bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of viral variant and vaccination status with the occurrence of symptoms compatible with post-acute sequelae after primary SARS-CoV-2 infection
Authors: Kahlert Christian R. , Strahm Carol , Güsewell Sabine , Cusini Alexia , Brucher Angela , Goppel Stephan , Möller J. Carsten , Ortner Manuela , Ruetti Markus , Stocker Reto , Vuichard-Gysin Danielle , Besold Ulrike , McGeer Allison , Risch Lorenz , Friedl Andrée , Schlegel Matthias , Vernazza Pietro , Kuster Stefan P. , Kohler Philipp ,   SURPRISE Study Group
Published: October 2022

ABSTRACTImportanceDisentangling the effects of different SARS-CoV-2 variants and of vaccination on the occurrence of post-acute sequelae of SARS-CoV-2 (PASC) is crucial to estimate and potentially reduce the future burden of PASC.ObjectiveTo determine the association of primary SARS-CoV-2 infection on the frequency of PASC symptoms by viral variant and vaccination status.DesignCross-sectional questionnaire and SARS-CoV-2 serology (May/June 2022) performed within a prospective healthcare worker cohort (SURPRISE study).SettingMulticenter study in nine healthcare networks from North-Eastern Switzerland.ParticipantsVolunteer sample of healthcare workers (HCW) from participating institutions. Of approximately 20’000 eligible participants, 3’870 registered for the cohort and 2’912 were included in this analysis.ExposuresSARS-CoV-2 infection documented by positive nasopharyngeal swab (>4 weeks ago), stratified by viral variant and vaccination status at time of infection, compared to absence of documented infection (no positive swab, negative serology).Main OutcomeSum score of eighteen self-reported PASC symptoms.ResultsAmong 2’912 participants (median age 44 years, 81.3% female), SARS-CoV-2 infection was reported by 1’685 (55.9%) participants, thereof 315 (18.7%) during Wild-type, 288 (17.1%) during Alpha/Delta, and 1’082 (64.2%) during Omicron circulation. Mean symptom number in previously infected participants significantly exceeded that of uninfected controls (0.39), but decreased with recency of the viral variant: 1.12 (p<0.001) for Wild-type (median time since infection 18.5 months), 0.67 (p<0.001) for Alpha/Delta (6.6 months), and 0.52 (p=0.005) for Omicron BA.1 (3.1 months) infected participants. After Omicron BA.1 infection, the mean symptom score was 0.49 (p=0.30) for those with ≥3 prior vaccinations and 0.71 (p=0.028) with 1-2 previous vaccinations compared to 0.36 for unvaccinated individuals. Adjusting for confounders, Wild-type (adjusted risk ratio [aRR] 2.81, 95% confidence interval [CI] 2.08-3.83) and Alpha/Delta infection (aRR 1.93, 95% CI 1.10-3.46) showed significant associations with the outcome, whereas Omicron BA.1 infection (aRR 1.29, 95% CI 0.69–2.43) and vaccination before infection (aRR 1.27, 95% CI 0.82–1.94) did not.Conclusions and RelevancePrevious infection with pre-Omicron variants was the strongest risk factor for reporting PASC symptoms in this HCW cohort. A definite influence of prior vaccination on the prevention of PASC after Omicron BA.1 infection was not measurable.
Systematic development and feasibility testing of a multibehavioural digital prehabilitation intervention for patients approaching major surgery (iPREPWELL): A study protocol
Authors: Durrand J , Livingston R , Tew G , Gillis C , Yates D , Gray J , Greaves CJ , Moore J , O’Doherty A F , Doherty P , Danjoux G , Avery L 
Published: October 2022

