bluuebunny/crossref_metadata_2025 huggingface dataset:
The impact of the origin of surgical sperm retrieval on placental and embryonic development: The Rotterdam Periconception cohort
Authors: Hoek Jeffrey , Boellaard Willem P. A. , van Marion Eva S. , Willemsen Sten P. , Baart Esther.B. , Steegers‐Theunissen Régine P. M. , Schoenmakers Sam
Published: November 2020

Background

In patients with azoospermia, pregnancy can be achieved after surgical techniques using sperm retrieved from the testis or epididymis, which can impact on DNA integrity and epigenetics. DNA of the fetus and placenta is equally derived from both parents; however, genes important for placental development are expressed from the paternal alleles. Therefore, the origin of sperm may affect fetal and placental development.

Objectives

To investigate whether first‐trimester trajectories of embryonic and placental development of pregnancies conceived after intracytoplasmic sperm injection (ICSI) with testicular sperm extraction (TESE) or microsurgical epididymal sperm aspiration (MESA), are different from pregnancies after ICSI with ejaculated sperm or natural conceptions.

Materials and methods

A total of 147 singleton ICSI pregnancies, including pregnancies conceived after TESE (n = 23), MESA (n = 25) and ejaculated sperm (n = 99), and 380 naturally conceived and 140 after IVF treatment without ICSI were selected from the prospective Rotterdam periconception cohort. Crown‐rump length (CRL), embryonic volume (EV), Carnegie stages, and placental volume (PV) at 7, 9, and 11 weeks of gestation were measured using 3D ultrasound and virtual reality technology.

Results

Linear mixed model analysis showed no differences in trajectories of CRL, EV, and Carnegie stages between pregnancies conceived after ICSI with testicular, epididymal, and ejaculated sperm. A significantly positive association was demonstrated for PV between pregnancies conceived after TESE‐ICSI (adjusted beta: 0.28(95%CI: 0.05‐0.50)) versus ICSI with ejaculated sperm. Retransformation to original values showed that the PV of pregnancies after TESE‐ICSI is 14.6% (95%CI: 1.4%‐25.5%) larger at 11 weeks of gestation compared to ICSI pregnancies conceived with ejaculated sperm.

Discussion and Conclusion

Here we demonstrate that the first‐trimester growth trajectory of the placenta is increased in pregnancies conceived after TESE‐ICSI compared to those conceived after ICSI with ejaculated sperm. Findings are discussed in the light of known differences in sperm DNA integrity, epigenetics, and placental gene expression.
Longitudinal versus transverse incision for common femoral artery exposure: a systematic review and meta‐analysis
Authors: Ng Jun Jie , Tan Jarrod K. H. , Lee James W. K. , Choong Andrew M. T. L.
Published: November 2020

Background

A longitudinal or a transverse incision is routinely used for common femoral artery (CFA) exposure. Some believe a transverse incision is associated with a lower incidence of postoperative complications. We performed a systematic review and meta‐analysis to evaluate the risk of postoperative surgical site infection, lymphatic complications, wound dehiscence and haematoma formation when using a longitudinal or transverse incision for CFA exposure.

Methods

Preferred Reporting Items for Systematic Reviews and Meta‐Analysis guidelines were adhered to. We searched various databases such as MEDLINE via PubMed and Embase for relevant studies from inception till 31 May 2020. Relevant search terms such as ‘longitudinal’, ‘transverse’, ‘vertical’, ‘horizontal’, ‘femoral’, ‘incision’ were used. We included both randomized controlled trials and case‐controlled studies, and extracted data related to study characteristics and postoperative complications. We assessed risk of bias using the Cochrane risk of bias tool and the Newcastle‐Ottawa scale. A random‐effects meta‐analysis was performed to obtain the pooled proportions and risk ratios (RR) for our study outcomes.

Results

We included seven studies with a total of 5922 groin incisions. A longitudinal incision was associated with a significantly higher incidence of wound infection (RR 2.93, 95% confidence interval (CI) 1.12–7.70, P = 0.03) and wound dehiscence (RR 2.87, 95% CI 1.06–7.77, P = 0.04). The risk of lymphatic complications (RR 1.09, 95% CI 0.39–3.05, P = 0.87) and wound haematoma (RR 2.85, 95% CI 0.88–9.21, P = 0.08) were similar.

Conclusions

A longitudinal incision may be associated with a higher incidence of wound infection and wound dehiscence, as compared to using a transverse incision for CFA exposure.
The discovery of bacterial biofilm in patients with muscle invasive bladder cancer
Authors: Nadler Naomi , Kvich Lasse , Bjarnsholt Thomas , Jensen Jørgen Bjerggaard , Gögenur Ismail , Azawi Nessn
Published: November 2020

The carcinogenic effects of microorganisms have been discovered in multiple cancer types. In urology, the development of squamous cell carcinoma of the bladder due to the parasitic infection with Schistosoma Mansoni is widely accepted. The oncogenic potential of biofilms has been studied in colorectal cancer and experimental studies have shown that bacteria such as Escherichia coli drive the development of colorectal cancer. Notably, Escherichia coli is responsible for 80% of all urinary tract infections. Recent findings suggest an altered urinary microbiome in patients with bladder cancer compared to healthy subjects. In this case series, we demonstrate our findings of biofilm formation in human bladder cancer tissue. Tissue samples from ten patients that underwent routine Transurethral Resection of Bladder Tumor (TURBT) were obtained from the Danish National Biobank. Pathological tissue was examined for presence of bacterial aggregates by Fluorescence in situ Hybridization. In two of ten patients, analysis showed abundant bacterial aggregation on the surface epithelium. Both positive cases had pT2 urothelial bladder cancer. Our findings suggest that biofilm occurs in urothelial cancer tissue indicating an association between biofilm formation and bladder cancer.
Severe congenital neutropenia‐associated JAGN1 mutations unleash a calpain‐dependent cell death programme in myeloid cells
Authors: Khandagale Avinash , Holmlund Teresa , Entesarian Miriam , Nilsson Daniel , Kalwak Krzysztof , Klaudel‐Dreszler Maja , Carlsson Göran , Henter Jan‐Inge , Nordenskjöld Magnus , Fadeel Bengt
Published: November 2020

