bluuebunny/crossref_metadata_2025_split huggingface dataset:
Feasibility and safety of shortened hypofractionated high dose palliative lung radiotherapy – A retrospective planning study
Authors: Jones Matthew , Rogers Jane , Shrimali Raj Kumar , Hamilton Jo , Athmanathan Senthil , Jones Bleddyn 
Published: November 2021

AbstractObjectiveAssess the safety and feasibility of shortened hypo-fractionated high dose palliative lung radiotherapy in a retrospective planning study.MethodsFifteen palliative lung radiotherapy patients previously treated with the standard 36 Gy in 12 fractions (12F) schedule were non-randomly selected to achieve a representative distribution of tumour sizes, volumes, locations and staging. Plans were produced using 30 Gy in 5 fractions (5F) and 30 Gy in 6 fractions (6F) using a 6MV FFF co-planar VMAT technique. These plans were optimised to meet dose constraints for both PTVs and OARs where established OAR constraints were expressed as BED. The potential safety of the delivery of these plans was assessed using these BEDs and also with reductions of 10% and 20% to account for effects of chemotherapy or surgery.ResultsFor all 5F and 6F plans the mandatory constraints using the full BED were met, as with all 6F plans with 10% BED reductions, but reduced to 6 patients using 5F. Three of 15 5F and 6 of 15 6F plans met the 20% BED reductions.ConclusionIt is potentially safe and feasible to deliver high dose palliative radiotherapy using the 5F or 6F regimes described, when carefully planned to comparable OAR BEDs as for 12F standard. It appears that the toxicity from either of these regimes should be within acceptable limits provided that the dose constraints described can be adhered to. A Phase II study would be required to fully assess the safety and feasibility. The outcomes from such a study could potentially reduce the number of patient hospital visits for radiotherapy, thus benefiting the patient and the clinical service by optimising resource utilisation.Advances in KnowledgeShortened hypo-fractionated high dose palliative lung radiotherapy is technically feasible provided OAR constraints are respected.
Inactivated virus vaccine BBV152/Covaxin elicits robust cellular immune memory to SARS-CoV-2 and variants of concern
Authors: Vikkurthi Rajesh , Ansari Asgar , Pai Anupama R , Jha Someshwar Nath , Sachan Shilpa , Pandit Suvechchha , Nikam Bhushan , Kalia Anurag , Jit Bimal Prasad , Parray Hilal Ahmad , Singh Savita , Kshetrapal Pallavi , Wadhwa Nitya , Shrivastava Tripti , Coshic Poonam , Kumar Suresh , Sharma Pragya , Sharma Nandini , Taneja Juhi , Pandey Anil K , Sharma Ashok , Thiruvengadam Ramachandran , Grifoni Alba , Bhatnagar Shinjini , Weiskopf Daniela , Sette Alessandro , Garg Pramod Kumar , Gupta Nimesh 
Published: November 2021

AbstractThe characteristics of immune memory established in response to inactivated SARS-CoV-2 vaccines remains unclear. We determined the magnitude, quality and persistence of cellular and humoral memory responses up to 6 months after vaccination with BBV152/Covaxin. Here, we show that the quantity of vaccine-induced spike- and nucleoprotein-antibodies is comparable to that following natural infection and the antibodies are detectable up to 6 months. The RBD-specific antibodies decline in the range of 3 to 10-fold against the SARS-CoV-2 variants in the order of alpha (B.1.1.7) > delta (B.1.617.2) > beta (B.1.351), with no observed impact of gamma (P.1) and kappa (B.1.617.1) variant. We found that the vaccine induces memory B cells, similar to natural infection, which are impacted by virus variants in the same order as antibodies. The vaccine further induced antigen-specific functionally potent multi-cytokine expressing CD4+ T cells in ∼85% of the subjects, targeting spike and nucleoprotein of SARS-CoV-2. Marginal ∼1.3 fold-reduction was observed in vaccine-induced CD4+ T cells against the beta variant, with no significant impact of the alpha and the delta variants. The antigen-specific CD4+ T cells were populated in the central memory compartment and persisted up to 6 months of vaccination. Importantly the vaccine generated Tfh cells that are endowed with B cell help potential, similar to the Tfh cells induced after natural infection. Altogether, these findings establish that the inactivated virus vaccine BBV152 induces robust immune memory to SARS-CoV-2 and variants of concern, which persist for at least 6 months after vaccination. This study provides insight into the attributes of BBV152-elicited immune memory, and has implication for future vaccine development, guidance for use of inactivated virus vaccine, and booster immunization.
COVID-19 vaccination, risk-compensatory behaviours, and contacts in the UK
Authors: Buckell John , Jones Joel , Matthews Philippa C , Diamond Sir Ian , Rourke Emma , Studley Ruth , Cook Duncan , Walker A Sarah , Pouwels Koen B ,   the COVID-19 Infection Survey Team
Published: November 2021