AbstractImproving outcomes for people undergoing major surgery, specifically reducing perioperative morbidity and mortality remains a global health challenge. Prehabilitation involves the active preparation of patients prior to surgery, including support to tackle risk behaviours that mediate and undermine physical and mental health and wellbeing. The majority of prehabilitation interventions are delivered in person, however many patients express a preference for remotely-delivered interventions that provide them with tailored support and the flexibility. Digital prehabilitation interventions offer scalability and have the potential to benefit perioperative healthcare systems, however there is a lack of robustly developed and evaluated digital programmes for use in routine clinical care. We aim to systematically develop and test the feasibility of an evidence and theory-informed multibehavioural digital prehabilitation intervention ‘iPREPWELL’ designed to prepare patients for major surgery. The intervention will be developed with reference to the Behaviour Change Wheel, COM-B model, and the Theoretical Domains Framework. Codesign methodology will be used to develop a patient intervention and accompanying training intervention for healthcare professionals. Training will be designed to enable healthcare professionals to promote, support and facilitate delivery of the intervention as part of routine clinical care. Patients preparing for major surgery and healthcare professionals involved with their clinical care from two UK National Health Service centres will be recruited to stage 1 (systematic development) and stage 2 (feasibility testing of the intervention). Participants recruited at stage 1 will be asked to complete a COM-B questionnaire and to take part in a qualitative interview study and co-design workshops. Participants recruited at stage 2 (up to twenty healthcare professionals and forty participants) will be asked to take part in a single group intervention study where the primary outcomes will include feasibility, acceptability, and fidelity of intervention delivery, receipt, and enactment. Healthcare professionals will be trained to promote and support use of the intervention by patients, and the training intervention will be evaluated qualitatively and quantitatively. The multifaceted and systematically developed intervention will be the first of its kind and will provide a foundation for further refinement prior to formal efficacy testing.
The genetic and phenotypic correlates of mtDNA copy number in a multi-ancestry cohort
Authors: Zaidi Arslan A. , Verma Anurag , Morse Colleen ,   Penn Medicine BioBank, Ritchie Marylyn D. , Mathieson Iain 
Published: October 2022

AbstractMitochondrial DNA copy number (mtCN) is often treated as a proxy for mitochondrial (dys)function and disease risk. Pathological changes in mtCN are common symptoms of rare mitochondrial disorders but reported associations between mtCN and common diseases vary considerably across studies. We sought to understand the biology of mtCN by carrying out genome and phenome-wide association studies of mtCN in 30,666 individuals from the Penn Medicine BioBank—a large, diverse cohort of largely African and European ancestry. We estimated mtCN in peripheral blood using exome sequence data, taking into account the effects of blood cell composition, particularly neutrophil and platelet counts. We replicated known genetic associations of mtCN in the PMBB and found that their effect sizes are highly correlated between individuals of European and African ancestry. However, the heritability of mtCN was much higher among individuals of largely African ancestry (h2= 0.3) compared to European ancestry individuals (h2= 0.1). Admixture mapping suggests that there are undiscovered variants underlying mtCN that are differentiated in frequency between individuals with African and European ancestry. We further show that mtCN is associated with many health-related phenotypes. We discovered robust associations between mtDNA copy number and diseases of metabolically active tissues, such as cardiovascular disease and liver damage that were consistent across African and European ancestry individuals. Other associations, such as epilepsy, prostate cancer, and disorders of iron metabolism were only discovered in either individuals with European or African ancestry, but not both. Even though we replicate known genetic and phenotypic associations of mtCN, we demonstrate that they are sensitive to blood cell composition and environmental modifiers, explaining why such associations are inconsistent across studies. Peripheral blood mtCN might therefore be used as a biomarker of mitochondrial dysfunction and disease risk, but such associations must be interpreted with care.
Characterizing the molecular impact ofKMT2Dvariants on the epigenetic and transcriptional landscapes in Kabuki Syndrome
Authors: Jung Youngsook L , Hung Christina , Choi Jaejoon , Lee Eunjung A , Bodamer Olaf 
Published: October 2022

