bluuebunny/crossref_metadata_2025 huggingface dataset:
Pathological complete response to neoadjuvant ceritinib of a crizotinib‐resistant, stage IIIB non‐small cell lung cancer with ALK rearrangement: A case report
Authors: Bing Zhongxing , Jia Ziqi , Wang Yadong , Xue Jianchao , Cao Lei , Cao Zhili , Liu Peng , Li Ji , Liang Naixin , Li Shanqing
Published: June 2021

The treatment of stage IIIB non‐small cell lung cancer (NSCLC) is complicated, the best strategy is chosen individually and surgery is usually not recommended. A 50‐year‐old female was diagnosed with locally advanced lung adenocarcinoma (stage IIIB, T2bN3M0). Fluorescence in situ hybridization (FISH) analysis revealed an ALK rearrangement. Crizotinib was administered and progression was seen after five months. The patient then received ceritinib with a palliative intent, which led to downstaging (IIIA[N2]) with a radiological and metabolic response. Right lower lobe lobectomy was performed at 12 months post‐surgery, and the patient is still disease‐free according to the last computed tomography (CT) scan. The unintended downstaging from ceritinib provided a chance for resection in our patient who had ALK‐positive stage IIIB NSCLC after the failure of first‐line crizotinib, indicating potential usage of ceritinib in the neoadjuvant setting. Future perspective trials are warranted to investigate the role of ceritinib in earlier stages as a primary drug.
Senolytics alleviate the degenerative disorders of temporomandibular joint in old age
Authors: Zhou Yueying , Al‐Naggar Iman M. A. , Chen Po‐Jung , Gasek Nathan S. , Wang Ke , Mehta Shivam , Kuchel George A. , Yadav Sumit , Xu Ming
Published: June 2021

Aging is one of the major risk factors for degenerative joint disorders, including those involving the temporomandibular joint (TMJ). TMJ degeneration occurs primarily in the population over 65, significantly increasing the risk of joint discomfort, restricted joint mobility, and reduced quality of life. Unfortunately, there is currently no effective mechanism‐based treatment available in the clinic to alleviate TMJ degeneration with aging. We now demonstrate that intermittent administration of senolytics, drugs which can selectively clear senescent cells, preserved mandibular condylar cartilage thickness, improved subchondral bone volume and turnover, and reduced Osteoarthritis Research Society International (OARSI) histopathological score in both 23‐ to 24‐month‐old male and female mice. Senolytics had little effect on 4 months old young mice, indicating age‐specific benefits. Our study provides proof‐of‐concept evidence that age‐related TMJ degeneration can be alleviated by pharmaceutical intervention targeting cellular senescence. Since the senolytics used in this study have been proven relatively safe in recent human studies, our findings may help justify future clinical trials addressing TMJ degeneration in old age.
Advanced maternal age causes premature placental senescence and malformation via dysregulated α‐Klotho expression in trophoblasts
Authors: Chen Zhi , Xiong Liling , Jin Huili , Yu Jiaxiao , Li Xin , Fu Huijia , Wen Li , Qi Hongbo , Tong Chao , Saffery Richard , Kilby Mark D. , Baker Philip N.
Published: June 2021

Advanced maternal age (AMA) pregnancy is associated with higher risks of adverse perinatal outcomes, which may result from premature senescence of the placenta. α‐Klotho is a well‐known antiaging protein; however, its expression and effect on the placenta in AMA pregnancies have not yet been fully elucidated. The expression patterns of α‐Klotho in mouse and human placentas from AMA pregnancies were determined by Western blotting and immunohistochemistry (IHC) staining. α‐Klotho expression in JAR cells was manipulated to investigate its role in trophoblastic senescence, and transwell assays were performed to assess trophoblast invasion. The downstream genes regulated by α‐Klotho in JAR cells were first screened by mRNA sequencing in α‐Klotho‐knockdown and control JAR cells and then validated. α‐Klotho‐deficient mice were generated by injecting klotho‐interfering adenovirus (Ad‐Klotho) via the tail vein on GD8.5. Ablation of α‐Klotho resulted in not only a senescent phenotype and loss of invasiveness in JAR cells but also a reduction in the transcription of cell adhesion molecule (CAM) genes. Overexpression of α‐Klotho significantly improved invasion but did not alter the expression of senescence biomarkers. α‐Klotho‐deficient mice exhibited placental malformation and, consequently, lower placental and fetal weights. In conclusion, AMA results in reduced α‐Klotho expression in placental trophoblasts, therefore leading to premature senescence and loss of invasion (possibly through the downregulation of CAMs), both of which ultimately result in placental malformation and adverse perinatal outcomes.
Alcohol consumption during the COVID‐19 pandemic in Europe: a large‐scale cross‐sectional study in 21 countries
Authors: Kilian Carolin , Rehm Jürgen , Allebeck Peter , Braddick Fleur , Gual Antoni , Barták Miroslav , Bloomfield Kim , Gil Artyom , Neufeld Maria , O'Donnell Amy , Petruželka Benjamin , Rogalewicz Vladimir , Schulte Bernd , Manthey Jakob ,   the European Study Group on Alcohol Use and COVID‐19
Published: June 2021

Aims

To investigate changes in alcohol consumption during the first months of the COVID‐19 pandemic in Europe as well as its associations with income and experiences of distress related to the pandemic.

Design

Cross‐sectional on‐line survey conducted between 24 April and 22 July 2020.

Setting

Twenty‐one European countries.

Participants

A total of 31 964 adults reporting past‐year drinking.

