bluuebunny/crossref_metadata_2025 huggingface dataset:
Brentuximab vedotin consolidation therapy after autologous stem‐cell transplantation in patients with high‐risk Hodgkin lymphoma: Multicenter retrospective study
Authors: Akay Olga Meltem , Ozbalak Murat , Pehlivan Mustafa , Yildiz Birol , Uzay Ant , Yigenoglu Tugce Nur , Elverdi Tugrul , Kaynar Leylagul , Ayyildiz Orhan , Yonal Hindilerden Ipek , Goksoy Hasan Sami , Izmir Guner Sebnem , Gunes Ahmet Kursad , Sonmez Mehmet , Kurt Yuksel Meltem , Civriz Bozdag Sinem , Ozkurt Zubeyde Nur , Toptas Tayfur , Dogu Mehmet Hilmi , Salim Ozan , Saydam Guray , Yavasoglu Irfan , Ayli Meltem , Ozet Gulsum , Albayrak Murat , Birtas Atesoglu Elif , Toprak Selami K. , Yildirim Rahsan , Mehtap Ozgur , Kalayoglu Besisik Sevgi , Nalcaci Meliha , Altuntas Fevzi , Ferhanoglu Burhan
Published: June 2021

The AETHERA trial reported an increased progression‐free survival (PFS) when brentuximab vedotin (BV) was used as maintenance therapy in high‐risk Hodgkin lymphoma (HL) after autologous stem cell transplantation (ASCT). Thus, we aimed to determine the impact and safety of BV as maintenance after ASCT in real‐world patients. Seventy‐five patients with relapsed/refractory HL started on BV consolidation therapy after ASCT due to high risk of relapse, between January 2016 and July 2019, from 25 institutions, were included in the study. The median follow‐up time was 26 months. The most common high‐risk features were primary refractory or relapsed disease <12 months (n = 61), lack of complete response (CR) to the last salvage regimen (n = 51), and having had at least two salvage regimens (n = 29). At the time of analysis, 42 patients completed consolidation courses, and BV was discontinued in 33 patients. Fifty patients had an ongoing response (CR in 41, PR in 6, and SD in 3 patients), 25 had progressed. Ten died in the follow‐up, eight with progressive disease and two due to infection while in CR. The 2‐year PFS and OS rates were 67.75% (95% confidence interval [CI]: 0.55–0.77) and 87.61% (95% CI: 0.76–0.94), respectively. Seventeen patients (23%) received BV in the pre‐ASCT treatment lines, and there was no survival difference between the BV‐naïve and BV‐exposed groups. The most common adverse events were neutropenia (27%) and peripheral neuropathy (21%). Sixteen patients (21.3%) experienced grade 3 or 4 toxicity. BV was discontinued due to adverse event in 12 patients. Consolidation with BV after ASCT can achieve a 2‐year PFS of 67.75% (95% CI: 0.55–0.75) with an acceptable toxicity profile.
Effects of mental health training on capacity, willingness and engagement in peer‐to‐peer support in rural New South Wales
Authors: Maddox Sarah , Powell Nicholas N. , Booth Angela , Handley Tonelle , Dalton Hazel , Perkins David
Published: June 2021

Issue addressed

Rural Australians experience significant barriers in accessing mental health services, some of which may be overcome by increasing mental health literacy in rural communities. This paper evaluates Mental Health Support Skills (MHSS), short training courses developed by the Rural Adversity Mental Health Program (RAMHP). MHSS was designed to build the capacity of community members and gatekeepers to identify people with mental health concerns and link them to appropriate resources or services.

Methods

Program data from April 2017 to March 2020 were analysed to assess the reach and outcomes of MHSS training. Training feedback was collected through a post‐training survey, completed directly after courses, and a follow‐up survey two months after training. An app used by RAMHP coordinators (the trainers) recorded the geographic and demographic reach of courses.

Results

MHSS was provided to 10,208 residents across rural New South Wales. Survey participation was 49% (n = 4,985) for the post‐training survey and 6% (n = 571), for the follow‐up survey, two months post‐training. The training was well‐received and increased the mental health understanding and willingness to assist others of most respondents (91%‐95%). Follow‐up survey respondents applied learnings to assist others; 53% (n = 301) asked a total of 2,252 people about their mental health in the two months following training. Those in clinical roles asked a median of 6 people about their mental health, compared to 3 for those in nonclinical roles. Most follow‐up survey respondents (59%, n = 339) reported doing more to look after their own mental health in the two months after training.

Conclusion

These results are encouraging as they suggest that short‐form mental health training can be an effective tool to address poorer mental health outcomes for rural residents by improving the ability of participants to help themselves and the people around them.

So what?