SUMMARYKabuki Syndrome (KS) is a rare, multisystem disorder with a variable clinical phenotype. The majority of KS is caused by dominant loss-of-function mutations inKMT2D(lysine methyltransferase 2D). KMT2D mediates chromatin accessibility by adding methyl groups to lysine residue 4 of histone 3, which plays a critical role in cell differentiation and homeostasis. The molecular underpinnings of KS remain elusive partly due to a lack of histone modification data from human samples. Consequently, we profiled and characterized alterations in histone modification and gene transcription in peripheral blood mononuclear cells (PBMCs) from 33 patients withKMT2Dmutations and 36 unaffected healthy controls. Our analysis identified unique enhancer signatures in H3K4me1 and H3K4me2 in KS compared to controls. Reduced enhancer signals were present for promoter-distal sites of immune-related genes for which co-binding of PBMC-specific transcription factors was predicted; thirty-one percent of super-enhancers of normal blood cells overlapped with disrupted enhancers in KS, supporting an association of reduced enhancer activity of immune-related genes with immune deficiency phenotypes. In contrast, increased enhancer signals were observed for promoter-proximal regions of metabolic genes enriched withEGR1andE2F2motifs, whose transcriptional levels were significantly increased in KS. Additionally, we identified approximately 100 de novo enhancers in genes, such as inMYO1FandAGAP2. Together, our results underscore the effect of KMT2D haploinsufficiency on (dys)regulation of enhancer states and gene transcription and provide a framework for the identification of therapeutic targets and biomarkers in preparation for clinical trial readiness.
Interventions to support parents, families and caregivers in caring for preterm or low birth weight infants at home: a systematic review
Authors: Bedwell C , Actis Danna V , Tate N , Dwan K , Portela A , Lavender T 
Published: October 2022

AbstractBackgroundPreterm and low birth weight (LBW) (<2500g) infants are at greater risk of mortality and morbidity. Interventions to support parents to care for their newborn infant in the home may help to improve outcomes.ObjectiveTo determine what interventions, approaches, or strategies to support mothers/fathers/caregivers and families in caring for preterm or LBW infants in the home have been effective in improving outcomes.MethodsA comprehensive search of relevant electronic databases, including MEDLINE, Embase, CINAHL and Cochrane Central Register of Controlled Trials was completed in September 22. Two reviewers screened papers in Covidence and extracted data from 41 included papers. Quality of papers and certainty of evidence were assessed using CASP and GRADE, respectively.ResultsThere is some evidence that support interventions may improve outcomes related to infant mortality, improvements in infant growth, exclusive breastfeeding, infant cognitive development, immunisation uptake, and reduction in maternal stress and depression. However, the overall certainty of evidence is low or very low in the majority of studies.ConclusionsInterventions providing support for parents to care for infants in the home may improve outcomes for this population. There is a need for well-considered large scale support interventions, prioritised and developed with women and families.
Graph-based Fusion Modeling and Explanation for Disease Trajectory Prediction
Authors: Tariq Amara , Tang Siyi , Sakhi Hifza , Celi Leo Anthony , Newsome Janice M. , Rubin Daniel L. , Trivedi Hari , Gichoy Judy Wawira , Patel Bhavik , Banerjee Imon 
Published: October 2022

AbstractWe propose a relational graph to incorporate clinical similarity between patients while building personalized clinical event predictors with a focus on hospitalized COVID-19 patients. Our graph formation process fuses heterogeneous data, i.e., chest X-rays as node features and non-imaging EHR for edge formation. While node represents a snap-shot in time for a single patient, weighted edge structure encodes complex clinical patterns among patients. While age and gender have been used in the past for patient graph formation, our method incorporates complex clinical history while avoiding manual feature selection. The model learns from the patient’s own data as well as patterns among clinically-similar patients. Our visualization study investigates the effects of ‘neighborhood’ of a node on its predictiveness and showcases the model’s tendency to focus on edge-connected patients with highly suggestive clinical features common with the node. The proposed model generalizes well by allowing edge formation process to adapt to an external cohort.
Increased Hindbrain Motion in Chiari Malformation I Patients Measured Through 3D Amplified MRI (3D aMRI)
Authors: Abderezaei Javid , Pionteck Aymeric , Chuang Ya-Chen , Carrasquilla Alejandro , Bilgili Gizem , Lu Tse An , Terem Itamar , Scadeng Miriam , Fillingham Patrick , Morgenstern Peter , Levitt Michael , Ellenbogen Richard G. , Yang Yang , Holdsworth Samantha J. , Shrivastava Raj , Kurt Mehmet 
Published: October 2022

