bluuebunny/crossref_metadata_2025 huggingface dataset:
Sclerostin Antibody Administration Increases the Numbers of Sox9creER+ Skeletal Precursors and Their Progeny
Authors: Balani Deepak H , Trinh Sophia , Xu Mingxin , Kronenberg Henry M
Published: January 2021

Blocking the Wnt inhibitor, sclerostin, increases the rate of bone formation in rodents and in humans. On a cellular level, the antibody against sclerostin acts by increasing osteoblast numbers partly by activating the quiescent bone-lining cells in vivo. No evidence currently exists, to determine whether blocking sclerostin affects early cells of the osteoblast lineage. Here we use a lineage-tracing strategy that uses a tamoxifen-dependent cre recombinase, driven by the Sox9 promoter to mark early cells of the osteoblast lineage. We show that, when adult mice are treated with the rat-13C7, an antibody that blocks sclerostin action in rodents, it increases the numbers of osteoblast precursors and their differentiation into mature osteoblasts in vivo. We also show that rat-13C7 administration suppresses adipogenesis by suppressing the differentiation of Sox9creER+ skeletal precursors into bone marrow adipocytes in vivo. Using floxed alleles of the CTNNB1 gene encoding β-catenin, we show that these precursor cells express the canonical Wnt signaling mediator, β-catenin, and that the actions of the rat-13C7 antibody to increase the number of early precursors is dependent on direct stimulation of Wnt signaling. The increase in osteoblast precursors and their progeny after the administration of the antibody leads to a robust suppression of apoptosis without affecting the rate of their proliferation. Thus, neutralizing the Wnt-inhibitor sclerostin increases the numbers of early cells of the osteoblast lineage osteoblasts and suppresses their differentiation into adipocytes in vivo. © 2021 American Society for Bone and Mineral Research (ASBMR).
Emerging role of RNF2 in cancer: From bench to bedside
Authors: Yan Qi , Chen Bang‐jie , Hu Shuang , Qi Shun‐li , Li Liang‐yun , Yang Jun‐fa , Zhou Hong , Yang Chen‐chen , Chen Li‐jian , Du Jian
Published: January 2021

RNF2 (also known as ding, Ring1B or Ring2) is a member of the Ring finger protein family, which functions as E3 ubiquitin ligase for monoubiquitination of histone H2A at lysine 119 (H2AK119ub). RNF2 gene is located at the 1q25.3 site of human chromosome and the coding region is composed of 9 exons, encoding 336 amino acids in total. Many studies have demonstrated that overexpressed RNF2 was involved in the pathological progression of multiple cancers and has an impact on their clinical features. For instance, the upregulated expression level of RNF2 is positively correlated with the occurrence and progression of hepatocellular carcinoma, melanoma, prostate cancer, breast cancer, pancreatic cancer, gastric cancer, and bladder urothelial carcinoma, as well as with the radioresistance of lung cancer and chemoresistance of ovarian cancer. This review provides an up‐to‐date perspective on the relationship between RNF2 and several cancers and highlights recent studies on RNF2 regulation. In particular, the relevant cellular signaling pathways and potential clinical value of RNF2 in cancers are also discussed, suggesting its potential as an epigenetic biomarker and therapeutic target for these cancers.
The use of engineering model‐building activities to elicit computational thinking: A design‐based research study
Authors: Lyon Joseph A. , Magana Alejandra J.
Published: January 2021

Background

Computation and computational thinking are of great interest to both engineering research and teaching communities. Effective learning environments are needed to incorporate computational thinking within the engineering disciplines. Design‐based research is uniquely positioned to address this need for designing effective learning environments.

Purpose

This design‐based research study characterizes the different ways in which students used computational thinking when building computational models. The design of the model‐building activities was grounded in productive failure and model‐eliciting activities.

Design

The design‐based research study implemented the computational modeling activities within an engineering capstone course. The research question was: What types of computational thinking outcomes emerge when engineering students build computational models? Thematic analysis was applied to individual student artifacts to identify key computational thinking outcomes that were elicited as a result of the intervention.

Results

Throughout the building of the model, students demonstrated the use of computational thinking outcomes, mainly abstraction, algorithmic thinking, evaluation, generalization, and decomposition. However, the diversity and density of use for each outcome were different and unique.

Conclusions

This study shows how building computational models, when guided by current educational theories, can allow for students to practice the use of computational thinking and for educators to incorporate these key practices into their engineering classrooms.
Computer vision for microscopic skin cancer diagnosis using handcrafted and non‐handcrafted features
Authors: Saba Tanzila
Published: January 2021

Skin covers the entire body and is the largest organ. Skin cancer is one of the most dreadful cancers that is primarily triggered by sensitivity to ultraviolet rays from the sun. However, the riskiest is melanoma, although it starts in a few different ways. The patient is extremely unaware of recognizing skin malignant growth at the initial stage. Literature is evident that various handcrafted and automatic deep learning features are employed to diagnose skin cancer using the traditional machine and deep learning techniques. The current research presents a comparison of skin cancer diagnosis techniques using handcrafted and non‐handcrafted features. Additionally, clinical features such as Menzies method, seven‐point detection, asymmetry, border color and diameter, visual textures (GRC), local binary patterns, Gabor filters, random fields of Markov, fractal dimension, and an oriental histography are also explored in the process of skin cancer detection. Several parameters, such as jacquard index, accuracy, dice efficiency, preciseness, sensitivity, and specificity, are compared on benchmark data sets to assess reported techniques. Finally, publicly available skin cancer data sets are described and the remaining issues are highlighted.
Rare cause of cystic liver lesions: Liver metastasis of gastrointestinal stromal tumors
Authors: Sakata Masahiro , Kaneyoshi Toshihiko , Fushimi Takashi , Watanabe Jiro
Published: January 2021