Serious consideration should be given to short mental health courses, such as MHSS, to increase literacy and connection to services, especially in rural areas.
Thinking of future as an older individual increases perceived risks for age‐related diseases but not for COVID‐19
Authors: Monzani Dario , Marinucci Marco , Pancani Luca , Rusconi Patrice , Mazzoni Davide , Pravettoni Gabriella
Published: June 2021

Actively thinking of one's future as an older individual could increase perceived risk and risk aversion. This could be particularly relevant for COVID‐19, if we consider the common representation of the risk of being infected by COVID‐19 as associated with being older. Increased perceived risk could bear consequences on the adoption of preventive behaviours. Thus, we investigated whether increasing the salience of individuals' future as an older adult would impact on their perceived risk for COVID‐19 and medical conditions varying for age‐relatedness. One hundred and forty‐four Italian adults (Mage = 27.72, range: 18–56) were randomly assigned to either a future as older adult thinking or control condition. Perceived risk for COVID‐19 and other strongly, and weakly age‐related medical conditions during the lifetime was measured. Results showed that thinking about the future as an older adult increased perceived risk for strongly and weakly age‐related diseases, but not for COVID‐19. The salience of the COVID‐19 outbreak may have raised the perceived risks in both experimental conditions, making the manipulation ineffective. In conclusion, manipulating future‐oriented thinking might be a successful communication strategy to increase people's perceived risk of common diseases, but it might not work for highly salient pathologies such as COVID‐19.
Searching for local order parameters to classify water structures at triple points
Authors: Doi Hideo , Takahashi Kazuaki Z. , Aoyagi Takeshi
Published: June 2021

The diversity of ice polymorphs is of interest in condensed‐matter physics, engineering, astronomy, and biosphere and climate studies. In particular, their triple points are critical to elucidate the formation of each phase and transitions among phases. However, an approach to distinguish their molecular structures is lacking. When precise molecular geometries are given, order parameters are often computed to quantify the degree of structural ordering and to classify the structures. Many order parameters have been developed for specific or multiple purposes, but their capabilities have not been exhaustively investigated for distinguishing ice polymorphs. Here, 493 order parameters and their combinations are considered for two triple points involving the ice polymorphs ice III‐V‐liquid and ice V‐VI‐liquid. Supervised machine learning helps automatic and systematic searching of the parameters. For each triple point, the best set of two order parameters was found that distinguishes three structures with high accuracy. A set of three order parameters is also suggested for better accuracy.
Psychologist homicide victims: The National Violent Death Reporting System and other sources
Authors: Robiner William N. , Li Tiffany
Published: June 2021

Objective: Homicide of healthcare workers has been reported but little is known about psychologists as victims of homicide. This study aimed to investigate what is known about homicide of psychologists. Methods: The Centers for Disease Control and Prevention's National Center for Injury Prevention and Control's National Violent Death Reporting System (NVDRS) provides insights into violent deaths, including homicide. This study interrogated the NVDRS and conducted Internet searches about psychologist decedents of homicide. Results: Between 2003 and 2018 the NVDRS identified 12 psychologist homicides. Internet searches revealed 15 psychologist homicides. Only three (11.1%) were known to have been killed by current or former patients. Another was by a colleague's patient. Another assailant was suspected to be a patient. We summarize patterns and circumstances of deaths, address issues related to violence in healthcare, and review selected resources addressing violence prevention. Conclusion: Psychologists, like other health professionals, may be victims of homicide. Such deaths have diverse contributing factors and are rarely perpetrated by patients. As concern about health professional safety mounts and the NVDRS becomes better established, it will hopefully become a more sensitive, precise, comprehensive and useful mechanism for tracking trends in violent deaths of psychologists and other health professionals and ultimately inform preventative strategies.
Cognizance of posttranslational modifications in vaccines: A way to enhanced immunogenicity
Authors: Ojha Rupal , Prajapati Vijay Kumar
Published: June 2021

Vaccination is a significant advancement or preventative strategy for controlling the spread of various severe infectious and noninfectious diseases. The purpose of vaccination is to stimulate or activate the immune system by injecting antigens, i.e., either whole microorganisms or using the pathogen's antigenic part or macromolecules. Over time, researchers have made tremendous efforts to reduce vaccine side effects or failure by developing different strategies combining with immunoinformatic and molecular biology. These newly designed vaccines are composed of single or several antigenic molecules derived from a pathogenic organism. Although, whole‐cell vaccines are still in use against various diseases but due to their ineffectiveness, other vaccines like DNA‐based, RNA‐based, and protein‐based vaccines, with the addition of immunostimulatory agents, are in the limelight. Despite this, many researchers escape the most common fundamental phenomenon of protein posttranslational modifications during the development of vaccines, which regulates protein functional behavior, evokes immunogenicity and stability, etc. The negligence about post translational modification (PTM) during vaccine development may affect the vaccine's efficacy and immune responses. Therefore, it becomes imperative to consider these modifications of macromolecules before finalizing the antigenic vaccine construct. Here, we have discussed different types of posttranslational/transcriptional modifications that are usually considered during vaccine construct designing: Glycosylation, Acetylation, Sulfation, Methylation, Amidation, SUMOylation, Ubiquitylation, Lipidation, Formylation, and Phosphorylation. Based on the available research information, we firmly believe that considering these modifications will generate a potential and highly immunogenic antigenic molecule against communicable and noncommunicable diseases compared to the unmodified macromolecules.
Stimulation of the four isoforms of receptor tyrosine kinase ErbB4, but not ErbB1, confers cardiomyocyte hypertrophy
Authors: Wang Zhen , Chan Hsiu‐Wen , Gambarotta Giovanna , Smith Nicola J. , Purdue Brooke W. , Pennisi David J. , Porrello Enzo R. , O'Brien Shannon L. , Reichelt Melissa E. , Thomas Walter G. , Paravicini Tamara M.
Published: June 2021

