bluuebunny/crossref_metadata_2025 huggingface dataset:
Preclinical pharmacology and toxicology evaluation of an anti-CD52 monoclonal antibody produced by perfusion fermentation process
Authors: Wang Yanchao , Zheng Chen , Zhuang Chao , Fu Qiang , Qin Jinyan , Zhang Baohong , Bian Yanling , Qi Nianmin , Zhu Jianwei
Published: October 2021

Anti-cluster of differentiation 52 (CD52) monoclonal antibody (mAb) has been employed in the treatment of chronic lymphoblastic leukemia and multiple sclerosis. Previously we developed a perfusion process to produce the biosimilar mAb named “Mab-TH.” A series of quality assessments was conducted in the fields of structural identification, purity analysis, and activity measurement. After these quality researches, this report laid emphasis on preclinical pharmacology and toxicology evaluation. Mab-TH was characterized in biological, pharmacological, and toxicological properties in comparison with the original drug, alemtuzumab. Binding activity and immune-dependent toxicity as in vitro activity were evaluated. Severe immunodeficient mice transplanted with a human leukemia cell line were also used as an in vivo pharmacological model and a 4-week repeated dosing study in cynomolgus monkeys was conducted to evaluate the safety differences. Our results demonstrated that Mab-TH, the anti-CD52 antibody generated by a perfusion process, had high similarity in in vitro and in vivo activities compared with alemtuzumab in relevant preclinical models. The results supported it as a biosimilar candidate for clinical evaluation.
Free vibration of a single-walled carbon nanotube based on the nonlocal Timoshenko beam model
Authors: Su Yu-Chi , Cho Tse-Yu
Published: October 2021

Free vibration of a single-walled carbon nanotube (SWCNT) embedded in an elastic medium is studied on the basis of the nonlocal Timoshenko beam model. Influences of the slenderness ratios, the boundary conditions, the atomic structures and the stiffness of the embedded medium on the natural frequencies and mode shapes of SWCNT are examined. The nonlocal effect is significant for the higher modes of SWCNT with a small slenderness ratio embedded in a soft elastic medium, and it softens the SWCNT except for the fundamental frequency of the clamped–free SWCNT.
Closed loop large bowel obstruction due to appendiceal signet cell carcinoma
Authors: Phan Du H , Teo Joshua Y , Nalliah Sasikaran
Published: October 2021

Signet cell carcinoma of the appendix is the rarest and the most aggressive subtype of appendiceal malignancy, typically presenting with non-specific symptoms. We describe a case of a 62-year-old male with large bowel obstruction, with computed tomography demonstrating dilated large bowels from caecum to proximal sigmoid colon and pneumoperitoneum. Intraoperatively, closed loop obstruction caused by dense adherence of sigmoid colon to caecum was noted, which had resulted in caecal perforation. Histopathology study indicated primary appendiceal malignancy of signet cell morphology with intraperitoneal spread to sigmoid colon. Large bowel obstruction from appendiceal malignancy has rarely been reported and similar presentations have not been described in the existing literature. When left-sided large bowel obstruction is suspected to be caused by a malignant stricture, it is essential to consider transperitoneal spread of appendiceal malignancy as potential aetiology, particularly in the elderly.
Hierarchical regulation of MYBPA1 by anthocyanin- and proanthocyanidin-related MYB proteins is conserved in Vaccinium species
Authors: Lafferty Declan J , Espley Richard V , Deng Cecilia H , Günther Catrin S , Plunkett Blue , Turner Janice L , Jaakola Laura , Karppinen Katja , Allan Andrew C , Albert Nick W
Published: October 2021

Members of the Vaccinium genus bear fruits rich in anthocyanins, a class of red-purple flavonoid pigments that provide human health benefits, although the localization and concentrations of anthocyanins differ between species: blueberry (V. corymbosum) has white flesh, while bilberry (V. myrtillus) has red flesh. Comparative transcriptomics between blueberry and bilberry revealed that MYBPA1.1 and MYBA1 strongly correlated with the presence of anthocyanins, but were absent or weakly expressed in blueberry flesh. MYBPA1.1 had a biphasic expression profile, correlating with both proanthocyanidin biosynthesis early during fruit development and anthocyanin biosynthesis during berry ripening. MYBPA1.1 was unable to induce anthocyanin or proanthocyanidin accumulation in Nicotiana benthamiana, but activated promoters of flavonoid biosynthesis genes. The MYBPA1.1 promoter is directly activated by MYBA1 and MYBPA2 proteins, which regulate anthocyanins and proanthocyanidins, respectively. Our findings suggest that the lack of VcMYBA1 expression in blueberry flesh results in an absence of VcMYBPA1.1 expression, which are both required for anthocyanin regulation. In contrast, VmMYBA1 is well expressed in bilberry flesh, up-regulating VmMYBPA1.1, allowing coordinated regulation of flavonoid biosynthesis genes and anthocyanin accumulation. The hierarchal model described here for Vaccinium may also occur in a wider group of plants as a means to co-regulate different branches of the flavonoid pathway.
Evaluation of vitamin D profile in juvenile idiopathic arthritis
Authors: Nandi Madhumita , Mullick Md Abu Sayeed , Nandy Arnab , Samanta Moumita , Sarkar Sumantra , Sabui Tapas Kumar
Published: October 2021

Objective

To observe the association between serum vitamin D level and disease activity in juvenile idiopathic arthritis (JIA).

Methods

The observational study was conducted at a tertiary care hospital during 2017-2019. Patients suffered from JIA were recruited through purposive sampling which was stratified by the disease activity based on the Juvenile Arthritis Disease Activity Score 27 (JADAS27) criteria. Serum vitamin D was estimated alongside other laboratory parameters. The numerical and categorical variables were analysed with appropriate statistical tests.

