bluuebunny/crossref_metadata_2025 huggingface dataset:
A validated integrated clinical and molecular glioblastoma long-term survival-predictive nomogram
Authors: Ferguson Sherise D , Hodges Tiffany R , Majd Nazanin K , Alfaro-Munoz Kristin , Al-Holou Wajd N , Suki Dima , de Groot John F , Fuller Gregory N , Xue Lee , Li Miao , Jacobs Carmen , Rao Ganesh , Colen Rivka R , Xiu Joanne , Verhaak Roel , Spetzler David , Khasraw Mustafa , Sawaya Raymond , Long James P , Heimberger Amy B
Published: October 2020

Background

Glioblastoma (GBM) is the most common primary malignant brain tumor in adulthood. Despite multimodality treatments, including maximal safe resection followed by irradiation and chemotherapy, the median overall survival times range from 14 to 16 months. However, a small subset of GBM patients live beyond 5 years and are thus considered long-term survivors.

Methods

A retrospective analysis of the clinical, radiographic, and molecular features of patients with newly diagnosed primary GBM who underwent treatment at The University of Texas MD Anderson Cancer Center was conducted. Eighty patients had sufficient quantity and quality of tissue available for next-generation sequencing and immunohistochemical analysis. Factors associated with survival time were identified using proportional odds ordinal regression. We constructed a survival-predictive nomogram using a forward stepwise model that we subsequently validated using The Cancer Genome Atlas.

Results

Univariate analysis revealed 3 pivotal genetic alterations associated with GBM survival: both high tumor mutational burden (P = .0055) and PTEN mutations (P = .0235) negatively impacted survival, whereas IDH1 mutations positively impacted survival (P < .0001). Clinical factors significantly associated with GBM survival included age (P < .0001), preoperative Karnofsky Performance Scale score (P = .0001), sex (P = .0164), and clinical trial participation (P < .0001). Higher preoperative T1-enhancing volume (P = .0497) was associated with shorter survival. The ratio of TI-enhancing to nonenhancing disease (T1/T2 ratio) also significantly impacted survival (P = .0022).

Conclusions

Our newly devised long-term survival-predictive nomogram based on clinical and genomic data can be used to advise patients regarding their potential outcomes and account for confounding factors in nonrandomized clinical trials.
Risk Factors for Severe Acute Respiratory Syndrome Coronavirus 2 Infection in Hospital Workers: Results From a Screening Study in New Jersey, United States in Spring 2020
Authors: Barrett Emily S , Horton Daniel B , Roy Jason , Xia Weiyi , Greenberg Patricia , Andrews Tracy , Gennaro Maria Laura , Parmar Veenat , Russell William D , Reilly Nancy , Uprety Priyanka , Gantner John J , Stockman Lydia , Trooskin Stanley Z , Blaser Martin J , Carson Jeffrey L , Panettieri Reynold A
Published: October 2020

Background

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a critical concern among healthcare workers (HCWs). Other studies have assessed SARS-CoV-2 virus and antibodies in HCWs, with disparate findings regarding risk based on role and demographics.

Methods

We screened 3904 employees and clinicians for SARS-CoV-2 virus positivity and serum immunoglobulin (Ig)G at a major New Jersey hospital from April 28 to June 30, 2020. We assessed positive tests in relation to demographic and occupational characteristics and prior coronavirus disease 2019 symptoms using multivariable logistic regression models.

Results

Thirteen participants (0.3%) tested positive for virus and 374 (9.6%) tested positive for IgG (total positive: 381 [9.8%]). Compared with participants with no patient care duties, the odds of positive testing (virus or antibodies) were higher for those with direct patient contact: below-median patient contact, adjusted odds ratio (aOR) = 1.71 and 95% confidence interval [CI] = 1.18–2.48; above-median patient contact, aOR = 1.98 and 95% CI = 1.35–2.91. The proportion of participants testing positive was highest for phlebotomists (23.9%), maintenance/housekeeping (17.3%), dining/food services (16.9%), and interpersonal/support roles (13.7%) despite lower levels of direct patient care duties. Positivity rates were lower among doctors (7.2%) and nurses (9.1%), roles with fewer underrepresented minorities. After adjusting for job role and patient care responsibilities and other factors, Black and Latinx workers had 2-fold increased odds of a positive test compared with white workers. Loss of smell, taste, and fever were associated with positive testing.

Conclusions

The HCW categories at highest risk for SARS-CoV-2 infection include support staff and underrepresented minorities with and without patient care responsibilities. Future work is needed to examine potential sources of community and nosocomial exposure among these understudied HCWs.
Evaluation of a Hyperbaric Oxygen Therapy Intervention in Individuals with Fibromyalgia
Authors: Curtis K , Katz J , Djaiani C , O’Leary G , Uehling J , Carroll J , Santa Mina D , Clarke H , Gofeld M , Katznelson R
Published: October 2020

Objective

To evaluate the feasibility and safety of hyperbaric oxygen therapy (HBOT) in patients with fibromyalgia (FM).

Design

A cohort study with a delayed treatment arm used as a comparator.

Setting

Hyperbaric Medicine Unit, Toronto General Hospital, Ontario, Canada.

Subjects

Eighteen patients diagnosed with FM according to the American College of Rheumatology and a score ≥60 on the Revised Fibromyalgia Impact Questionnaire.

Methods

Participants were randomized to receive immediate HBOT intervention (n = 9) or HBOT after a 12-week waiting period (n = 9). HBOT was delivered at 100% oxygen at 2.0 atmospheres per session, 5 days per week, for 8 weeks. Safety was evaluated by the frequency and severity of adverse effects reported by patients. Feasibility was assessed by recruitment, retention, and HBOT compliance rates. Both groups were assessed at baseline, after HBOT intervention, and at 3 months’ follow-up. Validated assessment tools were used to evaluate pain, psychological variables, fatigue, and sleep quality.