Epidermal growth factor (EGF) receptors (ErbB1–ErbB4) promote cardiac development and growth, although the specific EGF ligands and receptor isoforms involved in growth/repair versus pathology remain undefined. We challenged ventricular cardiomyocytes with EGF‐like ligands and observed that selective activation of ErbB4 (the receptor for neuregulin 1 [NRG1]), but not ErbB1 (the receptor for EGF, EGFR), stimulated hypertrophy. This lack of direct ErbB1‐mediated hypertrophy occurred despite robust activation of extracellular‐regulated kinase 1/2 (ERK) and protein kinase B. Hypertrophic responses to NRG1 were unaffected by the tyrosine kinase inhibitor (AG1478) at concentrations that are selective for ErbB1 over ErbB4. NRG1‐induced cardiomyocyte enlargement was suppressed by small interfering RNA (siRNA) knockdown of ErbB4 and ErbB2, whereas ERK phosphorylation was only suppressed by ErbB4 siRNA. Four ErbB4 isoforms exist (JM‐a/JM‐b and CYT‐1/CYT‐2), generated by alternative splicing, and their expression declines postnatally and following cardiac hypertrophy. Silencing of all four isoforms in cardiomyocytes, using an ErbB4 siRNA, abrogated NRG1‐induced hypertrophic promoter/reporter activity, which was rescued by coexpression of knockdown‐resistant versions of the ErbB4 isoforms. Thus, ErbB4 confers cardiomyocyte hypertrophy to NRG1, and all four ErbB4 isoforms possess the capacity to mediate this effect.
Defects of cohesin loader lead to bone dysplasia associated with transcriptional disturbance
Authors: Gu Weihuai , Wang Lihong , Gu Renjie , Ouyang Huiya , Bao Baicheng , Zheng Liwei , Xu Baoshan
Published: June 2021

Cohesin loader nipped‐B‐like protein (Nipbl) is increasingly recognized for its important role in development and cancer. Cornelia de Lange Syndrome (CdLS), mostly caused by heterozygous mutations of Nipbl, is an autosomal dominant disease characterized by multiorgan malformations. However, the regulatory role and underlying mechanism of Nipbl in skeletal development remain largely elusive. In this study, we constructed a Nipbl‐a Cas9‐knockout (KO) zebrafish, which displayed severe retardation of global growth and skeletal development. Deficiency of Nipbl remarkably compromised cell growth and survival, and osteogenic differentiation of mammalian osteoblast precursors. Furthermore, Nipbl depletion impaired the cell cycle process, and caused DNA damage accumulation and cellular senescence. In addition, nucleolar fibrillarin expression, global rRNA biogenesis, and protein translation were defective in the Nipbl‐depleted osteoblast precursors. Interestingly, an integrated stress response inhibitor (ISRIB), partially rescued Nipbl depletion‐induced cellular defects in proliferation and apoptosis, osteogenesis, and nucleolar function. Simultaneously, we performed transcriptome analysis of Nipbl deficiency on human neural crest cells and mouse embryonic fibroblasts in combination with Nipbl ChIP‐Seq. We found that Nipbl deficiency caused thousands of differentially expressed genes including some important genes in bone and cartilage development. In conclusion, Nipbl deficiency compromised skeleton development through impairing osteoblast precursor cell proliferation and survival, and osteogenic differentiation, and also disturbing the expression of some osteogenesis‐regulatory genes. Our study elucidated that Nipbl played a pivotal role in skeleton development, and supported the fact that treatment of ISRIB may provide an early intervention strategy to alleviate the bone dysplasia of CdLS.
Over 1‐year duration and age difference of SARS‐CoV‐2 antibodies in convalescent COVID‐19 patients
Authors: Zeng Fanfan , Wu Mengjun , Wang Jinbiao , Li Jianyu , Hu Guoyun , Wang Lin
Published: June 2021

Anti‐severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) immunoglouilin G (IgG) and immunoglouilin M (IgM) antibodies have been widely used to assist clinical diagnosis. Our previous study reported a discrepancy in SARS‐CoV‐2 antibody response between male and female coronavirus disease 2019 (COVID‐19) patients. However, the duration and discrepancy between ages as well as sexes of SARS‐CoV‐2 antibody in convalescent COVID‐19 patients have not been clarified. In this study, a total of 538 health‐examination individuals who were confirmed with SARS‐CoV‐2 infection a year ago were enrolled. Blood samples were collected and detected for IgM and IgG antibodies. Among these convalescent patients, 12.80% were detected positive for IgM antibodies. The positive rates for IgM antibody were close between sexes: for males, this is 9.17% and for females 13.75%. However, the IgG antibody was detected positive in as much as 82.90% convalescent patients and the positive rates were nearly the same between males (82.57%) and females (82.98%). Besides this, the level of IgM and IgG antibodies showed no difference between male and female convalescent patients. The level of IgG antibodies showed a significant difference between ages. The elder patients (over 35 years old) maintained a higher level of IgG antibody than the younger patients (under or equal 35 years old) after recovering for 1 year. In addition, IgG antibody was more vulnerable to disappear in younger patients than in elder patients. Overall, our study identified over 1‐year duration of SARS‐CoV‐2 antibody and age difference of IgG antibody response in convalescent COVID‐19 patients. These findings may provide new insights into long‐term humoral immune response, vaccines efficacy and age‐based personalized vaccination strategies.
Impact of ‘brown rot’ caused by Gnomoniopsis castanea on chestnut fruits during the post‐harvest process: critical phases and proposed solutions
Authors: Morales‐Rodriguez Carmen , Bastianelli Giorgia , Caccia Romina , Bedini Giacomo , Massantini Riccardo , Moscetti Roberto , Thomidis Thomas , Vannini Andrea
Published: June 2021

BACKGROUND

The brown rot fungus, Gnomoniopsis castanea, is the main organism responsible for the outbreak of chestnut postharvest decay that is threatening the sustainability of the chestnut market in Europe. Currently, no specific strategy is available to mitigate the impact and remediate the high losses of fruits in postharvest storage. In the present study, the different phases of chestnut handling in a standard facility plant were analyzed by evaluating the amount of fruit rot and infection by G. castanea at each phase.