Severe congenital neutropenia (SCN) of autosomal recessive inheritance, also known as Kostmann disease, is characterised by a lack of neutrophils and a propensity for life‐threatening infections. Using whole‐exome sequencing, we identified homozygous JAGN1 mutations (p.Gly14Ser and p.Glu21Asp) in three patients with Kostmann‐like SCN, thus confirming the recent attribution of JAGN1 mutations to SCN. Using the human promyelocytic cell line HL‐60 as a model, we found that overexpression of patient‐derived JAGN1 mutants, but not silencing of JAGN1, augmented cell death in response to the pro‐apoptotic stimuli, etoposide, staurosporine, and thapsigargin. Furthermore, cells expressing mutant JAGN1 were remarkably susceptible to agonists that normally trigger degranulation and succumbed to a calcium‐dependent cell death programme. This mode of cell death was completely prevented by pharmacological inhibition of calpain but unaffected by caspase inhibition. In conclusion, our results confirmed the association between JAGN1 mutations and SCN and showed that SCN‐associated JAGN1 mutations unleash a calcium‐ and calpain‐dependent cell death in myeloid cells.
Partial response or better at six months is prognostic of superior progression‐free survival in Waldenström macroglobulinaemia patients treated with ibrutinib
Authors: Castillo Jorge J. , Abeykoon Jithma P. , Gustine Joshua N. , Zanwar Saurabh , Mein Kirsten , Flynn Catherine A. , Demos Maria G. , Guerrera Maria L. , Kofides Amanda , Liu Xia , Munshi Manit , Tsakmaklis Nickolas , King Rebecca , Yang Guang , Hunter Zachary R. , Advani Ranjana H. , Palomba Maria Lia , Ansell Stephen M. , Gertz Morie A. , Kapoor Prashant , Treon Steven P.
Published: November 2020

Ibrutinib is associated with durable responses in patients with Waldenström macroglobulinaemia (WM). We hypothesized that response depth is predictive of progression‐free survival (PFS) in WM patients treated with ibrutinib. Using landmark analyses, we evaluated response depth in two cohorts of WM patients treated with ibrutinib monotherapy. The learning cohort was composed of 93 participants from two clinical trials, and the validation cohort of 190 consecutive patients treated off clinical trial. Rates of partial response (PR) or better at six months in learning and validation cohorts were 64% and 71% respectively (P = 0·29). In the learning cohort, three‐year PFS rates for patients who attained PR or better at six monthsversusnot were 81% and 57% respectively (P = 0·009). In the validation cohort, three‐year PFS rates for patients who attained PR or better at six monthsversusnot were 83% and 54% respectively (P = 0·008). In multivariate analyses, attaining PR or better at six months was associated with superior PFS in the learning [hazard ratio (HR) 0·38;P = 0·01] and validation cohorts (HR 0·18;P = 0·004). Attaining PR at six months on ibrutinib emerges as an intermediate outcome of interest and should be validated as surrogate for PFS in clinical trials evaluating Bruton tyrosine kinase inhibitors in WM.
Gastric cancer–secreted exosomal X26nt increases angiogenesis and vascular permeability by targeting VE‐cadherin
Authors: Chen Xiaocui , Zhang Shuqiong , Du Kun , Zheng Naisheng , Liu Yi , Chen Hui , Xie Guohua , Ma Yanhui , Zhou Yunlan , Zheng Yingxia , Zeng Lingfang , Yang Junyao , Shen Lisong
Published: November 2020

Angiogenesis is closely associated with tumorigenesis, invasion, and metastasis by providing oxygen and nutrients. Recently, increasing evidence indicates that cancer‐derived exosomes which contain proteins, coding, and noncoding RNAs (ncRNAs) were shown to have proangiogenic function in cancer. A 26‐nt‐long ncRNA (X26nt) is generated in the process of inositol‐requiring enzyme 1 alpha (IRE1α)‐induced unspliced XBP1 splicing. However, the role of X26nt in the angiogenesis of gastric cancer (GC) remains largely unknown. In the present study, we found that X26nt was significantly elevated in GC and GC exosomes. Then, we verified that X26nt could be delivered into human umbilical vein endothelial cells (HUVECs) via GC cell exosomes and promote the proliferation, migration, and tube formation of HUVECs. We revealed that exosomal X26nt decreased vascular endothelial cadherin (VE‐cadherin) by directly combining the 3′UTR of VE‐cadherin mRNA in HUVECs, thereby increasing vascular permeability. We further demonstrated that X26nt accelerates the tumor growth and angiogenesis in a mouse subcutaneous tumor model. Our findings investigate a unique intercellular communication mediated by cancer‐derived exosomes and reveal a novel mechanism of exosomal X26nt in the regulation of tumor vasculature.
Autism and attention‐deficit/hyperactivity disorder in children with cerebral palsy: high prevalence rates in a population‐based study
Authors: Påhlman Magnus , Gillberg Christopher , Himmelmann Kate
Published: November 2020

Aim

To assess a total population of school‐age children with cerebral palsy (CP) for autism and attention‐deficit/hyperactivity disorder (ADHD) with a view to determining their prevalence and to relate findings to motor function, intellectual disability, and other associated impairments.

