bluuebunny/crossref_metadata_2025 huggingface dataset:
Superior Hemimastectomy with Inferior Pedicle Nipple-Bearing Flap: A Five-Step Surgical Technique
Authors: Morante Lea , El Hajj Houssein , Delecourt Camille , Sabiani Laura , Bannier Marie , Rua Sandrine , Barrou Julien , Lambaudie Eric , Houvenaeghel Gilles , Cohen Monique
Published: December 2021

Oncoplastic breast surgery is an evolving field combining both breast aesthetic surgery and oncologic breast surgery. It aims to optimize cosmetic outcomes without interfering with oncologic safety. The superior hemimastectomy is a technique that can be considered for large upper-quadrant breast tumors or multifocal and multicentric breast tumors localized in the upper quadrants. As with mastectomy, axillary procedures can be performed through the same incision. The nipple-areola complex can be preserved and reimplanted. Superior hemimastectomy allows wide excision of the breast tissue, but its main disadvantage is the increased risk of necrosis of the free grafted nipple-areola complex. In this article, the authors present the surgical technique of superior hemimastectomy with an inferior pedicle nipple-bearing flap. This technique is presented as a simple five-step algorithm. A modified superior hemimastectomy with nipple-areola complex preservation using an inferior pedicle nipple-bearing flap is an alternative to the classic superior hemimastectomy technique. This modified technique decreases the risk of nipple-areola complex necrosis and preserves better nipple-areola complex sensitivity.
Sir Arnold Whittaker Wolfendale. 25 June 1927—21 December 2020
Authors: Ellis Richard S. , Watson Alan A.
Published: December 2021

For over 50 years Arnold Wolfendale was an international leader in the fields of cosmic ray and gamma ray astronomy, making many seminal contributions. His extensive studies of the muon particle culminated in 1965 when, using an installation in the Kolar Gold Mine in India, he played a major role in the first detection of the neutrinos associated with muons produced in the atmosphere. His interests in the origin of high-energy cosmic rays were extensive and required the development of a better understanding of particle physics at energies beyond those accessible at accelerators. Recognizing that high-energy gamma rays can arise from cosmic ray interactions with the interstellar gas, he used early satellite data to argue for the galactic origin of intermediate-energy cosmic rays and for studies of the distribution of molecular hydrogen. His interests in astronomy, which he firmly held to be a branch of physics, drove him to develop a world-class activity in this area at Durham University. This achievement, in part, led to him being appointed Astronomer Royal in 1991. He used this position, and his roles as president of the Royal Astronomical Society, the Institute of Physics and the European Physical Society, to lobby tirelessly for more governmental support for science. He was an early advocate for improvements in the public understanding of science, leading by example. In his later years Arnold's interests extended to cosmology and horology, and he argued against a possible connection between cosmic rays and global warming. A brilliant communicator, Arnold gave a huge number of lectures each year to general audiences, almost to the end of his life.
The wettability of electron spun membranes by synovial fluid
Authors: Hrouda Ales , Jirkovec Radek , Hamrikova Petra , Vanierschot Maarten , Denis Kathleen , Capek Lukas
Published: December 2021

Aseptic loosening due to periprosthetic osteolysis has been accepted as one of the leading causes of revision procedures in patients with previous joint arthroplasty. Recently, several strategies for suppression of osteolysis were proposed, mostly based on biological treatment such as mitigation of chronic inflammatory reactions. However, these biological treatments do not stop the debris migration but only reduce the inflammatory reaction. To address this shortcoming, we propose the concept of ultrahigh molecular weighted polyethylene particles filtration storage by electrospun membranes. Firstly, the surface tension of synovial fluid (SF) is obtained by use of a pendant droplet. Secondly, the contact angle of the electrospun membranes wetted by two different liquids is measured to obtain the free surface energy using of the Owens–Wendt model. Additionally, the wettability of electrospun membranes by SF as a function of technology parameters is studied.
A new approach for quantifying epithelial and stromal thickness changes after orthokeratology contact lens wear
Authors: Ran Ziying , Moore Joshua , Jiang Fan , Guo Hongmei , Eliasy Ashkan , Lopes Bernardo T. , Bao FangJun , Jiang Jun , Abass Ahmed , Elsheikh Ahmed
Published: December 2021

The aim of the study was to develop an automatic segmentation approach to optical coherence tomography (OCT) images and to investigate the changes in epithelial and stromal thickness profile and radius of curvature after the use of orthokeratology (Ortho-K) contact lenses. A total of 45 right eyes from 52 participants were monitored before, and after one month of, uninterrupted overnight Ortho-K lens wear. The tomography of their right eyes was obtained using optical OCT and rotating Scheimpflug imaging (OCULUS Pentacam). A custom-built MATLAB code for automatic segmentation of corneal OCT images was created and used to assess changes in epithelial thickness, stromal thickness, corneal and stromal profiles and radii of curvature before, and after one month of, uninterrupted overnight wear of Ortho-K lenses. In the central area (0–2 mm diameter), the epithelium thinned by 12.8 ± 6.0 µm (23.8% on average,
p
< 0.01) after one month of Ortho-K lens wear. In the paracentral area (2–5 mm diameter), the epithelium thinned nasally and temporally (by 2.4 ± 5.9 µm, 4.5% on average,
p
= 0.031). The stroma thickness increased in the central area (by 4.8 ± 16.1 µm,
p
= 0.005). The radius of curvature of the central corneal anterior surface increased by 0.24 ± 0.26 mm (3.1%,
p
< 0.01) along the horizontal meridian and by 0.34 ± 0.18 mm (4.2%,
p
< 0.01) along the vertical meridian. There were no significant changes in the anterior and posterior stromal radius of curvature. This study introduced a new method to automatically detect the anterior corneal surface, the epithelial posterior surface and the posterior corneal surface in OCT scans. Overnight wear of Ortho-K lenses caused thinning of the central corneal epithelium. The anterior corneal surface became flattered while the anterior and posterior surfaces of the stroma did not undergo significant changes. The results are consistent with the changes reported in previous studies. The reduction in myopic refractive error caused by Ortho-K lens wear was mainly due to changes in corneal epithelium thickness profile.
Laser-stimulated fluorescence reveals unseen details in fossils from the Upper Jurassic Solnhofen Limestones
Authors: Barlow Luke A. , Pittman Michael , Butcher Anthony , Martill David M. , Kaye Thomas G.
Published: December 2021