RESULTS

The warm bath (48 °C) was identified as the critical phase, requiring strict parametrization to effectively inactivate G. castanea in fruits. Laboratory tests indicated that maintaining fruits at 50 °C for a maximum of 45 min provided optimal conditions to completely inactivate G. castanea inoculum during postharvest handling. However, the warm bath at 50 °C and over was not effective in inactivating the complex of fungal taxa responsible for contamination and development of molds. Higher temperatures and extended treatment times caused significant losses in fruit quality, as indicated by taste panel evaluation. Upscaling of postharvest facilities is discussed and critically evaluated.

CONCLUSION

The warm bath (50 °C for 45 min) is effective in completely inactivating G. castanea in fruits but did not reduce the impacts of the complex of molds responsible for external contamination and mycotoxin production. © 2021 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.
Chikungunya Fever: Comparison Study of Synovitis and Tenosynovitis of the Hands and Wrists Using Physical Examination, Ultrasound, and MRI Findings
Authors: Leidersnaider Caio Leal , Sztajnbok Flávio Roberto , Coutinho Evandro Silva Freire , Vaz João Luiz Pereira , Porangaba Marina , Hamdan Paulo Cesar , Martins Pedro Henrique , Constantino Carolina Pesce Lamas , Ancillotti Roger Vinicius , Messeder Alexandre Malta , Monteiro Débora Guimarães , Folly Mayara Malta , Mogami Roberto
Published: June 2021

Objectives

To compare musculoskeletal changes on a physical examination (PE), ultrasound (US) and magnetic resonance imaging (MRI) of the hands and wrists of patients with Chikungunya fever (CF).

Methods

The sample consisted of 30 patients in the chronic phase of CF. The sites analyzed were the interphalangeal (IP), metacarpophalangeal (MCP) and wrist/mediocarpal (WMC) joints and periarticular soft tissue. The interval between the PE and imaging tests was 7 days, and the interval between US and MRI was 2 days. The kappa coefficient was calculated to estimate the agreement between the PE and US and MRI findings and between the US and MRI findings.

Results

Significant agreement was observed between PE and US in the diagnosis of synovitis. The only statistically significant agreement between US and MRI was the finding of flexor tenosynovitis; the agreement was moderate.

Conclusions

US has great potential for use in diagnosing synovitis suspected based on a PE. The limited agreement observed between US and MRI, in turn, may suggest a complementary role of these methods.
Decision aid and preference assessment of topical anesthesia for otolaryngology procedures
Authors: DeVore Elliana K. , Gray Stacey T. , Huston Molly N. , Song Phillip C. , Alkire Blake C. , Naunheim Matthew R.
Published: June 2021

Objectives

To determine preference patterns for topical anesthesia in patients undergoing endoscopy pre‐coronavirus (2019 coronavirus disease [COVID‐19]) pandemic and analyze outcomes based on preference, using a decision aid format.

Methods

A decision aid was developed with expert and patient input. New patients presenting to subspecialty clinics over a 2‐month pre‐COVID‐19 period completed a pre‐procedure survey about their priorities, then were asked to choose between topical oxymetazoline/lidocaine spray or none. A post‐procedure outcome survey followed.

Results

Of 151 patients, 90.1% patients elected to have topical anesthesia. Top patient priorities were “I want the scope to be easy for the doctor” and “I want to be as comfortable as possible.” Patients who strongly wanted to avoid medication (P = .002) and bad taste (P = .003) were more likely to select no spray, whereas those who wanted to avoid pain received anesthetic (P = .011). According to the post‐procedure assessment, 95.4% of patients were satisfied or strongly satisfied their choice, and this did not correlate with anesthetic vs none.

Conclusions

Patient preferences are easily elicited and correlate with treatment choices. Most patients chose to have topical anesthetic and were willing to tolerate side effects; however, both patients with and without topical anesthetic were satisfied with their choices. This decision aid can be used to optimize shared decision making in the otolaryngology clinic. Given the aerosolizing potential of both spray and no spray conditions, this insight may be consequential when devising office protocols for post‐COVID‐19 practice.

Level of evidence

II.
Typical relationships between phytoplankton biomass and transport time in river‐dominated coastal aquatic systems
Authors: Qin Qubin , Shen Jian
Published: June 2021

Both abiotic and biotic factors control phytoplankton dynamics. Among the multiple factors regulating the variability of phytoplankton production and biomass, physical transport that distributes both phytoplankton and other substances (e.g., nutrients, salts, and suspended solids) is one of the key factors in coastal aquatic systems. While the effect of transport processes is best understood by the relationship between phytoplankton biomass/production and transport time (e.g., flushing time, residence time, and age), diverse relationships have been broadly observed. No consensus on the existence of a general relationship has been reached. Using a simplified zero‐dimensional mathematical model, we show that diverse relationships between phytoplankton biomass/production and transport time under different conditions of light and nutrient limitations can be synthesized into four patterns in river‐dominated coastal aquatic systems. Three patterns show a non‐monotonic relationship and one pattern shows a positive relationship. The non‐monotonic relationship between biomass and flushing time is demonstrated well by two realistic examples. The revealed non‐monotonic relationship provides insight into the widely observed nonlinear responses of many biogeochemical processes to changes in transport processes.
ALKBH5‐mediated m6A‐demethylation of USP1 regulated T‐cell acute lymphoblastic leukemia cell glucocorticoid resistance by Aurora B
Authors: Gong Hongtao , Liu Liu , Cui Lina , Ma Hongyan , Shen Liyun
Published: June 2021