Gastrointestinal stromal tumors (GISTs) are rare mesenchymal neoplasms of the gastrointestinal tract with an annual incidence of 1–2 per 10 000 people. Although most GISTs are solid, they may present with predominantly cystic components. A 69‐year‐old Japanese woman presented with a recently elevated gamma‐glutamyl transpeptidase level. Computed tomography revealed multiple space‐occupying lesions (SOLs) in the liver. These SOLs appear cystic on magnetic resonance imaging and abdominal ultrasound and are associated with thick walls at the margins. In addition, these thick walls showed high intensity on diffusion‐weighted images. She was diagnosed with liver metastasis of GIST by diagnostic biopsies from the thick parts of the cystic liver lesion (thick walls at the margins). The primary lesion was thought to be located along the medial side of the descending part of the duodenum, but a duodenal biopsy was initially undiagnosed. Liver metastases due to GISTs are known to cause cystic changes after treatment, such as imatinib mesylate. However, to the best of our knowledge, only six cases where hepatic GIST with predominantly cystic changes (prior to any treatment) have been reported. It should be noted that GISTs appear cystic in all organs.
A survey of the external morphology, internal oral morphology, chondrocranium and hyobranchial apparatus of Elachistocleis larvae Parker, 1927 (Anura, Microhylidae)
Authors: Ferreira Johnny S. , Weber Luiz N.
Published: January 2021

The external morphology, internal oral morphology, the chondrocranium and the hyobranchial apparatus of Elachistocleis bumbameuboi, E. cf. piauiensis, E. cesarii and E. bicolor are described and compared with each other and with other species of microhylids using available descriptions from the literature. The general morphology of Elachistocleis species is conservative in many aspects. Differences between species are subtle and are found in the body shape, the edge of the snout, fin height, if the lateral line is evident, the presence of regular pustules in the buccal roof arena, the posterolateral edge of the cartilago suprarostralis, the shape of the fenestra in the occipital region, presence or absence of fenestra hypophysea, the margin of the processus antorbitalis, expansions in the ventrolateral process, the shape and inclination of the fenestra subocularis, whether the subotic process is single or slightly bifid, and the inclination of the processus anterolateralis hyalis.
In‐situ formation of Zn–Al layered double oxides on electrochemically anodized nanoporous aluminum film as sorbent for chlorophenols extraction from water and wastewater followed by determination using HPLC
Authors: Ghani Milad , Raoof Jahan Bakhsh , Masoum Saeed
Published: January 2021

Herein, we present a simple, cost‐effective, and robust strategy for the in‐situ preparation of Zn‐Al layered double oxides–anodized aluminum thin film via a facile hydrothermal method, followed by calcination treatment of the Zn‐Al layered double hydroxide in the air atmosphere. The in‐situ prepared Zn‐Al layered double oxide‐anodized aluminum film was implemented as sorbent for thin film microextraction of four selected chlorophenols (4‐chlorophenol, 2,4‐dichlorophenol, 2,4,6‐trichlorophenol, and pentachlorophenol), followed by high‐performance liquid chromatography‐ultraviolet detection. The different variables of the thin film microextraction were screened via Plackett–Burman design and then optimized through Box–Behnken design. Under the optimum condition, the method showed good linear ranges (0.2‐200 μg/L) with the coefficient of determinations higher than 0.9938. The calculated limit of detections were between 0.07 and 0.56 μg/L. Relative standard deviations of the method for determination of the analytes at 5 μg/L concentration level (n = 3) were ranged from 3.5 to 3.9% (as interday). The enrichment factors were between 39 and 58. This extraction method was demonstrated to be fast, efficient, and convenient. To study the capability of the developed method for real sample analysis, tap, well, river, and two types of wastewater samples were satisfactorily analyzed.
Using 5D flow MRI to decode the effects of rhythm on left atrial 3D flow dynamics in patients with atrial fibrillation
Authors: Ma Liliana , Yerly Jérôme , Di Sopra Lorenzo , Piccini Davide , Lee Jeesoo , DiCarlo Amanda , Passman Rod , Greenland Philip , Kim Daniel , Stuber Matthias , Markl Michael
Published: January 2021

Purpose

This study used a 5D flow framework to explore the influence of arrhythmia on thrombogenic hemodynamic parameters in patients with atrial fibrillation (AF).

Methods

A fully self‐gated, 3D radial, highly accelerated free‐running 5D flow sequence with interleaved four‐point velocity‐encoding was acquired using an in vitro arrhythmic flow phantom and in 25 patients with a history of AF (68 ± 8 y, 6 female). Self‐gating signals were used to calculate AF burden, bin data, and tag each k‐space line with its RRLength. Data were binned as an RR‐resolved dataset with four RR‐interval bins (RR1‐RR4, short‐to‐long) for compressed sensing reconstruction. AF burden was calculated as interquartile range of all intrascan RR‐intervals divided by median RR‐interval, and left atrial (LA) stasis as the percent of the cardiac cycle where the velocity was <0.1 m/s.