Measurements

Changes in alcohol consumption were measured by asking respondents about changes over the previous month in their drinking frequency, the quantity they consumed and incidence of heavy episodic drinking events. Individual indicators were combined into an aggregated consumption‐change score and scaled to a possible range of −1 to +1. Using this score as the outcome, multi‐level linear regressions tested changes in overall drinking, taking into account sampling weights and baseline alcohol consumption [Alcohol Use Disorder Identification Test (AUDIT‐C)] and country of residence serving as random intercept. Similar models were conducted for each single consumption‐change indicator.

Findings

The aggregated consumption‐change score indicated an average decrease in alcohol consumption of −0.14 [95% confidence interval (CI) = −0.18, −0.10]. Statistically significant decreases in consumption were found in all countries, except Ireland (−0.08, 95% CI = −0.17, 0.01) and the United Kingdom (+0.10, 95% CI = 0.03, 0.17). Decreases in drinking were mainly driven by a reduced frequency of heavy episodic drinking events (−0.17, 95% CI = −0.20, −0.14). Declines in consumption were less marked among those with low‐ or average incomes and those experiencing distress.

Conclusions

On average, alcohol consumption appears to have declined during the first months of the COVID‐19 pandemic in Europe. Both reduced availability of alcohol and increased distress may have affected consumption, although the former seems to have had a greater impact in terms of immediate effects.
First data about the preimaginal morphology of Austroscaeva occidentalis (Shannon, 1927) and re‐description of larvae and pupae of Dioprosopa clavata (Fabricius, 1794) (Diptera: Syrphidae)
Authors: Lillo Inés , Pérez‐Bañón Celeste , Arcaya Evelin , Mengual Ximo , Rojo Santos
Published: June 2021

Preimaginal morphology of Austroscaeva occidentalis (Shannon, 1927) is described for the first time, and the morphology of larvae and pupae of Dioprosopa clavata (Fabricius, 1794) is updated based on material obtained from captive rearing of wild females from Argentina and Venezuela, respectively. We describe the morphology of the third instar larva, head skeleton and puparium using optical microscopy, cryo‐scanning and scanning electron microscope. The immature stages of both New World flower fly species are analysed and compared with the known preimaginal morphology of other taxa that belong to the evolutionary lineage of Eupeodes‐Scaeva, where Austroscaeva Láska, Mazánek & Mengual, 2018, and Dioprosopa Hull, 1949, form a Neotropical radiation within, together with the genus Notosyrphus Vockeroth, 1969. Larvae of all members of this lineage have abdominal segments 5 and 6 with the tips of the locomotory prominences facing posteriorly, and the anal segment with a characteristic U‐shaped grasping organ. Two other larval synapomorphies of this group of genera are the presence of metathoracic setae accompanying ventral sensilla, and the abdominal segments 1–7 with an extra lobe on each locomotory prominence. These two last characters cannot be assessed for Macrosyrphus Matsumura, 1917, and Lapposyrphus Dušek & Láska, 1967, based on published information on larval descriptions. Despite a similar colouration pattern of the fully grown larvae, larval morphology of A. occidentalis and D. clavata are quite distinct. The preimaginal morphology of A. occidentalis has a mixture of morphological characters from the taxa Scaeva Fabricius, 1805, Semiscaeva Kuznetzov, 1985, and Dioprosopa. The larvae of D. clavata show several unique diagnostic features, such as the presence of a slightly serrate outline due to the great development of the segmental spines and a pinnate ornamentation of the setae of its dorsal and dorsolateral sensilla. Regarding their biological cycle, the length of the preadult stages of A. occidentalis is almost 5 days longer than the length observed for D. clavata. In addition, new DNA barcodes are provided for A. occidentalis.
Modelling current and future potential distributions of Vachellia tortilis (Forssk.) Hayne subsp. raddiana (Savi.) Brenan var. raddiana under climate change in Tunisia
Authors: Mechergui Kaouther , Altamimi Amal Saleh , Jaouadi Wahbi , Naghmouchi Souheila , El Wellani Sabri
Published: June 2021

In this study, we modelled the current and future distribution of the V. tortilis subsp. raddiana var. raddiana for the period from 2050 (RCP 2.6; RCP 4.5; RCP 8.5) to 2070 (RCP 2.6; RCP 4.5; RCP 8.5) using a maximum entropy (MaxEnt) species distribution model. Our results showed that the precipitation‐associated variables had the strongest effect on the distributions of this species. Among these variables, the precipitation of driest quarter (Bio17: 31.9 of percentage contribution) was the most important variable affecting the suitability of the habitats. Under the current climate conditions, the areas of the highly suitable (>0.6) habitat for V. tortilis in the arid land of Tunisia were 1142.532 km2. In the year 2050 (RCP 2.6) and 2070 (RCP 2.6), the highly suitable habitat areas for V. tortilis will continue to increase and eventually reach to 3300.704 and 5181.630 km2, respectively. In the year 2050 (RCP 8.5) and 2070 (RCP 8.5), the highly suitable habitat areas for V. tortilis will continue to increase and eventually reach to 9614.449 and 14684.870 km2, respectively. With the climate change, the highly suitable habitats of V. tortilis would shift to the southeast and northeast of Bled Talah.
Ferrous hemoglobin and hemoglobin‐based oxygen carriers acting as a peroxidase can inhibit oxidative damage to endothelial cells caused by hydrogen peroxide
Authors: Huo Shuangshuang , Lei Xiaofeng , He Dan , Zhang Hua , Yang Zhipeng , Mu Wenhua , Fang Ke , Xue Dan , Li He , Li Xiaoyan , Jia Nan , Zhu Hongli , Chen Chao , Yan Kunping
Published: June 2021

