bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy and Safety of Immune Checkpoint Inhibitors in Triple-negative Breast Cancer: A Study Based on 41 Cohorts Incorporating 6558 Participants
Authors: Wu Qing , Wu Chunlan , Xie Xianhe
Published: November 2022

The project was designed to investigate the efficacy and safety of immune checkpoint inhibitors (ICIs) in triple-negative breast cancer (TNBC). Electronic databases were screened to identify relevant trials. The primary endpoints were prognostic parameters and adverse events (AEs) through pooled rate, odds ratio, and hazard ratio (HR) with 95% CI. Totally, 6558 TNBC patients from 41 cohorts were included. The pooled pathologic complete response rate (odds ratio=2.03, 95% CI: 1.35–3.06, P=0.0007) and event-free survival (HR=0.84, 95% CI: 0.73–0.96, P=0.0100) of ICIs plus chemotherapy was higher than that of chemotherapy-alone in early-stage TNBC. For metastatic TNBC, compared with chemotherapy-alone, the addition of ICIs prolonged the progression-free survival (PFS) (HR=0.92, 95% CI: 0.88–0.96, P<0.0001); the improvement also existed in the following 3 subgroups: programmed cell death-ligand 1 positive, race of White and Asian, and patients without previous neoadjuvant or adjuvant chemotherapy; however, the benefit of the combined regimen was not observed in overall survival (OS) (HR=0.95; 95% CI: 0.89–1.03, P=0.2127). In addition, the pooled rates of OS, PFS, and objective response rate of ICIs plus chemotherapy were better than those of ICIs plus targeted therapy or ICIs-alone. In the safety analysis, compared with chemotherapy-alone, ICIs plus chemotherapy increased immune-related AEs and several serious AE. The regimen of ICIs plus chemotherapy is promising in both early-stage and metastatic TNBC, while the increased serious AE should not be neglected. Furthermore, the pooled rates of OS, PFS, and objective response rate of ICIs plus chemotherapy were better than those of ICIs plus targeted therapy or ICIs-alone.
Mycosis Fungoides in Skin of Color
Authors: Rager Taylor , Lake Eden
Published: November 2022

Mycosis fungoides is the most common primary cutaneous T-cell lymphoma. Although mycosis fungoides affects patients of all skin tones, mycosis fungoides has a higher incidence in patients with skin of color. Patients with skin of color who are diagnosed with mycosis fungoides have worse outcomes and poor prognosis compared with patients with lighter skin tones. Mycosis fungoides is difficult to diagnose in patients with skin of color as rare subtypes or clinical presentations are commonly seen in these populations. Increased awareness of the presentation of mycosis fungoides in skin of color and early detection could address the higher rates of morbidity and mortality in these populations.
Effectiveness of Cutaneous Melanoma Education on Knowledge, Confidence, and Practice Intent Among Graduate Nursing Students
Authors: Boozer Kathileen , Rossler Kelly L. , Saitta Jaclyn L.
Published: November 2022

Primary care nurse practitioners (NPs) are positioned to improve patient outcomes and reduce the global burden of skin cancers including cutaneous melanoma (CM). Improving skin cancer and CM educational opportunities, especially at the graduate student level, is a necessary step to overcome practice barriers and improve patient care. The purpose of this quality improvement project was to evaluate the effectiveness of an online graduate educational training program to improve knowledge, confidence, and practice intent. An exploratory, descriptive design guided this project with a nonprobability, convenience sample of NP graduate students. This project served as the first phase of a long-term research initiative focused on integrating CM education within an NP curriculum.
Percutaneous tracheostomy in the ICU: a review of the literature and recent updates
Authors: Romem Ayal , Gilboa Hadas
Published: November 2022

Purpose of review

The following article summarizes the current available knowledge regarding tracheostomy techniques, indications, contraindications, procedure timing, use of assisted technologies and tracheostomy feasibility and safety in high-risk populations. In light of the ongoing corona virus disease (COVID-19) pandemic, a focus was placed on tracheostomy in this unique patient group.

Recent findings

Percutaneous dilatation tracheostomy (PDT) is commonly used in the ICU setting. It has been shown to be well tolerated and feasible in a diverse patient population including those regarded to be at high risk such as the obese, coagulopathic and acute respiratory failure patient. This patient profile presented itself frequently in the recent COVID-19 pandemic. Indeed studies showed that PDT is well tolerated in COVID-19 ICU patients leading to reduced ICU length of stay (LOS), decrease in ventilator-associated pneumonia rate (VAP) and reduced duration on invasive mechanical ventilation (IMV). Despite initial concerns, virus transmission from patient to healthcare provider (HCP) was shown to be negligible when proper precautions are taken.

Bedside PDT in the ICU is a well tolerated procedure having the potential to benefit both the individual patient as well as to improve resource utilization of the healthcare system.
Long-term outcomes of acute kidney injury in children
Authors: Schuermans Art , Van den Eynde Jef , Mekahli Djalila , Vlasselaers Dirk
Published: November 2022

Purpose of review

Acute kidney injury (AKI) affects up to 35% of all critically ill children and is associated with substantial short-term morbidity and mortality. However, the link between paediatric AKI and long-term adverse outcomes remains incompletely understood. This review highlights the most recent clinical data supporting the role of paediatric AKI as a risk factor for long-term kidney and cardiovascular consequences. In addition, it stresses the need for long-term surveillance of paediatric AKI survivors.