Results

A total of 17 patients completed the study. One patient withdrew after randomization. HBOT-related adverse events included mild middle-ear barotrauma in three patients and new-onset myopia in four patients. The efficacy of HBOT was evident in most of the outcomes in both groups. This improvement was sustained at 3-month follow-up assessment.

Conclusion

HBOT appears to be feasible and safe for individuals with FM. It is also associated with improved global functioning, reduced symptoms of anxiety and depression, and improved quality of sleep that was sustained at 3-month follow-up assessment.
Reactive arthritis and undifferentiated peripheral spondyloarthritis share human leucocyte antigen B27 subtypes and serum and synovial fluid cytokine profiles
Authors: Parida Jyoti Ranjan , Kumar Sandeep , Ahmed Sakir , Chaurasia Smriti , Mukherjee Ratnadeep , Singh Rajeev , Ravindran Balachandran , Aggarwal Amita , Misra Ramnath
Published: October 2020

Objectives

Peripheral SpA (pSpA) is comprised of ReA, PsA, enteritis-associated arthritis and undifferentiated pSpA (upSpA). ReA and upSpA share T cell oligotypes and metabolomics in serum and SF. We investigated HLA-B27 subtypes and cytokines in serum and SF that were compared between ReA and upSpA.

Methods

ReA and upSpA were compared in two cohorts. In cohort I (44 ReA and 56 upSpA), HLA-B27 subtyping was carried out. In cohort II (17 ReA and 21 upSpA), serum and SF cytokines were compared using a multiplex cytokine bead assay (27 cytokines). A total of 28 healthy controls with similar age and sex to cohort II were included for comparison of serum cytokine levels.

Results

In cohort I, HLA-B27 was positive in 81.8% (36/44) of ReA and 85.71% (48/56) of upSpA patients. HLA-B27 typing was successful in 70 patients (30 ReA and 40 uSpA). HLA-B*2705 was the most common, followed by HLA-B*2704 and HLA-B*2707. Frequencies were the same between ReA and upSpA. In cohort II, 14 cytokines were detectable in the serum of patients. The levels of eight cytokines were higher than in the controls. The cytokine levels of ReA and upSpA were similar. Sixteen cytokines were detectable in the SF of patients. There was no statistical difference in the levels between ReA and upSpA. The cytokine profiles in sera and SF were also similar among HLA-B27-positive and negative patients.

Conclusion

ReA and upSpA have similar HLA-B27 subtype associations and similar cytokine profiles. They should be considered as a single entity during studies as well as clinical management.
In anti-CCP+ at-risk individuals, radiographic bone erosions are uncommon and are not associated with the development of clinical arthritis
Authors: Di Matteo Andrea , Mankia Kulveer , Nam Jacqueline L , Cipolletta Edoardo , Garcia-Montoya Leticia , Duquenne Laurence , Rowbotham Emma , Emery Paul
Published: October 2020

Objectives

To investigate the prevalence, distribution and predictive value for the development of inflammatory arthritis (IA) of conventional radiography (CR) bone erosions (BE) in anti-CCP positive (CCP+) at-risk individuals with musculoskeletal (MSK) symptoms but without clinical synovitis.

Methods

Baseline CR of the hands and feet of 418 CCP+ at-risk individuals were analysed. The presence of US-BE was explored in the anatomical areas in which CR-BE were reported. Hands and feet CR at the time of progression were analysed in a subset of individuals who developed IA (73/123, 59.3%). Logistic regression analyses were performed to calculate the predictive value of baseline CR-BE for the development of IA in 394 CCP+ individuals with ≥1 follow-up visit.

Results

BE were detected in 17/418 (4.1%) CCP+ at-risk individuals (median Simple Erosions Narrowing Score-BE = 2.0, IQR: 1.0–2.0; median Sharp van der Heijde score-BE = 4.0, IQR: 3.0–8.5), most frequently in the foot joints (11/17, 64.7% individuals). A total of 123/394 (31.2%) CCP+ at-risk individuals developed IA; 7/17 (41.2%) with, and 116/377 (30.8%) without BE on CR (P = 0.37). US-BE were found in 4/7 (57.1%) individuals with CR-BE who developed IA, but only in 1/10 (10.0%) who did not. At the time of progression, new BE were detected in 4/73 (5.5%) CCP+ individuals on repeated CR. In the regression analyses, baseline CR-BE were not predictive for the development of IA.

Conclusions

In CCP+ at-risk individuals with MSK symptoms, CR-detected BE are uncommon and do not predict the development of IA.
Refugee Participation Revisited: The Contributions of Refugees to Early International Refugee Law and Policy
Authors: Harley Tristan
Published: October 2020

This article challenges the assumption that until relatively recently refugees or persons with lived refugee experience have not been involved in the development of international refugee law and policy. By drawing on primary source material – including the preparatory work for international legal instruments such as the 1933 Convention relating to the International Status of Refugees and the 1951 Convention relating to the Status of Refugees, along with the operational work of the League of Nations, the International Refugee Organization and the early years of United Nations High Commissioner for Refugees – this article argues that refugees and persons with lived refugee experience exercised significant influence and thought-leadership in the development of international refugee law and policymaking during the foundational years between 1921 and 1955. These contributions to the development of international refugee law and policy are significant because they not only reorient our understanding of the ways in which international law and policy pertaining to refugees has been developed and negotiated to date, but also because they provide a practical example of how refugees can more meaningfully be included in the creation of laws and policies that affect them going forward.
Geochemistry drives the allometric growth of the hydrothermal vent tubewormRiftia pachyptila(Annelida: Siboglinidae)
Authors: Rimskaya-Korsakova Nadezhda , Fontaneto Diego , Galkin Sergey , Malakhov Vladimir , Martínez Alejandro
Published: October 2020