Method

Of 264 children, born between 1999 and 2006, from the CP register of western Sweden, 200 children (109 males, 91 females, median age at assessment 14y, range 7–18y) completed comprehensive screening and further neuropsychiatric clinical assessments.

Results

Ninety children (45%) were diagnosed with autism, ADHD, or both, 59 (30%) were diagnosed with autism, and 60 (30%) were diagnosed with ADHD. Intellectual disability was present in 51%. Two‐thirds had autism, ADHD, and/or intellectual disability. In regression models, autism was mainly predicted by intellectual disability (odds ratio [OR]=4.1) and ADHD (OR=3.2), and ADHD was predicted by intellectual disability (OR=2.3) and autism (OR=3.0). Autism was more common in children born preterm (OR=2.0). Gross motor function was not associated with autism. ADHD prevalence was low in children with severe motor impairment, possibly due to diagnostic limitations.

Interpretation

Autism and ADHD were common in this population of children with CP and were mainlyindependent of motor severity and CP type. The strongest predictor of autism/ADHD was intellectual disability. Assessment for autism and ADHD is warranted as part of the evaluation in CP.

What this paper adds

Forty‐five percent of the children with cerebral palsy also had autism, attention‐deficit/hyperactivity disorder (ADHD), or both.

Autism and ADHD were predicted mainly by intellectual disability.

Established diagnostic instruments worked well for all but the most disabled group of children.
An unusual presentation of prosthetic valve endocarditis: Utility of 3D transillumination rendering
Authors: Barbeito‐Caamaño Cayetana , Bouzas‐Zubeldía Beatriz , Martín‐Álvarez Esteban , Souto‐Caínzos Borja , Bouzas‐Mosquera Alberto
Published: November 2020

Prosthetic valve endocarditis is a rare but serious complication of cardiac valve replacement, and echocardiography plays a fundamental role in its diagnosis and management. However, there is not much information about the use of the 3D transillumination rendering in this context. In this report, we present an unusual case of prosthetic valve endocarditis that exemplifies the utility of this new tool.
Elevation filters seed traits and germination strategies in the eastern Tibetan Plateau
Authors: Wang Xuejing , Alvarez Mariano , Donohue Kathleen , Ge Wenjing , Cao Yueqian , Liu Kun , Du Guozhen , Bu Haiyan
Published: November 2020

Seeds are the colonizing propagules for many plants and may therefore contribute to the filtering of species during the process of colonization and community assembly. Environmental filtering of seed traits may occur among species and influence community composition, or within species and influence the environmental breadth that a given species inhabits. To test for evidence of such filtering of seed traits, we measured morphological and germination traits of seeds of 408 angiosperm species collected across an elevational gradient in the eastern Tibetan Plateau grasslands. We tested for elevational filtering of traits at the species level, as well as within 22 of those species that occurred at different elevations, in order to test whether within‐species variation reflected among‐species patterns. Elevational patterning occurred in both seed morphology and seed germination. Seeds were smaller, more elongated and had a higher surface area:volume ratio and shorter germination times at higher elevation. Seed morphology was associated with germination such that more elongated and smaller seeds with a higher surface area:volume ratio germinated faster, leading to earlier germination in seeds from high elevation. Within species, elevational variation in seed traits was observed in several species, but species differed in how those traits were distributed across elevation. These results suggest that taxonomic differences in seed traits may contribute to elevational variation in the species composition of plant communities, but that seed traits may be variably selected by elevation within species.
Combining species distribution models and population genomics underlines the determinants of range limitation in an emerging parasite
Authors: Mathieu‐Bégné Eglantine , Loot Géraldine , Mazé‐Guilmo Elise , Mullet Valentin , Genthon Clémence , Blanchet Simon
Published: November 2020

Understanding the drivers of species distribution is necessary in order to properly predict the future geographical ranges of colonizing species. Yet this task is challenging for species involved in intimate interactions, such as parasites, since their distribution is likely shaped by a complex interplay between environmental‐related and host‐related factors. Here we developed an original approach combining species distribution models (SDMs) and population genomics to test whether the local environmental conditions or the host genomic background most likely limits the colonization of an emerging freshwater fish ectoparasite, Tracheliastes polycolpus. We hypothesized that the absence of T. polycolpus in some areas may be due to an unsuitable environment in these areas (the ‘environmental suitability hypothesis') and/or to the presence of resistant hosts in these areas (the ‘genomic background hypothesis'). Using a SDM set at the French spatial extent, we first found that the environmental conditions of an uninfected area were as suitable for the parasite as those of infected areas. Then, using single nucleotide polymorphisms (SNPs) data at the host genome scale, we demonstrated that there was a strong association between the spatial occurrence of parasites and the host genomic background. In particular, the area in which the parasite was absent sustained a unique host population from a genomic standpoint, and ninety SNPs were significantly associated to the infection status (parasitized versus unparasitized) of individual hosts. We concluded that the spatial distribution of T. polycolpus (and its colonization potential) was more likely limited by intrinsic host characteristics associated to parasite resistance, rather than to the local environmental conditions. This study illustrates the usefulness of combining modeling and genomic approaches to reveal the determinants of species distribution and to improve predictions about their future ranges.
Precision Medicine: Academic dreaming or clinical reality?
Authors: Josephson Colin B. , Wiebe Samuel
Published: November 2020