Oxidative damage caused by the ferryl hemoglobin is one of the major clinical adverse reactions of hemoglobin‐based oxygen carriers (HBOCs), while the production of reactive oxygen species in a pathological state can oxidize hemoglobin (HbFe2+) to ferryl Hb, which can then enter the pseudoperoxidase cycle, making hemoglobin highly toxic. In this study, we found that ferrous hemoglobin and polymerized porcine hemoglobin (one of the HBOCs) have the peroxidase activity different from the pseudoperoxidase activity of ferric hemoglobin. Ferrous hemoglobin can catalyze the reaction of tyrosine (Tyr) with hydrogen peroxide. In addition, the results also indicated that ferrous hemoglobin and pPolyHb have a strong inhibitory effect on the pseudoperoxidase activity of ferric hemoglobin. Therefore, hydrogen peroxide was consumed in a large amount, which greatly prevented hemoglobin from becoming oxidized and entering the pseudoperoxidase cycle, thus inhibiting ferryl Hb toxicity. We further cultured human umbilical vein endothelial cells and monitored cell morphology, viability, cell cycle, apoptosis, lactate dehydrogenase (LDH) release, and malondialdehydes (MDAs) formation when incubated with H2O2, Tyr, and HbFe2+. HbFe2+ and pPolyHb reduced cell cycle arrest, apoptosis, LDH release, and MDA formation. These results showed that reducing oxidative damage induced by H2O2 and converted hemoglobin from a molecule that is toxic to one that inhibits oxidative damage, suggesting a new strategy for development of a safer HBOCs.
Molecular identification and relative abundance of microorganisms in douchi koji and salted egg white sufu during processing
Authors: Chen Yi‐Chao , Liaw Ren‐Bao , Liao Yu‐Sheng , Wanangkarn Amornrat , Chen Wen‐Shyan , Tan Fa‐Jui
Published: June 2021

A novel animal protein‐based douchi koji‐inoculated steamed salted egg white sufu (SEWS) has been developed. This study determined the relative abundance of microorganisms in the douchi koji and semi‐finished (5‐day fermentation) and finished (5‐day fermentation and 14‐day ripening) SEWS by using 16S and 18S ribosomal DNA and gene‐cloning methods. The results revealed that Bacillus spp. and Aspergillus oryzae were dominant in the douchi koji. In the semi‐finished SEWS, the percentages of Bacillus amyloliquefaciens and Bacillus subtilis were considerably lower, whereas those of Enterococcus and Staphylococcus were substantially higher. In the finished SEWS, Bacillus spp. became dominant again and A. oryzae was the only fungus detected. In conclusion, by using molecular techniques, microbial population dynamics in SEWS can be evaluated. During processing, the relative abundance of microorganisms in SEWS changed and Bacillus spp. and A. oryzae remained dominant. This study provides crucial information for designing starter cultures for producing SEWS.
Discussion on “Improving precision and power in randomized trials for COVID‐19 treatments using covariate adjustment for binary, ordinal, and time‐to‐event outcomes”
Authors: Proschan Michael A.
Published: June 2021

Benkeser et al. present a very informative paper evaluating the efficiency gains of covariate adjustment in settings with binary, ordinal, and time‐to‐event outcomes. The adjustment method focuses on estimating the marginal treatment effect averaged over the covariate distribution in both arms combined. The authors show that covariate adjustment can achieve power gains that could find answers more quickly. The suggested approach is an important weapon in the armamentarium against epidemics like COVID‐19. I recommend evaluating the procedure against more traditional approaches for conditional analyses (e.g., logistic regression) and against blinded methods of building prediction models followed by randomization‐based inference.
Treatment of lymphocyte‐variant hypereosinophilic syndrome (L‐HES): what to consider after confirming the elusive diagnosis
Authors: Williams Alastair K. , Dou Carol , Chen Luke Y. C.
Published: June 2021

Lymphocyte‐variant hypereosinophilic syndrome (L‐HES) is a rare disease driven by immunophenotypically aberrant T cells producing eosinophilopoetic cytokines such as interleukin‐5 (IL‐5). Treatment is challenging because L‐HES is relatively steroid resistant and not amenable to tyrosine kinase inhibitors. We searched the literature for clinical trials and observational studies, including case reports, of patients treated for L‐HES. In all, 25 studies were selected; two were randomised controlled trials of IL‐5 blockade, which included some patients with L‐HES, and the rest were observational studies. Corticosteroids are often used as first‐line therapy, but patients with L‐HES have lower response rates than other types of HES. Treatments that reduce symptoms and steroid dependence in some patients include interferon‐alpha (IFN‐α), anti‐IL‐5 monoclonal antibodies, cyclosporine and mycophenolate. These drugs target T‐cell activation and proliferation, or IL‐5 directly. Although effective, IFN‐α and cyclosporine were commonly reported to cause side‐effects resulting in discontinuation. Alemtuzumab can induce remissions, but these are generally short lived. The anti‐IL‐5 monoclonal antibodies mepolizumab and benralizumab are effective and well tolerated, but with a high rate of relapse once withdrawn. Hydroxyurea, methotrexate, imatinib were unsuccessful in most patients studied. More prospective clinical trials are needed for patients with L‐HES.
British Academia's Response to the coup d'état in Chile: The Case of Academics for Chile
Authors: Perry Mariana
Published: June 2021