The tubeworm Riftia pachyptila is a key primarily producer in hydrothermal vent communities due to the symbiosis with sulphur-oxidizing bacteria, which provide nourishment to the worm from sulphides, oxygen and carbon dioxide. These substances diffuse from the vent water into the bloodstream of the worm through their tentacular crowns, and then to the bacteria, hosted in a specialized organ of the worm, called a trophosome. The uptake rates of these substances depend on the surface/volume relationship of the tentacles. We here describe two morphotypes, ‘fat’ and ‘slim’, respectively, from the basalt sulphide-rich vents at 9 °N and 21 °N at the East Pacific Rise, and the highly sedimented, sulphide-poor vents at 27 °N in the Guaymas Basin. The ‘fat’ morphotype has a thicker body and tube, longer trunk and smaller tentacular crowns, whereas the ‘slim’ morphotype has shorter trunk, thinner body and tube, and presents longer tentacular crowns and has a higher number of tentacular lamellae. Given the dependence on sulphides for the growth of R. pachyptila, as well as high genetic connectivity of the worm’s populations along the studied localities, we suggest that such morphological differences are adaptive and selected to keep the sulphide uptake near to the optimum values for the symbionts. ‘Fat’ and ‘slim’ morphotypes are also found in the vestimentiferan Ridgeia piscesae in similar sulphide-rich and poor environments in the northern Pacific.
Bedding Plant Production and the Challenge of Fungal Diseases
Authors: Guarnaccia Vladimiro , Hand Francesca Peduto , Garibaldi Angelo , Gullino M. Lodovica
Published: November 2020

Bedding plants are a major group of ornamentals produced in greenhouses or nurseries worldwide and planted outdoors. Their economic importance has increased continuously in the last four decades in both the United States and the European Union. These plants are subject to a broad number of diseases that can negatively impact their production and cultivation. The initial steps of production strongly influence the health status of these plants and, consequently, their aesthetic appeal, which is a strong requisite for consumers. Seeds, cuttings, and other forms of propagative material, along with production systems and growing media, can influence the phytosanitary status of the final product. In this article, case studies of soilborne and foliar diseases are presented together with preventive measures to achieve innovative disease management strategies. Quarantine restrictions and eradication measures are also discussed, in consideration of the high likelihood for ornamental plants to be long-distance vectors of new pathogens and pests.
Information Needs and the Use of Documentation to Support Collaborative Decision-Making
Authors: Thate Jennifer A. , Couture Brittany , Schnock Kumiko O. , Rossetti Sarah Collins
Published: November 2020

It is clear that interdisciplinary communication and collaboration have the potential to mitigate healthcare-associated harm, yet there is limited research on how communication through documentation in the patient record can support collaborative decision making. Understanding what information is needed to support collaborative decision making is necessary to design electronic health information systems that facilitate effective communication and, ultimately, safe care. To explore this issue, we focused on information needs related to central venous catheter management and the prevention of central line–associated blood stream infections. Semistructured interviews were conducted with nurses working in an intensive care unit. Interview transcripts were analyzed using inductive thematic analysis. Three themes were identified: (1) challenges managing documentation in multiple places in the absence of formal documentation processes for central venous catheter management; (2) lack of standardized decision-making processes for managing central venous catheters; and (3) oral communication holds it together. Our findings provide a foundation for the development of EHR functional requirements that enhance communication regarding the management of central venous catheters and facilitate the prompt removal of unnecessary lines.
Effect of Brexpiprazole on Prolactin and Sexual Functioning
Authors: Clayton Anita H. , Ivkovic Jelena , Chen Dalei , George Vinu , Hobart Mary
Published: October 2020

Purpose/Background

Evidence supports use of adjunctive atypical antipsychotics in major depressive disorder (MDD). Impaired sexual functioning is common in MDD and may be worsened by antipsychotic adverse effects. We evaluated the effect of brexpiprazole on prolactin and sexual functioning in patients with MDD.

Methods/Procedures

In short-term studies, patients received adjunctive brexpiprazole 1, 2, or 3 mg or placebo. The long-term study was a flexible-dose (0.5–3 mg/d) open-label extension (OLE). Change from baseline and shifts in prolactin status and prolactin-related treatment-emergent adverse events (TEAEs) were assessed. Sexual functioning was assessed by the Massachusetts General Hospital Sexual Functioning Questionnaire.

Findings/Results

Median changes in prolactin levels from baseline to week 6 in short-term studies were as follows: brexpiprazole, 5.99 ng/mL (females) and 1.61 ng/mL (males); placebo, −0.15 ng/mL (females) and −0.08 ng/mL (males).

Median changes from baseline to week 52 in the OLE were as follows: 0.27 ng/mL (females) and 0.27 ng/mL (males). Prolactin levels in patients with baseline prolactin greater than 1× upper limit of normal values tended to decrease over time.

The proportion of brexpiprazole-treated patients with greater than 3× upper limit of normal postbaseline prolactin values in short-term studies for both sexes was low (0%–0.3%) and did not differ from placebo: OLE, 0.5% (females) and 0.8% (males).