Results

40 subjects were studied where inactive disease was observed in nine subjects (22.5%), five subjects (12.5%) were found to be in low disease activity and moderate disease activity groups each, and twenty-one subjects (52.5%) had high disease activity. Considering the total sample size of the study, the mean (SD) JADAS27 score and serum vitamin D level were observed to be 12.02 (11.31) and 23.10 (5.93) respectively. A negative correlation was found between the JADAS27 score and serum vitamin D (r= -0.67). The corrected Chi-square test had revealed significant association between the status of serum vitamin-D and disease activity groups (=16.28; p < .001).

Conclusions

In JIA, higher grade of disease activity was found to be significantly associated with lower serum vitamin D.
Real-world safety and efficacy of CT-P13, an infliximab biosimilar, in Japanese rheumatoid arthritis patients naïve to or switched from biologics
Authors: Takeuchi Tsutomu , Nishikawa Kiyohiro , Yamada Fumika , Ohshima Shiro , Inoue Makoto , Yoshioka Yutaka , Yamanaka Hisashi
Published: October 2021

Objectives

The aim of this post-marketing surveillance (PMS) study is to evaluate the real-world safety and efficacy of CT-P13, the first biosimilar of infliximab (IFX).

Methods

Japanese patients with rheumatoid arthritis were prospectively registered from November 2014 and followed up for 1 year.

Results

Of 794 patients in the analysis set, 318 patients naïve to biological disease-modifying antirheumatic drugs (bDMARDs) showed an immediate decrease in Disease Activity Score in 28 joints with C-reactive protein (DAS28-CRP) and increased remission rate (DAS28-CRP < 2.6). In patients who switched from IFX to CT-P13 for non-medical reasons (n = 374), the low DAS28-CRP due to previous IFX treatment decreased further with continued CT-P13 therapy. As in naïve patients, patients who switched from other bDMARDs, mainly for medical reasons (n = 102), responded similarly to CT-P13. CT-P13 in this PMS and IFX in a previous PMS had similar adverse reaction profiles, although the incidence rate in naïve patients in this current PMS was lower due to earlier initiation of CT-P13 therapy.

Conclusions

CT-P13 showed excellent effectiveness as first-line therapy, no clinical difficulties in switching from IFX, and clinical improvement in patients who failed other bDMARDs. CT-P13 could be a cost-effective alternative to IFX in the treatment of rheumatoid arthritis.
RiboDraw: semiautomated two-dimensional drawing of RNA tertiary structure diagrams
Authors: Das Rhiju , Watkins Andrew M
Published: October 2021

Publishing, discussing, envisioning, modeling, designing and experimentally determining RNA three-dimensional (3D) structures involve preparation of two-dimensional (2D) drawings that depict critical functional features of the subject molecules, such as noncanonical base pairs and protein contacts. Here, we describe RiboDraw, new software for crafting these drawings. We illustrate the features of RiboDraw by applying it to several RNAs, including the Escherichia coli tRNA-Phe, the P4–P6 domain of Tetrahymena ribozyme, a −1 ribosomal frameshift stimulation element from beet western yellows virus and the 5′ untranslated region of SARS-CoV-2. We show secondary structure diagrams of the 23S and 16S subunits of the E. coli ribosome that reflect noncanonical base pairs, ribosomal proteins and structural motifs, and that convey the relative positions of these critical features in 3D space. This software is a MATLAB package freely available at https://github.com/DasLab/RiboDraw.
A nonparametric method to assess the significance of events in the search for gravitational waves with false discovery rate
Authors: Yuzurihara Hirotaka , Mano Shuhei , Tagoshi Hideyuki
Published: October 2021

We present a consistent procedure to assess the significance of gravitational wave events observed by laser interferometric gravitational wave detectors based on the background distribution of the detection statistic. We propose a non-parametric method to estimate the p-value. Based on the estimated p-values, we propose a new procedure to assess the significance of a particular event with a q-value which is the minimum false discovery rate that can be attained when calling the event significant. The q-value gives us a criterion on the significance of events which is different from Pastro as used in the LIGO–Virgo analysis and others. The proposed procedure is applied to the 1-OGC and 2-OGC catalogs. For most of the events which were claimed significant in these catalogs, we obtain the same results. However, there are differences in the significance for several marginal events. Since the proposed procedure does not require any assumptions on signal and noise, it is very simple and straightforward. The procedure is also applicable to other searches for gravitational waves whose background distribution of the detection statistic is difficult to know.
A proposed system for standardization of colour-coding stages of escalating criticality in clinical incidents
Authors: Prineas Stavros , Culwick Martin , Endlich Yasmin
Published: October 2021

Purpose of review

This article proposes a standardized framework for colour-coding states of criticality in clinical situations and their respective escalated responses.

Recent findings

The first level is a green zone representing a ‘safe’ space (to proceed), where any hazards are controlled, latent or undetectable. The second is an amber zone, where hazards are known to be present, but one can proceed with caution and increased vigilance, and where defences are used to prevent escalation to a crisis. In the red phase -- a state of crisis -- a hazard is realized, clear and present. This is a time to decide what actions are required to mitigate the threat. Next, a blue phase refers to a life-threatening emergency, where the system is unstable, harm is evident and compounding upon itself, and immediate rescue action is needed to avert an irreversible outcome. Finally, dark grey represents the aftermath, where the situation has either stabilized or progressed to its final outcome, a time to reflect and learn.