Precision medicine can be distilled into a concept of accounting for an individual’s unique collection of clinical, physiologic, genetic, and sociodemographic characteristics to provide patient‐level predictions of disease course and response to therapy. Abundant evidence now allows us to determine how an average person with epilepsy will respond to specific medical and surgical treatments. This is useful, but not readily applicable to an individual patient. This has brought into sharp focus the desire for a more individualized approach through which we counsel people based on individual characteristics, as opposed to population‐level data. We are now accruing data at unprecedented rates, allowing us to convert this ideal into reality. In addition, we have access to growing volumes of administrative and electronic health records data, biometric, imaging, genetics data, microbiome, and other “omics” data, thus paving the way toward phenome‐wide association studies and “the epidemiology of one.” Despite this, there are many challenges ahead. The collating, integrating, and storing sensitive multimodal data for advanced analytics remains difficult as patient consent and data security issues increase in complexity. Agreement on many aspects of epilepsy remains imperfect, rendering models sensitive to misclassification due to a lack of “ground truth.” Even with existing data, advanced analytics models are prone to overfitting and often failure to generalize externally. Finally, uptake by clinicians is often hindered by opaque, “black box” algorithms. Systematic approaches to data collection and model generation, and an emphasis on education to promote uptake and knowledge translation, are required to propel epilepsy‐based precision medicine from the realm of the theoretical into routine clinical practice.
Changes to the structure and function of an albacore fishery reveal shifting social‐ecological realities for Pacific Northwest fishermen
Authors: Frawley Timothy H. , Muhling Barbara A. , Brodie Stephanie , Fisher Mary C. , Tommasi Desiree , Le Fol Gwendal , Hazen Elliott L. , Stohs Stephen S. , Finkbeiner Elena M. , Jacox Michael G.
Published: November 2020

Marine fisheries around the globe are increasingly exposed to external drivers of social and ecological change. Though diversification and flexibility have historically helped marine resource users negotiate risk and adversity, much of modern fisheries management treats fishermen as specialists using specific gear types to target specific species. Here, we describe the evolution of harvest portfolios amongst Pacific Northwest fishermen over 35+ years with explicit attention to changes in the structure and function of the albacore (Thunnus alalunga, Scombridae) troll and pole‐and‐line fishery. Our analysis indicates that recent social–ecological changes have had heterogenous impacts upon the livelihood strategies favoured by different segments of regional fishing fleets. As ecological change and regulatory reform have restricted access to a number of fisheries, many of the regional small (<45 ft) and medium (45–60 ft) boat fishermen who continue to pursue diverse livelihood strategies have increasingly relied upon the ability to opportunistically target albacore in coastal waters while retaining more of the value generated by such catch. In contrast, large vessels (>60 ft) targeting albacore are more specialized now than previously observed, even as participation in multiple fisheries has become increasingly common for this size class. In describing divergent trajectories associated with the albacore fishery, one of the US West Coast's last open‐access fisheries, we highlight the diverse strategies and mechanisms utilized to sustain fisheries livelihoods in the modern era while arguing that alternative approaches to management and licensing may be required to maintain the viability of small‐scale fishing operations worldwide moving forward.
PRC1 is a critical regulator for anaphase spindle midzone assembly and cytokinesis in mouse oocyte meiosis
Authors: Li Xiao‐Han , Ju Jia‐Qian , Pan Zhen‐Nan , Wang Hong‐Hui , Wan Xiang , Pan Meng‐Hao , Xu Yao , Sun Ming‐Hong , Sun Shao‐Chen
Published: November 2020

Protein regulator of cytokinesis 1 (PRC1) is a microtubule bundling protein that is involved in the regulation of the central spindle bundle and spindle orientation during mitosis. However, the functions of PRC1 during meiosis have rarely been studied. In this study, we explored the roles of PRC1 during meiosis using an oocyte model. Our results found that PRC1 was expressed at all stages of mouse oocyte meiosis, and PRC1 accumulated in the midzone/midbody during anaphase/telophase I. Moreover, depleting PRC1 caused defects in polar body extrusion during mouse oocyte maturation. Further analysis found that PRC1 knockdown did not affect meiotic spindle formation or chromosome segregation; however, deleting PRC1 prevented formation of the midzone and midbody at the anaphase/telophase stage of meiosis I, which caused cytokinesis defects and further induced the formation of two spindles in the oocytes. PRC1 knockdown increased the level of tubulin acetylation, indicating that microtubule stability was affected. Furthermore, KIF4A and PRC1 showed similar localization in the midzone/midbody of oocytes at anaphase/telophase I, while the depletion of KIF4A affected the expression and localization of PRC1. The PRC1 mRNA injection rescued the defects caused by PRC1 knockdown in oocytes. In summary, our results suggest that PRC1 is critical for midzone/midbody formation and cytokinesis under regulation of KIF4A in mouse oocytes.
Labor market and unpaid works implications of COVID‐19 for Bangladeshi women
Authors: Sarker Mou Rani
Published: November 2020

Crisis impacts are never gender‐neutral, and COVID‐19 is no exception. The pandemic has further exacerbated the gender and socioeconomic inequalities, therefore, crucial to undertake a gender impact analysis of COVID‐19. This perspective paper highlights women's vulnerability in the labor market and focused on the increasing unpaid workloads in the response to the COVID‐19 outbreak. Focusing on various surveys, feminized sectors such as agriculture, garments have been hardest hit by the pandemic. Female workers have been rapidly lost their means to earn income and confined to homes. Beyond lost jobs and reduced working hours, the pandemic has also increased the time poverty of women. While pre‐pandemic unpaid work burdens are well established as strong, the study indicates that burdens are escalated after‐pandemic. Women balanced intensified unpaid care and domestic works simultaneously or make a tradeoff, without or minimal help from men. Such results suggest a gender‐inclusive policy to minimize the effects of the pandemic, placing women at the center of focus.
Migraine With Exclusive Olfactory Aura: Case Report and Literature Review
Authors: Tiriticco Marco , Vanotti Alessandra , Mantica Davide , Coppola Alfonso
Published: November 2020

Objectives

To report the case of a patient enduring migraine attacks preceded by hallucinatory olfactory symptoms, with characteristics which typically define migraine with aura (MWA).