AbstractThe physiological effects of vaccination against SARS-CoV-2 (COVID-19) are well documented, yet the behavioural effects are largely unknown. Risk compensation suggests that gains in personal safety, as a result of vaccination, are offset by increases in risky behaviour, such as socialising, commuting and working outside the home. This is potentially problematic because transmission of SARS-CoV-2 is driven by contacts, which could be amplified by vaccine-related risk compensation behaviours. Here, we show that behaviours were overall unrelated to personal vaccination, but - adjusting for variation in mitigation policies - were responsive to the level of vaccination in the wider population: individuals in the UK were risk compensating when rates of vaccination were rising. This effect was observed across four nations of the UK, each of which varied policies autonomously.
Gut-bladder axis syndrome associated with recurrent UTIs in humans
Authors: Worby Colin J. , Schreiber Henry L. , Straub Timothy J. , van Dijk Lucas R. , Bronson Ryan A. , Olson Benjamin , Pinkner Jerome S. , Obernuefemann Chloe L. P. , Muñoz Vanessa L. , Paharik Alexandra E. , Walker Bruce J. , Desjardins Christopher A. , Chou Wen-Chi , Bergeron Karla , Chapman Sinéad B. , Klim Aleksandra , Manson Abigail L. , Hannan Thomas J. , Hooton Thomas M. , Kau Andrew L. , Lai H. Henry , Dodson Karen W. , Hultgren Scott J. , Earl Ashlee M. 
Published: November 2021

AbstractRecurrent urinary tract infections (rUTIs) are a major health burden worldwide, with history of infection being a significant risk factor. While the gut is a known reservoir for uropathogenic bacteria, the role of the microbiota in rUTI remains unclear. We conducted a year-long study of women with and without history of rUTIs, from whom we collected urine, blood and monthly fecal samples for multi-omic interrogation. The rUTI gut microbiome was significantly depleted in microbial richness and butyrate-producing bacteria compared to controls, reminiscent of other inflammatory conditions, though Escherichia coli gut and bladder dynamics were comparable between cohorts. Blood samples revealed signals of differential systemic immunity, leading us to hypothesize that rUTI susceptibility is in part mediated through a syndrome involving the gut-bladder axis, comprising gut dysbiosis and differential immune response to bacterial bladder colonization, manifesting in symptoms. This work highlights the potential for microbiome therapeutics to prevent and treat rUTIs.
A neonatal ward strengthening program improves survival for neonates treated with CPAP at district hospitals in Malawi
Authors: Carns Jennifer , Liaghati-Mobarhan Sara , Asibon Aba , Ngwala Samuel , Molyneux Elizabeth , Oden Maria , Richards-Kortum Rebecca , Kawaza Kondwani , Chalira Alfred , Lufesi Norman 
Published: November 2021

AbstractIntroductionFrom 2013-2015, a CPAP quality improvement program (QIP) was implemented to introduce and monitor CPAP usage and outcomes in the neonatal wards at all government district and central hospitals in Malawi. In 2016 the CPAP QIP was extended into healthcare facilities operated by the Christian Health Association of Malawi. Although clinical outcomes improved, ward assessments indicated that many rural sites lacked other essential equipment and a suitable space to adequately treat sick neonates, which likely limited the impact of improved respiratory care. The aim of this study was to determine if a ward strengthening program improved outcomes for neonates treated with CPAP.MethodsTo address the needs identified from ward assessments, a ward strengthening program was implemented from 2017-2018 at rural hospitals in Malawi to improve the care of sick neonates. The ward strengthening program included the distribution of a bundle of equipment, supplemental training, and, in some cases, health facility renovations. Survival to discharge was compared for neonates treated with CPAP at 12 rural hospitals for one year before and for one year immediately after implementation of the ward strengthening program.ResultsIn the year prior to ward strengthening, 189 neonates were treated with CPAP; in the year after, 232 neonates received CPAP. The overall rate of survival for those treated with CPAP improved from 46.6% to 57.3% after ward strengthening (p=0.03). For the subset of neonates with admission weights between 1.00 – 2.49 kg diagnosed with respiratory distress syndrome, survival increased from 39.4% to 60.3% after ward strengthening (p=0.001).ConclusionA ward strengthening program including the distribution of a bundle of equipment, supplemental training, and some health facility renovations, further improved survival among neonates treated with CPAP at district-level hospitals in Malawi.
Resistome characterization of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli isolated from wastewater treatment utilities in Oregon
Authors: Easler Maeghan , Cheney Clinton , Johnson Jared D. , Zadeh Marjan Khorshidi , Nguyen Jacquelynn N. , Yiu Sue Yee , Waite-Cusic Joy , Radniecki Tyler S. , Navab-Daneshmand Tala 
Published: November 2021