A standardized colour-coding system for assessing and responding to escalating levels of criticality has implications for clinical practice and adverse event reporting systems.
Scrambler therapy for noncancer neuropathic pain: a focused review
Authors: Abdi Salahadin , Chung Matthew , Marineo Giuseppe
Published: October 2021

Purpose of review

Therapeutic methods for neuropathic are limited; available drugs can be inadequate or have adverse effects that compromise quality of life. Interest has grown in alternatives to pharmacologic therapy for neuropathic pain. We present a focused review of the literature about the relatively novel noninvasive, nonpharmacologic electrocutaneous nerve stimulation technique called scrambler therapy for treating noncancer neuropathic pain.

Recent findings

Neuromodulation techniques targeting peripheral sites have changed rapidly in recent years. Several clinical studies have demonstrated the analgesic effect of scrambler therapy after 10 sessions of treatment for various types of pain. Although scrambler therapy was originally used for cancer pain, its indications have broadened to postoperative pain, chemotherapy-induced peripheral neuropathy, postherpetic neuralgia, low back pain, diabetic neuropathy, complex regional pain syndrome and central pain syndrome. That said, some of the studies are controversial owing to their small sample size, lack of appropriate scrambler therapy protocol and possible lack of experience of the operators.

We present the historical perspective, mechanism of action and trial outcomes of scrambler therapy, representing an avenue for managing neuropathic pain without drugs. Well designed phase II/III clinical trials must be conducted to confirm the positive findings reported using scrambler therapy technology. If validated, scrambler therapy could be a game changer.
Respiratory Drive in Patients with Sepsis and Septic Shock: Modulation by High-flow Nasal Cannula
Authors: Mauri Tommaso , Spinelli Elena , Pavlovsky Bertrand , Grieco Domenico Luca , Ottaviani Irene , Basile Maria Cristina , Dalla Corte Francesca , Pintaudi Gabriele , Garofalo Eugenio , Rundo Annalisa , Volta Carlo Alberto , Pesenti Antonio , Spadaro Savino
Published: October 2021

Background

Experimental and pilot clinical data suggest that spontaneously breathing patients with sepsis and septic shock may present increased respiratory drive and effort, even in the absence of pulmonary infection. The study hypothesis was that respiratory drive and effort may be increased in septic patients and correlated with extrapulmonary determinant and that high-flow nasal cannula may modulate drive and effort.

Methods

Twenty-five nonintubated patients with extrapulmonary sepsis or septic shock were enrolled. Each patient underwent three consecutive steps: low-flow oxygen at baseline, high-flow nasal cannula, and then low-flow oxygen again. Arterial blood gases, esophageal pressure, and electrical impedance tomography data were recorded toward the end of each step. Respiratory effort was measured as the negative swing of esophageal pressure (ΔPes); drive was quantified as the change in esophageal pressure during the first 500 ms from start of inspiration (P0.5). Dynamic lung compliance was calculated as the tidal volume measured by electrical impedance tomography, divided by ΔPes. The results are presented as medians [25th to 75th percentile].

Results

Thirteen patients (52%) were in septic shock. The Sequential Organ Failure Assessment score was 5 [4 to 9]. During low-flow oxygen at baseline, respiratory drive and effort were elevated and significantly correlated with arterial lactate (r = 0.46, P = 0.034) and inversely with dynamic lung compliance (r = –0.735, P < 0.001). Noninvasive support by high-flow nasal cannula induced a significant decrease of respiratory drive (P0.5: 6.0 [4.4 to 9.0] vs. 4.3 [3.5 to 6.6] vs. 6.6 [4.9 to 10.7] cm H2O, P < 0.001) and effort (ΔPes: 8.0 [6.0 to 11.5] vs. 5.5 [4.5 to 8.0] vs. 7.5 [6.0 to 12.6] cm H2O, P < 0.001). Oxygenation and arterial carbon dioxide levels remained stable during all study phases.

Conclusions

Patients with sepsis and septic shock of extrapulmonary origin present elevated respiratory drive and effort, which can be effectively reduced by high-flow nasal cannula.

Editor’s Perspective

What We Already Know about This Topic

What This Article Tells Us That Is New
Per-oral Endoscopic Myotomy
Authors: Liu-Burdowski Jennifer , Duarte-Chavez Rodrigo , Kahaleh Michel
Published: October 2021

For more than a decade, per-oral endoscopic myotomy (POEM) has been performed for the treatment of achalasia and other dysmotilities of the esophagus. POEM has become an accepted alternative to Heller myotomy, a salvation technique for patients not responding to Heller myotomy and the favorite intervention for diffuse esophageal spasm and jackhammer esophagus. POEM paved the way for endoscopic pyloromyotomy, Zenker’s diverticulum myotomy, and submucosal tunneling with endoscopic resection. This review will cover the technique and the most current literature of this revolutionary third space technique.
Esophagitis Mimicking Esophageal Cancer on 68Ga-FAPI PET/CT
Authors: Yang Xiao , You Zhouxiang , Mou Chunru , Hu Zhi , Liu Huipan
Published: October 2021

A 69-year-old man presented with dysphagia for 6 months. Endoscopic biopsy showed no sign of malignancy, but enhanced chest CT revealed thickening of the esophageal wall, which was considered likely a potential malignancy. The patient subsequently was enrolled in our clinical trial of 68Ga-FAPI study in tumors. Intense 68Ga-FAPI activity was noted in the thickened esophagus. However, repeated endoscopic biopsies and relief of symptoms after drug treatment rendered a diagnosis of Candida albicans esophagitis.
JAK Inhibitor Effectiveness in Giant-Cell Arteritis With Large-Vessel Involvement Assessed by 18F-FDG PET-CT
Authors: Prigent Kevin , Aouba Achille , Aide Nicolas , de Boysson Hubert
Published: October 2021

