bluuebunny/crossref_metadata_2025 huggingface dataset:
Ensuring that the outcome domains proposed for use in burns research are relevant to adult burn patients: a systematic review of qualitative research evidence
Authors: Mathers Jonathan , Moiemen Naiem , Bamford Amy , Gardiner Fay , Tarver Joanne
Published: July 2020

Background

There have been several attempts to define core outcome domains for use in research focused on adult burns. Some have been based in expert opinion, whilst others have used primary qualitative research to understand patients’ perspectives on outcomes. To date there has not been a systematic review of qualitative research in burns to identify a comprehensive list of patient-centred outcome domains. We therefore conducted a systematic review of qualitative research studies in adult burns.

Methods

We searched multiple databases for English-language, peer-reviewed, qualitative research papers. We used search strategies devised using the SPIDER tool for qualitative synthesis. Our review utilized an iterative three-step approach: (1) outcome-focused coding; (2) development of descriptive accounts of outcome-relevant issues; and (3) revisiting studies and the broader theoretical literature in order to frame the review findings.

Results

Forty-one articles were included. We categorized papers according to their primary focus. The category with the most papers was adaptation to life following burn injury (n = 13). We defined 19 outcome domains across the 41 articles: (1) sense of self; (2) emotional and psychological morbidity; (3) sensory; (4) scarring and scar characteristics; (5) impact on relationships; (6) mobility and range of joint motion; (7) work; (8) activities of daily living and self-care; (9) treatment burden; (10) engagement in activities; (11) wound healing and infection; (12) other physical manifestations; (13) financial impact; (14) impact on spouses and family members; (15) analgesia and side effects; (16) cognitive skills; (17) length of hospital stay; (18) access to healthcare; and (19) speech and communication. We suggest that sense of self is a core concern for patients that, to date, has not been clearly conceptualized in the burns outcome domain literature.

Conclusions

This outcome domain framework identifies domains that are not covered in previous attempts to outline core outcome domains for adult burn research. It does so with reference to existing theoretical perspectives from the sociology and psychology of medicine. We propose that this framework can be used as a basis to ensure that outcome assessment is patient-centred. Sense of self requires further consideration as a core outcome domain.
Oncogene HSPH1 modulated by the rs2280059 genetic variant diminishes EGFR-TKIs efficiency in advanced lung adenocarcinoma
Authors: Li Yankang , Zhang Nasha , Zhang Li , Song Yemei , Liu Jie , Yu Jinming , Yang Ming
Published: July 2020

Although epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy is effective for most advanced non-small-cell lung cancer (NSCLC) patients with mutant EGFR, some patients show little or no response. Germline variations, such as single-nucleotide polymorphisms (SNPs), have been proved to be involved in disease progression after EGFR-TKI therapy. In this study, we hypothesized that the functional HSPH1 SNP may affect gene expression and, thus, prognosis of NSCLC patients treated with EGFR-TKIs. We systematically examined impacts of HSPH1 SNPs on NSCLC survival in two independent cohorts consisted of 319 EGFR-TKI treated stage IIIB/IV NSCLC patients. The promoter rs2280059 polymorphism was significantly associated with patient survival in both cohorts. In vitro and In vivo assays elucidated that rs2280059 G allele shows higher capability to drive HSPH1 promoter activities. Silencing HSPH1 significantly increases the antineoplastic effects of gefitinib on NSCLC cells. Our findings demonstrated potential implications of HSPH1 in clinic, which may lead to better understanding and outcome assessment of EGFR-TKI treatment.
A Randomized, Double-blind, Multicenter Trial Comparing Efficacy and Safety of Imipenem/Cilastatin/Relebactam Versus Piperacillin/Tazobactam in Adults With Hospital-acquired or Ventilator-associated Bacterial Pneumonia (RESTORE-IMI 2 Study)
Authors: Titov Ivan , Wunderink Richard G , Roquilly Antoine , Rodríguez Gonzalez Daniel , David-Wang Aileen , Boucher Helen W , Kaye Keith S , Losada Maria C , Du Jiejun , Tipping Robert , Rizk Matthew L , Patel Munjal , Brown Michelle L , Young Katherine , Kartsonis Nicholas A , Butterton Joan R , Paschke Amanda , Chen Luke F
Published: July 2020

Background

Imipenem combined with the β-lactamase inhibitor relebactam has broad antibacterial activity, including against carbapenem-resistant gram-negative pathogens. We evaluated efficacy and safety of imipenem/cilastatin/relebactam in treating hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP).