Results

In vitro results demonstrated successful recovery of RR‐binned flow curves using RR‐resolved 5D flow compared to a real‐time PC reference standard. In vivo, 5D flow was acquired in 8:48 minutes. AF burden was significantly correlated with 5D flow‐derived peak (PV) and mean (MV) velocity and stasis (|ρ| = 0.54‐0.75, P < .001). Sensitivity analyses determined a threshold for low versus high AF burden at 9.7%. High burden patients had increased LA mean stasis (up to +42%, P < .01), and lower MV and PV (−30%, −40.6%, respectively, P < .01). RR4 deviated furthest from respiratory‐resolved reconstruction (end‐expiration) with increased mean stasis (7.6% ± 14.0%, P = .10) and decreased PV (−12.7 ± 14.2%, P = .09).

Conclusions

RR‐resolved 5D flow can capture temporal and RR‐resolved 3D hemodynamics in <10 minutes and offers a novel approach to investigate arrhythmias.
Ultrasound guidance may have advantages over landmark‐based guidance for some nerve conduction studies
Authors: Wei Kuo‐Chang , Chiu Yi‐Hsiang , Wu Chueh‐Hung , Liang Huey‐Wen , Wang Tyng‐Guey
Published: January 2021

Background

Precise placement of stimulating and recording electrodes is vital when performing nerve conduction studies (NCSs). In this study, we aimed to determine whether ultrasonography (US) was more precise in localizing the superficial radial nerve (SRN), dorsal ulnar cutaneous nerve (DUCN), ulnar nerve (UN) crossing the cubital tunnel, and radial nerve (RN) crossing the spiral groove (SG) compared to conventional techniques.

Methods

Thirty healthy young subjects (15 male) were recruited. Each subject underwent both landmark‐based and US‐guided NCS. Onset latencies and amplitudes of compound motor action potentials (CMAPs) and sensory nerve action potentials (SNAPs), and stimulation levels (ie, intensity × duration) required to obtain maximal CMAP amplitudes were compared between the two techniques.

Results

The mean CMAP amplitudes of the UN above the cubital tunnel (9.55 ± 1.96 vs 8.96 ± 1.94 mV, P = .030), UN below the cubital tunnel (10.11 ± 2.07 vs 9.37 ± 1.95 mV, P < .001), and RN below the SG (5.21 ± 1.56 vs 4.34 ± 1.03 mV, P < .001) were significantly greater using US‐guided NCSs compared to landmark‐based NCSs. The mean onset latency of the DUCN was significantly shorter using US‐guided NCSs (1.49 ± 0.15 vs 1.57 ± 0.14 ms, P = .020). The required stimulation level in the UN and RN was significantly lower using US‐guided NCSs.

Conclusions

When performing NCSs, US guidance provides a more precise localization of the stimulator and electrodes for the DUCN, UN, and RN, while providing comparable localization for the SRN, compared to landmark‐based techniques.
Experimental investigation and numerical simulation of the microinjection molding process through an expanding flow configuration
Authors: Benayad Anass , El Otmani Rabie , El Hakimi Abdelhadi , Boutaous M'hamed , Touache Abdelhamid , Musa Kamal R. , Derdouri Salim , Mahfoudi Nadjiba , Siginer Dennis
Published: January 2021

The dependence of the induced morphological layer variations on the processing conditions and parameters during injection molding of polymers is analyzed through a robust numerical framework of the complete microinjection molding cycle. Predicted temperature, heat transfer and viscous dissipation, spherulite diameters, and shear rates provide sufficient clarifications to develop a deeper understanding of the complex evolution of the induced thicknesses of layers. The evolution of the structure of polyoxymethylene (POM) under strong strain rates and high thermal gradients is investigated while flowing along an expanding flow configuration composed of three steps of increasing thickness. High and low mold temperatures and injection velocity levels are tested according to the design of the experiment method (DOE). Morphological development in each zone was examined to provide the induced crystalline layer thickness in the longitudinal as well as the transverse directions using polarized light microscopy (PLM). The thickness of the layers strongly depends on the local thickness of the stepped‐part and on the abrupt dimensional changes. The variation of bulk tensile properties obtained by dynamic mechanical analysis (DMA) is related to the thermomechanical history experienced by the melt.
Metastatic basal cell carcinoma in a cat with brief review of the human and veterinary literature
Authors: Moyer Ashley , Vinayak Arathi , Heo Jin , Moller Cheryl , Ehrhart E. J.
Published: January 2021

Feline basal cell carcinomas generally have a benign biological behaviour with a low metastatic rate, and little contemporary information exists regarding potential metastatic behaviour. The purpose of this report is to describe the protracted clinical course of metastatic basal cell carcinoma in a 10‐year‐old female spayed Persian cat affecting the right pelvic limb with nodal metastasis at the time of diagnosis and eventual metastasis to the lungs, lumbar spine, and skin 14 months after initial diagnosis. This report serves as a reminder that these tumours can metastasize and reviews information from human literature that may be helpful in understanding the metastatic pattern, treatment, and prognosis of basal cell carcinoma in veterinary medicine.
Small intestinal volvulus and colonic rupture in a dog after gastric dilation and volvulus
Authors: Düver Pia , Adamik Katja , Hettlich Bianca
Published: January 2021