We report the case of a 76-year-old woman with relapsing giant-cell arteritis and large-vessel vasculitis demonstrated on 18F-FDG-PET/CT. Methotrexate and tocilizumab failed to achieve remission, and the patient ultimately exhibited a favorable clinical and radiological response to baricitinib, a JAK inhibitor. This case suggests that baricitinib may be a promising treatment for giant-cell arteritis–related large-vessel vasculitis and that 18F-FDG-PET/CT may be used to monitor therapeutic response.
FDG PET/CT in Dendritic Fibromyxolipoma of the Thigh
Authors: Ji Xia , Nian Shensheng , Bai Yushu , Dong Aisheng
Published: October 2021

Dendritic fibromyxolipoma is a rare recently described benign soft tissue tumor, which may be misinterpreted histologically as myxoid liposarcoma or myxoid malignant fibrous histiocytoma. We describe FDG PET/CT and MRI findings of a dendritic fibromyxolipoma incidentally detected in a case with rectal adenocarcinoma. The dendritic fibromyxolipoma showed inhomogeneous FDG uptake with SUVmax of 4.0 mimicking malignancy.
FDG PET/CT in Cryptogenic Multifocal Ulcerating Stenosing Enteropathy
Authors: Zhang Jian , Li Zhi , Zhang Ling , Dong Aisheng , Zhu Yuzhao
Published: October 2021

Cryptogenic multifocal ulcerating stenosing enteropathy (CMUSE) is a rare and exclusive small intestine disease, characterized by repeated anemia or obstruction resulting from multiple shallow ulcers with strictures in the small intestine. We present a case of CMUSE showing multiple foci of activity in the small bowel on FDG PET/CT. This case indicates that CMUSE should be included in the differential diagnosis of multifocal FDG activity in the small bowel along with lymphoma, carcinoma, tuberculosis, Crohn disease, Behçet disease, and drug-induced enteropathy.
Plasmodium falciparum hydroxymethylbilane synthase does not house any cosynthase activity within the haem biosynthetic pathway
Authors: Scott Alan F. , Deery Evelyne , Lawrence Andrew D. , Warren Martin J.
Published: October 2021

Uroporphyrinogen III, the universal progenitor of macrocyclic, modified tetrapyrroles, is produced from aminolaevulinic acid (ALA) by a conserved pathway involving three enzymes: porphobilinogen synthase (PBGS), hydroxymethylbilane synthase (HmbS) and uroporphyrinogen III synthase (UroS). The gene encoding uroporphyrinogen III synthase has not yet been identified in Plasmodium falciparum, but it has been suggested that this activity is housed inside a bifunctional hybroxymethylbilane synthase (HmbS). Additionally, an unknown protein encoded by PF3D7_1247600 has also been predicted to possess UroS activity. In this study it is demonstrated that neither of these proteins possess UroS activity and the real UroS remains to be identified. This was demonstrated by the failure of codon-optimized genes to complement a defined Escherichia coli hemD
− mutant (SASZ31) deficient in UroS activity. Furthermore, HPLC analysis of the oxidized reaction product from recombinant, purified P. falciparum HmbS showed that only uroporphyrin I could be detected (corresponding to hydroxymethylbilane production). No uroporphyrin III was detected, showing that P. falciparum HmbS does not have UroS activity and can only catalyze the formation of hydroxymethylbilane from porphobilinogen.
A Randomized Clinical Trial of Bioimpedance Spectroscopy or Tape Measure Triggered Compression Intervention in Chronic Breast Cancer Lymphedema Prevention
Authors: Ridner Sheila H. , Dietrich Mary S. , Boyages John , Koelmeyer Louise , Elder Elisabeth , Hughes T. Michael , French James , Ngui Nicholas , Hsu Jeremy , Abramson Vandana G. , Moore Andrew , Shah Chirag
Published: October 2021

Background

This study compared rates of progression to chronic breast cancer-related lymphedema (defined as a ≥ 10% arm volume change from baseline requiring complex decongestive physiotherapy (CDP)) following an intervention for subclinical lymphedema (S-BCRL) triggered by bioimpedance spectroscopy (BIS) or by tape measurement (TM).

Methods and Results

This stratified, randomized, international trial enrolled new breast cancer patients undergoing: mastectomy/partial mastectomy, axillary treatment (dissection, sentinel lymph node biopsy >6 nodes or radiation), radiation therapy (chest wall/ breast, supraclavicular fossa), or taxane-based chemotherapy. Following post-surgery eligibility reassessment, centralized, 1:1 randomization to prospective surveillance by BIS or TM occurred. S-BCRL detection triggered a 4-week, 12-hour per day, compression sleeve and gauntlet intervention. The primary outcome (n=209), rates of post-intervention progression to CDP, were assessed over three years. Between June 24, 2014 and September 11, 2018, 1,200 patients were enrolled, 963 randomized (BIS n=482;TM n=481) and 879 analyzed (BIS n=442;TM n=437). Median follow-up was 32.9 months (IQR=22,35). BIS patients triggered an intervention at a lower rate than TM patients (20.1%, n=89 vs 27.5%, n=120, p = 0.011). Median months to trigger was longer with BIS than TM (9.7; 95%CI,8.2-12.6 vs 3.9; 95%CI,2.8-4.5, p = 0.001). Overall, 14.4%(n=30) progressed post-intervention, with reduced likelihood for BIS patients than TM patients (7.9%, n=7 vs 19.2%, n=23; RR=0.41; 95%CI,0.13-0.81; absolute reduction 11.3%; 95%CI,2.3%-20.3%; p = 0.016).

Conclusions

As compared to TM, BIS provides a more precise identification of patients likely to benefit from an early compression intervention.