In short-term studies, the incidence of prolactin-related TEAEs was 3.1% for brexpiprazole and 0.7% for placebo (OLE, 3.1%). There were overall numerical improvements from baseline in sexual functioning for females and males after short- and long-term brexpiprazole treatment, with statistically significant improvements for brexpiprazole versus placebo in females on the items ‘interest in sex’ (−0.19; 95% confidence interval [CI], −0.33 to −0.05; P = 0.0074), ‘sexually aroused’ (−0.17; 95% CI, −0.30 to −0.03; P = 0.0154), and ‘overall sexual satisfaction’ (−0.16; 95% CI, −0.30 to −0.03; P = 0.0184).

Implications/Conclusions

There were small changes in prolactin levels, low proportions of patients with postbaseline elevated prolactin values, low incidences of prolactin-related TEAEs, and modest improvements in sexual functioning with adjunctive brexpiprazole in MDD.
One-Year Outcome and Adherence to Pharmacological Guidelines in First-Episode Schizophrenia
Authors: Drosos Petros , Brønnick Kolbjørn , Joa Inge , Johannessen Jan Olav , Johnsen Erik , Kroken Rune Andreas , Stain Helen Joy , Hegelstad Wenche Ten Velden , Larsen Tor Ketil
Published: October 2020

Background

Remission in schizophrenia is difficult to achieve. Antipsychotic drugs are critical in the treatment of schizophrenia. International guidelines for the pharmacological treatment of schizophrenia recommend a 3-step algorithm with clozapine being the third-line antipsychotic agent. This study investigated the 1-year outcome and the application of the guidelines for the pharmacological treatment of nonremitted first-episode schizophrenia (FES) patients during the first year of follow-up.

Methods

A sample of 78 FES patients from the Norwegian TIPS (Early Treatment and Intervention in Psychosis) 2 study was assessed at the end of the first year of follow-up. The symptom remission criteria were those defined by the Remission in Schizophrenia Working Group. The adherence to the pharmacological guidelines was assessed by reading the medical files and by a digital search of the words “clozapine,” “klozapin,” and “Leponex” in the hospital electronic data system.

Results

The majority (n = 53, 67.9%) of the patients included were nonremitted at the 1-year follow-up. The majority of the nonremitted patients received either none (7.5%), one (56.6%), or 2 types (15.1%) of antipsychotic drugs during the first year of follow-up. Only 2 (3.8%) received treatment with clozapine, and 3 (5.7%) in total were offered it.

Conclusions

For our FES sample, there was a low 1-year remission rate and a poor adherence to the pharmacological guidelines. Higher adherence to treatment guidelines with a more intensified antipsychotic treatment, which in some cases will include clozapine, will enhance the quality of treatment and may enhance the rates of remission for schizophrenia.
Finger clubbing in inflammatory bowel disease: association with upper small bowel lesions and need of surgery in Crohn’s disease
Authors: Romeo Samanta , Neri Benedetto , Mossa Michelangela , Calabrese Emma , Lolli Elisabetta , Sena Giorgia , Gesuale Cristina , Chiaramonte Carlo , Biancone Livia
Published: November 2020

Objective

Finger clubbing has been associated with inflammatory bowel disease (IBD).

Aims

In a prospective single-center study, we aimed to assess the frequency of finger clubbing in a cohort of IBD patients. Whether finger clubbing is associated with clinical characteristics of IBD was also investigated.

Methods

IBD patients with a detailed clinical history were enrolled. Finger clubbing was assessed by visual inspection. Data were expressed as median (range), chi-square, t-test. Multivariate logistic regression analysis was used to assess risk factors for finger clubbing, when considering demographic and clinical characteristics, smoking habits and chronic pulmonary diseases (CPD).

Results

Finger clubbing was searched in 470 IBD patients: 267 Crohn’s disease and 203 ulcerative colitis. Finger clubbing was more frequent in Crohn’s disease than in ulcerative colitis: 45/267 (16.8%) vs. 15/203 (7.3%) [odds ratio (OR), 2.54 (1.37–4.70); P = 0.003]. Crohn’s disease involved the ileum (59.9%), colon (4.5%), ileum-colon (25.8%) and upper gastrointestinal (GI) (9.8%). Ulcerative colitis extent included proctitis (E1) (13.4%), left-sided (E2) (43.3%) and pancolitis (E3) (43.3%). Upper GI lesions, but not other Crohn’s disease localizations, were more frequent in patients with finger clubbing [9/45 (20%) vs. 17/222 (7.7%); P = 0.032]. Crohn’s disease-related surgery was more frequent in patients with finger clubbing [36/45 (80%) vs. 107/222 (48.1%); P < 0.001]. In Crohn’s disease, the only risk factors for finger clubbing were upper GI lesions and Crohn’s disease-related surgery [OR, 2.58 (1.03–6.46), P = 0.04; OR, 4.07 (1.86–8.91), P = 0.006]. Ulcerative colitis extent was not associated with finger clubbing [E1: OR, 0.27 (0.02–3.44), P = 0.33; E2: OR, 0.93 (0.24–3.60), P = 0.92; E3:OR, 0.64 (0.22–1.86), P = 0.59]. In ulcerative colitis, but not in Crohn’s disease, finger clubbing was more frequent in smokers [13/15 (86.6%) vs. 99/188 (52.6%); P = 0.01] and in patients with CPD [5/15 (33.3%) vs. 16/188 (8.5%); P = 0.002]. Smoking and CPD were the only risk factors for finger clubbing in ulcerative colitis [OR, 7.18 (1.44–35.78), P = 0.01; OR, 10.93 (2.51–47.45), P = 0.001].