Recent findings

Recent large-scale studies have led to an increasing understanding that paediatric AKI is a significant risk factor for adverse outcomes such as hypertension, cardiovascular disease and chronic kidney disease (CKD) over time. These long-term sequelae of paediatric AKI are most often observed in vulnerable populations, such as critically ill children, paediatric cardiac surgery patients, children who suffer from severe infections and paediatric cancer patients.

A growing body of research has shown that paediatric AKI is associated with long-term adverse outcomes such as CKD, hypertension and cardiovascular disease. Although therapeutic pathways tailored to individual paediatric AKI patients are yet to be validated, we provide a framework to guide monitoring and prevention in children at the highest risk for developing long-term kidney dysfunction.
Recent Advances in the Development of Antibody-Drug Conjugates in Urothelial Cancer
Authors: Alhalabi Omar , Altameemi Lina , Campbell Matthew T. , Meric-Bernstam Funda
Published: November 2022

Antibody-drug conjugates (ADCs) have joined the armamentarium against urothelial cancer (UC) as an effective therapy option. Since 2019, the US Food and Drug Administration has approved 2 ADCs for advanced previously treated UC: enfortumab vedotin, which targets nectin-4 and sacituzumab govitecan, which targets trophoblast cell-surface antigen 2. These ADCs are now being tested in earlier disease settings and in previously untreated patients. Furthermore, novel ADCs (e.g., anti–HER-2) are being tested in the clinic and show promising clinical benefit. The next frontier is to understand the mechanisms of resistance and response, gaining experience with ADC-related adverse events and learning the best strategy to sequence and combine these agents with existing therapies. Here, we highlight the recent advances in the development of ADCs for treating localized and metastatic UC.
Antibody-Drug Conjugates in Breast Cancer: Spotlight on HER2
Authors: Abelman Rachel Occhiogrosso , Medford Arielle , Spring Laura , Bardia Aditya
Published: November 2022

Antibody-drug conjugates (ADCs) are composed of monoclonal antibodies linked to a cytotoxic payload, enabling targeted delivery of more potent chemotherapy. In the past decade, there has been rapid development of ADCs aimed at different types of breast cancer. The success of the monoclonal antibody trastuzumab has led to the evolution of several ADCs targeting HER2-positive breast cancer. Trastuzumab-emtansine, the first approved ADC targeting HER2-positive breast cancer, has become standard of care for patients with high-risk early-stage HER2-positive breast cancer who have residual disease after neoadjuvant chemotherapy. More recently, the observation of the bystander effect, in which ADCs target both antigen-positive cells and adjacent antigen-negative cells, has led to the reclassification of “HER2-low” breast cancer and the development of trastuzumab-deruxtecan to target this population. This article reviews the history of HER2-directed ADCs in breast cancer as well as ongoing ADCs in development.
Antibody-Drug Conjugates in Myeloid Leukemias
Authors: Senapati Jayastu , Daver Naval G. , Pemmaraju Naveen
Published: November 2022

Targeted therapy in oncology brings with it the promise to maximize cancer cell cytotoxicity with minimal off-target effects. Antibody-drug conjugates (ADCs), an important group of such targeted agents, consist of a monoclonal antibody conjugated to a potent cytotoxic drug. In the field of leukemia, ADCs form an important component of therapeutic arsenal through the use of gemtuzumab ozogamicin in acute myeloid leukemia and inotuzumab ozogamicin (InO) in B-cell acute lymphoblastic leukemia, 2 approved agents. A recombinant fusion protein, tagraxofusp, which function similar to ADC, has gained approval for therapy in blastic plasmacytic dendritic cell neoplasm. The use of such agents as monotherapy or as part of a combination therapy has led to improved response rates and outcomes in certain specific disease subtypes and has led to further studies to identify novel cellular targets and improved delivery of cytotoxic agents using ADC. In this review, we will discuss about ADCs in myeloid leukemia and understand their development and current use in the field.
SPECKLE TRACKING QUANTIFICATION PARASTERNAL INTERCOSTAL MUSCLE LONGITUDINAL STRAIN TO PREDICT WEANING OUTCOMES: A MULTICENTRIC OBSERVATIONAL STUDY
Authors: Xu Qiancheng , Yang Xiao , Qian Yan , Hu Chang , Lu Weihua , Cai Shuhan , Li Jianguo , Hu Bo
Published: November 2022