Condensed Abstract

This stratified, multi-site, international trial enrolled newly diagnosed breast cancer patients, randomized them to prospective surveillance by bioimpedance spectroscopy (BIS) or tape measurement (TM), and screened them for lymphedema development at frequent intervals for three years after surgery. When subclinical lymphedema was detected a 4-week, 12-hour per day, compression sleeve and gauntlet intervention was implemented. Overall, 14.4% (n=30) progressed post-intervention to chronic lymphedema, with reduced likelihood for BIS patients than TM patients (7.9%, n=7 vs 19.2%, n=23; RR=0.41; 95%-CI,0.13-0.81; absolute reduction 11.3%; 95%-CI,2.3%-20.3%; p = 0.016). BIS best supported intervention success for prevention of chronic lymphedema compared to TM.
A second view on the evolution of flight in stick and leaf insects (Phasmatodea)
Authors: Bank Sarah , Bradler Sven
Published: October 2021

The re-evolution of complex characters is generally considered impossible, yet, studies of recent years have provided several examples of phenotypic reversals shown to violate Dollo’s law. Along these lines, the regain of wings in stick and leaf insects (Phasmatodea) was hypothesised to have occurred several times independently after an ancestral loss, a scenario controversially discussed among evolutionary biologists. Here, we revisit the recovery of wings by reconstructing a phylogeny based on a comprehensive taxon sample of over 500 representative phasmatodean species to infer the evolutionary history of wings. We additionally explored the presence of ocelli, the photoreceptive organs used for flight stabilisation in winged insects, which might provide further information for interpreting flight evolution. Our findings support an ancestral loss of wings and that the ancestors of most major lineages were wingless. While the evolution of ocelli was estimated to be dependent on the presence of (fully-developed) wings, ocelli are nevertheless absent in the majority of all examined winged species and only appear in the members of few subordinate clades, albeit winged and volant taxa are found in every lineage. The disjunct distribution of ocelli substantiates the hypothesis on trait reacquisition and that wings were regained in Phasmatodea.
Causality of Abdominal Obesity on Cognition: a Trans-ethnic Mendelian Randomization study
Authors: Wang Shi-Heng , Su Mei-Hsin , Chen Chia-Yen , Lin Yen-Feng , Feng Yen-Chen A. , Hsiao Po-Chang , Pan Yi-Jiun , Wu Chi-Shin
Published: October 2021

Obesity has been associated with cognition in observational studies; however, whether its effect is confounding, reverse causality, or causal remains inconclusive. Using two-sample Mendelian randomization (MR) analyses, we investigated the causality of overall obesity, measured by BMI, and abdominal adiposity, measured by waist–hip ratio adjusted for BMI (WHRadjBMI), on cognition. Using summary data from the GIANT consortium, COGENT consortium, and UK Biobank of European ancestry, there was no causal effect of BMI on cognition performance (beta[95% CI]=-0.04[-0.12,0.04], p-value=0.35); however, a 1-SD increase in WHRadjBMI was associated with 0.07 standardized decrease in cognition performance (beta[95% CI]=-0.07[-0.12,-0.02], p=0.006). Using raw data from the Taiwan Biobank of Asian ancestry, there was no causal effect of BMI on cognitive aging (beta[95% CI]=0.00[-0.09,0.09], p-value=0.95); however, a 1-SD increase in WHRadjBMI was associated with a 0.17 standardized decrease in cognitive aging (beta[95% CI]=-0.17[-0.30,-0.03], p=0.02). This trans-ethnic MR study reveals that abdominal adiposity impairs cognition.
Predicting COVID-19 Vaccine Efficacy from Neutralizing Antibody Levels
Authors: Abedi Majid R. , Dixon Samuel , Guyon Timothy , Hsu Serene , Jacobs Aviva R. , Nair Lakshmi , Terbrueggen Robert
Published: October 2021

Recent studies using data accrued from global SARS-CoV-2 vaccination efforts have demonstrated that breakthrough infections are correlated with levels of neutralizing antibodies. The decrease in neutralizing antibody titers of vaccinated individuals over time, combined with the emergence of more infectious variants of concern has resulted in waning vaccine efficacy against infection and a rise in breakthrough infections. Here we use a combination of neutralizing antibody measurements determined by a high throughput surrogate viral neutralization test (sVNT) together with published data from vaccine clinical trials and comparative plaque reduction neutralization test (PRNT) between SARS-CoV-2 variants to develop a model for vaccine efficacy (VE) against symptomatic infection. Vaccine efficacy estimates using this model show good concordance with real world data from the US and Israel. Our work demonstrates that appropriately calibrated neutralizing antibody measurements determined by high throughput sVNT can be used to provide a semi-quantitative estimate of protection against infection. Given the highly variable antibody levels among the vaccinated population, this model may be of use in identification of individuals with an elevated risk of breakthrough infections.
Variation at Spike position 142 in SARS-CoV-2 Delta genomes is a technical artifact caused by dropout of a sequencing amplicon
Authors: Sanderson Theo , Barrett Jeffrey C.
Published: October 2021

Public SARS-CoV-2 genomes from the Delta lineage show complex and confusing patterns of mutations at Spike codon 142, and at another nearby position, Spike codon 95. It has been hypothesised that these represent recurrent mutations with interesting evolutionary dynamics, and that these mutations may affect viral load. Here we show that these patterns, and the relationship with viral load, are artifacts of sequencing difficulties in this region of the Delta genome caused by a deletion in the binding site for the 72_RIGHT primer of the ARTIC V3 schema. Spike G142D should be considered a lineage-defining mutation of Delta.
How frequent are acute reactions to COVID-19 vaccination and who is at risk?
Authors: Dreyer Nancy A. , Reynolds Matthew W , Albert Lisa , Brinkley Emma , Kwon Tom , Mack Christina , Toovey Stephen
Published: October 2021

Introduction

Our objective was to describe and compare self-reported side effects of COVID-19 vaccines in the USA.