AbstractChiari Malformation type 1 (CM-I) is a neurological disorder characterized by morphological defects such as excessive cerebral tonsils herniation and vast associated symptomatology. Given that these structural defects cannot explain the underlying symptomatology, and might result in misdiagnosis, in this work, we studied the brain’s intrinsic motion to better understand the mechanisms of CM-I. We acquired 3D cine MRI of 14 healthy and 14 CM-I subjects and used 3D amplified MRI (3D aMRI) to visualize and measure the brain’s intrinsic motion during the cardiac cycle. We observed that the regional brain motion in CM-I was significantly higher than the healthy subjects, with anterior-posterior (AP) and superior-inferior (SI) displacements in cerebral tonsils and medulla having the highest differences between the healthy and CM-I (∽45% ∽73% increased motion in the CM-I group). The motion of the cerebellum, and brainstem in AP directions (∽42% and ∽31% increased motion in the CM-I group, respectively), followed by the motion of the cerebral tonsils and medulla in medial-lateral (ML) directions were other significant differences found between the two groups (∽16% increased motion in the CM-I group). Additionally, for the CM-I subjects, we measured morphological parameters including the tonsil herniation, ratio of neural tissue in the foramen magnum, and 4thventricle volume. We then used the morphometrics and brain’s intrinsic motion to analyze the symptomatology of the CM-I patients and their surgical outcomes. Interestingly, we found the ratio of neural tissue in the foramen to be directly correlated with the SI motion of the tonsils (r= 0.58). We also found the tonsil herniation to be directly correlated with the AP motion of the tonsils (r= 0.61), and AP and ML motions of the medulla (r= 0.66, andr= 0.57). Additionally, we found the ML motion of the tonsils to be the only indicator of the surgical outcome (AUC= 0.95), in which subjects with higher motion had an improved outcome. Although we did not observe a significant correlation between the brains motion and morphometrics on the CM-I symptoms due to our small sample size, illustrative cases increase our hope for the development of a future tool based on the brain biomechanics.
License to cut: Smart RNA guides for conditional control of CRISPR-Cas9
Authors: Baccouche Alexandre , Adel Arman , Yachie Nozomu , Fujii Teruo , Genot Anthony J. 
Published: October 2022

AbstractThe Cas9 enzyme is a programmable endonuclease, whose target sequence is directed by a companion RNA guide. Cas9 and RNA guides have revolutionized biology, enabling facile editing of the genome in almost all organisms. Controlling where and when Cas9 and the guide operate is indispensable for many fields ranging from developmental biology to therapeutics, but it remains a challenge. Most methods focus on controlling Cas9 with physico-chemical means (which lack finesse, precision or multiplexing), or transcriptional tools (which are slow and difficult to design). Rather than directly engineering Cas9, engineering the RNA guide itself has emerged as a more general and potent way to manage the activity of Cas9. Here we report smart RNA guides that are conditionally activated by the presence of a specific RNA opener. Contrary to most previous approaches, the design affords ample freedom as spacer and the opener are independent. We demonstrate this flexibility by operating SmartGuides activated by a panel of miRNA relevant for human health, and by composing SmartGuides in Boolean logic circuits. Lastly, we test the SmartGuides in mammalian cells - validating the basics tenets of the design, but also highlighting the challenges that remain to be lifted for in-vivo operation.
Cauliflower mosaic virusprotein P6 forms a microenvironment for RNA granule proteins and interferes with stress granule responses
Authors: Hoffmann Gesa , Lopéz-Gonzaléz Silvia , Mahboubi Amir , Hanson Johannes , Hafrén Anders 
Published: October 2022

AbstractBiomolecular condensation is a multipurpose cellular process that viruses use ubiquitously in their multiplication. CaMV replication complexes are condensates that differ from most viruses in being non-membranous assemblies and consist of RNA and protein, mainly viral protein P6. Despite description of these viral factories already half a century ago with many observations that followed since, functional details of the condensation process, their properties and relevance has remained enigmatic. Our main findings include a large dynamic mobility range of host proteins within viral factories, while the viral matrix protein P6 is immobile in accordance with representing the central node of these condensates. As novel components of VFs we identify stress granule (SG) nucleating factors G3BP7 and the UBP1 family. Similarly, as SG components localize in VFs during infection, ectopic P6 localizes to SGs and reduces their assembly after stress. Intriguingly, it appears that soluble rather than condensed P6 suppresses SGs and mediates also other essential P6 functions, suggesting that the increased condensation over the infection time-course may accompany a progressive shift in selected P6 functions. Together, this study highlights VFs as dynamic condensates and P6 as a complex modulator of SG responses.
Prefrontal control of actions in freely moving macaques
Authors: Voloh Benjamin , Maisson David , Cervera Roberto Lopez , Conover Indirah , Zambre Mrunal , Hayden Benjamin , Zimmermann Jan 
Published: October 2022