Methods

This was a randomized, controlled, double-blind phase 3 trial. Adults with HABP/VABP were randomized 1:1 to imipenem/cilastatin/relebactam 500 mg/500 mg/250 mg or piperacillin/tazobactam 4 g/500 mg, intravenously every 6 hours for 7–14 days. The primary endpoint was day 28 all-cause mortality in the modified intent-to-treat (MITT) population (patients who received study therapy, excluding those with only gram-positive cocci at baseline). The key secondary endpoint was clinical response 7–14 days after completing therapy in the MITT population.

Results

Of 537 randomized patients (from 113 hospitals in 27 countries), the MITT population comprised 264 imipenem/cilastatin/relebactam and 267 piperacillin/tazobactam patients; 48.6% had ventilated HABP/VABP, 47.5% APACHE II score ≥15, 24.7% moderate/severe renal impairment, 42.9% were ≥65 years old, and 66.1% were in the intensive care unit. The most common baseline pathogens were Klebsiella pneumoniae (25.6%) and Pseudomonas aeruginosa (18.9%). Imipenem/cilastatin/relebactam was noninferior (P < .001) to piperacillin/tazobactam for both endpoints: day 28 all-cause mortality was 15.9% with imipenem/cilastatin/relebactam and 21.3% with piperacillin/tazobactam (difference, −5.3% [95% confidence interval {CI}, −11.9% to 1.2%]), and favorable clinical response at early follow-up was 61.0% and 55.8%, respectively (difference, 5.0% [95% CI, −3.2% to 13.2%]). Serious adverse events (AEs) occurred in 26.7% of imipenem/cilastatin/relebactam and 32.0% of piperacillin/tazobactam patients; AEs leading to treatment discontinuation in 5.6% and 8.2%, respectively; and drug-related AEs (none fatal) in 11.7% and 9.7%, respectively.

Conclusions

Imipenem/cilastatin/relebactam is an appropriate treatment option for gram-negative HABP/VABP, including in critically ill, high-risk patients.

Clinical Trials Registration

NCT02493764.
Similarity of Sentences With Contradiction Using Semantic Similarity Measures
Authors: Krishna Siva Prasad M , Sharma Poonam
Published: July 2020

Short text or sentence similarity is crucial in various natural language processing activities. Traditional measures for sentence similarity consider word order, semantic features and role annotations of text to derive the similarity. These measures do not suit short texts or sentences with negation. Hence, this paper proposes an approach to determine the semantic similarity of sentences and also presents an algorithm to handle negation. In sentence similarity, word pair similarity plays a significant role. Hence, this paper also discusses the similarity between word pairs. Existing semantic similarity measures do not handle antonyms accurately. Hence, this paper proposes an algorithm to handle antonyms. This paper also presents an antonym dataset with 111-word pairs and corresponding expert ratings. The existing semantic similarity measures are tested on the dataset. The results of the correlation proved that the expert ratings are in order with the correlation obtained from the semantic similarity measures. The sentence similarity is handled by proposing two algorithms. The first algorithm deals with the typical sentences, and the second algorithm deals with contradiction in the sentences. SICK dataset, which has sentences with negation, is considered for handling the sentence similarity. The algorithm helped in improving the results of sentence similarity.
VE-PTP inhibition elicits eNOS phosphorylation to blunt endothelial dysfunction and hypertension in diabetes
Authors: Siragusa Mauro , Oliveira Justo Alberto Fernando , Malacarne Pedro Felipe , Strano Anna , Buch Akshay , Withers Barbara , Peters Kevin G , Fleming Ingrid
Published: July 2020

Aims

Receptor-type vascular endothelial protein tyrosine phosphatase (VE-PTP) dephosphorylates Tie-2 as well as CD31, VE-cadherin, and vascular endothelial growth factor receptor 2 (VEGFR2). The latter form a signal transduction complex that mediates the endothelial cell response to shear stress, including the activation of the endothelial nitric oxide (NO) synthase (eNOS). As VE-PTP expression is increased in diabetes, we investigated the consequences of VE-PTP inhibition (using AKB-9778) on blood pressure in diabetic patients and the role of VE-PTP in the regulation of eNOS activity and vascular reactivity.

Methods and results

In diabetic patients AKB-9778 significantly lowered systolic and diastolic blood pressure. This could be linked to elevated NO production, as AKB increased NO generation by cultured endothelial cells and elicited the NOS inhibitor-sensitive relaxation of endothelium-intact rings of mouse aorta. At the molecular level, VE-PTP inhibition increased the phosphorylation of eNOS on Tyr81 and Ser1177 (human sequence). The PIEZO1 activator Yoda1, which was used to mimic the response to shear stress, also increased eNOS Tyr81 phosphorylation, an effect that was enhanced by VE-PTP inhibition. Two kinases, i.e. abelson-tyrosine protein kinase (ABL)1 and Src were identified as eNOS Tyr81 kinases as their inhibition and down-regulation significantly reduced the basal and Yoda1-induced tyrosine phosphorylation and activity of eNOS. VE-PTP, on the other hand, formed a complex with eNOS in endothelial cells and directly dephosphorylated eNOS Tyr81 in vitro. Finally, phosphorylation of eNOS on Tyr80 (murine sequence) was found to be reduced in diabetic mice and diabetes-induced endothelial dysfunction (isolated aortic rings) was blunted by VE-PTP inhibition.