ABSTRACTInfections resistant to broad spectrum antibiotics due to the emergence of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae is of global concern. This study characterizes the resistome (i.e., entire ecology of resistance determinants) of 11 ESBL-producing Escherichia coli isolates collected from eight wastewater treatment utilities across Oregon. Whole genome sequencing was performed to identify the most abundant antibiotic resistance genes including ESBL-associated genes, virulence factors, as well as their sequence types. Moreover, the phenotypes of antibiotic resistance were characterized. ESBL-associated genes (i.e., blaCMY, blaCTX, blaSHV, blaTEM) were found in all but one of the isolates with five isolates carrying two of these genes (4 with blaCTX and blaTEM; 1 with blaCMY and blaTEM). The ampC gene and virulence factors were present in all the E. coli isolates. Across all the isolates, 31 different antibiotic resistance genes were identified. Additionally, all E. coli isolates harbored phenotypic resistance to beta-lactams (penicillins and cephalosporins), while eight of the 11 isolates carried multi-drug resistance phenotypes (resistance to three or more classes of antibiotics). Findings highlight the risks associated with the presence of ESBL-producing E. coli isolates in wastewater systems that have the potential to enter the environment and may pose direct or indirect risks to human health.
Investigating the source of increased bipolar and major depressive disorder polygenic risk in multiplex schizophrenia families
Authors: Ahangari Mohammad , Kirkpatrick Robert , Nguyen Tan-Hoang , Gillespie Nathan ,   Irish Schizophrenia Genomics Consortium, Kendler Kenneth S. , Bacanu Silviu-Alin , Webb Bradley T. , Verrelli Brian C. , Riley Brien P. 
Published: November 2021

AbstractPsychotic and affective disorders often aggregate in the relatives of probands with schizophrenia (SCZ), and genetic studies show substantial genetic correlation among SCZ, bipolar disorder (BIP) and major depressive disorder (MDD). However, the nature of this genetic overlap in polygenic risk score (PRS) analyses of multiplex families has not been fully dissected. In the current study, we investigated the polygenic risk burden of BIP and MDD in a sample of 257 multiplex SCZ families (N=1,005) and population controls (N=2,205). Furthermore, due to the strong genetic correlation among SCZ, BIP, and MDD, we examined whether increased BIP or MDD PRS in members of multiplex SCZ families can be attributed to latent genetic factors unique to BIP or MDD, or latent genetic factors that each of these two disorders share with SCZ. Our results indicate that members of multiplex SCZ families have an increased PRS for BIP and MDD, however, this observation is largely attributable to latent genetic factors that BIP or MDD share with SCZ, rather than latent genetic factors unique to them. These results provide new insight for cross-disorder PRS analyses of psychiatric disorders, by cautioning that for complete interpretation of observed cross-disorder PRS enrichment, we should account for genetic correlations across psychiatric disorders. Our findings further indicates that members of multiplex SCZ families may have an increased genetic vulnerability to both psychotic and affective disorders, and for full assessment of an individual’s genetic risk, familial backgrounds should be taken into consideration.
Automated Detection of Cerebral Microbleeds on MR images using Knowledge Distillation Framework
Authors: Sundaresan Vaanathi , Arthofer Christoph , Zamboni Giovanna , Murchison Andrew G. , Dineen Robert A. , Rothwell Peter M. , Auer Dorothee P. , Wang Chaoyue , Miller Karla L. , Tendler Benjamin C. , Alfaro-Almagro Fidel , Sotiropoulos Stamatios N. , Sprigg Nikola , Griffanti Ludovica , Jenkinson Mark 
Published: November 2021