An adult Standard Poodle was presented with gastric dilation and volvulus (GDV). An emergency laparotomy was performed, during which the stomach was derotated and an incisional gastropexy was performed. The dog recovered uneventfully from surgery and was stable for two days. Three days postoperatively, his condition declined markedly. Evidence of peritonitis was found on abdominal ultrasound, with no clearly identified underlying cause. The dog was euthanased and underwent gross postmortem examination. A small intestinal volvulus and macroscopic evidence of strangulation of a section of colon transversum with intestinal perforation was found. There were no lesions identified associated with the stomach or gastropexy site. This case report discusses possible reasons for the development of the intestinal volvulus and the strangulation and rupture of the colon in a dog after GDV surgery.
Toward computational design of chemical reactions with reaction phase diagram
Authors: Guo Chenxi , Fu Xiaoyan , Long Jun , Li Huan , Qin Gangqiang , Cao Ang , Jing Huijuan , Xiao Jianping
Published: January 2021

Density functional theory (DFT) was rapidly developed and achieved a great success in the last decades. As the advancement of general concepts in heterogeneous catalysis, theoretical study of chemical reactions based on DFT calculations has become more and more feasible, which provides a guideline for the rational design of novel catalysts toward higher reaction activity and specific selectivity. Here, we review an innovate scheme, namely reaction phase diagram (RPD), which can offer not only an in‐depth understanding of reaction mechanisms, but also the prediction of catalytic activity and selectivity trend over a collection of catalysts. The RPD analysis was successfully applied to understand the activity variation of CO2 electroreduction to CO and formic acid, as well as thermochemical hydrogenation and dehydrogenation. Meanwhile, the RPD analysis also exhibits a success of studying the product selectivity in syngas conversion to methane, ethanol, and methanol with complicated reaction pathways. At the end, we review a successful case of catalyst rational design with a target of NO selective electroreduction to ammonia. The foundation of RPD analysis is based on the scaling relation of adsorption energies and the correlation between kinetic barriers and reaction energies at elementary steps. Therefore, microkinetic modeling is complementary to the RPD analysis. A few of limitations and the prospect of the development regarding the RPD analysis are addressed in this review.

This article is categorized under:

Structure and Mechanism > Reaction Mechanisms and Catalysis
Rollen und Rollendynamiken in der partizipativen Forschungsgemeinschaft
Authors: Kümpers Susanne , Brandes Sven , Gebhardt Birte , Kühnemund Christina
Published: January 2021

Aus dem Ansatz der partizipativen Forschung ergeben sich für Forschende und Co-Forschende andere Rollen und Beziehungen als bei traditionellen Forschungskonzepten. Der Artikel beschreibt im Sinne eines Werkstattberichts Reflexionen und Erkenntnisse zu der Frage, wie Rollen im Rahmen partizipativer Gesundheitsforschung (PGF) wahrgenommen und ausgefüllt werden. Wissenschaftler*innen und Praxispartner*innen aus 2 Teilprojekten im Forschungsverbund PartKommPlus werteten dazu ihre Erfahrungen aus mehrjähriger Zusammenarbeit aus und entwickelten Erkenntnisse darüber, welche Dynamiken für die Rollengestaltung wichtig waren und worauf für eine konstruktive Gestaltung der Rollen zu achten ist.

Als 5 wichtige Elemente bei der Entwicklung von Rollen wurden herausgearbeitet: die Bedeutung der Handlungsspielräume, die sich aus den Bindungen an die jeweiligen Institutionen ergeben; die Veränderung der Rollen und Beziehungen über den (Projekt‑)Zeitraum; die Bedeutung von Vertrauen für funktionierende Kooperationsbeziehungen; die Problematik der Vertraulichkeit von Informationen für die wissenschaftliche Verwertung sowie der durch den Veränderungsanspruch partizipativer Forschung begründete politische Charakter der Kooperationen, der geteilte Grundhaltungen und Ziele voraussetzt. Abschließend wird die Bedeutung der gemeinsamen Reflexion der Rollengestaltung herausgearbeitet, die zum Erfolg oder Misserfolg partizipativer Forschungszusammenarbeit sowie zur Qualität ihrer Ergebnisse beiträgt.
Characteristics of dry eye patients with thick tear film lipid layers evaluated by a LipiView II interferometer
Authors: Lee Yunjin , Hyon Joon Young , Jeon Hyun Sun
Published: January 2021

Purpose

To investigate the characteristics of eyes with dry eye disease (DED) whose lipid layer thickness (LLT) measured 100 nm on a LipiView II interferometer and compare the DED parameters of them to those with LLT below 100 nm.

Methods

A total of 201 eyes of 102 enrolled DED patients (mean age 56.4 ± 11.8 years) were classified into 3 groups according to their average LLT; < 60 nm as thin-LLT (n = 49), 60–99 nm as normal-LLT (n = 77), and 100 nm as thick-LLT (n = 75). LLT, meiboscore, Schirmer I test, tear film break-up time (TBUT), ocular surface staining (OSS), and ocular surface disease index (OSDI) were assessed.

Results

The OSS and TBUT were significantly worse in the thick-LLT group than in the normal-LLT group (p = 0.020, and p = 0.028, respectively). The OSDI was significantly higher in the thick-LLT group than in the thin-LLT group (p = 0.006). However, the meiboscore was not different among the three groups (p = 0.33). Age, OSS, and OSDI showed a positive correlation with LLT (r = 0.16, p = 0.023; r = 0.213, p = 0.003; and r = 0.338, p = 0.001, respectively). In sensitivity analyses, eyes with corneal erosions had a significantly higher average LLT (p = 0.015), higher OSDI (p = 0.009), shorter TBUT (p < 0.001), and shorter Schirmer I value (p = 0.024) than those with clear corneas.