Conclusions

VE-PTP inhibition enhances eNOS activity to improve endothelial function and decrease blood pressure indirectly, through the activation of Tie-2 and the CD31/VE-cadherin/VEGFR2 complex, and directly by dephosphorylating eNOS Tyr81. VE-PTP inhibition, therefore, represents an attractive novel therapeutic option for diabetes-induced endothelial dysfunction and hypertension.
Trapped Factors and China’s Impact on Global Growth
Authors: Bloom Nicholas , Romer Paul , Terry Stephen J , Van Reenen John
Published: July 2020

After a recent increase in Chinese import competition, European firms increased innovation. We present and rationalise these patterns using ‘trapped factors’ at the micro level within a stylised equilibrium model of product-cycle trade and growth. Trade integration of the magnitude observed between the OECD and low-wage nations as a whole can considerably increase the long-run growth rate and welfare. In the short run exposed firms devote trapped factors to increased innovation, leading both to increased innovation at these individual firms as well as to a small amount of extra transitional growth overall. China accounts for half of the dynamic trade gains.
Skewed CD39/CD73/adenosine pathway contributes to B-cell hyperactivation and disease progression in patients with chronic hepatitis B
Authors: Zhou Shuang-Nan , Zhang Ning , Liu Hong-Hong , Xia Peng , Zhang Chao , Song Jin-Wen , Fan Xing , Shi Ming , Jin Lei , Zhang Ji-Yuan , Wang Fu-Sheng
Published: July 2020

Background

The mechanisms underlying B-cell hyperactivation in patients with chronic hepatitis B virus (HBV) infection remain largely undefined. The present study assessed the clinical characteristics of the CD39/CD73/adenosine pathway in patients with chronic hepatitis B (CHB).

Methods

We examined CD39 and CD73 expression and adenosine production by B-cells from 202 HBV-infected patients. B-cell-activation phenotypes were assessed by flow cytometry after CpG+CD40 ligand stimulation with or without blockade and activation of the adenosine pathway.

Results

CD39 and CD73 expression on circulating B-cells was decreased in CHB patients with high HBV DNA, HBeAg positivity, high HBsAg levels, and active liver inflammation, and was hierarchically restored in complete responders according to HBeAg seroconversion or HBsAg reduction. However, CD39 and CD73 expression on activated memory and tissue-like memory B-cell subsets in complete responders was not increased despite effective antiviral treatments. Furthermore, CD39 and CD73 expression on intra-hepatic B-cells was decreased in inflammatory livers. In vitro, B-cells from CHB patients showed a markedly reduced capacity to generate CD39/CD73-dependent extracellular adenosine and expressed increased levels of activation markers after adenosine-production blockade. Contrastingly, metformin significantly reduced activation-marker expression via regulating AMP-activated protein kinase.

Conclusions

The skewed CD39 and CD73 expression on B-cells was associated with a high viral burden, liver inflammation, and antiviral efficacy in CHB patients, and the skewed CD39/CD73/adenosine pathway contributed to B-cell hyperactivation. Regulation of the CD39/CD73/adenosine pathway using metformin may represent a therapeutic option to reverse HBV-induced immune pathogenesis.
Sequence Compression Benchmark (SCB) database—A comprehensive evaluation of reference-free compressors for FASTA-formatted sequences
Authors: Kryukov Kirill , Ueda Mahoko Takahashi , Nakagawa So , Imanishi Tadashi
Published: July 2020

Background

Nearly all molecular sequence databases currently use gzip for data compression. Ongoing rapid accumulation of stored data calls for a more efficient compression tool. Although numerous compressors exist, both specialized and general-purpose, choosing one of them was difficult because no comprehensive analysis of their comparative advantages for sequence compression was available.

Findings

We systematically benchmarked 430 settings of 48 compressors (including 29 specialized sequence compressors and 19 general-purpose compressors) on representative FASTA-formatted datasets of DNA, RNA, and protein sequences. Each compressor was evaluated on 17 performance measures, including compression strength, as well as time and memory required for compression and decompression. We used 27 test datasets including individual genomes of various sizes, DNA and RNA datasets, and standard protein datasets. We summarized the results as the Sequence Compression Benchmark database (SCB database, http://kirr.dyndns.org/sequence-compression-benchmark/), which allows custom visualizations to be built for selected subsets of benchmark results.