AbstractCerebral microbleeds (CMBs) are associated with white matter damage, various neu-rodegenerative and cerebrovascular diseases. CMBs occur as small, circular hypointense lesions on T2*-weighted gradient recalled echo (GRE) and susceptibility weighted imaging (SWI) images, and hyperintense on quantitative susceptibility mapping (QSM) images due to their paramagnetic nature. Accurate detection of CMBs would help to determine the CMB lesion count and distribution, which would be further useful to understand the clinical impact of CMBs and to obtain quantitative imaging biomarkers. In this work, we propose a fully automated, deep learning-based, 2-step algorithm, using structural and anatomical properties of CMBs from any single input image modality (e.g. GRE / SWI / QSM) for their accurate detection. Our method consists of an initial candidate detection step, that detects CMBs with high sensitivity and a candidate discrimination step using a knowledge distillation framework to classify CMB and non-CMB instances, followed by a morphological clean-up step. We used 4 datasets consisting of different modalities specified above, acquired using various protocols and with a variety of pathological and demographic characteristics. On cross-validation within datasets, our method achieved a cluster-wise true positive rate (TPR) over 90% with an average of less than 2 false positives per subject. Our method is flexible in terms of the input modality and provides comparable cluster-wise TPR and a better cluster-wise precision compared to existing state-of-the-art methods. When evaluated across different datasets, our method showed good generalisability with a cluster-wise TPR greater than 80% with different modalities.
Role of cation-chloride cotransporters, Na/K-pump, and channels in cell water/ionic balance regulation under hyperosmolar conditions: in silico and experimental studies of opposite RVI and AVD responses of U937 cells to hyperosmolar media
Authors: Yurinskaya Valentina E. , Vereninov Alexey A. 
Published: November 2021

AbstractThe work provides a modern mathematical description of animal cell electrochemical system under a balanced state and during the transition caused by an increase in external osmolarity, considering all the main ionic pathways in the cell membrane: the sodium pump, K+, Na+, Cl- electroconductive channels and cotransporters NC, KC, and NKCC. The description is applied to experimental data obtained on U937 cells cultured in suspension, which allows the required assays to be performed, including determination of cell water content using buoyant density, cell ion content using flame photometry, and optical methods using flow cytometry. The study of these cells can serve as a useful model for understanding the general mechanisms of regulation of cellular water and ionic balance, which cannot be properly analyzed in many important practical cases, such as ischemic disturbance of cellular ionic and water balance, when cells cannot be isolated. An essential part of the results is the developed software supplied with an executable file, which allows researchers with no programming experience to calculate unidirectional fluxes of monovalent ions through separate pathways and ion-electrochemical gradients that move ions through them, which is important for studying the functional expression of channels and transporters. It is shown how the developed approach is used to reveal changes in channels and transporters underlying the RVI and AVD responses to the hyperosmolar medium in the studied living U937 cells.
Atrans-acting long non-coding RNA represses flowering inArabidopsis
Authors: Jin Yu , Ivanov Maxim , Dittrich Anna Nelson , Nelson Andrew D. L. , Marquardt Sebastian 
Published: November 2021

AbstractEukaryotic genomes give rise to thousands of long non-coding RNAs (lncRNAs), yet the purpose of lncRNAs remains largely enigmatic. Functional characterization of lncRNAs is challenging due to multiple orthogonal hypothesis for molecular activities of lncRNA loci. Here, we identified afloweringassociatedintergeniclncRNA (FLAIL) that represses flowering inArabidopsis. An allelic series offlailloss-of-function mutants generated by CRISPR/Cas9 and T-DNA mutagenesis showed an early flowering phenotype. Gene expression analyses inflailmutants revealed differentially expressed genes linked to the regulation of flowering. A genomic rescue fragment ofFLAILintroduced inflailmutants complemented gene expression defects and early flowering, consistent withtrans-acting effects of theFLAILRNA. Knock-down ofFLAILRNA levels using the artificial microRNA approach revealed an early flowering phenotype shared with genomic mutations, indicating atrans-acting role ofFLAILRNA in the repression of flowering time. Genome-wide detection ofFLAIL-DNA interactions by ChIRP-seq suggested thatFLAILmay directly bind genomic regions.FLAILbound to genes involved in regulation of flowering that were differentially expressed inflail, consistent with the interpretation ofFLAILas atrans-acting lncRNA directly shaping gene expression. Our findings highlightFLAILas atrans-acting lncRNA that affects flowering inArabidopsis, likely through mediating transcriptional regulation of genes directly bound byFLAIL.
Defining the Transcriptional and Epigenetic Basis of Organotypic Endothelial Diversity in the Developing and Adult Mouse
Authors: Gutierrez Manuel E. Cantu , Hill Matthew C. , Largoza Gabrielle , Martin James F. , Wythe Joshua D. 
Published: November 2021