Laser-stimulated fluorescence (LSF) has seen increased use in palaeontological investigations in recent years. The method uses the high flux of laser light of visible wavelengths to reveal details sometimes missed by traditional long-wave ultraviolet (UV) methods using a lamp. In this study, we compare the results of LSF with UV-A-generated fluorescence on a range of fossils from the Upper Jurassic Solnhofen Limestone Konservat-Lagerstätte of Bavaria, Germany. The methodology follows previous protocols of LSF with modifications made to enhance laser beam intensity, namely keeping the laser at a constant distance from the specimen, using a camera track. Our experiments show that along with making surface details more vivid than UV-A or revealing them for the first time, LSF has the additional value of revealing shallow subsurface specimen detail. Fossil decapods from the Solnhofen Limestone reveal full body outlines, even under the matrix, along with details of segmentation within the appendages such as limbs and antennae. The results indicate that LSF can be used on invertebrate fossils along with vertebrates and may often surpass the information provided by traditional UV methods.
Rogue waves in the three-level defocusing coupled Maxwell–Bloch equations
Authors: Wang Xin , Wang Lei , Wei Jiao , Guo Bowen , Kang Jingfeng
Published: December 2021

The coupled Maxwell–Bloch (CMB) system is a fundamental model describing the propagation of ultrashort laser pulses in a resonant medium with coherent three-level atomic transitions. In this paper, we consider an integrable generalization of the CMB equations with the defocusing case. The CMB hierarchy is derived with the aid of a

3
×
3

matrix eigenvalue problem and the Lenard recursion equation, from which the defocusing CMB model is proposed as a special reduction of the general CMB equations. The

n

-fold Darboux transformation as well as the multiparametric

n

th-order rogue wave solution of the defocusing CMB equations are put forward in terms of Schur polynomials. As an application, the explicit rogue wave solutions from first to second order are presented. Apart from the traditional dark rogue wave, bright rogue wave and four-petalled rogue wave, some novel rogue wave structures such as the dark four-peaked rogue wave and the double-ridged rogue wave are found. Moreover, the second-order rogue wave triplets which contain a fixed number of these rogue waves are shown.
High-Quality and Easy-to-Regenerate Personal Filter
Authors: Fraenkl Max , Krbal Milos , Houdek Jakub , Zmrhalova Zuzana Olmrova , Prokes Borivoj , Hejda Petr , Slang Stanislav , Prikryl Jan , Ondracek Jakub , Makes Otakar , Kostyk Juraj , Nasadil Petr , Malcik Pavel , Zdimal Vladimir , Vlcek Miroslav
Published: December 2021

Proper respiratory tract protection is the key factor to limiting the rate of COVID-19 spread and providing a safe environment for health care workers. Traditional N95 (FFP2) respirators are not easy to regenerate and thus create certain financial and ecological burdens; moreover, their quality may vary significantly. A solution that would overcome these disadvantages is desirable. In this study a commercially available knit polyester fleece fabric was selected as the filter material, and a total of 25 filters of different areas and thicknesses were prepared. Then, the size-resolved filtration efficiency (40–400 nm) and pressure drop were evaluated at a volumetric flow rate of 95 L/min. We showed the excellent synergistic effect of expanding the filtration area and increasing the number of filtering layers on the filtration efficiency; a filter cartridge with 8 layers of knit polyester fabric with a surface area of 900 cm2 and sized 25 × 14 × 8 cm achieved filtration efficiencies of 98 % at 95 L/min and 99.5 % at 30 L/min. The assembled filter kit consists of a filter cartridge (14 Pa) carried in a small backpack connected to a half mask with a total pressure drop of 84 Pa at 95 L/min. In addition, it is reusable, and the filter material can be regenerated at least ten times by simple methods, such as boiling. We have demonstrated a novel approach for creating high-quality and easy-to-breathe-through respiratory protective equipment that reduces operating costs and is a green solution because it is easy to regenerate.
Evaluation of the Roche SARS-CoV-2 Rapid Antibody Test in samples from vaccinated individuals
Authors: Hayer Johannes , Urlaub Eva
Published: December 2021

Objective

The study aimed to establish the performance of the SARS-CoV-2 Rapid Antibody Test (IgG and IgM) and the Elecsys® Anti-SARS-CoV-2 S assay in vaccinated individuals.

Methods

A panel of serum samples from Boca Biolistics was utilized to assess antibodies following vaccination, consisting of samples drawn prior to vaccination, after the first dose, or at least 14 days after the second dose of Moderna mRNA-1273 or Pfizer-BioNTech BNT162b2 COVID-19 vaccines. Agreement between the two methods was measured and stratified by test evaluator and assay lot.