Conclusion

We found that modern compressors offer a large improvement in compactness and speed compared to gzip. Our benchmark allows compressors and their settings to be compared using a variety of performance measures, offering the opportunity to select the optimal compressor on the basis of the data type and usage scenario specific to a particular application.
Time-domain elastic Gauss–Newton full-waveform inversion: a matrix-free approach
Authors: Chen Ke , Sacchi Mauricio D
Published: July 2020

We present a time-domain matrix-free elastic Gauss–Newton full-waveform inversion (FWI) algorithm. Our algorithm consists of a Gauss–Newton update with a search direction calculated via elastic least-squares reverse time migration (LSRTM). The conjugate gradient least-squares (CGLS) method solves the LSRTM problem with forward and adjoint operators derived via the elastic Born approximation. The Hessian of the Gauss–Newton method is never explicitly formed or saved in memory. In other words, the CGLS algorithm solves for the Gauss–Newton direction via the application of implicit-form forward and adjoint operators which are equivalent to elastic Born modelling and elastic reverse time migration, respectively. We provide numerical examples to test the proposed algorithm where we invert for P- and S-wave velocities simultaneously. The proposed algorithm performs positively on mid-size problems where we report solutions of slight improvement than those computed using the conventional non-linear conjugate gradient method. In spite of the aforementioned limited gain, the theory developed in this paper contributes to a better understanding of time-domain elastic Gauss–Newton FWI.
Schizophrenic agendas in the EU's external actions in Mali
Authors: Cold-Ravnkilde Signe Marie , Nissen Christine
Published: July 2020

Because of its geographical proximity to the EU, the Sahel region's perceived cross-border security threats of terror, migration and organized crime have become a top European security policy priority. Contributing to existing debates on EU external actions, the article develops the idea that the EU's engagement in the Sahel has become an attempt to construct and confirm the Union's ability to act as a global security actor. Through the analytical lens of ‘translation’ emphasizing the continuous transformation of norms and ideas by actors and contexts, the article examines how EU staff implement shifting policy objectives in their security practices in Mali; the effects these intervention practices produce; and how, in turn, these effects reflect back upon the EU's role as a security actor. The article shows how the EU's actorness and ability to perform security are hampered by the lack of buy-in from their local partners, as narrating success in a context of escalating violence becomes increasingly implausible. Thus, we argue that while the EU's activities in Mali reinforce the idea of the EU as a security actor, the limited character and impact of the EU's activities on the ground also reinforce the idea of it as a limited or even ineffective actor. The article thereby provides fruitful input to discussions of the constitutive effects of everyday practices in interventions and the production of EU security actorness as played out in the Sahel.
Security for whom? Analysing hybrid security governance in Africa's extractive sectors
Authors: Enns Charis , Andrews Nathan , Grant J Andrew
Published: July 2020

In this article, we analyse the factors underpinning the shift towards hybrid security governance in Africa. Extant scholarship largely attributes this shift to broader global processes, such as histories of colonialism, neoliberalism and transformations in global governance, which have served to legitimize the role of private authority in security provision around sites of resource extraction. Our analysis seeks to understand the relative and relational influence of power and rules in international politics by offering empirical insights about what hybrid security arrangements look like ‘on the ground’. Drawing upon recently conducted fieldwork in Kenya, Uganda and Ghana, we examine how hybrid security arrangements affect the lives of those living near sites of natural resource extraction. Our analyses suggest that although hybrid security has emerged as the leading approach to security governance, this approach to security does not uniformly involve or serve the interests of all stakeholders. Rather, we find that hybrid security arrangements aid the security of extractive operations—securing investments in both physical and human capital—while sometimes undermining the security of nearby communities.
Cigarette Smoking, Coffee Consumption, Alcohol Intake, and Risk of Crohn’s Disease and Ulcerative Colitis: A Mendelian Randomization Study
Authors: Georgiou Andrea N , Ntritsos Georgios , Papadimitriou Nikos , Dimou Niki , Evangelou Evangelos
Published: July 2020

Background

Crohn’s disease (CD) and ulcerative colitis (UC) are widely associated with smoking in epidemiological studies, whereas there are conflicting results for the association between CD and UC for both coffee and alcohol consumption. Herein, we aimed to investigate whether cigarette smoking and alcohol and coffee consumption are causally associated with either CD or UC.