ABSTRACTOur natural behavioral repertoires include complex coordinated actions of characteristic types. To better understand the organization of action and its neural underpinnings, we examined behavior and neural activity in rhesus macaques performing a freely moving foraging task in an open environment. We developed a novel analysis pipeline that can identify meaningful units of behavior, corresponding to recognizable actions such as sitting, walking, jumping, and climbing. On the basis of action transition probabilities, we found that behavior was organized in a modular and hierarchical fashion. We found that, after regressing out many potential confounders, actions are associated with specific patterns of firing in each of six prefrontal brain regions and that, overall, representation of actions is progressively stronger in more dorsal and more caudal prefrontal regions. Conversely, we found that switching between actions resulted in changed firing rates, with more rostral and more ventral regions showing stronger effects. Together, these results establish a link between control of action state and neuronal activity in prefrontal regions in the primate brain.
Antibody-lectin chimeras for glyco-immune checkpoint blockade
Authors: Stark Jessica C. , Gray Melissa A. , Wisnovsky Simon , Ibarlucea-Benitez Itziar , Lustig Marta , Riley Nicholas M. , Ribi Mikaela K. , Errington Wesley J. , Bruncsics Bence , Sarkar Casim A. , Valerius Thomas , Ravetch Jeffrey V. , Bertozzi Carolyn R. 
Published: October 2022

AbstractDespite the curative potential of checkpoint blockade immunotherapy, most patients remain unresponsive to existing treatments. Glyco-immune checkpoints – interactions of cell-surface glycans with lectin, or glycan-binding, immunoreceptors – have emerged as prominent mechanisms of immune evasion and therapeutic resistance in cancer. Here, we describe antibody-lectin chimeras (AbLecs), a modular platform for glyco-immune checkpoint blockade. AbLecs are bispecific antibody-like molecules comprising a cell-targeting antibody domain and a lectin “decoy receptor” domain that directly binds glycans and blocks their ability to engage inhibitory lectin receptors. AbLecs potentiate anticancer immune responses including phagocytosis and cytotoxicity, outperforming most existing therapies and combinations tested. By targeting a distinct axis of immunological regulation, AbLecs synergize with blockade of established immune checkpoints. AbLecs can be readily designed to target numerous tumor and immune cell subsets as well as glyco-immune checkpoints, and therefore represent a new modality for cancer immunotherapy.
CRF receptor type 1 modulates the nigrostriatal dopamine projection and facilitates cognitive flexibility after acute and chronic stress
Authors: Becchi S , Burton CL , Tsoukalas M , Bowring J , Balleine BW , Mor D 
Published: October 2022

AbstractChronic unpredictable stress (CUS) impairs cognitive flexibility in rats, particularly when faced with additional mild acute stress (AS). We tested the hypothesis that this impairment is associated with alterations in dopamine activity in the dorsal striatum driven by corticotropin-releasing-factor receptor type 1 (CRFR1) in the substantia nigra pars compacta (SNpc). In experiment 1, rats received CUS or handling for 14 days, before learning two action-outcome associations (lever presses and food rewards). Learning was assessed using outcome devaluation. Cognitive flexibility was then assessed by reversing the outcome identities followed by a second outcome devaluation test, with half of the rats in each group receiving AS prior to reversal training. Dopamine and its metabolite were quantified in the dorsal striatum and CRFR1 mRNA was quantified in the SNpc. Increased dopaminergic activity in the left dorsal striatum and CRFR1 expression in the left SNpc were associated with resilience to AS in naïve rats but with impairment in CUS+AS rats, suggesting a transition in hemispheric control from left to right as a protective mechanism following CUS. This suggestion was tested in experiment 2, where SNpc CRFR1 was blocked unilaterally prior to AS and reversal training. Blocking CRFR1 in the left medial SNpc impaired cognitive flexibility following AS in naïve rats but restored it in CUS rats. Blocking CRFR1 in the left, but not right, lateral SNpc also impaired cognitive flexibility following AS in naïve rats but had no effect in CUS rats.