Conclusion

The average LLT of eyes with corneal erosions was thicker than those without erosions, suggesting that the LLT of 100 nm in the eyes with corneal erosions should not be regarded as a stable physiologic condition. Cautious interpretation of LLT along with other dry eye parameters is required.
Cost-sensitive probability for weighted voting in an ensemble model for multi-class classification problems
Authors: Rojarath Artittayapron , Songpan Wararat
Published: January 2021

Ensemble learning is an algorithm that utilizes various types of classification models. This algorithm can enhance the prediction efficiency of component models. However, the efficiency of combining models typically depends on the diversity and accuracy of the predicted results of ensemble models. However, the problem of multi-class data is still encountered. In the proposed approach, cost-sensitive learning was implemented to evaluate the prediction accuracy for each class, which was used to construct a cost-sensitivity matrix of the true positive (TP) rate. This TP rate can be used as a weight value and combined with a probability value to drive ensemble learning for a specified class. We proposed an ensemble model, which was a type of heterogenous model, namely, a combination of various individual classification models (support vector machine, Bayes, K-nearest neighbour, naïve Bayes, decision tree, and multi-layer perceptron) in experiments on 3-, 4-, 5- and 6-classifier models. The efficiencies of the propose models were compared to those of the individual classifier model and homogenous models (Adaboost, bagging, stacking, voting, random forest, and random subspaces) with various multi-class data sets. The experimental results demonstrate that the cost-sensitive probability for the weighted voting ensemble model that was derived from 3 models provided the most accurate results for the dataset in multi-class prediction. The objective of this study was to increase the efficiency of predicting classification results in multi-class classification tasks and to improve the classification results.
Carry the past into the future: the effects of CEO temporal focus on succession planning in family firms
Authors: Lu Feifei , Kwan Ho Kwong , Ma Bin
Published: January 2021

In this study, the relationship between CEO temporal focus and family business succession planning is examined and the moderating effects of family interactions and environmental uncertainty are assessed. Based on data from 198 CEOs of family businesses and additional data from 15 semi-structured interviews in China, we find that CEO temporal focus (i.e., past, present, or future focus) is positively associated with succession planning. In addition, family interactions strengthen the relationship between CEO past focus and succession planning and weaken the relationship between CEO future focus and succession planning. Moreover, in uncertain environments, past-focused CEOs are more likely to plan for succession than present-focused CEOs. The theoretical contributions and practical implications of the study are also discussed.
Promising Therapy for Heart Failure in Patients with Severe COVID-19: Calming the Cytokine Storm
Authors: Peng Xiang , Wang Yani , Xi Xiangwen , Jia Ying , Tian Jiangtian , Yu Bo , Tian Jinwei
Published: January 2021

The coronavirus disease 19 (COVID-19) pandemic poses a serious global threat to human health and the economy. Based on accumulating evidence, its continuous progression involves not only pulmonary injury but also damage to the cardiovascular system due to intertwined pathophysiological risks. As a point of convergence in the pathophysiologic process between COVID-19 and heart failure (HF), cytokine storm induces the progression of COVID-19 in patients presenting pre-existing or new onset myocardial damage and even HF. Cytokine storm, as a trigger of the progression of HF in patients with COVID-19, has become a novel focus to explore therapies for target populations. In this review, we briefly introduce the basis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and illuminate the mechanism and links among COVID-19, cytokine storm, and HF. Furthermore, we discuss drugs and therapeutic targets for patients with COVID-19 and HF.
Nephrotoxicity in patients with solid tumors treated with anti-PD-1/PD-L1 monoclonal antibodies: a systematic review and meta-analysis
Authors: Li Han , Xu Jinsheng , Bai Yaling , Zhang Shenglei , Cheng Meijuan , Jin Jingjing
Published: January 2021

Background Programmed death-1 (PD-1) and programmed death ligand 1 (PD-L1) have dramatically improved cancer therapy for many patients. Adverse kidney effects have been found to be an important complication but have unclear mechanisms. Methods We searched Embase, PubMed, and the Cochrane Library to identify potential eligible studies. All included studies were randomized controlled trials (RCTs) examining patients with solid tumors treated with anti-PD-1/PD-L1 monoclonal antibodies (mAbs) and/or chemotherapy. The relative risk (RR) was used to assess the risk of nephrotoxic events. Results We included 27 clinical trials (15,063 patients). Compared with chemotherapy, the RR of all-grade nephritis was significantly increased with anti-PD-1/PD-L1 mAbs (RR = 2.77, 95% CI: 1.09–6.99, P = 0.03). Furthermore, anti-PD-1/PD-L1 mAbs plus chemotherapy can significantly increase the RR of all-grade nephritis (RR = 2.99, 95% CI: 1.07–8.35, P = 0.04). There was also a significant increase in the RRs of all-grade increased blood creatinine (RR = 1.88, 95% CI: 1.24–2.86, P = 0.003) and acute kidney injury (AKI) (RR =3.35, 95% CI: 1.48–7.60, P = 0.004). Conclusions Anti-PD-1/PD-L1 mAbs can significantly increase nephrotoxicity in patients with solid tumors, especially when combined with chemotherapy. During the application of these drugs, we should remain aware of nephrotoxicity for better efficacy. Trial registration number and date of registration Not applicable.
Phase II study of selumetinib, an orally active inhibitor of MEK1 and MEK2 kinases, in KRASG12R-mutant pancreatic ductal adenocarcinoma
Authors: Kenney Cara , Kunst Tricia , Webb Santhana , Christina Devisser , Arrowood Christy , Steinberg Seth M. , Mettu Niharika B. , Kim Edward J. , Rudloff Udo
Published: January 2021