Methods

A web-based registry enrolled volunteers who received a COVID-19 vaccine between March 19 –July 15, 2021. We collected self-reported short-term side effects, medical consultation, hospitalization, and quality of life impact following completed vaccination regimens (Pfizer, Moderna, J&J).

Results

We recruited 6,966 volunteers who completed their full course of vaccination (median age 48 years, IQR 35.0-62.0; 83.6% female): Pfizer 3,486; Moderna 2,857; J&J 623. Few (3.1%) sought medical care for post-vaccination side effects. Hospitalization (n=17; 0.3%) and severe allergic reactions (n=39; 0.6%) also were rare. Those with autoimmune disease or lung disease were approximately twice as likely to seek medical care (adjusted odds ratio (aOR) 2.01 [95% CI: 1.39;2.92] and 1.70 [95% CI: 1.12;2.58] respectively). 92.4% of participants reported ≥1 side effect (median 3), with injection site reactions (78.9%), fatigue (70.3%), headache (49.0%) reported most frequently. More side effects were reported after the second dose of two-dose vaccines (medians: 1 vs. 2 for Pfizer and 1 vs. 3 for Moderna for first and second doses respectively) versus 3 for J&J’s single-dose vaccine. For the employed, the median number of workdays missed was one. Diabetics and those vaccinated against influenza were substantially less likely to report ≥3 symptoms (aOR 0.68, 95% CI 0.56,0.82 and aOR 0.82, 95% CI 0.73,0.93, respectively.)

Discussion

The total side effect burden was, not unexpectedly, greater with two-dose regimens but all three vaccines appear relatively safe. Very few subjects reported side effects serious enough to warrant medical care or reported post-vaccination hospitalization. While these findings do not address possible long-term effects, they do inform on their short-term safety and tolerability and will hopefully provide some reassurance and positively inform the benefit-risk and pharmacoeconomic assessment for all three vaccines.

Clinicaltrials.govNCT04368065
Evaluation of viral loads in patients with SARS-CoV-2 Delta variant infection: Higher loads do not translate into different testing scenarios
Authors: Gomez Marti Juan Luis , Mays Ashley , McCullough Melissa , Wells Alan , Phan Tung
Published: October 2021

The Delta SARS-CoV-2 variant is very infectious, and it is spreading quickly during this pandemic. In the study, we compared viral loads in surging cases infected with the SARS-CoV-2 Delta variant in the fourth wave of COVID-19 with the three prior waves. The data comprised viral loads from positive cases detected within the UPMC health care system in Allegheny County, Pennsylvania. A total of 2,059 upper airway samples were collected and tested for SARS-CoV-2 positive by RT-PCR during March 2020-September 2021. We did not observe significant difference in viral load difference between the third (December 2020 – January 2021) and fourth (June 2021 – September 2021) waves; however, they had the higher viral load than the first (March 2020 – June 2020) and second waves (June 2020 – August 2020). We did find an age-related effect with the elderly presenting with lower viral loads, which was also seen in the earlier waves. However, the level of viral load in the fourth wave was not sufficient higher to qualitatively change our expected detected rates using various testing modalities.
Second-generation optoacoustic imaging of breast cancer patients
Authors: Kukačka Jan , Metz Stephan , Dehner Christoph , Muckenhuber Alexander , Paul-Yuan Korbinian , Karlas Angelos , Rummeny Ernst , Jüstel Dominik , Ntziachristos Vasilis
Published: October 2021

Since the initial breast transillumination almost a century ago, breast cancer imaging using light has been considered in different implementations aiming to improve diagnostics, minimize the number of available biopsies, or monitor treatment. However, due to strong photon scattering, conventional optical imaging yields low resolution images, challenging quantification and interpretation. Optoacoustic imaging addresses the scattering limitation and yields high-resolution visualization of optical contrast, offering great potential value for breast cancer imaging. Nevertheless, the image quality of experimental systems remains limited due to a number of factors, including signal attenuation with depth and partial view angle and motion effects, particularly in multi-wavelength measurements. We developed data analytics methods to improve the accuracy of handheld optoacoustic breast cancer imaging, yielding second-generation optoacoustic imaging performance operating in tandem with ultrasonography. We produced the best images yet with handheld optoacoustic examinations of the human breast and breast cancer, in terms of resolution and contrast. Using these advances, we examined optoacoustic markers of malignancy, including vasculature abnormalities, hypoxia, and inflammation, on images obtained from breast cancer patients. We achieved the best optoacoustic images of the human breast ever obtained using handheld examination, advancing the diagnostic and theranostic potential of the hybrid optoacoustic-ultrasound (OPUS) examination over routine ultrasonography.
Prediction of severe COVID-19 infection at the time of testing: A machine learning approach
Authors: Khoshbakhtian Faraz , Lagman Ardian , Aleman Dionne M. , Giffen Randy , Rahman Proton
Published: October 2021