This article seeks to shed light on British academia's response to the coup d'état in Chile in 1973 from a global history approach, arguing that the concern expressed from the academic world transcended the bipolarity of the global context to appeal to a cross‐cutting defence of human rights and university autonomy. To this end, the Judith Hart and the Chilean Solidarity Campaign collections were reviewed in the Labour History Archive in Manchester, in addition to documents from the British Foreign and Commonwealth Office at the National Archives. The above bibliography was complemented by secondary source bibliography.
Regulatory mechanisms of lipid biosynthesis in microalgae
Authors: Chen Hui , Wang Qiang
Published: June 2021

Microalgal lipids are highly promising feedstocks for biofuel production. Microalgal lipids, especially triacylglycerol, and practical applications of these compounds have received increasing attention in recent years. For the commercial use of microalgal lipids to be feasible, many fundamental biological questions must be addressed based on detailed studies of algal biology, including how lipid biosynthesis occurs and is regulated. Here, we review the current understanding of microalgal lipid biosynthesis, with a focus on the underlying regulatory mechanisms. We also present possible solutions for overcoming various obstacles to understanding the basic biology of microalgal lipid biosynthesis and the practical application of microalgae‐based lipids. This review will provide a theoretical reference for both algal researchers and decision makers regarding the future directions of microalgal research, particularly pertaining to microalgal‐based lipid biosynthesis.
Endoscopic near‐infrared photoimmunotherapy in an orthotopic head and neck cancer model
Authors: Okada Ryuhei , Furusawa Aki , Inagaki Fuyuki , Wakiyama Hiroaki , Kato Takuya , Okuyama Shuhei , Furumoto Hideyuki , Fukushima Hiroshi , Choyke Peter L. , Kobayashi Hisataka
Published: June 2021

Near‐infrared photoimmunotherapy (NIR‐PIT) is a cell selective cancer therapy that uses an antibody‐photoabsorber (IRDye700DX, IR700) conjugate (APC) and NIR light. NIR‐PIT targeting epidermal growth factor receptor (EGFR) in head and neck cancer (HNC) was conditionally approved in Japan in 2020. APC‐bound tumors can be detected using endoscopic fluorescence imaging, whereas NIR light can be delivered using endoscopic fiber optics. The aims of this study were: (1) to assess the feasibility of endoscopic NIR‐PIT in an orthotopic HNC model using a CD44‐expressing MOC2‐luc cell line; and (2) to evaluate quantitative fluorescence endoscopic imaging prior to and during NIR‐PIT. The results were compared in 3 experimental groups: (1) untreated controls, (2) APC injection without light exposure (APC‐IV), and (3) APC injection followed by NIR light exposure (NIR‐PIT). APC injected groups showed significantly higher fluorescence signals for IR700 compared with the control group prior to therapeutic NIR light exposure, and the fluorescence signal significantly decreased in the NIR‐PIT group after light exposure. After treatment, the NIR‐PIT group showed significantly attenuated bioluminescence compared with the control and the APC‐IV groups. Histology demonstrated diffuse necrotic death of the cancer cells in the NIR‐PIT group alone. In conclusion, endoscopically delivered light combined with quantitative fluorescence imaging can be used to “see and treat” HNC. This method could also be applied to other types of cancer approachable with endoscopy.
Multifaceted features of immunoglobulin G anti‐GM1 antibodies in Guillain–Barré syndrome
Authors: Koga Michiaki
Published: June 2021

Immunoglobulin G (IgG) anti‐GM1 antibodies, the most common autoantibodies in Guillain–Barré syndrome (GBS), have diverse characteristics regarding IgG subclass, complement activation, affinity and fine specificity. In this review, an update on multifaceted aspects of IgG anti‐GM1 antibodies is provided, emphasizing their roles in creating a varying clinical picture of GBS and in developing pure motor neuropathy after antecedent infection. Diversity in IgG subclass and cross‐reactivity, both of which are closely related to the type of antecedent infection, appears to cause the variation in clinical features and severity of the disease. The environment around GM1 expression in neural tissue is thought to interfere with the binding of anti‐GM1 antibodies by modulating the immunoreactive epitope, allowing only anti‐GM1 antibodies with specific fine specificity to bind to the GM1 ganglioside. This might create the characteristic clinical picture of pure motor neuropathy in anti‐GM1‐positive GBS, although GM1 is present equally in motor and sensory nerves. The environment around the GM1 epitope on Campylobacter jejuni, the most frequently identified agent in antecedent infections of GBS, might also be important in creating diversity in the fine specificity of anti‐GM1 antibodies, possibly preventing the development of GBS in most patients with enteritis by the GM1 epitope‐bearing C. jejuni. Because there remains no direct evidence indicative that diversity of anti‐GM1 antibodies is involved in the development of GBS, further study is required.
Learning from neighboring farmers: Does spatial dependence affect adoption of drought‐tolerant wheat varieties in China?
Authors: Zheng Hongyun , Ma Wanglin , Li Gucheng
Published: June 2021

The adoption of improved crop varieties, such as drought‐tolerant varieties, plays a crucial role in addressing climate change. In this study, we explore how and to what extent spatial interactions between farmers and neighboring farmers affect the adoption of drought‐tolerant wheat varieties (DTWVs), using data collected from rural households in China. A spatial Durbin probit model is utilized to identify the spatial patterns in DTWVs adoption. Results show that spatial dependence exists in DTWVs adoption. Spatial dependence is positively associated with wheat farmers’ DTWVs adoption decisions, and the spatial effects mainly arise from the neighboring farmers’ adoption decisions and information spillover via smartphone use and extension service contacts. Further analysis reveals that DTWVs adoption improves farm performance by increasing both wheat yields and farm profits significantly. Our findings underscore the necessity of considering spatial interactions between farmers when designing and promoting innovative agricultural technologies in rural areas.
Preferences and emotional response to weight‐related terminology used by healthcare professionals to describe body weight in people living with overweight and obesity
Authors: Brown Adrian , Flint Stuart W.
Published: June 2021