Results

Agreement between the SARS-CoV-2 Rapid Antibody Test (IgG) and Elecsys Anti-SARS-CoV-2 S assay qualitative measurements at the different assessment points for both mRNA-1273 and BNT162b2 ranged between 97.06% (95% confidence interval [CI] 84.67, 99.93) to 100% (95% CI 82.35, 100). Agreement of the SARS-CoV-2 Rapid Antibody Test (IgG) with the Elecsys Anti-SARS-CoV-2 S assay was not highly influenced by either lot or evaluator. There was a medium-to-strong correlation between the semi-quantitative SARS-CoV-2 Rapid Antibody Test (IgG) result and quantitative Elecsys Anti-SARS-CoV-2 S assay in samples taken after both doses of the vaccines, with higher intensity bands being associated with higher total anti-S antibody titer (mRNA-1273, p=0.0019; BNT162b2, p<0.0001).

Conclusion

Semi-quantitative SARS-CoV-2 Rapid Antibody Test (IgG) and quantitative Elecsys Anti-SARS-CoV-2 S assay correlated well, suggesting that the SARS-CoV-2 Rapid Antibody Test (IgG) is helpful in understanding the immune response post-vaccination. The current data support the use of the SARS-CoV-2 Rapid Antibody Test (IgG) in the vaccinated population.

Importance

Serologic assays are an essential tool for seroprevalence surveys, for quality control of vaccines, and to determine the response to vaccination. Although a correlate of immunity has not yet been established for COVID-19 vaccines, antibody titers after natural infection and vaccination have been associated with protection from symptomatic SARS-CoV-2 infection. Rapid point-of-care assays can be of use in this context with advantages over centralized testing, such as speed and ease of use. The point-of-care SARS-CoV-2 Rapid Antibody Test (IgG) compared favorably to the Elecsys Anti-SARS-CoV-2 S assay with agreement rates above 97.06%, after one or two doses of Moderna mRNA-1273 or Pfizer-BioNTech BNT162b2. Semi-quantitative SARS-CoV-2 Rapid Antibody Test (IgG) and quantitative Elecsys Anti-SARS-CoV-2 S assay results correlated well, suggesting that SARS-CoV-2 Rapid Antibody Test (IgG) is helpful in understanding the immune response post-vaccination. The current data support the use of the SARS-CoV-2 Rapid Antibody Test (IgG) in the vaccinated population.
Outpatient therapies for COVID-19: How do we choose?
Authors: Lee Todd C. , Morris Andrew M. , Grover Steven A. , Murthy Srinivas , McDonald Emily G.
Published: December 2021

Background

Several outpatient COVID-19 therapies have reduced hospitalization in randomized controlled trials. The choice of therapy may depend on drug efficacy, toxicity, pricing, availability, and access to administration infrastructure. To facilitate comparative decision making, we evaluated the efficacy of each treatment in clinical trials and then estimated the associated cost per hospitalization prevented.

Methods

Wherever possible, we obtained relative risk for hospitalization from published randomized controlled trials. Otherwise, we extracted data from press releases, conference abstracts, government submissions, or preprints. If more than one study was published, the results were meta-analyzed. Using relative risk, we estimated the number needed to treat (NNT), assuming a baseline hospitalization risk of 5%. Drug pricing was based on Canadian formularies, government purchases, or manufacturer estimates.

Administrative and societal costs were not included. Results will be updated online as new studies emerge or final publication numbers become available.

Results

At a 5% risk of hospitalization the estimated NNTs were: 87 for colchicine, 80 for fluvoxamine, 72 for inhaled corticosteroids, 24 for nirmatrelvir/ritonavir, 25 for sotrovimab, 24 for remdesivir, 29 for casirivimab/imdevimab, 29 for bamlanivimab/etesevimab and 52 for molnupiravir. Colchicine, fluvoxamine, inhaled corticosteroids, and nirmatrelvir/ritonavir had cost per hospitalization prevented point estimates below the CIHI estimated cost of hospitalization ($23000).

Interpretation

Canada is fortunate to have access to several effective outpatient therapies to prevent COVID-19 hospitalization. Given differences in efficacy, toxicity, cost and administration complexities, this assessment serves as one tool to help guide policy makers and clinicians in their treatment selection.
RESISTANCE CONFERRING MUTATIONS IN SARS-CoV-2 DELTA FOLLOWING SOTROVIMAB INFUSION
Authors: Rockett Rebecca J , Basile Kerri , Maddocks Susan , Fong Winkie , Agius Jessica E , Mackinnon Jessica Johnson , Arnott Alicia , Chandra Shona , Gall Mailie , Draper Jenny , Martinez Elena , Sim Eby M , Lee Clement , Ngo Christine , Ramsperger Marc , Ginn Andrew N , Wang Qinning , Fennell Michael , Ko Danny , Lim H Ling , Gilroy Nicky , O’Sullivan Matthew V N , Chen Sharon C-A , Kok Jen , Dwyer Dominic E , Sintchenko Vitali
Published: December 2021

Several Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) neutralising monoclonal antibodies (mAbs) have received emergency use authorisation by regulatory agencies for treatment and prevention of Coronavirus Disease 2019 (COVID-19), including in patients at risk for progression to severe disease. Here we report the persistence of viable SARS-CoV-2 in patients treated with sotrovimab and the rapid development of spike gene mutations that have been shown to confer high level resistance to sotrovimab in vitro. We highlight the need for SARS-CoV-2 genomic surveillance in at risk individuals to inform stewardship of mAbs use and prevent potential treatment failures.
Interleukin-10 knockout mice do not reliably exhibit macroscopic inflammation: a natural history endoscopic surveillance study
Authors: Kim Seung Young , Park Jaeho , Leite Gabriela , Pimentel Mark , Rezaie Ali
Published: December 2021

Background

Interleukin (IL)-10 knockout (KO) mice, used as a model for inflammatory bowel disease (IBD), develop chronic enterocolitis. Endoscopy, the gold standard for evaluation of human mucosal health, is not widely available for murine models. We aimed to assess the natural history of left-sided colitis in IL-10 KO mice via serial endoscopies.