Methods

We utilized 540 genome-wide significant single-nucleotide polymorphisms for 3 potentially addictive substances—nicotine, alcohol, and caffeine—to assess the association of smoking, coffee, and alcohol consumption with CD and UC (12,194 CD cases, 12,366 UC cases, and 25,042 controls of European ancestry), using Mendelian randomization analysis. Mendelian randomization estimates were used to evaluate the effect of the exposure factors on CD and UC risk. Sensitivity analysis was employed to test for any directional pleiotropy.

Results

We found evidence for a positive causal association between the age of smoking initiation and UC risk and between alcohol consumption and CD risk, which disappeared after sensitivity analysis for both associations (P > 0.05). No evidence for a causal association between cigarettes per day, smoking initiation, smoking cessation, and coffee consumption variables and UC or CD was found.

Conclusions

We found no clear evidence that either genetically predicted smoking, coffee consumption, or alcohol consumption are causally associated with the risk for CD or UC, although our findings indicate a potential positive association between the age of smoking and UC and between alcohol consumption and CD.
Systematic Review with Meta-analysis: The Impact of Co-occurring Immune-mediated Inflammatory Diseases on the Disease Course of Inflammatory Bowel Diseases
Authors: Attauabi Mohamed , Zhao Mirabella , Bendtsen Flemming , Burisch Johan
Published: July 2020

Background and Aims

Patients with inflammatory bowel diseases (IBDs) are at risk of developing a variety of other immune-mediated inflammatory diseases (IMIDs). The influence of co-occurring IMIDs on the disease course of IBD remains unknown. The aim of this study was therefore to conduct a systematic review and meta-analysis of the impact of IMIDs on phenotypic presentation and outcome in patients with IBD.

Methods

PubMed and Embase were searched from their earliest records through December 2018 and updated in October 2019 for studies reporting proportions or ratios of IBD-related disease outcomes in patients with and without co-occurring IMIDs. Meta-analyses were performed to estimate summary proportions and risks of the main outcomes. PRISMA guidelines were used, and study quality was assessed according to the Newcastle-Ottawa Scale.

Results

A total of 93 studies were identified, comprising 16,064 IBD patients with co-occurring IMIDs and 3,451,414 IBD patients without IMIDs. Patients with IBD and co-occurring IMIDs were at increased risk of having extensive colitis or pancolitis (risk ratio, 1.38; 95% Cl, 1.25–1.52; P < 0.01, I2 = 86%) and receiving IBD-related surgeries (risk ratio, 1.17; 95% Cl, 1.01–1.36; P = 0.03; I2 = 85%) compared with patients without IMIDs. Co-occurrence of IMIDs other than primary sclerosing cholangitis in patients with IBD was associated with an increased risk of receiving immunomodulators (risk ratio, 1.15; 95% Cl, 1.06–1.24; P < 0.01; I2 = 60%) and biologic therapies (risk ratio, 1.19; 95% Cl, 1.08–1.32; P < 0.01; I2 = 53%).

Conclusion

This meta-analysis found that the presence of co-occurring IMIDs influences the disease course of IBD, including an increased risk of surgery and its phenotypical expression.
A Challenging Colectomy for Acute Severe Ulcerative Colitis Complicated by COVID-19
Authors: Di Ruscio Mirko , Variola Angela , Angheben Andrea , Resimini Silvia , Geccherle Andrea , Ruffo Giacomo , Barugola Giuliano
Published: July 2020

We present the case of a patient with acute severe ulcerative colitis and concomitant COVID-19-related pneumonia who required a colectomy after a prolonged and complicated hospitalization during the initial stages of the SARS-CoV-2 pandemic, before the establishment of official procedures.
Networks of export markets and export market diversification
Authors: Guo Qi , Zhu Shengjun , Boschma Ron
Published: July 2020

In the era of globalization, policy makers in both developing and developed countries have sought to expand their export destinations, with the expectation that export market diversification can boost export upgrading and economic development. Although extant literature has confirmed that exporters search for new markets in two distinct ways: direct search underpinned by the gravity effect and remote search driven by the extended gravity effect, it has not advanced very far due to the lack of adequate measures of those effects. This article presents a technique that uses available export data to develop measures of those two effects that capture a larger range of factors and thus allow us to more easily predict export market diversification. Our new indicator also simplifies the prediction by combining gravity and extended gravity effects. Empirical results show that the explanatory and predictive power of our new method is better than that of the traditional one based on gravity and extended gravity models.
Local spillovers from high-growth businesses: do gazelles cannibalize or promote employment growth?
Authors: Crown Daniel , Wojan Timothy , Rupasingha Anil
Published: July 2020