Previous studies have explored people's perceptions of weight‐related terminology; however, to date, limited data has explored the emotional response to weight‐related terms used by healthcare professionals (HCPs). This study explored the preferences and emotional responses of terms used by HCPs to describe body weight and of parents to describe their children's weight. A total of 2911 adults completed an online cross‐sectional survey, with 1693 living with overweight or obesity (mean age 49.2 years [SD 12.5], female (96%), median body mass index (BMI) 31.4 kg/m2 [28.1, 36.5]). The survey explored preferences of 22 weight‐related terms using a 5‐point Likert scale and their emotional response to these terms (using 7‐core emotions). Parents also indicated preferences and emotional responses to terms used to describe their children's weight. Respondents completed the modified weight bias internalization scale to examine how this may impacted preferences. 'Weight', “unhealthy weight” and “overweight” were the three preferred terms, while “super obese”, “chubby”, and “extra‐large” were least preferred in people living with overweight and obesity. Parents preferred 'weight', “unhealthy weight” and “body mass index”, and least preferred “fat”, “extra‐large” and “extremely obese” when describing their children's weight. All terms elicited a negative emotional response. The most commonly emotion was sadness for terms to describe adult's bodyweight, and anger for terms used to describe children's weight. All BMI categories reported disgust with terms incorporating “obese”. Our results offer novel insight into the preferred terminology and emotional responses to terminology used by HCPs for both adults and parents to describe their children's weight.
A clinical model to predict fibrosis on liver biopsy in paediatric subjects with nonalcoholic fatty liver disease
Authors: Kulkarni Sakil , Naz Nadia , Gu Hongjie , Stoll Janis M. , Thompson Michael D. , DeBosch Brian J.
Published: June 2021

The incidence of nonalcoholic fatty liver disease (NAFLD) in children is rapidly increasing. Liver fibrosis is a poor prognostic feature that independently predicts cirrhosis. The time that intercedes the first medical encounter and biopsy is rate‐limiting to multi‐modal treatment. This study aimed to identify non‐invasive parameters to predict advanced NAFLD and fibrosis. We conducted a single‐center, retrospective 10‐year analysis of 640 paediatric patients who underwent liver biopsy. 55 patients, age 3–21 years, had biopsy‐confirmed NAFLD. We assessed primary outcomes, NAFLD activity score (NAS) and fibrosis scores, against non‐invasive parameters by linear regression, by using binary cutoff values, and by a multivariate logistic regression fibrosis prediction model. NAS correlated with platelets and female sex. Fibrosis scores correlated with platelet counts, gamma glutamyl transferase (GGT), and ultrasound shear wave velocity. 25‐hydroxy‐vitamin D and GGT differentiated mild versus moderate‐to‐advanced fibrosis. Our multivariate logistical regression model‐based scoring system predicted F2 or higher (parameters: BMI%, vitamin D, platelets, GGT), with sensitivity and specificity of 0.83 and 0.95 (area under the ROC curve, 0.944). We identify a clinical model to identify high‐risk patients for expedited biopsy. Stratifying patients to abbreviate time‐to‐biopsy can attenuate delays in aggressive therapy for high‐risk patients.
Environmental liability litigation could remedy biodiversity loss
Authors: Phelps Jacob , Aravind Sakshi , Cheyne Susan , Dabrowski Pedrini Isabella , Fajrini Rika , Jones Carol A. , Lees Alexander C. , Mance Anna , Nagara Grahat , Nugraha Taufiq P. , Pendergrass John , Purnamasari Umi , Rodriguez Maribel , Saputra Roni , Sharp Stuart P. , Sokolowki Amir , Webb Edward L.
Published: June 2021

Many countries allow lawsuits to hold responsible parties liable for the environmental harm they cause. Such litigation remains largely untested in most biodiversity hotspots and is rarely used in response to leading drivers of biodiversity loss, including illegal wildlife trade. Yet, liability litigation is a potentially ground‐breaking conservation strategy to remedy harm to biodiversity by seeking legal remedies such as species rehabilitation, public apologies, habitat conservation and education, with the goal of making the injured parties ‘whole’. However, precedent cases, expert guidance, and experience to build such conservation lawsuits is nascent in most countries. We propose a simplified framework for developing conservation lawsuits across countries and conservation contexts. We explain liability litigation in terms of three dimensions: (1) defining the harm that occurred, (2) identifying appropriate remedies to that harm, and (3) understanding what remedies the law and courts will allow. We illustrate the framework via a hypothetical lawsuit against an illegal orangutan trader in Indonesia. We highlight that conservationists’ expertise is essential to characterizing harm and identifying remedies, and could more actively contribute to strategic, science‐based litigation. This would identify priority contexts, target defendants responsible for egregious harm, propose novel and meaningful remedies, and build new transdisciplinary collaborations.
SHED aggregate exosomes shuttled miR‐26a promote angiogenesis in pulp regeneration via TGF‐β/SMAD2/3 signalling
Authors: Wu Meiling , Liu Xuemei , Li Zihan , Huang Xiaoyao , Guo Hao , Guo Xiaohe , Yang Xiaoxue , Li Bei , Xuan Kun , Jin Yan
Published: June 2021

Objectives

Pulp regeneration brings big challenges for clinicians, and vascularization is considered as its determining factor. We previously accomplished pulp regeneration with autologous stem cells from deciduous teeth (SHED) aggregates implantation in teenager patients, however, the underlying mechanism needs to be clarified for regenerating pulp in adults. Serving as an important effector of mesenchymal stem cells (MSCs), exosomes have been reported to promote angiogenesis and tissue regeneration effectively. Here, we aimed to investigate the role of SHED aggregate‐derived exosomes (SA‐Exo) in the angiogenesis of pulp regeneration.