ABSTRACTSignificant phenotypic differences exist between the vascular endothelium of different organs, including cell-cell junctions, paracellular fluid transport, shape, and mural cell coverage. These organ-specific morphological features ultimately manifest as different functional capacities, as demonstrated by the dramatic differences in capillary permeability between the leaky vessels of the liver compared to the almost impermeable vasculature found in the brain. While these morphological and functional differences have been long appreciated, the molecular basis of endothelial organ specialization remains unclear. To determine the epigenetic and transcriptional mechanisms driving this functional heterogeneity, we profiled accessible chromatin, as well as gene expression, in six different organs, across three distinct time points, during murine development and in adulthood. After identifying both common, and organ-specific DNA motif usage and transcriptional signatures, we then focused our studies on the endothelium of the central nervous system. Using single cell RNA-seq, we identified key gene regulatory networks governing brain blood vessel maturation, including TCF/LEF and FOX transcription factors. Critically, these unique regulatory regions and gene expression signatures are evolutionarily conserved in humans. Collectively, this work provides a valuable resource for identifying the transcriptional regulators controlling organ-specific endothelial specialization and provides novel insight into the gene regulatory networks governing the maturation and maintenance of the cerebrovasculature.
Structure of the Quenched Cyanobacterial OCP-Phycobilisome Complex
Authors: Dominguez-Martin Maria Agustina , Sauer Paul V. , Sutter Markus , Kirst Henning , Bina David , Greber Basil J. , Nogales Eva , Polívka Tomáš , Kerfeld Cheryl A. 
Published: November 2021

AbstractPhotoprotection is an essential mechanism in photosynthetic organisms to balance the harvesting of light energy against the risks of photodamage. In cyanobacteria, photoprotective non-photochemical quenching relies on the interaction between a photoreceptor, the Orange Carotenoid Protein (OCP), and the antenna, the phycobilisome (PBS). Here we report the first structure of the OCP-PBS complex at 2.7 Å overall resolution obtained by cryo-electron microscopy. The structure shows that the 6.2 MDa PBS is quenched by four 34 kDa OCP organized as two dimers. The complex also reveals that the structure of the active form of the OCP is drastically different than its resting, non-quenching form, with an ∼60 Å displacement of its regulatory domain. These results provide a high-resolution blueprint of the structural basis of the protective quenching of excess excitation energy that enables cyanobacteria to harvest light energy and fix CO2 across environmentally diverse and dynamic surface of our planet.
From online data collection to identification of disease mechanisms: The IL-1ß, IL-6 and TNF-α cytokine triad is associated with post-acute sequelae of COVID-19 in a digital research cohort
Authors: Schultheiß Christoph , Willscher Edith , Paschold Lisa , Gottschick Cornelia , Klee Bianca , Henkes Svenja-Sibylla , Bosurgi Lidia , Dutzmann Jochen , Sedding Daniel , Frese Thomas , Girndt Matthias , Höll Jessica I. , Gekle Michael , Mikolajczyk Rafael , Binder Mascha 
Published: November 2021

AbstractPost-acute sequelae of COVID-19 (PASC) emerge as a global problem with unknown molecular drivers. In a digital epidemiology approach, we rapidly recruited 8,077 individuals out of 129,733 households in Halle (Saale) to the cohort study for digital health research in Germany (DigiHero). These responded to a basic questionnaire followed by a PASC-focused survey and blood sampling in case of prior positive SARS-CoV-2 testing in their household. The presented analysis is based on the first 318 DigiHero participants, the majority thereof after mild infections. PASC were reported in 67.8% of cases, consisted predominantly in fatigue, dyspnea and concentration deficit, persisted in 60% over the follow-up period of on average eight months and their resolution was unaffected by post-infection vaccination. PASC was not associated with post-COVID-19 autoantibodies, but with elevated levels of IL-1ß, IL-6 and TNF-α. Blood profiling and single-cell data from validation cohorts with early infection suggested the induction of these cytokines in COVID-19 lung pro-inflammatory macrophages creating a self-sustaining feedback loop. Our data indicate a long-lasting cytokine triad -potentially underlying PASC symptoms - to be driven by macrophage primed during infection. We demonstrate how the combination of digital epidemiology with selective biobanking can rapidly generate hints towards disease mechanisms.