Background Preclinical evidence has suggested that a subset of pancreatic cancers with the G12R mutational isoform of the KRAS oncogene is more sensitive to MAPK pathway blockade than pancreatic tumors with other KRAS isoforms. We conducted a biomarker-driven trial of selumetinib (KOSELUGO™; ARRY-142886), an orally active, allosteric mitogen-activated protein kinase 1 and 2 (MEK1/2) inhibitor, in pancreas cancer patients with somatic KRASG12R mutations. Methods In this two-stage, phase II study (NCT03040986) patients with advanced pancreas cancer harboring somatic KRASG12R variants who had received at least one standard-of-care systemic therapy regimen received 75 mg selumetinib orally twice a day until disease progression or unacceptable toxicity occurred. The primary outcome of the study was best objective response (BOR). Results From August 2017 to February 2018 a total of 8 patients with confirmed somatic KRASG12R mutations and a median age of 61.5 years were treated with selumetinib. Seven out of eight (87.5%) had received two or more lines of prior systemic chemotherapy. After a median follow-up period of 8.5 months (range 2 to 20), three patients had stable disease for more than 6 months while receiving selumetinib. No patients achieved an objective partial response. Median progression-free survival (PFS) was 3.0 months (95% CI, 0.8–8.2) and median overall survival (OS) 9 months (95% CI, 2.5–20.9). Conclusion This study in heavily pre-treated pancreatic adenocarcinoma patients suggests alternative strategies beyond single agent MEK inhibition are required for this unique, molecular subset of pancreatic cancer patients. The trial was registered on February 2nd, 2017 under identifier NCT03040986 with ClinicalTrials.gov.
Genetic diversity of ‘Candidatus Liberibacter africanus’ in South Africa based on microsatellite markers
Authors: Roberts Ronel , Lin Hong , Pietersen Gerhard
Published: January 2021

Citrus Greening disease (CG) in South Africa (SA) is associated with the fastidious bacterium ‘CandidatusLiberibacter africanus’ (Laf). It has been observed that Laf isolates obtained from different geographic localities in SA differed in the rate of transmission during grafting experiments leading to the hypothesis that genetic variation of Laf may exist in this country. To determine this, 167 Laf isolates obtained from Limpopo, North West, Mpumalanga and the Western Cape were subjected to microsatellite analyses, using four polymorphic markers. From UPGMA and STRUCTURE analysis, it was shown that most sources belong to one of two major genetic groups of Laf and these comprise 25 distinct haplotypes. Four samples included within this study did not group with these two major groups, suggesting a potential third and fourth genetic group of Laf being present, which can be validated by further sampling. Results further indicate that Laf populations in SA are formed by geographic locality. The high genetic diversity observed for Laf within this study is consistent with the hypothesis that Laf originated on the African continent, warranting further genetic analysis of Laf populations from Africa. This is the first study to unveil the genetic diversity of Laf.
Vertical turbulent nitrate flux from direct measurements in the western subarctic and subtropical gyres of the North Pacific
Authors: Kaneko Hitoshi , Yasuda Ichiro , Itoh Sachihiko , Ito Shin-ichi
Published: January 2021

Vertical turbulent nitrate fluxes were estimated in the western North Pacific from direct measurements of vertical turbulent mixing and vertically continuous nitrate profiles during the summer of 2008. We made three north–south transects that covered the area from the subarctic to the subtropics including a section along the Emperor Sea Mounts. Subsurface fluxes generally showed an increasing trend with increasing vertical gradient of nitrate from oligotrophic subtropical to non-oligotrophic subarctic waters. Enhanced fluxes [O(10−6) mmol m−2 s−1] due to elevated mixing [vertical diffusivity: O(10−5) m2 s−1] were observed, especially over the Emperor Sea Mounts. It is suggested that the internal tide generated by the topography enhanced the vertical mixing. In other subarctic areas, the fluxes were estimated as O(10−7) mmol m−2 s−1. The same order of fluxes was also found in the frontal area between the subarctic and subtropical gyres, the Kuroshio–Oyashio Transition Area. Enhancement of fluxes in the frontal area, including the Kuroshio Extension, was also observed at mid-depth regions, and their vertical divergence suggested nitrate transport from North Pacific Intermediate Water to lighter densities. In the frontal areas, the enhancement of turbulence is caused by the surface wind rather than the internal tide. In contrast, in the subtropical regions, subsurface fluxes were estimated as O(10−8) mmol m−2 s−1 owing to the small nitrate gradient even where diffusivity was enhanced. In these regions, enhancement of diffusivity, including that at mid-depths, corresponded to the elevation of the internal-tide dissipation, in addition to that of surface turbulence.
Indoor radon levels in Hungarian kindergartens
Authors: Csordás Anita , Szabó Katalin Zsuzsanna , Sas Zoltán , Kocsis Erika , Kovács Tibor
Published: January 2021

Annual average indoor radon activity concentration was studied in 88 Hungarian kindergartens in 76 towns of 10 different counties. Annual average indoor radon activity concentration in the kindergartens was 61 Bq m− 3, maximum was 160 Bq m− 3. In the kindergartens the seasonal variation of radon is not so strong like in dwellings, because of the permanent ventilation and the closed period during the summer break.
Hypervolume scalarization for shape optimization to improve reliability and cost of ceramic components
Authors: Schultes Johanna , Stiglmayr Michael , Klamroth Kathrin , Hahn Camilla
Published: January 2021