Recent studies evidence that ubiquitin‐specific proteases (USPs) are associated with the occurrence and chemoresistance of T‐cell acute lymphoblastic leukemia (T‐ALL). N6‐methyladenosine (m6A) demethylase AlkB homolog 5 (ALKBH5) exerts a carcinogenic effect in human cancers and improves the mRNA stability of USPs. Whether ubiquitin‐specific protease 1 (USP1) controls chemoresistance of T‐ALL is unknown. Our study demonstrated that USP1 expression was upregulated in glucocorticoid (GC)‐resistant T‐ALL patients and cells (CEM‐C1). High expression of USP1 was correlated to the poor prognosis in T‐ALL patients. Silencing USP1 increased CEM‐C1 cell sensitivity to dexamethasone (Dex), reduced cell invasion, promoted cell apoptosis, and ameliorated glucocorticoid receptor (GR) expression. USP1 mediated T‐ALL chemoresistance by interacting with and deubiquitination of Aurora B. Overexpression of USP1 reversed the amelioration effect of Aurora B inhibitor on CEM‐C1 cell resistance to Dex. Mechanistically, ALKBH5 enhanced USP1 expression by reducing m6A level and mRNA stability in USP1 mRNA transcript. Downregulation of ALKBH5 reduced the levels of USP1 and Aurora B, facilitated CEM‐C1 cell sensitivity to Dex, apoptosis, and GR expression, suppressed cell invasion. However, overexpression of USP1 reversed all the effects of ALKBH5 on CEM‐C1 cells. In vivo results showed that tail vein injection of sh‐USP1 resulted in a significant prolongation of mouse survival, suppressed tumor growth, maintained the normal weight of mice, reduced USP1 expression and facilitated GR expression. In conclusion, inhibition of ALKBH5‐mediated m6A modification decreased USP1 expression and downregulation of USP1 ameliorated GC resistance of T‐ALL through suppressing Aurora B expression and elevating GR level.
Frequency dependent parametric radiation through a nonlinear fundamentally slow travelling wave structure
Authors: Li Shuping , Zhu Minning , Yuan Yichao , Wu Chung‐Tse Michael
Published: June 2021

This article presents a nonlinear leaky wave antenna (LWA) with frequency dependent parametric radiation based on a fundamentally slow‐wave transmission line (TL) structure. Unlike a conventional LWA that radiates at the excitation frequency, the radiation for the proposed travelling wave structure relies on the parametric frequencies based on the injected pump signals. The proposed nonlinear fundamentally slow wave structure utilizes a periodic sharply bend TL loaded by varactor diodes as nonlinear elements. By utilizing the n = −1 spatial harmonic, the fundamentally slow wave structure can enter the leaky wave region at higher frequencies, where the parametric radiation results from the bifurcation of the injected pump signals. Such TL‐based nonlinear LWA reduces the design complexity and fabrication difficulty. The resulting parametric frequency radiation can be used for beam steering, which provides additional degree of design freedom.
Silicon photomultiplier‐based scintillation detectors for photon‐counting CT: A feasibility study
Authors: van der Sar Stefan J. , Brunner Stefan E. , Schaart Dennis R.
Published: June 2021

Purpose

The implementation of photon‐counting detectors is widely expected to be the next breakthrough in X‐ray computed tomography (CT) instrumentation. A small number of prototype scanners equipped with direct‐conversion detectors based on room‐temperature semiconductors, such as CdTe and CdZnTe (CZT), are currently installed at medical centers. Here, we investigate the feasibility of using silicon photomultiplier (SiPM)‐based scintillation detectors in photon‐counting computed tomography (PCCT) scanners, as a potential alternative to CdTe and CZT detectors.

Methods

We introduce a model that allows us to compute the expected energy resolution as well as the expected pulse shape and associated rate capability of SiPM‐based PCCT detectors. The model takes into account SiPM saturation and optical crosstalk, because these phenomena may substantially affect the performance of SiPM‐based PCCT detectors with sub‐mm pixels. We present model validation experiments using a single‐pixel detector consisting of a 0.9 × 0.9 × 1.0 mm3 LuAP:Ce scintillation crystal coupled to a 1 × 1 mm2 SiPM. We subsequently use the validated model to compute the expected performance of the fast scintillators LYSO:Ce, LuAP:Ce, and LaBr3:Ce, coupled to currently available SiPMs, as well as to a more advanced SiPM prototype with improved dynamic range, for sub‐mm pixel sizes.