Methods

BALB/cJ IL10 KO mice underwent regular endoscopic assessments from 2 up to 8 months of age. Procedures were recorded and blindly evaluated using a 4-component endoscopic score: mucosal wall transparency, intestinal bleeding, focal lesions and perianal lesions (0-3 points each). An endoscopic score ≥1 point was considered as the presence of colitis/flare.

Results

IL-10 KO mice (N=40, 9 female) were assessed. Mean age at first endoscopy was 62.5±2.5 days; average number of procedures per mouse was 6.0±1.3. A total of 238 endoscopies were conducted every 24.8±8.3 days, corresponding to 124.1±45.2 days of surveillance per mouse (13.6 years cumulative surveillance). Thirty-three endoscopies in 24 mice (60%) detected colitis, mean endoscopy score 2.5±1.3 (range: 1-6.3). Nineteen mice (47.5%) had one episode of colitis and 5 (12.5%) had 2-3 episodes. All exhibited complete spontaneous healing on subsequent endoscopies.

Conclusions

In this largest endoscopic surveillance study of IL-10 KO mice, 40% of mice did not develop endoscopic left-sided colitis. Furthermore, IL-10 KO mice did not exhibit persistent colitis and universally exhibited complete spontaneous healing without treatment. The natural history of colitis in IL-10 KO mice may not be comparable with that of IBD in humans and requires careful consideration.
Quantifying the patterns of metabolic plasticity and heterogeneity along the epithelial-hybrid-mesenchymal spectrum in cancer
Authors: Muralidharan Srinath , Sahoo Sarthak , Saha Aryamaan , Chandran Sanjay , Majumdar Sauma Suvra , Levine Herbert , Jolly Mohit Kumar
Published: December 2021

Cancer metastasis is the leading cause of cancer-related mortality and the process of Epithelial to Mesenchymal Transition (EMT) is crucial for cancer metastasis. Either a partial or complete EMT have been reported to influence the metabolic plasticity of cancer cells in terms of switching among oxidative phosphorylation, fatty acid oxidation and glycolysis pathways. However, a comprehensive analysis of these major metabolic pathways their associations with EMT across different cancers is lacking. Here, we analyse more than 180 cancer cell datasets and show diverse associations of these metabolic pathways with the EMT status of cancer cells. Our bulk data analysis shows that EMT generally positively correlates with glycolysis but negatively with oxidative phosphorylation and fatty acid metabolism. These correlations are also consistent at the level of their molecular master regulators, namely AMPK and HIF1α. Yet, these associations are shown to not be universal. Analysis of singlecell data of EMT induction shows dynamic changes along the different axes of metabolic pathways, consistent with general trends seen in bulk samples. Together, our results reveal underlying patterns of metabolic plasticity and heterogeneity as cancer cells traverse through the epithelial-hybrid-mesenchymal spectrum of states.
GRaNIE and GRaNPA: Inference and evaluation of enhancer-mediated gene regulatory networks applied to study macrophages
Authors: Kamal Aryan , Arnold Christian , Claringbould Annique , Moussa Rim , Servaas Nila H. , Kholmatov Maksim , Daga Neha , Nogina Daria , Mueller-Dott Sophia , Reyes-Palomares Armando , Palla Giovanni , Sigalova Olga , Bunina Daria , Pabst Caroline , Zaugg Judith B.
Published: December 2021

Among the biggest challenges in the post-GWAS (genome-wide association studies) era is the interpretation of disease-associated genetic variants in non-coding genomic regions. Enhancers have emerged as key players in mediating the effect of genetic variants on complex traits and diseases. Their activity is regulated by a combination of transcription factors (TFs), epigenetic changes and genetic variants. Several approaches exist to link enhancers to their target genes, and others that infer TF-gene connections. However, we currently lack a framework that systematically integrates enhancers into TF-gene regulatory networks. Furthermore, we lack an unbiased way of assessing whether inferred regulatory interactions are biologically meaningful. Here we present two methods, implemented as user-friendly R packages: GRaNIE (Gene Regulatory Network Inference including Enhancers) for building enhancer-based gene regulatory networks (eGRNs) and GRaNPA (Gene Regulatory Network Performance Analysis) for evaluating GRNs. GRaNIE jointly infers TF-enhancer, enhancer-gene and TF-gene interactions by integrating open chromatin data such as ATAC-Seq or H3K27ac with RNA-seq across a set of samples (e.g. individuals), and optionally also Hi-C data. GRaNPA is a general framework for evaluating the biological relevance of TF-gene GRNs by assessing their performance for predicting cell-type specific differential expression. We demonstrate the power of our tool-suite by investigating gene regulatory mechanisms in macrophages that underlie their response to infection and cancer, their involvement in common genetic diseases including autoimmune diseases, and identify the TF PURA as putative regulator of pro-inflammatory macrophage polarisation.