Background: The purpose of this study was to determine the feasibility, reliability, and reproducibility of parasternal intercostal muscle longitudinal strain (LSim) quantification by speckle tracking and the value of maximal LSim to predict weaning outcomes. Methods: This study was divided into three phases. Phases 1 and 2 comprehended prospective observational programs to evaluate the feasibility, reliability, and repeatability of speckle tracking to assess LSim in healthy subjects and mechanically ventilated patients. Phase 3 was a multicenter retrospective study to evaluate the value of maximal LSim, intercostal muscle thickening fraction (TFim), diaphragmatic thickening fraction, diaphragmatic excursion, and rapid shallow breathing index to predict weaning outcomes. Results: A total of 25 healthy subjects and 20 mechanically ventilated patients were enrolled in phases 1 and 2, respectively. Maximal LSim was easily accessible, and the intraoperator reliability and interoperator reliability were excellent in eupnea, deep breathing, and mechanical ventilation. The intraclass correlation coefficient ranged from 0.85 to 0.96. Moreover, 83 patients were included in phase 3. The areas under the receiver operating characteristic curve of maximal LSim, TFim, diaphragmatic thickening fraction, diaphragmatic excursion, and rapid shallow breathing index were 0.91, 0.79, 0.71, 0.70, and 0.78 for the prediction of successful weaning, respectively. The best cutoff values of LSim and TFim were >−6% (sensitivity, 100%; specificity, 64.71%) and <7.6% (sensitivity, 100%; specificity, 50.98%), respectively. Conclusions: The quantification of LSim by speckle tracking was easily achievable in healthy subjects and mechanically ventilated patients and presented a higher predictive value for weaning success compared with conventional weaning parameters. Trial registration no. ChiCTR2100049817
Surgical Cost Awareness Program Study: Impact of a Novel, Real-Time, Cost Awareness Intervention on Operating Room Expenses in Thoracoscopic Lobectomy
Authors: Dayan Gabriel , Soder Stephan A , Dahan Zachary , Langleben Ian , Pollock Clare , Mignault Alexandre , Ferraro Pasquale , Nasir Basil , Potter Brian , Liberman Moishe
Published: November 2022

BACKGROUND:

For surgical patients, operating room expenses are significant drivers of overall hospitalization costs. Surgical teams often lack awareness of the costs associated with disposable surgical supplies, which may lead to unnecessary expenditures. The aim of this study is to evaluate whether a Surgical Cost Awareness Program would reduce operating room costs.

STUDY DESIGN:

A prototype software displays the types and costs of disposable instruments used in real-time during surgery and generates insight-driven operative cost reports, which are automatically sent to the surgeons. A prospective pre–post controlled trial of thoracoscopic lobectomy procedures performed by 7 surgeons at a single academic center was conducted. Control and intervention groups consisted of consecutive cases from February 2nd through June 23, 2021, and from June 28th through December 22, 2021, respectively. The primary outcome was mean per case surgical disposables cost.

RESULTS:

Three hundred twenty-two lobectomies were evaluated throughout the study period (control: n = 164; intervention: n = 158). Baseline characteristics were comparable between groups. Mean disposables cost per case was $3,320.73 ± $814.83 in the control group compared with $2,567.64 ± $594.59 in the intervention group, representing a mean cost reduction of $753.08 (95% CI, $622.29 to $883.87; p < 0.001). All surgeons experienced a reduction in disposable costs after the intervention. Intraoperative and postoperative outcomes did not differ between the cohorts.

CONCLUSIONS:

Providing real-time educational feedback to surgical teams significantly reduced costs associated with disposable surgical equipment without compromising perioperative outcomes for lobectomy. Integrating the novel AssistIQ software across other procedural settings may generate further data insights with the potential for significant cost savings on a larger scale.
Loss ofGFAPcauses optico-retinal dysplasia and vision impairment
Authors: Sarusie Menachem Viktor Khamo , Rönnbäck Cecilia , Jespersgaard Cathrine , Baungaard Sif , Ali Yeasmeen , Kessel Line , Christensen Søren Tvorup , Nielsen Karen Brøndum- , Møllgård Kjeld , Rosenberg Thomas , Larsen Lars Allan , Grønskov Karen
Published: November 2022

Diagnosis of genetic diseases has taken tremendous steps forward since the human genome project and technical advancements such as next generation sequencing. However, in the past years it has become evident that the classical “one gene – one phenotype” model is insufficient to encompass the intricacies of human genetics. Examples are emerging that variants in a gene can cause quite diverging phenotypes depending on the specific location in the gene or on the specific type of variant. In the era of precision medicine this is important knowledge, both when interpreting genomic data, but also when designing treatment strategies.

Gain-of-function variants inGFAPleads to protein aggregation and is the cause of the severe neurodegenerative disorder Alexander Disease (AxD), while loss of GFAP function has been considered benign. Here, we report a loss-of-function variant inGFAPas the cause of optico-retinal dysplasia and vision impairment in a six-generation family.

Whole genome sequencing analysis of family members with gliosis of the optic nerve head and visual impairment revealed a frameshift variant inGFAP(c.928dup, p.(Met310Asnfs*113)) segregating with disease. Analysis of human embryonic tissues revealed strong expression of GFAP in retinal neural progenitors. A zebrafish model verified that c.928dup does not result in extensive GFAP protein aggregation and zebrafishgfaploss-of-function mutants showed vision impairment and retinal dysplasia, characterized by a significant loss of Müller glia cells and photoreceptor cells.

Our findings show how different mutational mechanisms can cause diverging phenotypes and reveal a novel function of GFAP in human eye development.
KATPChannel Prodrugs Reduce Inflammatory and Neuropathic Hypersensitivity, Morphine Induced Hypersensitivity, and Precipitated Withdrawal in Mice
Authors: Doucette Alexis , Johnson Kayla , Hulke Shelby , Mujteba Sunna , Miller Elena , Dosa Peter I. , Klein Amanda H.
Published: November 2022