This article estimates the employment spillover effect of high-growth businesses on establishment-level employment growth. We assess whether the impact depends on the rurality of the region, and whether nearby establishments are high-growth businesses themselves. We also estimate the within-industry impact of high-growth establishments (HGEs). The findings show no impact of HGEs on net employment growth, due to equal gross job creation and job destruction on average. However, we find that within the same industry, HGEs contribute to positive net employment growth, with large and nearly equal impacts on existing HGEs across both Metropolitan Statistical Areas regions and non-metro counties.
Feedback control based on discrete-time state observations for stabilization of coupled regime-switching jump diffusion with Markov switching topologies
Authors: Wu Yongbao , Pi Haotian , Li Wenxue
Published: July 2020

In this paper, the stabilization of coupled regime-switching jump diffusion with Markov switching topologies (CRJDM) is discussed. Particularly, we remove the restrictions that each of the switching subnetwork topologies is strongly connected or contains a directed spanning tree. Furthermore, a feedback control based on discrete-time state observations is proposed to make the CRJDM asymptotically stable. In most existing literature, feedback control only depends on discrete-time observations of state processes, while switching processes are observed continuously. Different from previous literature, feedback control depends on discrete-time observations of state processes as well as switching processes in this paper. Meanwhile, based on graph theory, stationary distribution of switching processes and Lyapunov method, some sufficient conditions are deduced to ensure the asymptotic stability of CRJDM. By applying the theoretical results to second-order oscillators with Markov switching topologies, a stability criterion is obtained. Finally, the effectiveness of the results is illustrated by a numerical example.
The Emerging Role for CTL Epitope Specificity in HIV Cure Efforts
Authors: Kaseke Clarety , Tano-Menka Rhoda , Senjobe Fernando , Gaiha Gaurav D
Published: July 2020

The development of an effective human immunodeficiency virus (HIV) cure is a critical global health priority. A major obstacle to this effort is the establishment of a latent reservoir of HIV infected cells, which necessitates lifelong therapy, causing both logistical and adherence burdens for infected individuals. However, in a subset of these individuals, cytotoxic T lymphocytes (CTLs) can durably suppress viral outgrowth in the absence of therapy, providing a path towards a viable HIV cure. In this review, we discuss the emerging role that CTLs have in HIV cure efforts, with particular emphasis on epitope specificity. Recent studies have demonstrated that successful in vivo containment of the virus is rooted in the specific targeting of fitness-constrained, mutation-resistant regions of the HIV proteome. We highlight these new insights, providing context with previous observations in HIV and other models of viral control, and delineate their translation into a therapeutic vaccine.
Direct Observation of Repeated Infections With Endemic Coronaviruses
Authors: Galanti Marta , Shaman Jeffrey
Published: July 2020

Background

Although the mechanisms of adaptive immunity to pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are still unknown, the immune response to the widespread endemic coronaviruses HKU1, 229E, NL63, and OC43 provide a useful reference for understanding repeat infection risk.

Methods

Here we used data from proactive sampling carried out in New York City from fall 2016 to spring 2018. We combined weekly nasal swab collection with self-reports of respiratory symptoms from 191 participants to investigate the profile of recurring infections with endemic coronaviruses.

Results

During the study, 12 individuals tested positive multiple times for the same coronavirus. We found no significant difference between the probability of testing positive at least once and the probability of a recurrence for the betacoronaviruses HKU1 and OC43 at 34 weeks after enrollment/first infection. We also found no significant association between repeat infections and symptom severity, but found strong association between symptom severity and belonging to the same family.

Conclusions

This study provides evidence that reinfections with the same endemic coronavirus are not atypical in a time window shorter than 1 year and that the genetic basis of innate immune response may be a greater determinant of infection severity than immune memory acquired after a previous infection.
Sociodemographic, Ecological, and Spatiotemporal Factors Associated with Human Immunodeficiency Virus Drug Resistance in Florida: A Retrospective Analysis
Authors: Rich Shannan N , Poschman Karalee , Hu Hui , Mavian Carla , Cook Robert L , Salemi Marco , Spencer Emma C , Prosperi Mattia
Published: July 2020

Background

Persons living with human immunodeficiency virus (HIV) with resistance to antiretroviral therapy are vulnerable to adverse HIV-related health outcomes and can contribute to transmission of HIV drug resistance (HIVDR) when nonvirally suppressed. The degree to which HIVDR contributes to disease burden in Florida—the US state with the highest HIV incidence– is unknown.