Availability

- GRaNIE:https://bioconductor.org/packages/release/bioc/html/GRaNIE.html

- GRaNPA:https://git.embl.de/grp-zaugg/GRaNPA

Graphical abstract
HiC-TE: a computational pipeline for Hi-C data analysis shows a possible role of repeat family interactions in the genome 3D organization
Authors: Lexa Matej , Cechova Monika , Nguyen Son Hoang , Jedlicka Pavel , Tokan Viktor , Kubat Zdenek , Hobza Roman , Kejnovsky Eduard
Published: December 2021

The role of repetitive DNA in the 3D organization of the interphase nucleus in plant cells is a subject of intensive study. High-throughput chromosome conformation capture (Hi-C) is a sequencing-based method detecting the proximity of DNA segments in nuclei. We combined Hi-C data, plant reference genome data and tools for the characterization of genomic repeats to build a Nextflow pipeline identifying and quantifying the contacts of specific repeats revealing the preferential homotypic interactions of ribosomal DNA, DNA transposons and some LTR retrotransposon families. We provide a novel way to analyze the organization of repetitive elements in the 3D nucleus.
The Place of Fluvoxamine in the Treatment of Non-critically ill Patients with COVID-19: A Living Systematic Review and Meta-analysis
Authors: Oussama Kacimi Salah Eddine , Greca Elona , Haireche Mohamed Amine , ElHawary Ahmed Sallam , Setti Mounir Ould , Caruana Rebecca , Rizwan Sahar , Benyettou Hidayet , Essar Mohammad Yasir , Shah Jaffer , Ghozy Sherief
Published: December 2021

Background

Fluvoxamine is a selective serotonin reuptake inhibitor that is known to be used as antidepressant. Repurposing of Fluvoxamine for the treatment of COVID-19 is theorized to help in the prevention of the clinical deterioration of SARS CoV-2 patients. In our systematic review and meta-analysis, we aim to assess the safety and efficacy of the drug under study in terms of its effect on the mortality and the risk of hospitalization and mechanical ventilation in non-critically ill COVID-19 patients.

Methods

We performed a systematic search of seven electronic databases. The search results were screened based on the previously determined inclusion and exclusion criteria. We determined the data related to our objectives. The mortality rates, rates of hospitalization, risk of mechanical ventilation and serious side effects were extracted from the studies that successfully met our inclusion and exclusion criteria. Then, the extracted data from the included studies was included in the meta-analysis.

Results

Three studies, two randomized clinical trials and one observational cohort study, with 1762 patients, were the final outcome of our search and screening processes. Among all participants, 886 patients received Fluvoxamine while 876 were controls. Follow up periods ranged from 7 days to 28 days. There was no significant difference in the intention-to-treat mortality rates between the two groups (RR = 0.66; 95% CI: 0.36 - 1.21, p-value = 0.18; I2 = 0%). However, Fluvoxamine decreased the per-protocol mortality compared to both placebo alone or placebo/standard care (RR = 0.09; 95% CI: 0.01 - 0.64, p-value = 0.02; I2 = 0% and RR = 0.09; 95% CI: 0.01 - 0.72, respectively). As compared to placebo or standard care, the all-cause hospitalization was significantly reduced in the fluvoxamine group (RR = 0.71; 95% CI: 0.54 - 0.93, p-value = 0.01; I2 = 61%). This risk reduction was not significant when compared to placebo alone (RR = 0.76; 95% CI: 0.57 - 1.00; p-value = 0.051; I2 = 48%). Furthermore, the risk of mechanical ventilation was not improved in the fluvoxamine group as compared to placebo (RR = 0.71; 95% CI: 0.43 - 1.16, p-value = 0.17; I2 = 0%). The serious adverse effects were almost the same in the treatment group and the control (13% and 12% respectively).

Conclusion

Fluvoxamine does not significantly reduce the mortality rates or the risk of mechanical ventilation in SARS CoV-2 patients. Nonetheless, it was found to have a good impact on reducing all cause hospitalization among patients with COVID-19 disease. Therefore, further clinical studies are needed to determine the effectiveness of the drug and its mechanisms of action.
Variant-to-gene-mapping followed by cross-species genetic screening identifies GPI-anchor biosynthesis as novel regulator of sleep
Authors: Palermo Justin , Chesi Alessandra , Zimmerman Amber , Sonti Shilpa , Lasconi Chiara , Brown Elizabeth B. , Pippin James A. , Wells Andrew D. , Doldur-Balli Fusun , Mazzotti Diego R. , Pack Allan I. , Gehrman Phillip R. , Grant Struan F.A. , Keene Alex C.
Published: December 2021

Sleep is nearly ubiquitous throughout the animal kingdom, with deficiencies in sleep having been linked to a wide range of human disorders and diseases. While genome wide association studies (GWAS) in humans have identified loci robustly associated with several heritable diseases or traits, little is known about the functional roles of the underlying causal variants in regulating sleep duration or quality. We applied an ATAC-seq/promoter focused Capture C strategy in human iPSC-derived neural progenitors to carry out a ‘variant-to-gene’ mapping campaign that identified 88 candidate sleep effector genes connected to relevant GWAS signals. To functionally validate the role of the implicated effector genes in sleep regulation, we performed a neuron-specific RNAi screen in the fruit fly,Drosophila melanogaster. This approach identified a number of genes that regulated sleep, including phosphatidylinositol N-acetylglucosaminyltransferase subunit Q (PIG-Q), a gene that encodes an enzyme involved in the first step of glycosylphosphatidylinositol (GPI)- anchor biosynthesis. We show that flies deficient forPIG-Qhave longer sleep during both day and night due to an increase in the total number of sleep bouts. Subsequent systematic investigation of other PIG-family genes identified increased sleep in flies for multiple different genes within the PIG pathway. We then mutated thePIG-Qlocus in zebrafish and identified similar increases in sleep to those observed inDrosophila, confirming deep homology ofPIG-Qmediated sleep regulation. These results provide the first physical variant-to-gene mapping of human sleep genes followed by a model organism-based prioritization, revealing a novel and conserved role for GPI-anchor biosynthesis in sleep regulation.
rareSurvival: rare variant association analysis for “time-to-event” outcomes
Authors: Syed Hamzah , Jorgensen Andrea L. , Morris Andrew P.
Published: December 2021

Rare variants have been proposed as contributing to the “missing heritability” of complex human traits. There has been much recent development of methodology to investigate association of complex traits with multiple rare variants within pre-defined “units” from sequence and array-based studies of the exome or genome. However, software for modelling time to event outcomes for rare variant associations has been under developed in comparison with binary and quantitative traits. We introduce a new command line application, rareSurvival, used for the analysis of rare variants with time to event outcomes. The program is compatible with high performance computing (HPC) clusters for batch processing. rareSurvival implements statistical methodology, which are a combination of widely used survival and gene-based analysis techniques such as the Cox proportional hazards model and the burden test. We introduce a novel piece of software that will be at the forefront of efforts to discover rare variants associated with a variety of complex diseases with survival endpoints.