In engineering applications one often has to trade-off among several objectives as, for example, the mechanical stability of a component, its efficiency, its weight and its cost. We consider a biobjective shape optimization problem maximizing the mechanical stability of a ceramic component under tensile load while minimizing its volume. Stability is thereby modeled using a Weibull-type formulation of the probability of failure under external loads. The PDE formulation of the mechanical state equation is discretized by a finite element method on a regular grid. To solve the discretized biobjective shape optimization problem we suggest a hypervolume scalarization, with which also unsupported efficient solutions can be determined without adding constraints to the problem formulation. FurthIn this section, general properties of the hypervolumeermore, maximizing the dominated hypervolume supports the decision maker in identifying compromise solutions. We investigate the relation of the hypervolume scalarization to the weighted sum scalarization and to direct multiobjective descent methods. Since gradient information can be efficiently obtained by solving the adjoint equation, the scalarized problem can be solved by a gradient ascent algorithm. We evaluate our approach on a 2 D test case representing a straight joint under tensile load.
The development of risk aversion and prudence in Chinese children and adolescents
Authors: Heinrich Timo , Shachat Jason
Published: January 2021

This study experimentally evaluates the risk preferences of children and adolescents living in an urban Chinese environment. We use a simple binary choice task that tests risk aversion, as well as prudence. This is the first test for prudence in children and adolescents. Our results reveal that subjects from grades 5 to 11 (10 to 17 years) make mostly risk-averse and prudent choices. The choices of 3rd graders (8 to 9 years) do not differ statistically from risk neutral benchmarks, but at the same time they make mostly prudent choices. We also find evidence for a transmission of risk preferences. There is positive correlation between all children’s and their parents’ tendency to make risk-averse choices. There is also positive correlation between girls’ and their parents’ tendency to make prudent choices.
Review of recent developments in manufacturing lightweight multi-metal gears
Authors: Politis Denis J. , Politis Nicholas J. , Lin Jianguo
Published: January 2021

This paper provides a review of recent developments in the manufacturing of lightweight multi-metal components, and in particular gears. The literature has shown that significant efforts have been made in manufacturing light gears and numerous technical challenges exist when designing for and manufacturing with dissimilar metals including challenges in heating technologies, mechanical performance, processing parameters, metal compatibility and the interface layer between adjacent materials, as well as difficulties in multi-metal simulations. Whilst the scope of multi-metal manufacturing is vast, the main concentration of this study is on the main stages of multi-metal gear production, and specifically on preform production, multi-metal heating, intermetallic bonding, and modelling of essential forming parameters. The effects of each of these methods as well as the numerous approaches studied in the literature are presented, with a recommendation being made as to a processing route that may lead to a robust multi-metal gear with minimal production line modifications to conventional steel gears.
The Association Between Arterial Oxygen Level and Outcome in Neurocritically Ill Patients is not Affected by Blood Pressure
Authors: Humaloja Jaana , Skrifvars Markus B. , Raj Rahul , Wilkman Erika , Pekkarinen Pirkka T. , Bendel Stepani , Reinikainen Matti , Litonius Erik
Published: January 2021

Background

In neurocritically ill patients, one early mechanism behind secondary brain injury is low systemic blood pressure resulting in inadequate cerebral perfusion and consequent hypoxia. Intuitively, higher partial pressures of arterial oxygen (PaO2) could be protective in case of inadequate cerebral circulation related to hemodynamic instability.

Study purpose

We examined whether the association between PaO2and mortality is different in patients with low compared to normal and high mean arterial pressure (MAP) in patients after various types of brain injury.

Methods

We screened the Finnish Intensive Care Consortium database for mechanically ventilated adult (≥ 18) brain injury patients treated in several tertiary intensive care units (ICUs) between 2003 and 2013. Admission diagnoses included traumatic brain injury, cardiac arrest, subarachnoid and intracranial hemorrhage, and acute ischemic stroke. The primary exposures of interest were PaO2(recorded in connection with the lowest measured PaO2/fraction of inspired oxygen ratio) and the lowest MAP, recorded during the first 24 h in the ICU. PaO2was grouped as follows: hypoxemia (< 8.2 kPa, the lowest 10th percentile), normoxemia (8.2–18.3 kPa), and hyperoxemia (> 18.3 kPa, the highest 10th percentile), and MAP was divided into equally sized tertiles (< 60, 60–68, and > 68 mmHg). The primary outcome was 1-year mortality. We tested the association between hyperoxemia, MAP, and mortality with a multivariable logistic regression model, including the PaO2, MAP, and interaction of PaO2*MAP, adjusting for age, admission diagnosis, premorbid physical performance, vasoactive use, intracranial pressure monitoring use, and disease severity. The relationship between predicted 1-year mortality and PaO2was visualized with locally weighted scatterplot smoothing curves (Loess) for different MAP levels.

Results

From a total of 8290 patients, 3912 (47%) were dead at 1 year. PaO2was not an independent predictor of mortality: the odds ratio (OR) for hyperoxemia was 1.16 (95% CI 0.85–1.59) and for hypoxemia 1.24 (95% CI 0.96–1.61) compared to normoxemia. Higher MAP predicted lower mortality: OR for MAP 60–68 mmHg was 0.73 (95% CI 0.64–0.84) and for MAP > 68 mmHg 0.80 (95% CI 0.69–0.92) compared to MAP < 60 mmHg. The interaction term PaO2*MAP was nonsignificant. In Loess visualization, the relationship between PaO2and predicted mortality appeared similar in all MAP tertiles.