Previous studies show ATP-sensitive potassium (KATP) channel openers can reduce hypersensitivity associated with chronic pain models in rodents, and reduce morphine tolerance. Many agonists of KATPchannels are not soluble in physiologically relevant vehicles, requiring adaptation for clinical use. This study compared the antinociception activity of novel KATPchannel targeting prodrugs, CKLP1, CKLP2, and CF3-CKLP. These prodrugs are activated by endogenous alkaline phosphatase enzymes present in the peripheral and central nervous systems. Analgesic capabilities of intrathecally injected prodrugs were tested in rodent models of spinal nerve ligation (SNL) and Complete Freund’s Adjuvant (CFA) as models for neuropathic and inflammatory pain, respectively. CKLP1 and CKLP2 significantly increased mechanical paw withdrawal thresholds 1-2 hours after intrathecal administration in the SNL model, but all three prodrugs were able to attenuate hypersensitivity up to 7 days after CFA treatment. The reduction of opioid tolerance and opioid-induced hypersensitivity in mice treated chronically with morphine was significantly reduced in CKLP1 and CKLP2 treated animals. Prodrug cleavage was confirmed in mouse spinal cords using liquid chromatography. These studies may aid in the further development of KATPchannel prodrugs for use in treatments of chronic pain, opioid tolerance, and withdrawal.
FASSO: An AlphaFold based method to assign functional annotations by combining sequence and structure orthology
Authors: Andorf Carson M , Sen Shatabdi , Hayford Rita K , Portwood John L , Cannon Ethalinda K , Harper Lisa C , Gardiner Jack M , Sen Taner Z , Woodhouse Margaret R
Published: November 2022

Methods to predict orthology play an important role in bioinformatics for phylogenetic analysis by identifying orthologs within or across any level of biological classification. Sequence-based reciprocal best hit approaches are commonly used in functional annotation since orthologous genes are expected to share functions. The process is limited as it relies solely on sequence data and does not consider structural information and its role in function. Previously, determining protein structure was highly time-consuming, inaccurate, and limited to the size of the protein, all of which resulted in a structural biology bottleneck. With the release of AlphaFold, there are now over 200 million predicted protein structures, including full proteomes for dozens of key organisms. The reciprocal best structural hit approach uses protein structure alignments to identify structural orthologs. We propose combining both sequence- and structure-based reciprocal best hit approaches to obtain a more accurate and complete set of orthologs across diverse species, called Functional Annotations using Sequence and Structure Orthology (FASSO). Using FASSO, we annotated orthologs between five plant species (maize, sorghum, rice, soybean, Arabidopsis) and three distance outgroups (human, budding yeast, and fission yeast). We inferred over 270,000 functional annotations across the eight proteomes including annotations for over 5,600 uncharacterized proteins. FASSO provides confidence labels on ortholog predictions and flags potential misannotations in existing proteomes. We further demonstrate the utility of the approach by exploring the annotation of the maize proteome.
Inflammation in the tumor-adjacent lung as a predictor of clinical outcome in lung adenocarcinoma
Authors: Dolgalev Igor , Zhou Hua , Shenker-Tauris Nina , Le Hortense , Sakellaropoulos Theodore , Coudray Nicolas , Zhu Kelsey , Vasudevaraja Varshini , Yeaton Anna , Goparaju Chandra V. , Li Yonghua , Sulaiman Imran , Tsay Jun-Chieh J. , Meyn Peter , Mohamed Hussein , Sydney Iris , Ramaswami Sitharam , Narula Navneet , Kulicke Ruth , Davis Fred P. , Stransky Nicolas , Smolen Gromoslaw A. , Cheng Wei-Yi , Cai James , Punekar Salman , Velcheti Vamsidhar , Poirier J.T. , Neel Ben , Wong Kwok-Kin , Chiriboga Luis , Heguy Adriana , Papagiannakopoulos Thales , Snuderl Matija , Segal Leopoldo N. , Moreira Andre L. , Pass Harvey I. , Tsirigos Aristotelis
Published: November 2022

Early-stage lung adenocarcinoma is typically treated by surgical resection of the tumor. While in the majority of cases surgery can lead to cure, approximately 30% of patients progress. Despite intense efforts to map the genetic landscape of early-stage lung tumors, there has been limited success in discovering accurate biomarkers that can predict clinical outcomes. Meanwhile, the role of the tumor-adjacent tissue in cancer progression has been largely ignored. To test whether tumor-adjacent tissue can be informative of progression-free survival and to probe the underlying molecular pathways involved, we designed a multi-omic study in both tumor and matched tumor-adjacent histologically normal lung tissue from the same patient. Our study includes 143 treatment naive stage I cases with long-term patient follow-up and is, to our knowledge, the largest such study with the longest follow-up. We performed a comprehensive histologic characterization of all tumors, mapped the mutational landscape and probed the transcriptome of both tumor and adjacent normal tissue. We evaluated the predictive power of each data modality and showed that the transcriptome of tumor-adjacent histologically normal lung tissue is the only reliable predictor of clinical outcome. Unbiased discovery of co-expressed gene modules revealed that inflammatory pathways are upregulated in the tumor-adjacent tissue of patients at high risk for disease progression. Furthermore, single-cell transcriptome analysis in the tumor-adjacent lung demonstrated that progression-associated inflammatory signatures were broadly expressed by both immune and non-immune cells including mesothelial cells, alveolar type 2 cells and fibroblasts, CD1 dendritic cells and MAST cells. Collectively, our studies suggest that molecular profiling of tumor-adjacent tissue can identify patients that are at high risk for disease progression.
Genetic pathways regulating the longitudinal acquisition of cocaine self-administration in inbred and recombinant inbred mice
Authors: Khan Arshad H. , Bagley Jared R. , LaPierre Nathan , Gonzalez-Figueroa Carlos , Spencer Tadeo C. , Choudhury Mudra , Xiao Xinshu , Eskin Eleazar , Jentsch James D. , Smith Desmond J.
Published: November 2022