Background

MWA accounts for about 30‐40% of the total cases of migraine and is almost always preceded by visual disorders; and in rare cases migraine attacks are preceded by olfactory hallucinations which have not been so far recognized as a type of aura.

Results

We describe a 51‐year‐old male whose migraine attacks are preceded, unusually for migraine sufferers, only by olfactory hallucinations; in 10% of the attacks, the olfactory symptoms are not followed by any pain but always appear with the same characteristics. These hallucinations began with the onset of a history of cephalea.

Conclusion

This case suggests that olfactory hallucinations should be considered as actual pre‐migraine symptoms, like visual symptoms or other disorders, and added to the criteria for the diagnosis of MWA.
Assessment of treatment options for patients with hepatitis C virus recombinant form 2k/1b
Authors: Zakalashvili Mamuka , Zarkua Jaba , Gish Robert G. , Zhamutashvili Maia , Sartania Vakhtang , Weizenegger Michael , Bartel Jan , Raabe Monika , Gvinjilia Lia , Metreveli Sophia , Barnova Maka , Abramishvili Nikoloz , Rtskhiladze Irakli , Metreveli David
Published: November 2020

Aim

Hepatitis C virus (HCV) intergenotype recombinant form (RF) 2k/1b has been actively circulating in HCV‐infected patients, and the prevalence of this RF virus in the Republic of Georgia is one of the highest reported worldwide. The aim of this study was to define the optimal treatment regimen for patients with RF_2k/1b.

Methods

We analyzed the data of 2735 patients who started treatment at the Medical Center Mrcheveli within Georgia's hepatitis C elimination program from May 2015 through December 2019. The patients were treated with sofosbuvir (SOF)‐based regimens. For identification of RF_2k/1b variants, refinement of standard (INNO‐LiPA) genotyping results for all patient samples assigned the unspecific HCV genotypes (GT) 2a/2c was carried out by sequencing of core and non‐structural protein 5B genes.

Results

Overall, 444 patients, representing 66% of GT2 and 16% of the total samples, were RF_2k/1b. Treatment of patients with RF_2k/1b with SOF/ledipasvir and SOF/velpatasvir was highly effective and viral cure rates did not differ among genotypes treated with the same regimen: RF_2k/1b, 99% (343/346); GT1, 99% (876/885); GT2, 96% (156/162); and GT3, 99% (545/552). A separate comparison analysis of sustained virologic response rate, treated with SOF plus ribavirin, showed significantly higher sustained virologic response (96%) in patients with confirmed GT2 (by sequencing) compared to unspecified GT2 (by INNO‐LiPA) (79%) (P < 0.05).

Conclusion

Sofosbuvir‐based regimens are highly effective for treatment of RF 2k/1b patients, and with availability of new pan‐genotypic direct‐acting antivirals, genotyping to identify RF 2k/1b patients might not be necessary.
Recent developments in immunotherapy of cancers caused by human papillomaviruses
Authors: Fakhr Elham , Modic Živa , Cid‐Arregui Angel
Published: November 2020

A subset of oncogenic human papillomaviruses (HPVs) is the main cause of genital cancers, most importantly cervical cancer and an increasing number of head and neck cancers. Despite the availability of prophylactic vaccines against the most prevalent oncogenic HPV types, HPV‐induced malignancies are still a major health and economic burden. Besides conventional treatment with surgery, chemotherapy and radiation, immunotherapy is emerging as an efficient adjuvant option. Here, we review relevant studies and ongoing clinical trials using immune checkpoint inhibitors, therapeutic vaccines, gene editing approaches and adoptive T cell therapies, with special focus on engineered TCR T cells, which are showing encouraging results and could lead to significant improvement in the treatment of HPV+‐infected cancer patients.
Assisting Rebels Abroad: The Ethics of Violence at the Limits of the Defensive Paradigm
Authors: Finlay Christopher J.
Published: November 2020

In this article, I analyse the theory and practice of interventions in foreign civil wars to assist rebels fighting against violently oppressive government. I argue that the indirect nature of this kind of intervention gives rise to political complications that are either absent from or less obvious in humanitarian interventions aimed chiefly at defending human rights from imminent threats. An adequate theory must therefore accommodate three additional components. First, it requires a theory of indirect warfare accounting for how the ends of the interveners’ added violence relate to those of the rebels’ violence. Second, it requires a theory of indirect political leadership, paying careful attention both to the political status of the rebel leaders vis‐à‐vis the people on whose behalf they fight and to the relationship between those leaders and the interveners. Third, the peculiarities of indirect military intervention mean that the violence it introduces isn’t easily explained purely in terms of defensive goals. An adequate account needs additionally to pay attention to the role of violence in shaping new political movements and institutions. The value of such goals is less easily quantified than those of humanitarian intervention, making it harder to set upper limits on permissible ‘proportionate’ harm.
Liability for Wrongful Assistance: On Causing Unjust Harm in the Course of Suboptimal Rescue
Authors: Frowe Helen
Published: November 2020

Several states, including the United Kingdom, the United States, and France, have recently engaged in the high‐profile supporting of foreign rebel fighters, providing them with training, weapons, and financial resources. Justifications for providing this assistance usually invoke, at least in part, our obligations to prevent harm to the citizens of oppressive and violent regimes. Providing such assistance is often presented as a morally safe ‘middle ground’ between doing nothing and putting one’s own troops at risk. Yet this assistance typically enables rebels to cause unjust harms, since armed uprisings almost invariably cause harm to innocent people.