Methods

We explored sociodemographic, ecological, and spatiotemporal associations of HIVDR. HIV-1 sequences (n = 34 447) collected during 2012–2017 were obtained from the Florida Department of Health. HIVDR was categorized by resistance class, including resistance to nucleoside reverse-transcriptase , nonnucleoside reverse-transcriptase , protease , and integrase inhibitors. Multidrug resistance and transmitted drug resistance were also evaluated. Multivariable fixed-effects logistic regression models were fitted to associate individual- and county-level sociodemographic and ecological health indicators with HIVDR.

Results

The HIVDR prevalence was 19.2% (nucleoside reverse-transcriptase inhibitor resistance), 29.7% (nonnucleoside reverse-transcriptase inhibitor resistance), 6.6% (protease inhibitor resistance), 23.5% (transmitted drug resistance), 13.2% (multidrug resistance), and 8.2% (integrase strand transfer inhibitor resistance), with significant variation by Florida county. Individuals who were older, black, or acquired HIV through mother-to-child transmission had significantly higher odds of HIVDR. HIVDR was linked to counties with lower socioeconomic status, higher rates of unemployment, and poor mental health.

Conclusions

Our findings indicate that HIVDR prevalence is higher in Florida than aggregate North American estimates with significant geographic and socioecological heterogeneity.
Phexpo: a package for bidirectional enrichment analysis of phenotypes and chemicals
Authors: Hawthorne Christopher , Simpson David A , Devereux Barry , López-Campos Guillermo
Published: July 2020

Phenotypes are the result of the complex interplay between environmental and genetic factors. To better understand the interactions between chemical compounds and human phenotypes, and further exposome research we have developed “phexpo,” a tool to perform and explore bidirectional chemical and phenotype interactions using enrichment analyses. Phexpo utilizes gene annotations from 2 curated public repositories, the Comparative Toxicogenomics Database and the Human Phenotype Ontology. We have applied phexpo in 3 case studies linking: (1) individual chemicals (a drug, warfarin, and an industrial chemical, chloroform) with phenotypes, (2) individual phenotypes (left ventricular dysfunction) with chemicals, and (3) multiple phenotypes (covering polycystic ovary syndrome) with chemicals. The results of these analyses demonstrated successful identification of relevant chemicals or phenotypes supported by bibliographic references. The phexpo R package (https://github.com/GHLCLab/phexpo) provides a new bidirectional analyses approach covering relationships from chemicals to phenotypes and from phenotypes to chemicals.
Genetic dissection of Ragulator structure and function in amino acid-dependent regulation of mTORC1
Authors: Nada Shigeyuki , Okada Masato
Published: July 2020

Ragulator is a heteropentameric protein complex consisting of two roadblock heterodimers wrapped by the membrane anchor p18/Lamtor1. The Ragulator complex functions as a lysosomal membrane scaffold for Rag GTPases to recruit and activate mechanistic target of rapamycin complex 1 (mTORC1). However, the roles of Ragulator structure in the regulation of mTORC1 function remain elusive. In this study, we disrupted Ragulator structure by directly anchoring RagC to lysosomes and monitored the effect on amino acid-dependent mTORC1 activation. Expression of lysosome-anchored RagC in p18-deficient cells resulted in constitutive lysosomal localization and amino acid-independent activation of mTORC1. Co-expression of Ragulator in this system restored the amino acid dependency of mTORC1 activation. Furthermore, ablation of Gator1, a suppressor of Rag GTPases, induced amino acid-independent activation of mTORC1 even in the presence of Ragulator. These results demonstrate that Ragulator structure is essential for amino acid-dependent regulation of Rag GTPases via Gator1. In addition, our genetic analyses revealed new roles of amino acids in the regulation of mTORC1 as follows: amino acids could activate a fraction of mTORC1 in a Rheb-independent manner, and could also drive negative-feedback regulation of mTORC1 signalling via protein phosphatases. These intriguing findings contribute to our overall understanding of the regulatory mechanisms of mTORC1 signalling.
Indigenous Peoples and Litigation: Strategies for Legal Empowerment
Authors: Gilbert* Jérémie
Published: July 2020

Across the globe indigenous peoples are increasingly using litigation to seek remedies for violation of their fundamental human rights. The rise of litigation is to be placed in the larger context of increased land grabbing, exploitation of natural resources, and the general lack of recognition of indigenous peoples’ rights at the national level. This lack of legal rights is usually coupled with a lack of political will to address the issues faced by indigenous peoples, often leading to serious human rights violations, leaving indigenous advocates with few options but to turn to courts as a last resort to seek remedies. This article examines some of the issues faced by indigenous peoples and their advocates when engaging in human rights litigation. The goal is to offer a practice-based reflection on the encounter between courts and indigenous peoples with a specific focus on analysing strategies to support indigenous peoples’ legal empowerment. This is particularly important knowing the technicalities, externalities and complexities of the process of litigation, and the fact that many decisions do not get implemented. In this context this article explores how the process of litigation in itself can support legal empowerment and the wider fight for justice.
History in International Criminal Trials
Authors: Zammit Borda Aldo
Published: July 2020