Materials and Methods

We extracted exosomes from SHED aggregates and utilized them in the pulp regeneration animal model. The pro‐angiogenetic effects of SA‐Exo on SHED and human umbilical vein endothelial cells (HUVECs) were evaluated. The related mechanisms were further investigated.

Results

We firstly found that SA‐Exo significantly improved pulp tissue regeneration and angiogenesis in vivo. Next, we found that SA‐Exo promoted SHED endothelial differentiation and enhanced the angiogenic ability of HUVECs, as indicated by the in vitro tube formation assay. Mechanistically, miR‐26a, which is enriched in SA‐Exo, improved angiogenesis both in SHED and HUVECs via regulating TGF‐β/SMAD2/3 signalling.

Conclusions

In summary, these data reveal that SA‐Exo shuttled miR‐26a promotes angiogenesis via TGF‐β/SMAD2/3 signalling contributing to SHED aggregate‐based pulp tissue regeneration. These novel insights into SA‐Exo may facilitate the development of new strategies for pulp regeneration.
Type‐2 airway inflammation in mild asthma patients with high blood eosinophils and high fractional exhaled nitric oxide
Authors: Southworth Thomas , Van Geest Marleen , Singh Dave
Published: June 2021

Type‐2 (T2) inflammation is a characteristic feature of asthma. Biological therapies have been developed to target T2‐inflammation in asthma. IL‐13 is a key component of T2‐inflammation in asthma, driving mucus hypersecretion, IgE‐induction, and smooth muscle contraction. Early phase clinical trials for treatments that target T2‐inflammation require biomarkers to assess pharmacological effects. The aim of this study was to examine levels of IL‐13 inducible biomarkers in the airway epithelium of patients with mild asthma compared to healthy controls. Ten patients with mild asthma with high blood eosinophil and high fractional exhaled nitric oxide (FeNO) were recruited, and six healthy subjects. Blood eosinophil and FeNO reproducibility was assessed prior to bronchoscopy. Epithelial brushings were collected and assessed for IL‐13 inducible gene expression. Blood eosinophil and FeNO levels remained consistent in both patients with asthma and healthy subjects. Of the 11 genes assessed, expression levels of 15LOX1, POSTN, CLCA1, SERPINB2, CCL26, and NOS2 were significantly higher in patients with asthma compared to healthy controls. These six genes, present in patients with mild asthma with T2 inflammation, have the potential to be used in translational early phase asthma clinical trials of novel therapies as bronchial epithelial biomarkers.
Comparison of radiation exposure between endoscopic ultrasound‐guided drainage and transpapillary drainage by endoscopic retrograde cholangiopancreatography for pancreatobiliary diseases
Authors: Takenaka Mamoru , Hosono Makoto , Rehani Madan M. , Chiba Yasutaka , Ishikawa Rei , Okamoto Ayana , Yamazaki Tomohiro , Nakai Atsushi , Omoto Shunsuke , Minaga Kosuke , Kamata Ken , Yamao Kentaro , Hayashi Shiro , Nishida Tsutomu , Kudo Masatoshi
Published: June 2021

Objectives

The transpapillary drainage by endoscopic retrograde cholangiopancreatography (ERCP‐D) cannot be performed without fluoroscopy, and there are many situations in which fluoroscopy is required even in endoscopic ultrasound‐guided drainage (EUS‐D). Previous studies have compared the efficacy, but not the radiation exposure of EUS‐D and ERCP‐D. While radiation exposure in ERCP‐D has been previously evaluated, there is a paucity of information regarding radiation doses in EUS‐D. This study aimed to assess radiation exposure in EUS‐D compared with that in ERCP‐D.

Methods

This retrospective single‐center cohort study included consecutive patients who underwent EUS‐D and ERCP‐D between October 2017 and March 2019. The air kerma (AK, mGy), kerma‐area product (KAP, Gycm2), fluoroscopy time (FT, min), and procedure time (PT, min) were assessed. The invasive probability weighting method was used to qualify the comparisons.

Results

We enrolled 372 and 105 patients who underwent ERCP‐D and EUS‐D, respectively. The mean AK, KAP, and FT in the EUS‐D group were higher by 53%, 28%, and 27%, respectively, than those in the ERCP‐D group, whereas PT was shorter by approximately 11% (AK, 135.0 vs. 88.4; KAP, 28.1 vs. 21.9; FT, 20.4 vs. 16.0; PT, 38.7 vs. 43.5). The sub‐analysis limited to biliary drainage cases showed the same trend (AK, 128.3 vs. 90.9; KAP, 27.0 vs. 22.2; FT, 16.4 vs. 16.1; PT, 32.5 vs. 44.4).