I argue that enabling these unjust harms can render the provision of assistance unjustified. When a state could prevent at least as much harm by using its resources in other ways, such as preventing disease, without thereby causing comparable unjust harm and without incurring a (significantly greater) supererogatory cost, the state acts unjustifiably if it nonetheless funds the rebellion. When assistors unjustifiably enable unjust harms, they are morally liable to bear costs for the sake of people who suffer those harms. This is true even if the rebels act justifiably in directly inflicting those harms.
SHP‐1 suppresses endotoxin‐induced uveitis by inhibiting the TAK1/JNK pathway
Authors: Zhuang Xiaonan , Ma Jun , Xu Sisi , Sun Zhongcui , Zhang Rong , Zhang Meng , Xu Gezhi
Published: November 2020

We investigated how Src‐homology 2‐domain phosphatase‐1 (SHP‐1) regulates the inflammatory response in endotoxin‐induced uveitis (EIU), and the signalling pathways involved. One week after intravitreal injection of short hairpin RNA targeting SHP‐1 or SHP‐1 overexpression lentivirus in rats, we induced ocular inflammation with an intravitreal injection of lipopolysaccharide (LPS). We then assessed the extent of inflammation and performed full‐field electroretinography. The concentrations and retinal expression of various inflammatory mediators were examined with enzyme‐linked immunosorbent assays and Western blotting, respectively. SHP‐1 overexpression and knockdown were induced in Müller cells to study the role of SHP‐1 in the LPS‐induced inflammatory response in vitro. Retinal SHP‐1 expression was up‐regulated by LPS. SHP‐1 knockdown exacerbated LPS‐induced retinal dysfunction and increased the levels of proinflammatory mediators in the retina, which was abrogated by a c‐Jun N‐terminal kinase (JNK) inhibitor (SP600125). SHP‐1 overexpression had the opposite effects. In Müller cells, the LPS‐induced inflammatory response was enhanced by SHP‐1 knockdown and suppressed by SHP‐1 overexpression. SHP‐1 negatively regulated the activation of the transforming growth factor‐β‐activated kinase‐1 (TAK1)/JNK pathway, but not the nuclear factor‐κB pathway. These results indicate that SHP‐1 represses EIU, at least in part, by inhibiting the TAK1/JNK pathway and suggest that SHP‐1 is a potential therapeutic target for uveitis.
Glucocorticoids decreased Cx43 expression in osteonecrosis of femoral head: The effect on proliferation and osteogenic differentiation of rat BMSCs
Authors: Zhao Xin , Alqwbani Mohammed , Luo Yue , Chen Changjun , A Ge , Wei Yang , Li Donghai , Wang Qiuru , Tian Meng , Kang Pengde
Published: November 2020

Glucocorticoid (GC)‐induced osteonecrosis of the femoral head (GC‐ONFH) is considered as one of the most serious side effects of long‐term or over‐dose steroid therapy. However, the underlying cause mechanisms are still not fully investigated. We firstly established a rat model of GC‐ONFH and injected lipopolysaccharide (LPS) and methylprednisolone (MPS). We found that the expressions of Cx43, Runx2, ALP and COLⅠ were more decreased than the normal group. Secondly, the isolated rat bone marrow stem cells (BMSCs) were treated with dexamethasone (Dex) in vitro, and the expressions of Cx43, Runx2, ALP and COLⅠ were decreased significantly. Moreover, the results of immunofluorescence staining, alizarin red staining, EdU assay and CCK8 showed that the osteogenic differentiation and the proliferation capacity of BMSCs were decreased after induced by Dex. A plasmid of lentivirus‐mediated Cx43 (Lv‐Cx43) gene overexpression was established to investigate the function of Cx43 in BMSCs under the Dex treatment. Findings demonstrated that the proliferation and osteogenic differentiation abilities were enhanced after Lv‐Cx43 transfected to BMSCs, and these beneficial effects of Lv‐Cx43 were significantly blocked when PD988059 (an inhibitor of ERK1/2) was used. In conclusion, the overexpression of Cx43 could promote the proliferation and osteogenic differentiation of BMSCs via activating the ERK1/2 signalling pathway, which provide a basic evidence for further study on the detailed function of Cx43 in GC‐ONFH.
Association between the dermoscopic morphology of peripheral globules and melanocytic lesion diagnosis
Authors: Reiter O. , Chousakos E. , Kurtansky N. , Nanda J.K. , Dusza S.W. , Marchetti M.A. , Jaimes N. , Moraes A. , Marghoob A.A.
Published: November 2020

Background

The presence of peripheral globules is associated with enlarging melanocytic lesions; however, there are numerous patterns of peripheral globules distribution and it remains unknown whether specific patterns can help differentiate enlarging naevi from melanoma.

Objective

To investigate whether morphological differences exist between the peripheral globules seen in different subsets of naevi and in melanoma.