Conclusion

In the tested IBD population, finger clubbing was more frequent in Crohn’s disease than in ulcerative colitis. In Crohn’s disease, upper GI lesions and history of Crohn’s disease-related surgery were risk factors for finger clubbing, suggesting the possible role of finger clubbing as a subclinical marker of Crohn’s disease severity.
JINLING (Judicious INdex of Luminal INflammation Grade) score, an effective indicator to assess inflammation severity in Crohn’s disease
Authors: Gong Wenbin , Guo Kun , Zheng Tao , Xie Haohao , Li Weijie , Li Mengxuan , Hong Zhiwu , Ren Huajian , Gu Guosheng , Wang Gefei , Wu Xiuwen , Ren Jianan
Published: November 2020

Background

With the increasing demand for individualized treatment in Crohn’s disease, a score for accurate evaluation of inflammation grade will be of great significance. We have developed the JINLING score to assess inflammation severity for Crohn’s disease, which incorporates an endoscopic score (SES-CD) and a 2-item patient-reported outcome (PRO2). The aim of this study was to examine the performance of JINLING score in evaluating inflammation grade and the correlation with the clinical outcomes.

Methods

The correlation between JINLING score and Global Histologic Disease Activity Score (GHAS), fecal calprotectin (FCP), and C-reactive protein (CRP) level was performed in an exploration phase with a retrospective data set. The data on clinical outcomes including medication effects, Crohn’s disease-related surgery and biochemical results were collected from a single-center prospective validation cohort.

Results

JINLING score correlated significantly with FCP, CRP, and hemoglobin in the exploration cohort (all P < 0.05). The receiver operating characteristic (ROC) curves based on a threshold Crohn’s disease activity index value of 150, GHAS of 4, and FCP of 60 μg/g to identify disease activity, all showed a higher area under the curve with JINLING score than SES-CD or PRO2 alone. In the validation cohort, patients with high inflammation grade (JINLING ≥4) had higher GHAS, CRP, and FCP than low inflammation grade patients. High JINLING score was associated with an increased risk of treatment failure (hazard ratio 2.93; 95% confidence interval 1.13–7.61, P = 0.021).

Conclusion

This newly developed index served well for quantifying inflammation grade and predicting clinical outcomes. JINLING score has the potential to facilitate clinical decision-making and personalized therapy for Crohn’s disease patients.
Risk factors and characteristics associated with nonalcoholic fatty liver disease in patients with ischemic colitis
Authors: Zhao Xixian , Li Haiou , Zhou Yunjiao , Qiu Peishan , Zhang Mengna , Yang Zhenwei , Zhao Qiu , Liu Jing
Published: November 2020

Background

Ischemic colitis (IC) was investigated to be associated with dyslipidemia and subcutaneous adipose tissue. Nonalcoholic fatty liver disease (NAFLD) is associated with ischemic diseases such as coronary heart disease, ischemic stroke. But there is a paucity of data regarding the association between NAFLD and IC. NAFLD may be associated with the treatment and prognosis of IC. We investigated risk factors and characteristics associated with NAFLD in patients with IC.

Methods

Patients with IC (NAFLD: 34 and controls: 81) from Zhongnan Hospital were investigated retrospectively from January 2012 to December 2018. Clinical data were compared by chi-square tests or independent samples T-tests. Binary logistic regressions and Kaplan–Meier analysis were performed to evaluate risk factors and prognosis, respectively.

Results

NAFLD was diagnosed in 28.19% patients with IC. In the logistic regression analysis, hypertension [odds ratio (OR) 3.523; P = 0.019], elevated alanine aminotransferase (ALT) (OR 6.278; P = 0.048), elevated triglyceride (OR 4.667; P = 0.003) and increased weight (OR 1.055; P = 0.039) were risk factors of NAFLD in patients with IC. Patients with NAFLD were more likely to require the vasodilators (P = 0.011) and get a relapse of IC (P = 0.011).

Conclusion

NAFLD was found in 28.19% of patients with IC. Hypertension, increased weight, elevated ALT and triglyceride are independent predictors of NAFLD in patients with IC. NAFLD in patients with IC is associated with a greater probability of requiring for the vasodilators. NAFLD in IC and period of bowel rest are risk factors for the recurrence of IC.
Optically Pumped Magnetoencephalography in Epilepsy
Authors: Vivekananda Umesh , Mellor Stephanie , Tierney Tim M , Holmes Niall , Boto Elena , Leggett James , Roberts Gillian , Hill Ryan , Litvak Vladimir , Brookes Matthew J. , Bowtell Richard , Barnes Gareth R , Walker Matthew C
Published: October 2020

Our aim was to demonstrate the first use of Optically Pumped Magnetoencephalography (OP-MEG) in an epilepsy patient with unrestricted head movement. Current clinical MEG uses a traditional SQUID system for recording MEG signal, where sensors are cryogenically cooled and housed in a helmet in which the patient’s head is fixed. Here we use a different type of sensor (OPM), which operates at room temperature and can be placed directly on the patient’s scalp, permitting free head movement. We performed two 30 minute OP-MEG recording sessions in a patient with refractory focal epilepsy and compared these with clinical scalp EEG performed earlier. OP-MEG was able to identify analogous interictal activity to scalp EEG, and source localise this activity to an appropriate brain region. This is the first application of OP-MEG in human epilepsy. Future directions include simultaneous EEG/OP-MEG recording and prolonged OP-MEG telemetry.
Brilacidin, a COVID-19 Drug Candidate, Exhibits PotentIn VitroAntiviral Activity Against SARS-CoV-2
Authors: Bakovic Allison , Risner Kenneth , Bhalla Nishank , Alem Farhang , Chang Theresa L. , Weston Warren , Harness Jane A. , Narayanan Aarthi
Published: October 2020