To identify genetic pathways for addiction, we analyzed intravenous self-administration of cocaine or saline in a panel of 84 inbred and recombinant inbred mouse strains over 10 days. We integrated the behavior data with RNA-Seq data from the medial frontal cortex and nucleus accumbens from 41 strains. The self-administration of cocaine and saline showed distinct genetic bases. We maximized power to map loci for cocaine intake by using a linear mixed model to account for this longitudinal phenotype while correcting for population structure. A total of 15 unique significant loci were identified in the genome-wide association study (GWAS). A transcriptome-wide association study (TWAS) highlighted theTrpv2ion channel as a key locus for cocaine self-administration from the GWAS. In addition, 17 genes supplementary to the GWAS were identified includingArhgef26, Slc18b1andSlco5a1. We found numerous instances where alternate splice site selection or RNA editing altered transcript abundance. Our work emphasizes the importance ofTrpv2, a known cannabinoid receptor, for the response to cocaine as well as identifying further relevant loci.
Nucleation of Biomolecular Condensates from Finite-Sized Simulations
Authors: Li Lunna , Paloni Matteo , Finney Aaron R. , Barducci Alessandro , Salvalaglio Matteo
Published: November 2022

The nucleation of protein condensates is a concentration-driven process of assembly. When modelled in the canonical ensemble, condensation is affected by finite-size effects. Here, we present a general and efficient route to obtain ensemble properties of protein condensates in the macroscopic limit from finite-sized nucleation simulations. The approach is based on a theoretical description of droplet nucleation in the canonical ensemble and enables estimating thermodynamic and kinetic parameters, such as the macroscopic equilibrium density of the dilute protein phase, the condensates surface tension and nucleation free energy barriers. We apply the method to coarse-grained simulations of NDDX4 and FUS-LC, two phase-separating disordered proteins with different physicochemical characteristics. Our results show that NDDX4 condensate droplets, characterised by lower surface tension, higher solubility, and faster monomer exchange dynamics than FUS-LC, form with negligible nucleation barriers. In contrast, FUS-LC condensates form via an activated process over a wide range of concentrations.

Abstract Figure

Graphical Table of Contents.
A simple approach for image-based modelling of the heart that enables robust simulation of highly heterogeneous electrical excitation
Authors: Colman Michael A , Benson Alan P
Published: November 2022

Remodelling of cardiac tissue structure, including intercellular electrical coupling, is a major determinant of the complex and heterogeneous excitation patterns associated with cardiac arrhythmias. Evaluation of the precise mechanisms by which local tissue structure determines global arrhythmic excitation patterns is a major challenge that may be critically important for the development of effective treatment strategies. Computational modelling is a key tool in the study of cardiac arrhythmias, yet the established approaches for organ-scale modelling are unsuitable to capture the impact of local conduction heterogeneities; a novel approach is required to provide this multi-scale mechanistic insight.

We present a fundamentally simple yet powerful approach to simulate electrical excitation in highly heterogeneous whole-heart models that exploits the underlying discreteness of the myocardium. Preliminary simulations demonstrate that this approach can capture lower conduction velocities and reproduce wave breakdown and the development of re-entry in conditions where the established approaches cannot.
VarSCAT: A computational tool for sequence context annotations of genomic variants
Authors: Wang Ning , Khan Sofia , Elo Laura L.
Published: November 2022

The sequence contexts of genomic variants play important roles in understanding biological significances of variants and potential sequencing related variant calling issues. However, methods for assessing the diverse sequence contexts of genomic variants such as tandem repeats and unambiguous annotations have been limited. Herein, we describe the Variant Sequence Context Annotation Tool (VarSCAT) for annotating the sequence contexts of genomic variants, including breakpoint ambiguities, flanking sequences, variant nomenclatures, adjacent variants, and tandem repeats with user customizable options. Our analysis demonstrate that VarSCAT is more versatile and customizable than current methods or strategies for annotating variants in short tandem repeat (STR) regions. Variant sequence context annotations of high-confidence human variant sets with VarSCAT revealed that more than 75% of all human individual germline and clinically relevant insertions and deletions (indels) have breakpoint ambiguities. Moreover, we illustrate that more than 80% of human individual germline small variants in STR regions are indels and that the sizes of these indels correlated with STR motif sizes. VarSCAT is available athttps://github.com/elolab/VarSCAT.