Conclusions

This is the first study to assess radiation exposure in EUS‐D compared with that in ERCP‐D. Radiation exposure was significantly higher in EUS‐D than in ERCP‐D, despite the shorter procedure time.
Nintendo Wii Balance Board therapy for postural control in children with cerebral palsy: a systematic review and meta‐analysis
Authors: Montoro‐Cárdenas Desirée , Cortés‐Pérez Irene , Zagalaz‐Anula Noelia , Osuna‐Pérez María C , Obrero‐Gaitán Esteban , Lomas‐Vega Rafael
Published: June 2021

Aim

To analyse the efficacy of Nintendo Wii therapy (NWT) on functional balance in children with cerebral palsy (CP).

Method

A systematic review with meta‐analysis (PROSPERO identification number CRD42020169510) was performed using randomized controlled trials (RCTs) that examined the effect of NWT on functional, dynamic, and static balance in children with CP, assessed with the Pediatric Balance Scale, the Timed Get Up and Go Test, and the One Leg Stance Test respectively. The pooled effect was calculated using the Cohen's standardized mean difference (SMD).

Results

Eleven RCTs with 270 children (when sex was reported: 43% females, 57% males) with CP (mean age [SD] 10y 1mo [1y 1mo], range 5–16y) were included. On functional balance, we found very low‐quality evidence with a large effect of NWT compared with no intervention (SMD 0.95, 95% confidence interval [CI] 0.02–1.89) and moderate‐quality evidence for using NWT plus conventional physical therapy (CPT) versus CPT (SMD 0.78, 95% CI 0.20–1.35) in sessions of approximately 30 minutes (SMD 0.86, 95% CI 0.20–1.52) and interventions lasting longer than 3 weeks (SMD 1.03, 95% CI 0.58–1.47). For dynamic balance, very low‐quality evidence for a medium effect for using NWT plus CPT versus CPT (SMD 0.70, 95% CI 0.12–1.29) was found.

Interpretation

NWT can be considered an effective treatment for improving functional and dynamic balance in children with CP, especially when combined with CPT in 30‐minute sessions with interventions lasting longer than 3 weeks.

What this paper adds

Moderate‐quality evidence with a large effect of Nintendo Wii therapy (NWT) on functional balance, compared with conventional physical therapy (CPT).

Moderate‐quality evidence with medium effect of NWT plus CPT on functional and dynamic balance, compared with CPT.

Appropriate NWT sessions should be equal to or slightly less than 30 minutes.

NWT interventions must be longer than 3 weeks.
Nonverbal content and trust: An experiment on digital communication
Authors: Babutsidze Zakaria , Hanaki Nobuyuki , Zylbersztejn Adam
Published: June 2021

We experimentally study the effect of the mode of digital communication on the emergence of trust in a principal‐agent relationship. We consider three modes of communication that differ in the capacity to transmit nonverbal content: plain text, audio, and video. Communication is pre‐play, one‐way, and unrestricted, but its verbal content is homogenized across treatments. Overall, both audio and video messages have a positive (and similar) effect on trust as compared to plain text; however, the magnitude of these effects depends on the verbal content of agent's message (promise to act trustworthily vs. no such promise). In all conditions, we observe a positive effect of the agent's promise on the principal's trust. We also report that trust in female principals is sensitive to the availability of nonverbal cues about their partners.
Reforms that keep you at home: The effects of economic transition on migration
Authors: Guzi Martin , Mikula Štěpán
Published: June 2021

Theory asserts that individuals’ migration decisions depend more on their expectations about future income levels than on their current income levels. We find that the implementation of market‐oriented reforms in post‐communist countries, by forming positive economic prospects, has reduced emigration as predicted by theory. Our estimates show that migration flows are highly responsive to reforms supporting private enterprises and financial services, which provide individuals with strong signals about their future prospects. We show that reforms that improve the management of infrastructure services have no link with migration patterns, which may be an important lesson for government policy.
Organ sparing total marrow irradiation compared to total body irradiation prior to allogeneic stem cell transplantation
Authors: Haraldsson André , Wichert Stina , Engström Per E. , Lenhoff Stig , Turkiewicz Dominik , Warsi Sarah , Engelholm Silke , Bäck Sven , Engellau Jacob
Published: June 2021

Objectives

Total body irradiation (TBI) is commonly used prior to hematopoietic stem cell transplantation (HSCT) in myeloablative conditioning regimens. However, TBI may be replaced by total marrow irradiation (TMI) at centres with access to Helical TomoTherapy, a modality that has the advantage of delivering intensity‐modulated radiotherapy to long targets such as the entire bone marrow compartment. Toxicity after organ sparing TMI prior to HSCT has not previously been reported compared to TBI or with regard to engraftment data.

Methods

We conducted a prospective observational study on 37 patients that received organ sparing TMI prior to HSCT and compared this cohort to retrospective data on 33 patients that received TBI prior to HSCT.

Results

The 1‐year graft‐versus‐host disease‐free, relapse‐free survival (GRFS) was 67.5% for all patients treated with TMI and 80.5% for patients with matched unrelated donor and treated with TMI, which was a significant difference from historical data on TBI patients with a hazard ratio of 0.45 (P = .03) and 0.24 (P < .01). Engraftment with a platelet count over 20 [K/µL] and 50 [K/µL] was significantly shorter for the TMI group, and neutrophil recovery was satisfactory in both treatment cohorts. There was generally a low occurrence of other treatment‐related toxicities.