Results

The model was found to be in good agreement with the validation experiments, both with respect to energy resolution and pulse shape. It shows how saturation progressively degrades the energy resolution of detectors equipped with currently available SiPMs as the pixel size decreases. Moreover, the expected pulse duration is relatively long (~200 ns) with these SiPMs. However, when LuAP:Ce and LaBr3:Ce are coupled to the more advanced SiPM prototype, the pulse duration improves to less than 60 ns, which is in the same order of magnitude as pulses from CdTe and CZT detectors. It follows that sufficient rate capability can be achieved with pixel sizes of 400 μm or smaller. Moreover, LaBr3:Ce detectors can provide an energy resolution of 11.5%‐13.5% at 60 keV, comparable to CdTe and CZT detectors.

Conclusions

This work provides first evidence that it may be feasible to develop SiPM‐based scintillation detectors for PCCT that can compete with CdTe and CZT detectors in terms of energy resolution and rate capability.
Technical Note: The nearest neighborhood‐based approach for estimating basis line‐integrals using photon‐counting detector
Authors: Nam Jeonghyeon , Lee Okkyun
Published: June 2021

Purpose

This study aims to develop a calibration‐based estimator for the photon‐counting detector (PCD)‐based x‐ray computed tomography.

Methods

We propose the nearest neighborhood (NN)‐based estimator, which searches for the nearest calibration data for a given PCD output and sets the associated basis line‐integrals as the estimate. Searching for the nearest neighbors can be accelerated using the pre‐calculated k‐d tree for the data.

Results

The proposed method is compared to the model‐based maximum likelihood (ML) estimator. For slab phantom study, both ML and NN‐based methods achieve the Cramér‐Rao lower bound and are unbiased for various combinations of three basis materials (water, bone, and gold). The proposed method is also validated for K‐edge imaging and presents almost unbiased Au concentrations in the region of interest.

Conclusions

The proposed NN‐based method is demonstrated to be as accurate as the model‐based ML estimator, but it is computationally efficient and requires only calibration measurements.
Complexity of agricultural economies in the Yiluo region in the late Neolithic and bronze age (3500–221 BC): An integrated stable isotope and archeobotanical study from the Tumen site, North China
Authors: Tao Dawei , Liu Fei , Ren Guang , Richards Michael P. , Zhang Guowen
Published: June 2021

The region of Yiluo in North China witnessed the development of social complexity in the Neolithic period and the emergence of the first Chinese state society in the early Bronze Age. However, the agricultural economies in the Neolithic–Bronze Age periods of this region and its influence on the social complexity in this area have not been adequately understood, owing to the relative lack of evidence from archeobotany, chronology, and stable isotope analysis in this region. Archeobotanical and isotopic evidence, together with chronological data from the Tumen site, reveals that the complexity of the agricultural economy composed of millet and rice appeared during the late Yangshao period in the Yiluo region and became more intensified in the following Longshan and Bronze Age periods. During the Yangshao and Longshan periods, environmental factors such as landform and hydrology were likely important factors for the diverse agricultural patterns. The complexity of the agricultural economy has an influence on settlement hierarchy and population growth, suggesting that the rise and intensification of the complex agricultural economy was an important driving force in societal development in the Yiluo region.
Prostate cancer cells survive anti‐androgen and mitochondrial metabolic inhibitors by modulating glycolysis and mitochondrial metabolic activities
Authors: Basu Hirak S. , Wilganowski Nathaniel , Robertson Samantha , Reuben James M. , Cohen Evan N. , Zurita Amado , Ramachandran Sumankalai , Xiao Lian‐Chun , Titus Mark , Wilding George
Published: June 2021

Background

Most cancer cells are more glycolytic even under aerobic conditions compared with their normal counterparts. Recent evidence of tumor cell metabolism, however, shows that some tumors also increase mitochondrial oxidative phosphorylation (ox‐phos) at some disease states during progression and/or development of drug resistance. Our data show that anti‐androgen enzalutamide (ENZA) resistant prostate cancer (PCa) cells use more mitochondrial metabolism leading to higher ox‐phos as compared to the ENZA‐sensitive cells and can become vulnerable to mitochondrial metabolism targeted therapies.

Methods

Seahorse assay, mass spectrometry and high resolution fluorescence confocal microscopy coupled with image analysis has been used to compare mitochondrial metabolism in ENZA‐treated and ‐untreated anti‐androgen‐sensitive LNCaP and ‐resistant C4‐2, CWR22ν1, and PCa2b cells. Ex vivo fluorescence microscopy and image analysis has been standardized to monitor mitochondrial electron transport (ETS) activity that likely increases ox‐phos in circulating tumor cells (CTCs) isolated fom patients undergoing AR‐targeted therapies.

Results

Our data show that PCa cells that are resistant to anti‐androgen ENZA switch from glycolysis to ox‐phos leading to an increased ETS activity. ENZA pretreated cells are more vulnerable to ETS component complex I inhibitor IACS‐010759 (IACS) and mitochondrial glutaminase inhibitor CB‐839 that reduces glutamate supply to tricarboxylic acid cycle. CTCs isolated from 6 of 20 patient blood samples showed relatively higher ETS activity than the rest of the patients. All six patients have developed ENZA resistance within less than 6 months of the sample collection.