Availability & Implementation

rareSurvival is implemented in C#, available on Linux, Windows and Mac OS X operating systems. It is freely available (GNU General Public License, version 3) to download from https://www.liverpool.ac.uk/translational-medicine/research/statistical-genetics/software/. Download Mono for Linux or Mac OS X to run software.

Contact

hamzah.syed@liverpool.ac.uk

Supplementary information

Links to additional figures and tables are available at Bioinformatics online.
In the back of your mind: Cortical mapping of paraspinal afferent inputs
Authors: Cole David M. , Stämpfli Philipp , Gandia Robert , Schibli Louis , Gantner Sandro , Schuetz Philipp , Meier Michael L.
Published: December 2021

Topographic organization is a hallmark of vertebrate cortex architecture, characterized by ordered projections of the body’s sensory surfaces onto brain systems. High-resolution functional magnetic resonance imaging (fMRI) has proven itself as a valuable tool to investigate the cortical landscape and its (mal-)adaptive plasticity with respect to various body part representations, in particular extremities such as the hand and fingers. Less is known, however, about the cortical representation of the human back. We therefore validated a novel, MRI-compatible method of mapping cortical representations of sensory afferents of the back, using vibrotactile stimulation at varying frequencies and paraspinal locations, in conjunction with fMRI. We expected high-frequency stimulation to be associated with differential neuronal activity in the primary somatosensory cortex (S1) compared to low-frequency stimulation and that somatosensory representations would differ across the thoracolumbar axis. We found significant differences between neural representations of high- and low-frequency stimulation and between representations of thoracic and lumbar paraspinal locations, in several bilateral S1 sub-regions, and in regions of the primary motor cortex (M1). High-frequency stimulation preferentially activated Brodmann Area (BA) regions BA3a and BA4p, while low-frequency stimulation was more encoded in BA3b and BA4a. Moreover, we found clear topographic differences in S1 for representations of the upper and lower back during high-frequency stimulation. We present the first neurobiological validation of a method for establishing detailed cortical maps of the human back, which might serve as a novel tool to evaluate the pathological significance of neuroplastic changes in clinical conditions such as chronic low back pain.

Key points

Detailed investigations of cortical representations of somatosensory paraspinal afferents along the thoracolumbar axis are lacking.

Using fMRI combined with a novel vibrotactile stimulation device (“pneuVID”) we investigated different sensorimotor cortical representations of the back and explored topographic differences between the upper and lower back.

We found differential sub-regional sensorimotor neural representations of high- and low-frequency stimulation, as well as revealing initial evidence of the somatotopy of upper and lower paraspinal representations.

The current approach might serve as a promising tool to elucidate the role of cortical reorganisation in the pathophysiology of clinical conditions such as chronic low back pain.
Pentosan polysulfate inhibits attachment and infection by SARS-CoV-2 in vitro: insights into structural requirements for binding
Authors: Bertini Sabrina , Alekseeva Anna , Elli Stefano , Pagani Isabel , Zanzoni Serena , Eisele Giorgio , Krishnan Ravi , Maag Klaus P , Reiter Christian , Lenhart Dominik , Gruber Rudolf , Yates Edwin A , Vicenzi Elisa , Naggi Annamaria , Bisio Antonella , Guerrini Marco
Published: December 2021

Two years since the outbreak of the novel coronavirus SARS-CoV-2 pandemic, there remain few clinically effective drugs to complement vaccines. One is the anticoagulant, heparin, which in 2004 was found able to inhibit invasion of SARS CoV (CoV-1) and which has been employed during the current pandemic to prevent thromboembolic complications and moderate potentially damaging inflammation. Heparin has also been shown experimentally to inhibit SARS-CoV-2 attachment and infection in susceptible cells. At high therapeutic doses however, heparin increases the risk of bleeding and prolonged use can cause heparin-induced thrombocytopenia, a serious side-effect. One alternative, with structural similarities to heparin is the plant-derived, semi-synthetic polysaccharide, pentosan polysulfate (PPS). PPS is an established drug for the oral treatment of interstitial cystitis, is well-tolerated and exhibits weaker anticoagulant effects than heparin. In an established Vero cell model, PPS and its fractions of varying molecular weights, inhibited invasion by SARS-CoV-2. Intact PPS and its size-defined fractions were characterized by molecular weight distribution and chemical structure using NMR spectroscopy and LC-MS, then employed to explore the structural basis of interactions with SARS-CoV-2 spike protein receptor-binding domain (S1 RBD) and the inhibition of Vero cell invasion. PPS was as effective as unfractionated heparin, but more effective at inhibiting cell infection than low molecular weight heparin (on a weight/volume basis). Isothermal titration calorimetry and viral plaque-forming assays demonstrated size-dependent binding to S1 RBD and inhibition of Vero cell invasion, suggesting the potential application of PPS as a novel inhibitor of SARS-CoV-2 infection.
Cerebellar GABA change during visuomotor adaptation relates to adaptation performance and cerebellar network connectivity: A Magnetic Resonance Spectroscopic Imaging study
Authors: Nettekoven Caroline R , Mitchell Leah , Clarke William T , Emir Uzay , Campbell Jon , Johansen-Berg Heidi , Jenkinson Ned , Stagg Charlotte J
Published: December 2021

Motor adaptation is crucial for performing accurate movements in a changing environment and relies on the cerebellum. Although cerebellar involvement has been well characterized, the neurochemical changes in the cerebellum underpinning human motor adaptation remain unknown.