Methods

A cross‐sectional study of clinical notes that mentioned peripheral globules, in addition to all melanoma images with peripheral globules on the International Skin Imaging Collaboration archive. Dermoscopic images were reviewed and annotated. Associations between diagnosis and categorical features were measured with odds ratios. Non‐parametric tests were used for continuous factors.

Results

184 lesions with peripheral globules from our clinic were included in the analysis; only 6 of these proved to be melanoma. 109 melanomas with peripheral globules from the International Skin Imaging Collaboration archive were added to the analysis. Melanomas were more common on the extremities and among older individuals. Melanomas were more likely to display atypical, tiered and/or focal peripheral globules. Only 5% of melanomas lacked dermoscopic melanoma‐specific structures compared to 48% of naevi.

Conclusions

Melanocytic lesions with atypical or asymmetrically distributed peripheral globules, especially when located on the extremities, should raise suspicion for malignancy. Melanocytic lesions with typical and symmetrically distributed peripheral globules, and with no other concerning dermoscopic features, are unlikely to be malignant.
Developing a predictive model for distinguishing invasive nail unit melanoma from nail unit melanoma in situ
Authors: Ohn J. , Hur K. , Cho Y. , Park J. , Kim J.Y. , Lee S.‐J. , Park H. , Mun J.‐H.
Published: November 2020

Background

Clinical information that distinguishes invasive nail unit melanoma from nail unit melanoma in situ before surgery would aid physicians in the decision‐making process and estimating prognosis. However, limited information is available on the detailed demographic and dermoscopic features of invasive nail unit melanoma and nail unit melanoma in situ for differential diagnosis.

Objective

This study aimed to investigate the demographic data and dermoscopic features of invasive nail unit melanoma and nail unit melanoma in situ and establish a predictive model for differentiating these two forms of nail unit melanoma.

Methods

A retrospective observational study of ninety‐seven patients diagnosed with nail unit melanoma (59 in situ and 38 invasive cases) in four healthcare centres in South Korea (three tertiary referral hospitals and one second referral hospital) from March 2014 to December 2019.

Results

A multivariable analysis revealed that ulcer (odds ratio = 21.6, confidence interval = 2.1–219.8, P = 0.009), total melanonychia (odds ratio = 17.6, confidence interval = 3.0–104.0, P = 0.002), nail plate destruction (odds ratio = 10.9, confidence interval = 2.0–59.4, P = 0.006) and polychromia (odds ratio = 5.3, confidence interval = 1.36–20.57, P = 0.016) were distinctive dermoscopic features of invasive nail unit melanoma. A predictive model with scores ranging from 0 to 6 points demonstrated a reliable diagnostic value (C‐statistic = 0.902) in differentiating invasive nail unit melanoma from nail unit melanoma in situ.

Conclusions

Invasive nail unit melanoma and nail unit melanoma in situ have different dermoscopic features. A predictive model based on morphologic dermoscopic features could aid in differentiating invasive nail unit melanoma from nail unit melanoma in situ.
Air Pollution and the Dynamic Association Between Depressive Symptoms and Memory in Oldest‐Old Women
Authors: Petkus Andrew J. , Younan Diana , Wang Xinhui , Beavers Daniel P. , Espeland Mark A. , Gatz Margaret , Gruenewald Tara L. , Kaufman Joel D. , Chui Helena C. , Manson JoAnn E. , Resnick Susan M. , Wellenius Gregory A. , Whitsel Eric A. , Widaman Keith , Chen Jiu‐Chiuan
Published: November 2020

BACKGROUND/OBJECTIVES

Exposure to air pollution may contribute to both increasing depressive symptoms and decreasing episodic memory in older adulthood, but few studies have examined this hypothesis in a longitudinal context. Accordingly, we examined the association between air pollution and changes in depressive symptoms (DS) and episodic memory (EM) and their interrelationship in oldest‐old (aged 80 and older) women.

DESIGN

Prospective cohort data from the Women's Health Initiative Memory Study‐Epidemiology of Cognitive Health Outcomes.

SETTING

Geographically diverse community‐dwelling population.

PARTICIPANTS

A total of 1,583 dementia‐free women aged 80 and older.

MEASUREMENTS

Women completed up to six annual memory assessments (latent composite of East Boston Memory Test and Telephone Interview for Cognitive Status) and the 15‐item Geriatric Depression Scale (GDS‐15). We estimated 3‐year average exposures to regional particulate matter with aerodynamic diameter below 2.5 μm (PM2.5) (interquartile range [IQR] = 3.35 μg/m3) and gaseous nitrogen dioxide (NO2) (IQR = 9.55 ppb) at baseline and during a remote period 10 years earlier, using regionalized national universal kriging.

RESULTS

Latent change structural equation models examined whether residing in areas with higher pollutant levels was associated with annual changes in standardized EM and DS while adjusting for potential confounders. Remote NO2 (β = .287 per IQR; P = .002) and PM2.5 (β = .170 per IQR; P = .019) exposure was significantly associated with larger increases in standardized DS, although the magnitude of the difference, less than 1 point on the GDS‐15, is of questionable clinical significance. Higher DS were associated with accelerated EM declines (β = −.372; P = .001), with a significant indirect effect of remote NO2 and PM2.5 exposure on EM declines mediated by DS. There were no other significant indirect exposure effects.