Conclusion

The enhanced growth inhibitory effects of mitochondrial metabolic inhibitors IACS and CB‐839 in ENZA pretreated PCa cells provides a rationale for designing a drug combination trial. Patients can be selected for such trials by monitoring the mitochondrial ETS activities in their CTCs to maximize success.
Repurposing of FDA‐approved drugs against active site and potential allosteric drug‐binding sites of COVID‐19 main protease
Authors: Yuce Merve , Cicek Erdem , Inan Tugce , Dag Aslihan Basak , Kurkcuoglu Ozge , Sungur Fethiye Aylin
Published: June 2021

The novel coronavirus disease 2019 (COVID‐19) caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) still has serious negative effects on health, social life, and economics. Recently, vaccines from various companies have been urgently approved to control SARS‐CoV‐2 infections. However, any specific antiviral drug has not been confirmed so far for regular treatment. An important target is the main protease (Mpro), which plays a major role in replication of the virus. In this study, Gaussian and residue network models are employed to reveal two distinct potential allosteric sites on Mpro that can be evaluated as drug targets besides the active site. Then, Food and Drug Administration (FDA)‐approved drugs are docked to three distinct sites with flexible docking using AutoDock Vina to identify potential drug candidates. Fourteen best molecule hits for the active site of Mpro are determined. Six of these also exhibit high docking scores for the potential allosteric regions. Full‐atom molecular dynamics simulations with MM‐GBSA method indicate that compounds docked to active and potential allosteric sites form stable interactions with high binding free energy (∆Gbind) values. ∆Gbind values reach −52.06 kcal/mol for the active site, −51.08 kcal/mol for the potential allosteric site 1, and − 42.93 kcal/mol for the potential allosteric site 2. Energy decomposition calculations per residue elucidate key binding residues stabilizing the ligands that can further serve to design pharmacophores. This systematic and efficient computational analysis successfully determines ivermectine, diosmin, and selinexor currently subjected to clinical trials, and further proposes bromocriptine, elbasvir as Mpro inhibitor candidates to be evaluated against SARS‐CoV‐2 infections.
Meta‐analysis and review of pesticide non‐target effects on phytoseiids, key biological control agents
Authors: Schmidt‐Jeffris Rebecca A , Beers Elizabeth H , Sater Chris
Published: June 2021

Understanding pesticide non‐target effects on natural enemies is a key element of successful conservation biological control. Due to their importance in agroecosystems worldwide, the phytoseiid mites are the most well‐studied natural enemies in pesticide selectivity research. The wealth of literature associated with this topic allows for a thorough meta‐analysis of pesticide non‐target effects and may also indicate general trends relevant to many cropping systems. We conducted a meta‐analysis using 2386 observations from 154 published papers examining the impact of pesticides on lethal (adult and juvenile mortality) and sublethal (fecundity, egg hatch) effects. Insecticides and herbicides did not statistically differ in toxicity to phytoseiids, but research on herbicide non‐target effects is scarce. Specific insecticides, fungicides, and miticides were sorted into least and most harmful categories. Phytoseiid species also differed in sensitivity, with Galendromus occidentalis (Nesbitt), Neoseiulus californicus (McGregor), and Typhlodromus pyri Scheuten among the least sensitive species. Sensitivity variation may be partly due to pesticide resistance; the greatest differences between species were within older mode of action (MOA) groups, where resistance development has been documented. It has been speculated that specialist phytoseiids, which closely associate with Tetranychus spp. spider mites, have more opportunities for resistance development due to their necessary proximity to a pest that rapidly develops resistance. Effect sizes were higher for generalist phytoseiid species, supporting this hypothesis. This meta‐analysis highlights pesticide types (herbicides) and MOA groups where more research is clearly needed. Our analysis also allows for more robust generalizations regarding which pesticides are harmful or selective to phytoseiids. © 2021 Society of Chemical Industry. This article has been contributed to by US Government employees and their work is in the public domain in the USA.
Theoretical Mapping of Interaction between Alkali Metal Atoms Adsorbed on Graphene‐Like BC3 Monolayer
Authors: Zhour Kazem , Postnikov Andrei
Published: June 2021

First‐principles calculations using density functional theory and two methods in comparison, Quantum ESPRESSO and Siesta, are done on large supercells which describe different placements of two identical adsorbed alkali metal atoms (of either Na or K species) on the monolayer of boron carbide BC3. The energy of single‐atom adsorption over the center of C6 ring, the center of C4B2 hexagon, and over a boron atom are preliminarily estimated, the effect of applying the Grimme D2 correction on the adsorption characteristics is evaluated, and the comparison of these results with available data is discussed. The interaction of two identical Na or K atoms adsorbed at close enough distances (less than ≃10 Å) is negligible if the adsorption occurs at the opposite sides of the BC3 layer, but creates a steep repulsive potential at distances less than ≃8 Å if both atoms are adsorbed on the same side of the monolayer. Relaxation patterns resulting from the two K atoms being trapped at adjacent adsorption sites in the lattice are explained. The results suggest that the density of adsorbed K atoms on BC3 can be interestingly high.
Lightweight, Ultra‐Wideband, and Polarization‐Insensitive Metamaterial Absorber Using a Multilayer Dielectric Structure for C‐ and X‐Band Applications
Authors: Phan Duy Tung , Nguyen Thi Kim Thu , Nguyen Ngoc Hieu , Le Dac Tuyen , Bui Xuan Khuyen , Vu Dinh Lam , Truong Chi Lam , Nguyen Thi Quynh Hoa
Published: June 2021