We used a novel Magnetic Resonance Spectroscopic Imaging (MRSI) technique to measure changes in the inhibitory neurotransmitter γ-aminobutyric acid (GABA) in the human cerebellum during visuomotor adaptation. Participants used their right hand to adapt to a rotated cursor in the scanner, compared with a control task requiring no adaptation. We spatially resolved adaptation-driven GABA changes at the cerebellar nuclei and cerebellar cortex in the left and the right cerebellar hemisphere independently and found that simple right-hand movements increase GABA in the right cerebellar nuclei and decreases GABA in the left. When isolating adaptation-driven GABA changes, we found an increase in GABA in the left cerebellar nuclei and decrease in GABA in the right cerebellar nuclei. Early adaptation-driven GABA change in the right cerebellar nuclei correlated with adaptation performance: Participants showing greater GABA decrease adapted better, suggesting early GABA change is behaviourally relevant. Early GABA change also correlated with functional connectivity change in a cerebellar network: Participants showing greater decreases in GABA showed greater strength increases in cerebellar network connectivity. Results were specific to GABA, to adaptation and to the cerebellar network.

This study provides first evidence for plastic changes in cerebellar neurochemistry during motor adaptation. Characterising these naturally occurring neurochemical changes may provide a basis for developing therapeutic interventions to facilitate human motor adaptation.

Significance Statement

Despite motor adaptation being fundamental to maintaining accurate movements, its neurochemical basis remains poorly understood, perhaps because measuring neurochemicals in the human cerebellum is technically challenging. Using a novel magnetic resonance spectroscopic imaging method, this study provides evidence for GABA changes in the left and right cerebellar nuclei driven by both simple movement and motor adaptation. The adaptation-driven GABA change in the right cerebellar nuclei correlated with adaptation performance, and with functional connectivity change in a cerebellar network. These results show the first evidence for plastic changes in cerebellar neurochemistry during a cerebellar learning task. This provides the basis for developing therapeutic interventions that facilitate these naturally occurring changes to amplify cerebellar-dependent learning.
Economic burden and catastrophic health expenditure associated with COVID-19 hospitalisations in Kerala, South India
Authors: Thomas Ronnie , Jacob Quincy Mariam , Eliza Sharon Raj , Mini Malathi , Jose Jobinse , Sobha A
Published: December 2021

Introduction

Catastrophic health expenditure during COVID-19 hospitalization has altered the economic picture of households especially in low resource settings with high rates of COVID-19 infection. This study aimed to estimate the Out of Pocket (OOP) expenditure and the proportion of households that incurred catastrophic health expenditures due to COVID-19 hospitalisation in Kerala, South India.

Materials and Methods

A cross-sectional study was conducted among a representative sample of 155 COVID-19 hospitalised patients in Kottayam district over four months, using a pretested interview schedule. The direct medical and non-medical costs incurred by the study participant during hospitalisation and the total monthly household expenditure were obtained from the respective COVID-19 affected households. Catastrophic health expenditure was defined as direct medical expenditure exceeding 40% of effective household income.

Results

From the study, median and mean Out of Pocket (OOP) expenditures were obtained as USD 93.57 and USD 502.60 respectively. The study revealed that 49.7% of households had Catastrophic health expenditure, with 32.9% having incurred Distress financing. Multivariate analysis revealed being Below poverty line, hospitalisation in private healthcare facility and presence of co-morbid conditions as significant determinants of Catastrophic health expenditure.

Conclusion

High levels of Catastrophic health expenditure and distress financing revealed by the study unveils major unaddressed challenges in the road to Universal health coverage.
Associations between intimate partner violence and mental health in German men and women: a cross-sectional analysis of the German Health Interview and Examination Survey for Adults (DEGS1)
Authors: Graßkemper Lena , Costa Diogo
Published: December 2021

This work explores the cross-sectional associations between Intimate Partner Violence (IPV) and anxiety, depressive symptoms, stress symptoms, and health-related quality of life (HRQoL), in a representative sample of German adult men (n=2,789) and women (n=3,149), and considers their involvement as victims or perpetrators of physical and psychological IPV. In this sample, physical IPV victimization was associated with anxiety and stress among men. Psychological IPV victimization was associated with depression among men, and with stress among both sexes. Physical IPV perpetration was significantly associated only with women’s depressive and stress symptoms. Psychological IPV perpetration was associated with stress for both men and women. The mental component of HRQoL was significantly lower for men and women involved in any type of IPV. These results support the need to consider the mental health consequences of IPV involvement for both men and women.
A nationwide deep learning pipeline to predict stroke and COVID-19 death in atrial fibrillation
Authors: Handy Alex , Wood Angela , Sudlow Cathie , Tomlinson Christopher , Kee Frank , Thygesen Johan H , Mamouei Mohammad , Sofat Reecha , Dobson Richard , Ip Samantha , Denaxas Spiros
Published: December 2021