CONCLUSION

These findings in oldest‐old women point to potential adverse effects of late‐life exposure to air pollution on subsequent interplay between DS and EM, highlighting air pollution as an environmental health risk factor for older women.
LRRK2 at the pre‐synaptic site: A 16‐years perspective
Authors: Pischedda Francesca , Piccoli Giovanni
Published: November 2020

Parkinson's disease is a common neurodegenerative disorder and is clinically characterized by bradykinesia, rigidity, and resting tremor. Missense mutations in the leucine‐rich repeat protein kinase‐2 gene (LRRK2) are a recognized cause of inherited Parkinson's disease. The physiological and pathological impact of LRRK2 is still obscure, but accumulating evidence indicates that LRRK2 orchestrates diverse aspects of membrane trafficking, such as membrane fusion and vesicle formation and transport along actin and tubulin tracks. In the present review, we focus on the special relation between LRRK2 and synaptic vesicles. LRRK2 binds and phosphorylates key actors within the synaptic vesicle cycle. Accordingly, alterations in dopamine and glutamate transmission have been described upon LRRK2 manipulations. However, the different modeling strategies and phenotypes observed require a critical approach to decipher the outcome of LRRK2 at the pre‐synaptic site.

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Mulberroside A repairs high fructose diet‐induced damage of intestinal epithelial and blood–brain barriers in mice: A potential for preventing hippocampal neuroinflammatory injury
Authors: Yu Rong , Wen Shiyu , Wang Qiaona , Wang Congying , Zhang Liping , Wu Xingxin , Li Jianmei , Kong Lingdong
Published: November 2020

Our previous studies showed that high fructose diet (HFrD)‐driven gut dysbiosis caused fecal short‐chain fatty acids (SCFAs) reduction and intestinal epithelial barrier (IEB) damage in mice, which might play an important role in hippocampal neuroinflammatory injury. Mulberroside A is reported to have neuroprotective effects in animal experiments, while the underlying mechanisms are not yet fully elucidated. Here, we investigated whether and how mulberroside A prevented HFrD‐induced neuroinflammatory injury. HFrD‐fed mice were treated orally with mulberroside A (20 and 40 mg/kg) for 8 weeks. Mulberroside A was found to inhibit hippocampal neuroinflammation and neurogenesis reduction in HFrD‐fed mice. It reshaped gut dysbiosis, increased fecal and serum SCFAs contents, reactivated signaling of the colonic NLR family, pyrin domain containing 6 (NLRP6) inflammasome, and up‐regulated Muc2 expression to prevent IEB damage, as well as subsequently, reduced serum endotoxin levels in this animal model. Additionally, mulberroside A inhibited oxidative stress in colon of HFrD‐fed mice and hydrogen peroxide (H2O2)‐stimulated Caco‐2 cells. Blood–brain barrier (BBB) structure defects were also observed in HFrD‐driven hippocampal neuroinflammatory injury of mice. Interestingly, mulberroside A maintained astrocyte morphology and up‐regulated tight junction proteins to repair BBB structure defects in hippocampus dentate gyrus (DG). Our results demonstrated that mulberroside A was capable of preventing HFrD‐induced damage of IEB and BBB in mice, which might contribute to the suppression of hippocampal neuroinflammatory injury.

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Relationship between acne and the use of cosmetics: Results of a questionnaire study in 539 Korean individuals
Authors: Suh Dong‐Hye , Oh Haneul , Lee Sang Jun , Kim Hyun Joo , Ryu Hwa Jung
Published: November 2020

Background

Acne vulgaris is one of the most common dermatological diseases, and it is known that various factors are related to triggering this condition in a patient. In particular, although the use of cosmetics is thought to be associated with the onset of a patient developing acne, there are few studies that have been conducted to date on this disease and its related factors.

Methods

To begin with, a total of 539 patients with acne vulgaris, who visited three dermatologic clinics in Korea, were asked to complete a questionnaire regarding their condition in relation to clinical features and exacerbating factors, including the use of cosmetics. The patients all provided an accurate acne treatment history as well.

Results

Among the respondents, 38.1% of patients who failed treatment answered that the condition of their acne was worsened by the continued use of cosmetics, which was significantly higher than 26.3% of the surveyed treatment‐naive patients (P < .05). In this relation, double cleansing (cleansing twice using oil and water‐based cleanser) and the number of cosmetics in use were also noted in higher numbers than in the treatment‐failure patients. As noted, the liquid‐type foundation and concealer were frequently used in this group.

Conclusions

This study showed the influence of cosmetics, especially in acne patients with a history of treatment failures. These results also show differences according to specific cosmetic types and formulations. Therefore, overall dermatologists should consider advising about cosmetic use to acne patients along with medical treatment options for the patients with acne.
Obstetric management of a patient with Andersen–Tawil syndrome: A case report
Authors: Inagaki Mai , Tatsumi Takayuki , Yomogita Hiroshi , Hirose Asuka , Kubo Takuyuki , Sekiguchi Masaki , Miyasaka Naoyuki
Published: November 2020

Andersen–Tawil syndrome (ATS) is a rare hereditary long QT syndrome type 7 caused by a missense mutation in the KCNJ2 gene. ATS is characterized by ventricular arrhythmia, periodic limb paralysis and minor external malformations. Although only three reports of pregnant women with Andersen–Tawil syndrome have been reported to date, no exacerbation of ventricular arrhythmia was observed from pre‐partum to delivery in all cases compared to that before pregnancy, and it was suggested that the risk of arrhythmic events from pre‐partum to delivery is not high. Unlike these previous reports, we herein present a case of Andersen–Tawil syndrome in which ventricular arrhythmias increased and sustained ventricular tachycardia was developed during labor progression. We also advise caution that pregnant patients with Andersen–Tawil syndrome may have varying times of exacerbation of the arrhythmia, and ventricular arrhythmias may be associated with painful uterine contractions.