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the newly emergent causative agent of coronavirus disease-19 (COVID-19), has resulted in more than one million deaths worldwide since it was first detected in 2019. There is a critical global need for therapeutic intervention strategies that can be deployed to safely treat COVID-19 disease and reduce associated morbidity and mortality. Increasing evidence shows that both natural and synthetic antimicrobial peptides (AMPs), also referred to as Host Defense Proteins/Peptides (HDPs), can inhibit SARS-CoV-2, paving the way for the potential clinical use of these molecules as therapeutic options. In this manuscript, we describe the potent antiviral activity exerted by brilacidin—ade novodesigned synthetic small molecule that captures the biological properties of HDPs—on SARS-CoV-2 in a human lung cell line (Calu-3) and a monkey cell line (Vero). These data suggest that SARS-CoV-2 inhibition in these cell culture models is primarily a result of the impact of brilacidin on viral entry and its disruption of viral integrity. Brilacidin has demonstrated synergistic antiviral activity when combined with remdesivir. Collectively, our data demonstrate that brilacidin exerts potent inhibition of SARS-CoV-2 and thus supports brilacidin as a promising COVID-19 drug candidate.

Highlights

Brilacidin potently inhibits SARS-CoV-2 in an ACE2 positive human lung cell line.

Brilacidin achieved a high Selectivity Index of 426 (CC50=241μM/IC50=0.565μM).

Brilacidin’s main mechanism appears to disrupt viral integrity and impact viral entry.

Brilacidin and remdesivir exhibit excellent synergistic activity against SARS-CoV-2.

Significance Statement

SARS-CoV-2, the emergent novel coronavirus, has led to the current global COVID-19 pandemic, characterized by extreme contagiousness and high mortality rates. There is an urgent need for effective therapeutic strategies to safely and effectively treat SARS-CoV-2 infection. We demonstrate that brilacidin, a synthetic small molecule with peptide-like properties, is capable of exerting potentin vitroantiviral activity against SARS-CoV-2, both as a standalone treatment and in combination with remdesivir, which is currently the only FDA-approved drug for the treatment of COVID-19.
A cell-free antibody engineering platform rapidly generates SARS-CoV-2 neutralizing antibodies
Authors: Chen Xun , Gentili Matteo , Hacohen Nir , Regev Aviv
Published: October 2020

Antibody engineering technologies face increasing demands for speed, reliability and scale. We developed CeVICA, a cell-free antibody engineering platform that integrates a novel generation method and design for camelid heavy-chain antibody VHH domain-based synthetic libraries, optimizedin vitroselection based on ribosome display and a computational pipeline for binder prediction based on CDR-directed clustering. We applied CeVICA to engineer antibodies against the Receptor Binding Domain (RBD) of the SARS-CoV-2 spike proteins and identified >800 predicted binder families. Among 14 experimentally-tested binders, 6 showed inhibition of pseudotyped virus infection. Antibody affinity maturation further increased binding affinity and potency of inhibition. Additionally, the unique capability of CeVICA for efficient and comprehensive binder prediction allowed retrospective validation of the fitness of our synthetic VHH library design and revealed direction for future refinement. CeVICA offers an integrated solution to rapid generation of divergent synthetic antibodies with tunable affinitiesin vitroand may serve as the basis for automated and highly parallel antibody generation.
The role of anxiety in the perception of pain: exploring the cumulative & temporal mechanisms of hypercapnic analgesia
Authors: Kharko Anna Yurievna , Hansford Kirralise J , Klein Frederico B , Furlong Paul L , Hall Stephen D , Roser Matthew E
Published: October 2020

Background

Anxiety, evoked by continuous inspiration of a 5 – 8% CO2mixture, has been found to have an analgesic eLect on self-reported pain. The precise mechanism whereby this effect obtains remains unknown.

Methods

The present study tested whether temporal summation, the psychological counterpart of wind-up, is involved in hypercapnic analgesia. 21 healthy participants received painful transcutaneous electrical stimuli of varied intensity, during continuous inhalation of 7.5% CO2mixture and medical air, presented in a single-blinded counterbalanced order. Continuous pain ratings were acquired to measure the temporal development of the pain response. Several points and events of interest that characterise the pain response profile were extracted from the continuous data.

Results

Mixed-eLects modelling demonstrated a reduction of all pain measures during inspiration of the anxiogenic mixture, but not air. This was accompanied by an increase in the psychological and physiological measures of anxiety. Analyses of the characteristic measures of temporal summation suggested that the hypercapnic mixture has an analgesic property evident from the start of the pain response. The same was true for the remainder of the response, the adaptation period, where pain ratings were also inhibited. The reduced pain ratings persisted during the remainder of the response. Anxiety was found to be a mediating factor for summative pain ratings but not the temporally sensitive TS measures, suggesting an overall, cumulative effect.