Early and effective detection of severe infection cases during a pandemic can significantly help patient prognosis and resource allocation. We develop a machine learning framework for detecting severe COVID-19 cases at the time of RT-PCR testing. We retrospectively studied 988 patients from a small Canadian province that tested positive for SARS-CoV-2 where 42 (4%) cases wereat-risk(i.e., resulted in hospitalization, admission to ICU, or death), and 8 (< 1%) cases resulted in death. The limited information available at the time of RT-PCR testing included age, comorbidities, and patients’ reported symptoms, totaling 27 features. Vaccination status was unavailable. Due to the severe class imbalance and small dataset size, we formulated the problem of detecting severe COVID as anomaly detection and applied three models: one-class support vector machine (OCSVM), weight-adjusted XGBoost, and weight-adjusted Ad-aBoost. The OCSVM was the best performing model for detecting the deceased cases with an average 95% true positive rate (TPR) and 27.2% false positive rate (FPR). Meanwhile, the XGBoost provided the best performance for detecting the at-risk cases with an average 96.2% TPR and 19% FPR. In addition, we developed a novel extension to SHAP interpretability to explain the outputs from the models. In agreement with conventional knowledge, we found that comorbidities were influential in predicting severity, however, we also found that symptoms were generally more influential, noting that machine learning combines all available data and is not a single-variate statistical analysis.
Hierarchical Representation of Complex Intervention Sequences for Automated Subgroup Analysis in Critical Care Settings
Authors: Trivedi Amee , Ogallo William , Tadesse Girmaw Abebe
Published: October 2021

Our understanding of the impact of interventions in critical care is limited by the lack of techniques that represent and analyze complex intervention spaces applied across heterogeneous patient populations. Existing work has mainly focused on selecting a few interventions and representing them as binary variables, resulting in oversimplification of intervention representation. The goal of this study is to find effective representations of sequential interventions to support intervention effect analysis. To this end, we have developed Hi-RISE (Hierarchical Representation of Intervention Sequences), an approach that transforms and clusters sequential interventions into a latent space, with the resulting clusters used for heterogenous treatment effect analysis. We apply this approach to the MIMIC III dataset and identified intervention clusters and corresponding subpopulations with peculiar odds of 28-day mortality. Our approach may lead to a better understanding of the subgrouplevel effects of sequential interventions and improve targeted intervention planning in critical care settings.
Ab initio phasing macromolecular structures using electron-counted MicroED data
Authors: Martynowycz Michael W. , Clabbers Max T.B. , Hattne Johan , Gonen Tamir
Published: October 2021

Structures of two globular proteins were determined ab initio using microcrystal electron diffraction (MicroED) data that was collected on a direct electron detector in counting mode. Microcrystals were identified using a scanning electron microscope (SEM) and thinned with a focused ion-beam (FIB) to produce crystalline lamellae of ideal thickness. Continuous rotation data were collected using an ultra-low exposure rate on a Falcon 4 direct electron detector in electron-counting mode. For the first sample, triclinic lysozyme extending to 0.87 Å resolution, an ideal helical fragment of only three alanine residues provided initial phases. These phases were improved using density modification, allowing the entire atomic structure to be built automatically. A similar approach was successful on a second macromolecular sample, proteinase K, which is much larger and diffracted to a modest 1.5 Å resolution. These results demonstrate that macromolecules can be determined to sub-Ångström resolution by MicroED and that ab initio phasing can be successfully applied to counting data collected on a direct electron detector.
The role of oxytocin in modulating self-other distinction in human brain: a pharmacological fMRI study
Authors: Wang Yuanchen , Wang Ruien , Wu Haiyan
Published: October 2021

The self-other distinction is crucial in human social cognition and social interaction. Studies have found that oxytocin (OT) sharpens the self-other perceptual boundary but with mixed results. Further, little is known if the effect of OT on self-resemblance facial perception exists, especially on its neural basis. Moreover, it is unclear if OT would influence the judgment in self-other discrimination when the other is a child or an adult. In the current double-blinded, placebo-controlled study, we investigated the effect of OT on self-face perception at both behavioral and neural levels. We morphed participants’ faces and strangers’ faces to create four stimuli conditions. After being treated by either OT or placebo (PL), participants reported whether a morphed face resembles themselves, or was morphed with their own faces, while being scanned with fMRI. Behavioral results showed that people judged adult-morphed faces better than child-morphed faces. fMRI results showed that the OT group exhibited generally increased activities in the visual area and IFG for self-morphed faces. Such difference was more pronounced in the adult face compared to child face conditions. Multivariate fMRI analysis revealed that the OT group showed better classification between self-morphed versus other-morphed faces, indicating that OT increased self-other distinction, especially for adult faces and in the left hemisphere. Our study shows the significant effect of OT on self-referential brain processes, providing evidence for the potential OT’s effect on a left hemisphere self network.
The ESX-1 secretion system senses bacterial contact and prepares mycobacteria for environmental adaptation
Authors: Herrera Nadia , Odermatt Pascal D. , Voorhies Mark , Nakagawa Rachel , Sil Anita , Chang Fred , Rosenberg Oren S.
Published: October 2021

The ESX-1 system (6-kDa early secretory antigenic target (ESAT-6) secretion system-1) is essential for Mycobacterium tuberculosis pathogenesis and conjugal transfer in Mycobacterium smegmatis, yet little is known about how its function is regulated. Live-cell fluorescence microscopy showed natively expressed ESX-1 was organized into distinct foci predominantly observed at cell-cell contacts. These foci formed when two cells touched and required a fully assembled ESX-1 system in both bacteria, suggesting the generation of an ESX-1 megacomplex across multiple membranes. The emergence of ESX-1 foci and ESX-1 secretion was environmentally dependent: foci formed in low nitrogen environments in which secretion was suppressed, yet with increasing concentrations of nitrogen, ESX-1 systems diffused along the plasma membrane and secretion was activated. Genome-wide transcriptional profiling revealed ESX-1 dependent induction of genes required for the SOS response and error prone DNA replication in high nitrogen. Based on these findings, we propose a new model of ESX-1 function where ESX-1 localization and secretion are responsive to nitrogen levels and form an integral node in the mycobacterial response to neighboring cells and environmental adaptation.
Repurposing Tranexamic Acid as an Anticancer Agent
Authors: Law Mary E. , Davis Bradley J. , Ghilardi Amanda F. , Yaaghubi Elham , Dulloo Zaafir M. , Wang Mengxiong , Guryanova Olga , Heldermon Coy D. , Castellano Ronald K. , Law Brian K.
Published: October 2021