Conclusions

Despite small cohorts, some significant differences were found; TMI as part of the myeloablative conditioning yields a high 1‐year GRFS, fast and robust engraftment, and low occurrence of acute toxicity.
Combining range and phenology shifts offers a winning strategy for boreal Lepidoptera
Authors: Hällfors Maria H. , Pöyry Juha , Heliölä Janne , Kohonen Ilmari , Kuussaari Mikko , Leinonen Reima , Schmucki Reto , Sihvonen Pasi , Saastamoinen Marjo
Published: June 2021

Species can adapt to climate change by adjusting in situ or by dispersing to new areas, and these strategies may complement or enhance each other. Here, we investigate temporal shifts in phenology and spatial shifts in northern range boundaries for 289 Lepidoptera species by using long‐term data sampled over two decades. While 40% of the species neither advanced phenology nor moved northward, nearly half (45%) used one of the two strategies. The strongest positive population trends were observed for the minority of species (15%) that both advanced flight phenology and shifted their northern range boundaries northward. We show that, for boreal Lepidoptera, a combination of phenology and range shifts is the most viable strategy under a changing climate. Effectively, this may divide species into winners and losers based on their propensity to capitalize on this combination, with potentially large consequences on future community composition.
Outcome analysis of 95 harness racehorses with confirmed dorsal displacement of the soft palate treated with laryngeal tie‐forward surgery
Authors: Vermedal Hanna , O’Leary John Mark , Fjordbakk Cathrine T. , McAloon Conor G. , Løkslett Hege , Stadsnes Birgitte , Fretheim‐Kelly Zoe L. , Strand Eric
Published: June 2021

Background

The laryngeal tie‐forward (LTF) procedure is commonly used to treat intermittent dorsal displacement of the soft palate (iDDSP). There is a wide range in reported efficacy of treating horses with and without a definitive diagnosis of iDDSP.

Objectives

To evaluate the racing performance of harness racehorses in which iDDSP had been definitely diagnosed and treated solely with the LTF procedure.

Study design

Retrospective case series.

Methods

Ninety‐five harness racehorses were treated with LTF for confirmed iDDSP. A definite diagnosis of iDDSP was made with high‐speed treadmill or overground endoscopy. Upper respiratory tract (URT) disorders, short‐term complications, and horses returning for recurrence of URT problems were recorded. Performance before and after LTF was assessed by reviewing career race records and comparing performance index (PI), and racing speed marks from the baseline, preoperative, and postoperative periods. The effect of basihyoid‐cricoid (BC) net distance shortened on racing performance was assessed.

Results

Postoperatively, PI increased in 36/54 (67%, 95% CI 54%‐79%) of experienced racehorses, and 44/67 (66%, 54%‐77%) established or improved their racing speed mark relative to the preoperative period. As a group, PI decreased by a mean (SE) of 0.9 (0.17) points (P < .001) prior to diagnosis/surgery. Postoperatively, PI increased by 0.5 (0.16) points (P = .003), and racing speed improved by 0.83 (0.22) s (P < .001). Twenty‐five percent (17%‐34%) and 49% (39%‐60%) of horses did not demonstrate a decline in PI and racing speed prior to diagnosis, respectively. Net BC distance shortening did not affect performance postoperatively. Twenty of 95 horses (21%, 13%‐29%) had confirmed recurrence of iDDSP 46‐708 days postoperatively.

Main limitations

Not all horses were evaluated with exercising endoscopy postoperatively. Racehorses inevitably develop other racing‐related problems which confound studies of this nature.

Conclusions

This study provides scientific support for the use of LTF to treat iDDSP in harness racehorses although iDDSP seems to affect harness racehorses differently as individuals.
Effect of food intake on the pharmacokinetics of rivoceranib in healthy subjects
Authors: Sachar Madhav , Park Cheol Hee , Pesco‐Koplowitz Luana , Koplowitz Barry , McGinn Arlo
Published: June 2021

Rivoceranib is a selective inhibitor of VEGFR‐2 being developed for the treatment of solid tumor. The objective of the study was to evaluate the effect of food on bioavailability as well as single‐ and multiple‐dose pharmacokinetics (PKs) of 81 and 201 mg doses of rivoceranib. The study was conducted as a two‐part study. In Part 1 (single ascending dose (SAD), open‐label, crossover study design), 2 oral doses of rivoceranib (81 mg or 201 mg) were given to all healthy subjects with a minimum 3‐day washout period between dosing. Part 2 was a multiple ascending dose (MAD), open‐label, crossover design where subjects were divided based on 81 and 201 mg doses. Both doses were administered with and without food in a crossover manner for the SAD and MAD parts. 24 healthy subjects completed Part 1 and 20 subjects completed Part 2. For the 81 mg dose in the SAD and MAD parts of the study, their food effect was not observed. For the 201 mg dose in both parts, food appeared to increase bioavailability by 20%–30% in Part 1, and 30%–40% in Part 2. Median tmax value was delayed when rivoceranib was administered with food at each dose level in both parts of the study. Dose proportionality was confirmed only for the AUC0‐∞ value from Part 1‐fasted cohort but inconclusive for Cmax and AUC parameters under other dosing regimens. In conclusion, rivoceranib when taken with food delays tmax appears to increase bioavailability at 201 mg dose.
Financial consequences of reputational damage: Evidence from government economic incentives
Authors: Blank D. Brian , Hadley Brandy , Unsal Omer
Published: June 2021

We investigate and quantify the financial consequences of corporate reputation by using manually assembled litigation, fraud, and cyberattack data from 2000 to 2018 to measure reputation changes following events that are often tied to public scrutiny. We examine the role of reputation in government subsidy awards and find reputational damage is linked to lower subsidies and Mega Deals, particularly tax‐related and state government awards. Moreover, subsidies only relate to higher firm value for firms without reputational damage. Our findings suggest that reputation is an important determinant of relatively opaque economic incentive awards and that reputational damage constrains the benefits thereof.