Deep learning (DL) and machine learning (ML) models trained on long-term patient trajectories held as medical codes in electronic health records (EHR) have the potential to improve disease prediction. Anticoagulant prescribing decisions in atrial fibrillation (AF) offer a use case where the benchmark stroke risk prediction tool (CHA2DS2-VASc) could be meaningfully improved by including more information from a patient’s medical history. In this study, we design and build the first DL and ML pipeline that uses the routinely updated, linked EHR data for 56 million people in England accessed via NHS Digital to predict first ischaemic stroke in people with AF, and as a secondary outcome, COVID-19 death. Our pipeline improves first stroke prediction in AF by 17% compared to CHA2DS2-VASc (0.61 (0.57-0.65) vs 0.52 (0.52-0.52) area under the receiver operating characteristics curves, 95% confidence interval) and provides a generalisable, opensource framework that other researchers and developers can build on.
SARS-CoV-2 vaccine effectiveness and breakthrough infections in maintenance dialysis patients
Authors: Manley Harold J. , Aweh Gideon N. , Hsu Caroline M. , Weiner Daniel E. , Miskulin Dana , Harford Antonia M. , Johnson Doug , Lacson Eduardo K.
Published: December 2021

Background

SARS-CoV-2 vaccine effectiveness during the Delta period and immunogenicity threshold associated with protection against COVID-19 related hospitalization or death in the dialysis population is unknown.

Methods

A retrospective, observational study assessed SARS-CoV-2 vaccine effectiveness and immunogenicity threshold in all adult maintenance dialysis patients without COVID-19 history treated between February 1 and October 2, 2021. All COVID-19 infections, composite of hospitalization or death following COVID-19 and available SARS-CoV-2 anti-spike immunoglobulin (Ig) G values were extracted from electronic medical record. COVID-19 cases per 10,000 days at risk and vaccine effectiveness during pre-Delta and Delta periods were determined.

Results

Of 15,718 patients receiving dialysis during the study period, 11,191 (71%) were fully vaccinated, 733 (5%) were partially vaccinated and 3,794 (24%) were unvaccinated. 967 COVID-19 were cases identified: 511 (53%) occurred in unvaccinated patients and 579 (60%) occurred during the Delta period. COVID-19 related hospitalization or death was less likely among vaccinated versus unvaccinated patients for all vaccines (adjusted HR 0.19 [0.12, 0.30]) and for BNT162b2/Pfizer, mRNA-1273/Moderna, and Ad26.COV2.S/Janssen (adjusted HR=0.25 [0.16, 0.40], 0.14 [0.08, 0.22], and 0.34 [0.17, 0.68] respectively). Among those with anti-spike IgG levels, those with IgG level ≥ 7 had significantly lower risk of a COVID-19 diagnosis (HR=0.25 [0.15, 0.42]) and none experienced a COVID-related hospitalization or death.

Conclusions

Among maintenance dialysis patients, SARS-CoV-2 vaccination was associated with a lower risk of COVID-19 diagnosis and associated hospitalization or death. Among vaccinated patients, low anti-spike IgG level is associated with worse COVID-19 related outcomes.

Significance Statement

SARS-CoV-2 vaccine effectiveness and association between antibody levels and clinical outcomes in maintenance dialysis patients is not known. Between February 1 and October 2, 2021, vaccine effectiveness was 85% against COVID-19 infection and 81% against composite of COVID-related hospitalization or death. COVID-19 case rates and severe outcomes were higher during the Delta dominant period (June 27-October 2, 2021). Increasing time (weeks) since full vaccination status was associated with increased risk for COVID-19 related hospitalization or death. Anti-spike IgG level ≥ 7 had lower risk of a COVID-19 diagnosis and no COVID-related hospitalization or death. Our findings supports utilization of SARS-CoV-2 vaccination and suggests that monitoring SARS-CoV-2 antibody levels and administering additional vaccine doses to maintain adequate immunity will be beneficial.
Cardiovascular Complications of Modern Multiple Myeloma Therapy: Analysis of FDA Adverse Event Reporting System
Authors: Al-Yafeai Zaki , Ananthaneni Anil , Ghoweba Mohamed , Abduljabar Hamzah , Aziz David , Grewal Udhayvir
Published: December 2021

Purpose

Multiple myeloma accounts for over 15% of hematological malignancies. In attempt to tackle this malady, the FDA approved four drugs in 2015 which has propagated further development of new anti-multiple myeloma since. However, the health safety of these new agents is still ill-defined. The aim of this study is to delineate the cardiovascular adverse events of these drugs.

Methods

We searched the cardiac adverse events of the newly approved FDA drugs since 2015 using the U.S. Food and Drug Administration Adverse Events Reporting System database (FAERS). We calculated the reporting odds ratio (ROR) with 95% confidence for four drugs that have the highest incidence of cardiovascular adverse events.

Results

Among the medications that have approved for MM Between 2015-2020, four novel drugs showed the highest incidence of cardiotoxicity. ROR (95% CI) for atrial fibrillation due to elotuzumab, Ixazomib, daratumumab, and panobinostat compared to other FAERS drugs was 5.8 (4.4-7.7), 1.93 (1.5-2.3), 4.8 (4.2-5.6), and 5.7 (4.1-8.1), respectively. The ROR (95% CI) for cardiac failure was 8.2 (6.4-10.5), 4.7 (4.1-5.4), 5.8 (4.9-6.7), and 5.6 (3.8-8.1) and ROR (95% CI) for coronary disease was 2.7 (1.9-3.9), 2.7 (2.3-3.2), 2,3 (1.9-2.8), and 4.6 (3.2-6.6) due to elotuzumab, Ixazomib, daratumumab, and panobinostat versus all other drugs in FAERS.

Conclusions

The newly approved multiple myeloma therapy (elotuzumab, Ixazomib, daratumumab, panobinostat) are significantly associated with cardiotoxicity. These results highlight the importance of considering the cardiac history of patients with multiple myeloma when utilizing these novel agents.