Author Summary

The sequence contexts have significant impacts on the biological and technical aspects of genomic variants. The sequence contexts, such as tandem repeats or nearby indels, may increase the mutation rate of a region compared to other genome regions. Besides, variants in specific sequence contexts like STRs may also have distinguished biological consequences, which can lead to certain human diseases and thus they may be used as biomarkers for disease diagnosis and treatments. Moreover, potential ambiguous variant representations such as equivalent or redundant indels are also related with their sequence contexts, which may complicate variant harmonization from different sources. Our previous study demonstrated that more than half of false positive indel calls detected through next generation sequencing data are related with STRs. Thus, the sequence contexts of genomic variants are important and cannot be ignored. However, the current methods or strategies for assessing the sequence contexts of genomic variants are limited and not feasible to use. Here, we developed a computational tool VarSCAT for sequence contexts annotation of genomic variants. Our tool provides diverse sequence contexts annotations providing users information to further explore the variants of their interests. By applying VarSCAT to high confidence human variant sets, we demonstrate the influence of sequence context of genomic variants and emphasize the importance of sequence context assessment.
Extinction drives a discontinuous temporal pattern of species-area relationships in a microbial microcosm system
Authors: Deng Wei , Li Na , Zhang Chao-Zhi , An Rui , Yang Xiao-Yan , Xiao Wen
Published: November 2022

The species area relationship (SAR) can be a general law in ecology only if its formation mechanisms are clarified. Essentially, the SAR addresses the relationship between regional area and biodiversity, which is shaped by processes of speciation, extinction and dispersal. Since those three processes has temporal dynamics, we propose the hypothesis that the occurrence of SAR should also have temporal dynamics. Here, we designed independent closed microcosm systems, in which dispersal/speciation can be excluded/neglected, to reveal the role of extinction in shaping the temporal dynamics pattern of SAR. We find that extinction can shape SAR in this system independently. Due to the temporal dynamics of the extinction, SAR was temporally discontinuous. We also observe that small-scale extinctions modified community structure to promote ecosystem stability and shaped SAR, while mass extinction pushed the microcosm system into the next successional stage and dismissed SAR. Our result suggested that SAR could serve as an indicator of ecosystem stability; moreover, temporal discontinuity can be the explaination for many controversies in SAR studies.
PIK3R3is a candidate regulator of platelet count in people of Bangladeshi ancestry
Authors: Burley Kate , Fitzgibbon Lucy , van Heel David ,   Genes & Health Research Team, Vuckovic Dragana , Mumford Andrew D
Published: November 2022

Platelets are mediators of cardiovascular disease and are regulated by complex sets of interacting genes. To reveal new regulatory loci for platelet count (PLT), we performed genome-wide association studies (GWAS) in 20,218 Bangladeshi (BAN) and 9,198 Pakistani (PAK) individuals from the Genes and Health study. Most significantly associated loci (p <5 ×10−8) replicated findings in prior transethnic GWAS. However, the BAN locus defined by rs946528 (chr1:46019890) did not associate with PLT in the PAK analysis but was in the same linkage disequilibrium block as PLT-associated variants in prior East Asian GWAS. The single independent association signal was refined to a 95% credible set of 343 variants spanning eight coding genes. Functional annotation, mapping to megakaryocyte regulatory regions and colocalization with whole blood eQTLs identified the most likely mediator of the PLT phenotype to bePIK3R3encoding a regulator of phosphoinositol 3-kinase, widely linked elsewhere to adverse cardiovascular phenotypes.
From Pigs to Silkworms: Cognition and Welfare across 10 Farmed Taxa
Authors: Miller Rachael , Schiestl Martina , Trevarthen Anna , Gaffney Leigh , Lavery J. Michelle , Fischer Bob , Schnell Alexandra
Published: November 2022

Billions of animals across many taxa are extensively farmed, with critical impacts on animal welfare. Societal efforts to reduce animal suffering lack rigorous and systematic approaches that facilitate maximising welfare improvements, such as informed funding allocation decisions. We present a multi-measure, cross-taxa framework for modelling differences in pain, suffering, and related cognition to assess whether certain animals have larger welfare ranges (how well or badly animals can fare). Measures include behavioural flexibility, cognitive sophistication, and general learning. We evaluated 90 empirically detectable proxies for cognition and welfare range (henceforth ‘proxies’) in pigs, chickens, carp, salmon, octopus, shrimp, crabs, crayfish, bees, and silkworms. We grouped a subset of proxies into: A) 10 ideal proxies and B) 10 less ideal proxies but with sufficient data for interspecies comparisons. We graded the strength of evidence per proxy across taxa, and constructed a cognition and welfare range profile, with overall judgement scores (ranging from likely no/low confidence to yes/very high confidence). We discuss the implications of comparisons and highlight key avenues for future research. This work is timely, given recent indications of significant political will towards reducing animal suffering, such as the inclusion of cephalopods and decapods in the Animal Welfare (Sentience) Bill following a UK government-commissioned research review. Given the novelty and robustness of our review, we believe it sets a new standard for investigating interspecies comparisons of cognition and welfare ranges and helps inform future research. This should help streamline funding allocations and improve the welfare of millions of farmed animals.

Graphical/ Visual Abstract and Caption

Cognition and welfare in farmed animals - from pigs to silkworms (Free stock images:http://www.pixabay.com)
Preselection of QTL markers enhances accuracy of genomic selection in Norway spruce
Authors: Chen Zhi-Qiang , Klingberg Adam , Hallingbäck Henrik R. , Wu Harry X.
Published: November 2022