Conclusions

The findings provide an explanation for the previously observed low self-reported pain during the inhalation of an anxiogenic hypercapnic mixture.
Sea anemone genomes reveal ancestral metazoan chromosomal macrosynteny
Authors: Zimmermann Bob , Montenegro Juan D. , Robb Sofia M.C. , Fropf Whitney J. , Weilguny Lukas , He Shuonan , Chen Shiyuan , Lovegrove-Walsh Jessica , Hill Eric M. , Chen Cheng-Yi , Ragkousi Katerina , Praher Daniela , Fredman David , Schultz Darrin , Moran Yehu , Simakov Oleg , Genikhovich Grigory , Gibson Matthew C. , Technau Ulrich
Published: October 2020

Draft genome sequences of non-bilaterian species have provided important insights into the evolution of the metazoan gene repertoire. However, there is little information about the evolution of gene clusters, genome architectures and karyotypes during animal evolution. In this regard, slowly evolving anthozoan Cnidaria, the sister group of Bilateria, are particularly informative. Here we report chromosome-level genome assemblies of two related cnidarians, the sea anemonesNematostella vectensisandScolanthus callimorphus. We find a robust set of 15 chromosomes with a clear one-to-one correspondence between the two species. Both sea anemone genomes show remarkable chromosomal conservation with other cnidarians, several bilaterians and the spongeEphydatia muelleri, allowing us to reconstruct ancestral cnidarian and metazoan chromosomal blocks, consisting of at least 19 and 16 ancestral linkage groups, respectively. We show that, in contrast to Bilateria, the Hox and NK clusters of investigated cnidarians are largely disintegrated, despite the presence of staggeredhox/gbxexpression inNematostella. This loss of microsynteny conservation may be facilitated by shorter distances between cis-regulatory sequences and their cognate transcriptional start sites. In line with that, we find no clear evidence for topologically associated domains, suggesting fundamental differences in long-range gene regulation compared to vertebrates. These data suggest that large sets of ancestral metazoan genes have been retained in ancestral linkage groups of some extant lineages, yet, higher order gene regulation with associated 3D architecture may have evolved only after the cnidarian-bilaterian split.
PRAK-03202: A triple antigen VLP vaccine candidate against SARS CoV-2
Authors: Mazumder Saumyabrata , Rastogi Ruchir , Undale Avinash , Arora Kajal , Arora Nupur Mehrotra , Pratim Biswa , Kumar Dilip , Joseph Abyson , Mali Bhupesh , Arya Vidya Bhushan , Kalyanaraman Sriganesh , Mukherjee Abhishek , Gupta Aditi , Potdar Swaroop , Roy Sourav Singha , Parashar Deepak , Paliwal Jeny , Singh Sudhir Kumar , Naqvi Aelia , Srivastava Apoorva , Singh Manglesh Kumar , Kumar Devanand , Bansal Sarthi , Rautray Satabdi , Singh Indrajeet , Fengade Pankaj , Kumar Bibekanand , Saini Manish , Jain Kshipra , Gupta Reeshu , Kundu Prabuddha Kumar
Published: October 2020

The rapid development of safe and effective vaccines against SARS CoV-2 is the need of the hour for the coronavirus outbreak. Here, we have developed PRAK-03202, the world’s first triple antigen VLP vaccine candidate in a highly characterizedS. cerevisiae-basedD-CryptTMplatform, which induced SARS CoV-2 specific neutralizing antibodies in BALB/c mice. Immunizations using three different doses of PRAK-03202 induces antigen specific (Spike, envelope and membrane proteins) humoral response and neutralizing potential. PBMCs from convalescent patients, when exposed to PRAK-03202, showed lymphocyte proliferation and elevated IFN-γ levels suggestive of conservation of epitopes and induction of T helper 1 (Th1)–biased cellular immune responses. These data support the clinical development and testing of PRAK-03202 for use in humans.
Antigenic Sensitivity of Membrane-Proximal Targeting Chimeric Antigen Receptors can be Fine-Tuned through Hinge Truncation
Authors: McComb Scott , Nguyen Tina , Shepherd Alex , Henry Kevin A. , Bloemberg Darin , Marcil Anne , Maclean Susanne , Gilbert Rénald , Gadoury Christine , Pon Rob , Sulea Traian , Zhu Qin , Weeratna Risini D.
Published: October 2020

Background

Chimeric antigen receptor (CAR) technology has revolutionized the treatment of B-cell malignancies and steady progress is being made towards CAR-immunotherapies for solid tumours. Epidermal growth factor family receptors EGFR or HER2 are commonly overexpressed in cancer and represent proven targets for CAR-T therapy; given their expression in healthy tissues it is imperative that any targeting strategy consider the potential for on-target off-tumour toxicity.

Methods

Herein, we utilize high-throughput CAR screening to identify novel camelid single-domain antibody CARs (sdCARs) with high EGFR-specific CAR-T response. To optimize antigenic sensitivity of this EGFR-sdCAR, we performed progressive N-terminal truncation of the human CD8 hinge domain used as a spacer in many CAR constructs. Hinge truncation resulted in decreased CAR sensitivity to EGFR and improved selectivity for EGFR-overexpressing cells over EGFR-low target cells or healthy donor derived EGFR-positive fibroblasts. To investigate the molecular mechanism of hinge truncation, we test hinge-truncated scFv-based CARs targeting membrane proximal or membrane distal domains of EGFR-family proteins, HER2 and EGFRvIII. Finally, we proceed to test hinge variant EGFR-sdCAR functionality throughin vitroandin vivoassessments in primary T cells derived from multiple donors.

Results

For CARs targeting membrane-proximal epitopes, hinge truncation by even a single amino acid provided fine control of the antigenic sensitivity, whereas CARs targeting membrane distal domains were not sensitive to even complete hinge domain removal. Hinge-modified EGFR-sdCARs showed consistent and predictable responses in Jurkat-CAR cells and primary human CAR-T cellsin vitroandin vivo.

Conclusions

Overall, these results indicate that membrane-proximal epitope targeting CARs can be modified through hinge length tuning for programmable antigenic sensitivity and improved tumour selectivity.