Conclusions

During the first 24 h of ICU treatment in mechanically ventilated brain injured patients, the association between PaO2and mortality was not different in patients with low compared to normal MAP.
Monoclonal gammopathy of renal significance
Authors: Reiter Thomas , Nackenhorst Maja
Published: January 2021

Monoclonal gammopathy of renal significance (MGRS) encompasses a group of kidney disorders in which a monoclonal immunoglobulin secreted by a B cell or plasma cell clone causes renal damage, without meeting hematological criteria for malignancy. The underlying disorder in patients with MGRS is generally consistent with monoclonal gammopathy of undetermined significance (MGUS). Because of the wide spectrum of MGRS-associated diseases, defined through the location and mechanism of renal injury, it is often challenging to establish the right diagnosis. Kidney biopsy must be considered early; hence, close cooperation between hematologist and nephrologists is crucial in diagnosis and treatment from the beginning to prevent irreversible organ damage. Anti B‑cell or plasma-cell clone directed therapy with cytostatic or immunomodulatory agents can save and ameliorate renal function significantly. This is underlined by the fact that, untreated, MGRS-associated disease shows early recurrence in patients after kidney transplantation.
Fake Pharmaceuticals: How They and Relevant Legislation or Lack Thereof Contribute to Consistently High and Increasing Drug Prices
Authors: Moken Merri C.
Published: January 2021

The use of pharmaceutical products in the United States has increased more than the use of any other health resource from 1960 to 1990. In excess of 9,600 drugs were on the market in 1984, and the Food and Drug Administration (“FDA”) approves approximately 30 new drugs and countless new applications for alterations of already existing drugs each year. In 2001, the $300 billion pharmaceutical industry sold $154 billion worth of prescription drugs in the United States alone, nearly doubling its $78.9 billion in sales in 1997. With such a rapid increase in market domination and expenditures, the U.S. government and many hospitals have focused their attention on the sales and pricing practices of pharmaceutical companies, as well as other potential factors contributing to these escalating prices. One such cause of the steadily increasing prices of brand name pharmaceuticals is the sale of fake or counterfeit pharmaceuticals (also called “look-alike” drugs).
Externalizing the threat from within: A new direction for researching associations between suicide and psychotic experiences
Authors: Murphy Jamie , Shevlin Mark , Arseneault Louise , Bentall Richard , Caspi Avshalom , Danese Andrea , Hyland Philip , Moffitt Terrie E. , Fisher Helen L.
Published: January 2021

A recent suicidal drive hypothesis posits that psychotic experiences (PEs) may serve to externalize internally generated and self-directed threat (i.e., self-injurious/suicidal behavior [SIB]) in order to optimize survival; however, it must first be demonstrated that such internal threat can both precede and inform PEs. The current study conducted the first known bidirectional analysis of SIB and PEs to test whether SIB could be considered as a plausible antecedent for PEs. Prospective data were utilized from the Environmental Risk (E-Risk) Longitudinal Twin Study, a nationally representative birth cohort of 2232 twins, that captured SIB (any self-harm or suicidal attempt) and PEs at ages 12 and 18 years. Cross-lagged panel models demonstrated that the association between SIB at age 12 and PEs at age 18 was as strong as the association between PEs at age 12 and SIB at age 18. Indeed, the best representation of the data was a model where these paths were constrained to be equal (OR = 2.48, 95% CI = 1.63–3.79). Clinical interview case notes for those who reported both SIB and PEs at age 18, revealed that PEs were explicitly characterized by SIB/threat/death-related content for 39% of cases. These findings justify further investigation of the suicidal drive hypothesis.
Functional mutants of Azospirillum brasilense elicit beneficial physiological and metabolic responses in Zea mays contributing to increased host iron assimilation
Authors: Housh A B , Powell G , Scott S , Anstaett A , Gerheart A , Benoit M , Waller S , Powell A , Guthrie J M , Higgins B , Wilder S L , Schueller M J , Ferrieri R A
Published: January 2021

Iron (Fe), an essential element for plant growth, is abundant in soil but with low bioavailability. Thus, plants developed specialized mechanisms to sequester the element. Beneficial microbes have recently become a favored method to promote plant growth through increased uptake of essential micronutrients, like Fe, yet little is known of their mechanisms of action. Functional mutants of the epiphytic bacterium Azospirillum brasilense, a prolific grass-root colonizer, were used to examine mechanisms for promoting iron uptake in Zea mays. Mutants included HM053, FP10, and ipdC, which have varying capacities for biological nitrogen fixation and production of the plant hormone auxin. Using radioactive iron-59 tracing and inductively coupled plasma mass spectrometry, we documented significant differences in host uptake of Fe2+/3+ correlating with mutant biological function. Radioactive carbon-11, administered to plants as 11CO2, provided insights into shifts in host usage of ‘new’ carbon resources in the presence of these beneficial microbes. Of the mutants examined, HM053 exhibited the greatest influence on host Fe uptake with increased plant allocation of 11C-resources to roots where they were transformed and exuded as 11C-acidic substrates to aid in Fe-chelation, and increased C-11 partitioning into citric acid, nicotianamine and histidine to aid in the in situ translocation of Fe once assimilated.