Tranexamic Acid (TA) is a clinically used antifibrinolytic that acts as a lysine mimetic to block binding of Plasminogen with Plasminogen activators, preventing conversion of Plasminogen to its proteolytically activated form, Plasmin. Previous studies suggested that TA may exhibit anticancer activity by blockade of extracellular Plasmin formation. Plasmin-mediated cleavage of the CDCP1 protein may increase its oncogenic functions through several downstream pathways. Results presented herein demonstrate that TA blocks Plasmin-mediated excision of the extracellular domain of the oncoprotein CDCP1.In vitrostudies indicate that TA reduces the viability of a broad array of human and murine cancer cell lines, and breast tumor growth studies demonstrate that TA reduces cancer growthin vivo. Based on the ability of TA to mimic lysine and arginine, we hypothesized that TA may perturb multiple processes that involve Lys/Arg-rich protein sequences, and that TA may alter intracellular signaling pathways in addition to blocking extracellular Plasmin production. Indeed, TA-mediated suppression of tumor cell viability is associated with multiple biochemical actions, including inhibition of protein synthesis, reduced activating phosphorylation of STAT3 and S6K1, decreased expression of the MYC oncoprotein, and suppression of Lys acetylation. These findings suggest that TA or TA analogs may serve as lead compounds and inspire the production of new classes of anticancer agents that function by mimicking Lys and Arg.
MiR-339-3p aggravates rat vascular inflammation induced by AT1R autoantibodies by down-regulating BKα protein expression
Authors: Li Yang , Sun Yan , Yue Mingming , Gao Ming , Wang Li , Wu Ye , Yin Xiaochen , Zhang Suli , Liu Huirong
Published: October 2021

The abnormality of large-conductance calcium-activated potassium channels (BK channels) is an important factor in inducing vascular inflammation. BK channel agonists can readily recover BK channel function and improve vascular inflammation. However, it is not clear how to improve BK dysfunction caused by downregulation of BK channel protein expression. This study found that angiotensin II-1 receptor autoantibodies (AT1-AA), which are widely present in the body of various types of cardiovascular diseases, can down-regulate the expression of BK channel protein and induce vascular inflammation. Further research found that the elevated neural precursor cells expressed developmentally downregulated 4-like (NEDD4L) protein level is involved in the down-regulation of BK channel α subunit (BKα) protein level by AT1-AA. Bioinformatics analysis and experiments have confirmed that miR-339-3p plays an irreplaceable role in the high expression of NEDD4L and the low expression of BKα, and aggravates the vascular inflammation induced by AT1-AA. Overall, AT1-AA increased miR-339-3p expression (targeting BKα via the miR-339-3p/NEDD4L axis or miR-339-3p alone), reduced BKα protein expression in VSMCs, and induced vascular inflammation. The results of the study indicate that miR-339-3p may become a new target for reversing vascular inflammation in AT1-AA-positive patients.
Palmitoylation of PD-L1 Regulates Its Membrane Orientation and Immune Evasion
Authors: Zhang Siya , Wang Hongyin , Chen Zhongwen , Levental Ilya , Lin Xubo
Published: October 2021

Recently identified palmitoylation of PD-L1 is essential for immune regulation. To elucidate the underlying molecular mechanism, we performed giant plasma membrane vesicle (GPMV) experiments, µs-scale all-atom molecular dynamics (MD) simulations and immune killing experiments. GPMV experiments indicated that PD-L1 palmitoylation enhanced its lipid raft affinity. MD simulations revealed dramatically different membrane orientation states of PD-L1 in liquid-ordered (Lo, lipid raft) compared to liquid-disordered (Ld, non-raft) membrane environments. Ld region promoted the “lie-down” orientation of PD-L1, which could inhibit its association with the PD-1 protein on immune cells and thus promote the immune killing of cancer cells. This hypothesis was supported by immune killing experiments using γδT cells as effector cells and NCI-H1299 lung cancer cells as target cells. In short, our study demonstrates that the palmitoylation affects PD-L1’s membrane localization and then membrane orientation, which thus regulates its binding with T cell PD-1 and the immune regulation. These observations may guide therapeutic strategies by explicating the regulation of immune checkpoint proteins by post-translational modifications and membrane environments.
Multilateral surface analysis of the CeB6 electron-gun cathode used at SACLA XFEL
Authors: Ohkochi Takuo , Muro Takayuki , Ikenaga Eiji , Togawa Kazuaki , Yasui Akira , Kotsugi Masato , Oura Masaki , Tanaka Hitoshi
Published: October 2021

The CeB6(001) single crystal used as a cathode in a low-emittance electron gun and operated at the free-electron laser facility SACLA was investigated using cathode lens electron microscopy combined with X-ray spectroscopy at SPring-8 synchrotron radiation facility. Multilateral analysis using thermionic emission electron microscopy, low-energy electron microscopy, ultraviolet and X-ray photoemission electron microscopy and hard X-ray photoemission spectroscopy revealed that the thermionic electrons are emitted strongly and evenly from the CeB6 surface after pre-activation treatment (annealing at 1500°C for >1 h) and that the thermionic emission intensity as well as elemental composition vary between the central area and the edge of the old CeB6 surface.