Abstract Figure

Single amino acid truncations of CD8-hinge domain provide precise control of CAR antigen sensitivity

Truncated hinge CARs show enhanced selectivity for antigen overexpressing tumour cells and decreased activity towards healthy antigen-expressing cells

Epitope location is a critical factor in determining hinge sensitivity for a CAR

Hinge tuning can modulate CAR-T antigenic sensivityin vitroandin vivo
UCSC Cell Browser: Visualize Your Single-Cell Data
Authors: Speir Matthew L , Bhaduri Aparna , Markov Nikolay S , Moreno Pablo , Nowakowski Tomasz J , Papatheodorou Irene , Pollen Alex A , Seninge Lucas , Kent W James , Haeussler Maximilian
Published: October 2020

As the use of single-cell technologies has grown, so has the need for tools to explore these large, complicated datasets. The UCSC Cell Browser is a tool that allows scientists to visualize gene expression and metadata annotation distribution throughout a single-cell dataset or multiple datasets.

Availability and implementation

We provide the UCSC Cell Browser as a free website where users can explore a growing collection of single-cell datasets and a freely available python package for scientists to create stable, self-contained visualizations for their own single-cell datasets. Learn more athttps://cells.ucsc.edu.

Contact

cells@ucsc.edu
Gene-by-environment interactions in agricultural pest management: population effects on diet-Btinteractions in a caterpillar
Authors: Deans Carrie , Sword Gregory , Behmer Spencer , Burkness Eric , Pusztai-Carey Marianne , Hutchison W.D.
Published: October 2020

Given that plant nutrient content is both spatially and temporally dynamic (Lenhart et al., 2015; Deans et al., 2016, 2018), insect herbivores are exposed to an incredible amount of nutritional variability. This variability can constrain insects to feeding on sub-optimal resources, but it can also provide an opportunity for insects to regulate their intake of specific nutrients to obtain an optimal balance. Nutrient regulation has implications for pest control strategies in agricultural systems, as the nutritional state of pest species may impact their susceptibility to insecticides. Deans et al. (2017) showed that diet macronutrient balance has significant effects on the susceptibility ofHelicoverpa zealarvae to Cry1Ac, an endotoxin expressed in transgenicBtcrops. This was demonstrated using a highly inbred laboratory strain ofH. zea,limiting the applicability of these results to field populations that encompass greater genetic diversity. In this study, we assessed the impact of field-relevant macronutrient variability on the efficacy of twoBtendotoxins, Cry1Ab and Cry1Ac, using three field populations collected from different geographic regions. This was done to further understand the impact of nutritional variability onBtsusceptibility and also to determine the relevance of these effects in the field. While we saw limited differences in Cry susceptibility across populations, dietary effects were highly variable. Across populations there were distinct population-level differences in the interactions between Cry concentration and diet, the type of Cry toxin impacted by diet, and the treatment diet that produced optimal survival and performance. These results show that nutrition can have strong impacts onBtsusceptibility but also that these impacts are strongly affected by genetic background inH. zea. To accurately assessBtsusceptibility in the field, including resistance monitoring, bioassay methods should incorporate the appropriate nutritional parameters and be as localized as possible.
Amino acid transporter B0AT1 influence on ADAM17 interactions with SARS-CoV-2 receptor ACE2 putatively expressed in intestine, kidney, and cardiomyocytes
Authors: Andring Jacob T. , McKenna Robert , Stevens Bruce R.
Published: October 2020

SARS-CoV-2 exhibits significant experimental and clinical gastrointestinal, renal, and cardiac muscle tropisms responsible for local tissue-specific and systemic pathophysiology capriciously occurring in about half of COVID-19 patients. The underlying COVID-19 mechanisms engaged by these extra-pulmonary organ systems are largely unknown. We approached this knowledge gap by recognizing that neutral amino acid transporter B0AT1 (alternately called NBB, B, B0in the literature) is a common denominator expressed nearly exclusively by three particular cell types: intestinal epithelia, renal proximal tubule epithelium, and cardiomyocytes. B0AT1 provides uptake of glutamine and tryptophan. The gut is the main depot expressing over 90% of the body’s entire pool of SARS-CoV-2 receptor angiotensin converting enzyme-2 (ACE2) and B0AT1. Recent cryo-EM studies established that ACE2 forms a thermodynamically favored dimer-of-heterodimers complex with B0AT1 assembled in the form of a dimer of two ACE2:B0AT1 heterodimers anchored in plasma membranes. Prior epithelial cell studies demonstrated ACE2 chaperone trafficking of B0AT1. This contrasts with monomeric expression of ACE2 in lung pneumocytes, in which B0AT1 is undetectable. The cell types in question also express a disintegrin and metalloproteinase-17 (ADAM17) known to cleave and shed the ectodomain of monomeric ACE2 from the cell surface, thereby relinquishing protection against unchecked renin-angiotensin-system (RAS) events of COVID-19. The present study employed molecular docking modeling to examine the interplaying assemblage of ACE2, ADAM17 and B0AT1. We report that in the monomer form of ACE2, neck region residues R652-N718 provide unimpeded access to ADAM17 active site pocket, but notably R708 and S709 remained >10-15 Å distant. In contrast, interference of ADAM17 docking to ACE2 in a dimer-of-heterodimers arrangement was directly correlated with the presence of a neighboring B0AT1 subunit complexed to the partnering ACE2 subunit of the 2ACE2:2B0AT1] dimer of heterodimers, representing the expression pattern putatively exclusive to intestinal, renal and cardiomyocyte cell types. The monomer and dimer-of-heterodimers docking models were not influenced by the presence of SARS-CoV-2 receptor binding domain (RBD) complexed to ACE2. The results collectively provide the underpinnings for understanding the role of B0AT1 involvement in COVID-19 and the role of ADAM17 steering ACE2 events in intestinal and renal epithelial cells and cardiomyocytes, with implications useful for consideration in pandemic public hygiene policy and drug development.