0.025). The ipsilateral threshold was significantly correlated with the visual analog score (r = 0.894, p < 0.001) and frequency of the attacks (r = 0.696, p = 0.004), but not correlated with photophobia.

Conclusion

The VTDTs are prolonged both ictally and interictally in patients with migraine without aura attacks. Ipsilateral threshold prolongation is more pronounced during lateralized migraine attacks. The results suggest dysfunctional visual perception is not limited to the migraine attack period, and a defective sensory processing/modulation in the visual pathways may involve the superior colliculus.