Genomic prediction (GP) or genomic selection is a method to predict the accumulative effect of all quantitative trait loci (QTLs) effects by capturing the linkage disequilibrium between markers and QTLs. Thus, marker preselection is considered a promising method to capture Mendelian segregation effects, especially for an oligogenic trait. Using QTLs detected in the genome-wide association study (GWAS) could improve genomic prediction, including informative marker selection and adding a QTL with the largest effect size as a fixed effect. Here, we performed GWAS and genomic selection studies in a population with 904 clones from 32 full-sib families using a newly developed 50k SNP Norway spruce array. In total, GWAS identified 41 SNPs associated with budburst stage (BB) and the SNP with the largest effect size explained 5.1% of the phenotypic variation (PVE). For the other five traits like growth and wood quality traits, only 2 – 13 SNPs were detected and PVE of the strongest effects ranged from 1.2% to 2.0%. GP with approximately 100 preselected SNPs based on the smallestp-values from GWAS showed the largest predictive ability (PA) for the oligogenic trait BB. But for the other polygenic traits, approximate 2000-4000 preselected SNPs, indicated by the smallest Akaike information criterion to offer the best model fit, still resulted in PA being similar to that of GP models using all markers. Analyses on both real-life and simulated data also showed that the inclusion of a large QTL SNP in the model as a fixed effect could improve PA and accuracy of GP provided that the PVE of the QTL was ≥2.5%.
BeEM: fast and faithful conversion of mmCIF format structure files to PDB format
Authors: Zhang Chengxin
Published: November 2022

Although mmCIF is the current official format for deposition of protein and nucleic acid structures to the Protein Data Bank (PDB) database, the legacy PDB format is still the primary supported format for many structural bioinformatics tools. Therefore, reliable software to convert mmCIF structure files to PDB files is needed. Unfortunately, existing conversion programs fail to correctly convert many mmCIF files, especially those with many atoms and/or long chain identifies. This study proposed BeEM, which converts any mmCIF format structure files to PDB format. BeEM conversion faithfully retains all atomic and chain information, including chain IDs with more than 2 characters, which are not supported by any existing mmCIF to PDB converters. The conversion speed of BeEM is at least ten times faster than existing converters such as MAXIT and Phenix. BeEM is available under the BSD licence athttps://github.com/kad-ecoli/BeEM/.
SARS-CoV-2 vaccination of laboratory rhesus monkeys (Macaca mulatta): Monitoring and efficacy
Authors: Oh Dan Qi Priscilla , Grothe Iris , Lukaß Herbert , Kreiter Andreas K. , Hoffmann Markus , Wegener Detlef
Published: November 2022

The availability of effective vaccines and a high vaccination rate allowed the recent mitigation, or even withdrawal, of many protective measures for containing the SARS CoV-2 pandemic. At the same time, new and highly mutated variants of the virus are found to have significantly higher transmissibility and reduced vaccine efficacy, thus causing high infection rates during the third year of the pandemic. The combination of reduced measures and increased infectivity poses a particular risk for unvaccinated individuals, including animals susceptible to the virus. Among the latter, non-human primates (NHPs) are particularly vulnerable. They serve as important models in various fields of biomedical research and because of their cognitive capabilities, they receive particular attention in animal welfare regulations around the world. Yet, although they played an extraordinarily important role for developing and testing vaccines against SARS-CoV-2, the protection of captive rhesus monkeys against Covid-19 has rarely been discussed. We here report upon twofold mRNA vaccination of a cohort of 19 rhesus monkeys (Macaca mulatta) against infection by SARS-CoV-2. All animals were closely monitored on possible side effects of vaccination, and were tested for neutralising antibodies against the virus. The data show that vaccination of rhesus monkeys is a safe and reliable measure to protect these animals against SARS-CoV-2.
OpenMEA: Open-Source Microelectrode Array Platform for Bioelectronic Interfacing
Authors: O’Leary Gerard , Khramtsov Iouri , Ramesh Rakshith , Perez-Ignacio Aidan , Shah Prajay , Moradi Chameh Homeira , Gierlach Adam , Genov Roman , Valiante Taufik A.
Published: November 2022

Bioelectronic interfaces have the potential to revolutionize the treatment of medical disorders and augment physiology. Implantable devices such as pacemakers and deep brain stimulators have already been deployed to control activity in diseases including Parkinson’s disease and epilepsy. These devices typically operate by delivering electrical stimulation at pre-programmed intervals (known as open-loop stimulation). Recent advances in machine learning and low-power integrated circuits have led to the emergence of personalized medical devices that monitor the user’s state and stimulate in response to measured biological activity (known as closed-loop stimulation). There are two key questions that require fundamental research to achieve breakthroughs in personalized devices: 1) What biomarkers and algorithms are best suited to detecting biological states (e.g. seizures in epilepsy)? and 2) What types of electrical stimuli are optimal for controlling these states? The answer to these questions can be exploredin vitrousing multielectrode array (MEA) systems that interface with biological tissue with reduced experimental complexity, better reproducibility, and fewer confounding variables present in whole organisms. However, existing MEA systems have functional limitations and closed-source designs that prevent researchers from developing improvements. This paper introduces OpenMEA, an open-source platform for closed-loop bioelectronics research. OpenMEA includes designs for the components necessary to build a benchtopin vitrolaboratory, including electrophysiological recording and stimulation electronics, a microfluidic perfusion system, and physical designs for multielectrode arrays. The system is demonstrated with the electrical recording and stimulation of epileptogenic human and rodent brain slices. The aim of OpenMEA is to democratize bioelectronic research tools to accelerate the deployment of devices for the treatment of disorders and beyond.
PSYCHOLOGICAL FACTORS PREDICTING OUTCOMES OF CONSERVATIVE TREATMENT IN FROZEN SHOULDER PATIENTS (PSY-FS)
Authors: Brindisino Fabrizio , Silvestri E , Fioretti A , Giovannico G , Di Giacomo G , Feller D , Chiarotto A
Published: November 2022

Frozen shoulder contracture syndrome (FSCS) is characterized by underhand onset, severe shoulder daily and night pain, active and passive range of motion (ROM) limitation, disturbing sleep, and shoulder-related disability.