The design of a lightweight and ultra‐wideband absorber for C and X bands is still a challenge as the dimension of the absorber is relatively large in such a relatively low‐frequency band. Herein, an ultra‐wideband and lightweight metamaterial absorber (MMA) is presented for C‐ and X‐band applications. The unit cell of the proposed MMA consists of four copper sectors loaded by lumped resistors and a continuous copper ground plane, which is printed on two FR‐4 substrates. Furthermore, an airgap separating the FR‐4 layers is used as the active substrate medium of the MMA to achieve both ultra‐wideband absorption spectra and lightweight design. The MMA is investigated by simulation and measurement, showing that a good agreement is achieved. The result indicates that the absorptivity of the MMA under both transverse electric (TE) and transverse magnetic (TM) polarizations is greater than 90% in a wide range from 3.7 to 13.6 GHz for all polarization angles. Compared to other reported broadband absorbers, the proposed MMA shows an ultra‐wide absorption bandwidth and a lightweight design, which demonstrates a great potential for C‐and X‐band applications.
Identifying treatment effects using trimmed means when data are missing not at random
Authors: Ocampo Alex , Schmidli Heinz , Quarg Peter , Callegari Francesca , Pagano Marcello
Published: June 2021

Patients often discontinue from a clinical trial because their health condition is not improving or they cannot tolerate the assigned treatment. Consequently, the observed clinical outcomes in the trial are likely better on average than if every patient had completed the trial. If these differences between trial completers and non‐completers cannot be explained by the observed data, then the study outcomes are missing not at random (MNAR). One way to overcome this problem—the trimmed means approach for missing data due to study discontinuation—sets missing values as the worst observed outcome and then trims away a fraction of the distribution from each treatment arm before calculating differences in treatment efficacy (Permutt T, Li F. Trimmed means for symptom trials with dropouts. Pharm Stat. 2017;16(1):20–28). In this paper, we derive sufficient and necessary conditions for when this approach can identify the average population treatment effect. Simulation studies show the trimmed means approach's ability to effectively estimate treatment efficacy when data are MNAR and missingness due to study discontinuation is strongly associated with an unfavorable outcome, but trimmed means fail when data are missing at random. If the reasons for study discontinuation in a clinical trial are known, analysts can improve estimates with a combination of multiple imputation and the trimmed means approach when the assumptions of each hold. We compare the methodology to existing approaches using data from a clinical trial for chronic pain. An R package trim implements the method. When the assumptions are justifiable, using trimmed means can help identify treatment effects notwithstanding MNAR data.
Comparative liquid chromatography/tandem mass spectrometry lipidomics analysis of macaque heart tissue flash‐frozen or embedded in optimal cutting temperature polymer (OCT): Practical considerations
Authors: Vaswani Ashish , Alcazar Magana Armando , Zimmermann Eric , Hasan Wohaib , Raman Jaishankar , Maier Claudia S.
Published: June 2021

Rationale

Biobanks of patient tissues have emerged as essential resources in biomedical research. Optimal cutting temperature compound (OCT) blends have shown to provide stability to the embedded tissue and are compatible with spectroscopic methods, such as infrared (IR) and Raman spectroscopy. Data derived from omics‐methods are only useful if tissue damage caused by storage in OCT blends is minimal and well understood. In this context, we investigated the suitability of OCT storage for heart tissue destined for liquid chromatography/tandem mass spectrometry (LC/MS/MS) lipidomic studies.

Methods

To determine the compatibility of OCT storage with LC/MS/MS lipidomics studies. The lipid profiles of macaque heart tissue snap‐frozen in liquid nitrogen or stored in an OCT blend were evaluated.

Results

We have evaluated a lipid extraction protocol suitable for OCT‐embedded tissue that is compatible with LC/MS/MS. We annotated and evaluated the profiles of 306 lipid species from tissues stored in OCT or liquid nitrogen. For most of the lipid species (95.4%), the profiles were independent of the storage conditions. However, 4.6% of the lipid species; mainly plasmalogens, were affected by the storage method.

Conclusions

This study shows that OCT storage is compatible with LC–MS/MS lipidomics of heart tissue, facilitating the use of biobanked tissue samples for future studies.
Rational design of allosteric modulators: Challenges and successes
Authors: Chatzigoulas Alexios , Cournia Zoe
Published: June 2021

Recent advances in structural biology and computational techniques have revealed allosteric mechanisms for an abundance of targets leading to the establishment of rational design of allosteric modulators as a new avenue for drug discovery. Considering that allostery is an intrinsic property of the protein conformational ensemble, allosteric drug design has the potential to develop into an innovative approach to modulate the dysregulation of therapeutic targets that are considered to be undruggable at their orthosteric site, explore strategic design opportunities to tackle new chemical space, or develop mutant‐specific therapies to target mutations occurring far from the enzyme active site. Traditionally, allosteric drug discovery has been performed through high‐throughput screening or through serendipitous discoveries; however, recent developments in structure‐based and ligand‐based methods have led to exciting advancements of designing bioactive allosteric ligands rationally. In this review article, we highlight the advantages and disadvantages of allosteric modulators and present structure‐based and ligand‐based drug design methodologies for the identification of allosteric binding sites and allosteric modulators. We also illustrate representative studies for the design allosteric modulators for proteins belonging to a wide range of protein families, also considering irreversible binding with covalent allosteric modulators. Additionally, we analyze challenges and successes in the rational design of allosteric inhibitors and activators. Finally, we present the future of rational allosteric ligand design with newly built computational tools that we expect to be applied in future studies, concluding to theoretical and practical guidelines for allosteric ligand design strategies and identify knowledge gaps that need to be addressed to improve efficiency in allosteric drug design.

This article is categorized under:

Structure and Mechanism > Computational Biochemistry and Biophysics

Structure and Mechanism > Molecular Structures