FSCS has a cryptogenetics etiology and is more prevalent in people with diabetes, autoimmune and thyroid disease, with higher prevalence in the age range between 50 and 60. Notably no deal is about higher incidence in people with physically low activity and female sex. Moreover, although some patients report complete symptom recovery, others report residual motion impairments and pain.

Research on prognostic factors was applied on FSCS, and Eljabu et colleagues (2016) stated that diabetes, comorbidities, bilateral presentation and onset higher pain and disability are negative prognostic factors that could direct patient to early surgery; however, little is known about the prognostic influence of psychological factors in FSCS patients. On the other hand, in other shoulder pathologies, the presence of psychological factors is well documented, and evidence confirms that some of these features could represent prognostic factors that impact the prognosis.

A recent systematic review reported that psychological factors were associated with increased pain perception and decreased function and quality of life at baseline in patients with FSCS, and pain-beliefs seem to be associated with a worst perception of arm function; however, little is known about the prognostic value of such factors in FSCS recovery.

Knowing about the presence and the role of all types of prognostic factors is important because they can aid treatment and lifestyle decisions, improving individual risk prediction, providing novel targets for new treatments, and enhancing collaboration between different professionals.

This study aims to determine if pain, function, disability, quality of life, ROM and time for recovery were influenced by psychological factors in FSCS patients.
Attendance-related healthcare resource utilisation and costs in patients with long QT syndrome in Hong Kong: A retrospective cohort study
Authors: Chung Cheuk To , Chou Oscar Hou In , Lee Teddy Tai Loy , Radford Danny , Jeevaratnam Kamalan , Wong Wing Tak , Cheng Shuk Han , Mok Ngai Shing , Liu Tong , Tse Gary , Lee Sharen
Published: November 2022

Introduction

The understanding of healthcare resource utilisation and its related costs is crucial for optimizing resource allocation in the healthcare setting. There is currently a paucity of published studies investigating healthcare costs related to long QT syndrome (LQTS).

Method

This was a retrospective study of LQTS patients from Hong Kong, China. The healthcare resource utilisation for Accident and Emergency (A&E), inpatient and specialist outpatient settings across a 19-year period was extracted and analysed. Costs in US dollars were calculated using unit costs.

Results

The cohort consists of 125 LQTS patients with a mean presentation age of 26.7 ± 22.0 years old. Of these, 45 patients presented with ventricular tachycardia/ventricular fibrillation (VT/VF) and 44 patients had an implantable cardioverter-defibrillator (ICD) implementation. At the individual patient level, the median annualised costs were $69 (30-183) at the A&E setting, $10270 (2248-64006) at the inpatient setting and $675 (393-1329) at the special outpatient setting. Patients who presented with VT/VF initially had significantly higher annualised median costs in the inpatient ($59843 [13812-214930] vs. $5480 [1162-23111], p<0.0001) and specialist outpatient setting ($823 [539-1694] vs $609 [383-1269], p=0.133) compared to patients without VT/VF initially.

Conclusion

There is an increasing healthcare demand in the inpatient and specialist outpatient settings for LQTS patients. The most expensive attendance type was inpatient setting stay at $10270 per year. The total median annualised cost of LQTS patients without VT/VF was 90% lower compared to patients with VT/VF.
Decoding the variant-to-function relationship forLIPA, a risk locus for coronary artery disease
Authors: Li Fang , Flynn Elise , Ha Philip , Zebak Mazal N. , Cheng Haoxiang , Xue Chenyi , Shi Jianting , Wu Xun , Wang Ziyi , Meng Yujiao , Cui Jian , Zhu Yizhou , Rozenblyum Annie , Chun Jeana , Hernandez-Ono Antonio , Javaheri Ali , Razani Babak , Westerterp Marit , Bauer Robert C , Suh Yousin , Hao Ke , Lappalainen Tuuli , Zhang Hanrui
Published: November 2022

Translating human genomic discoveries into mechanistic insights requires linking genetic variations to candidate genes and their causal functional phenotypes. Genome-wide association studies have consistently identifiedLIPAas a risk locus for coronary artery disease (CAD), with previous expression quantitative trait loci (eQTL) analyses prioritizingLIPAas a candidate causal gene. However, functional studies elucidating the causal variants, regulatory mechanisms, target cell types, and their causal impact on atherosclerosis have been lacking. To address this gap, we applied functional genomics and experimental mouse models to establish the variant-to-function relationship at theLIPAlocus. Our findings show that CAD risk alleles in theLIPAlocus increase LIPA expression and enzyme activity specifically in monocytes/macrophages by enhancing PU.1 binding to an intronic enhancer region that interacts with theLIPApromoter. In myeloidLipa-overexpressing mice, we observed larger atherosclerotic lesions accompanied by altered macrophage function, including increased macrophage accumulation due to enhanced monocyte recruitment, reduced neutral lipid accumulation, and upregulation of integrin and extracellular matrix pathways. Our work establishes a direct causal link betweenLIPArisk alleles and increased monocyte/macrophage LIPA that exacerbates atherosclerosis, bridging human functional genomic evidence to the mechanistic understanding of CAD.

Graphical Abstract