While the question of whether international criminal courts and tribunals (ICTs) ought to write historical narratives of armed conflicts is an old one, it has gained renewed relevance in the context of the recent turn to history in international criminal law and the minimal attention paid to historical context in the first judgment of the International Criminal Court. The ‘proper’ place of history-writing in international criminal adjudication remains controversial, and even though some judges have preferred to de-emphasize it, the fact remains that ICTs are epistemic engines, systematically and inevitably producing knowledge about the conflicts that come before them. This article develops a framework for analysing the historical knowledge generated by ICTs, namely, the ‘crime-driven lens’. It argues that this lens is characterized by two important constraints, one qualitative, relating to interpretation and the other quantitative, relating to scope, both of which may give rise to blind spots. In the final analysis, while the important contributions of ICTs to deepening understanding of the histories of armed conflicts should not be underestimated, the constraints of the ‘crime-driven lens’ and its blind spots have to be taken into account when assessing their historical legacies.
Long-term ureteroscopic management of upper tract urothelial carcinoma: 28-year single-centre experience
Authors: Maruyama Yuki , Araki Motoo , Wada Koichiro , Yoshinaga Kasumi , Mitsui Yosuke , Sadahira Takuya , Nishimura Shingo , Edamura Kohei , Kobayashi Yasuyuki , Watanabe Masami , Watanabe Toyohiko , Monga Manoj , Nasu Yasutomo , Kumon Hiromi
Published: July 2020

Background

Long-term survival outcomes of patients who undergo endoscopic management of non-invasive upper tract urothelial carcinoma remain uncertain. The longest mean follow-up period in previous studies was 6.1 years. This study reports the long-term outcomes of patients with upper tract urothelial carcinoma who underwent ureteroscopic ablation at a single institution over a 28-year period.

Methods

We identified all patients who underwent ureteroscopic management of upper tract urothelial carcinoma as their primary treatment at our institution between January 1991 and April 2011. Survival outcomes, including overall survival, cancer-specific survival, upper-tract recurrence-free survival and renal unit survival, were estimated using Kaplan−Meier methodology.

Results

A total of 15 patients underwent endoscopic management, with a mean age at diagnosis of 66 years. All patients underwent ureteroscopy, and biopsy-confirmed pathology was obtained. Median (range; mean) follow-up was 11.7 (2.3–20.9, 11.9) years. Upper tract recurrence occurred in 87% (n = 13) of patients. Twenty percent (n = 3) of patients proceeded to nephroureterectomy. The estimated cancer-specific survival rate was 93% at 5, 10, 15 and 20 years. Estimated overall survival rates were 86, 80, 54 and 20% at 5, 10, 15 and 20 years. Only one patient experienced cancer-specific mortality. The estimated mean and median overall survival times were 14.5 and 16.6 years, respectively. The estimated mean cancer-specific survival time was not reached.

Conclusions

Although upper tract recurrence is common, endoscopic management of non-invasive upper tract urothelial carcinoma provides a 90% cancer-specific survival rate at 20 years in selected patients.
High day and night temperatures distinctively disrupt fatty acid and jasmonic acid metabolism, inducing male sterility in cotton
Authors: Khan Aamir Hamid , Min Ling , Ma Yizan , Wu Yuanlong , Ding Yuanhao , Li Yanlong , Xie Sai , Ullah Abid , Shaban Muhammad , Manghwar Hakim , Shahid Muhammad , Zhao Yunlong , Wang Chaozhi , Zhang Xianlong
Published: July 2020

High temperature stress is an inevitable environmental factor in certain geographical regions. To study the effect of day and night high temperature stress on male reproduction, the heat-sensitive cotton line H05 was subjected to high temperature stress. High day/normal night (HN) and normal day/high night (NH) temperature treatments were compared with normal day/normal night (NN) temperature as a control. At the anther dehiscence stage, significant differences were observed, with a reduction in flower size and filament length, and sterility in pollen, seen in NH more than in HN. A total of 36 806 differentially expressed genes were screened, which were mainly associated with fatty acid and jasmonic acid (JA) metabolic pathways. Fatty acid and JA contents were reduced more in NH than HN. Under NH, ACYL-COA OXIDASE 2 (ACO2), a JA biosynthesis gene, was down-regulated. Interestingly, aco2 CRISPR-Cas9 mutants showed male sterility under the NN condition. The exogenous application of methyl jasmonate to early-stage buds of mutants rescued the sterile pollen and indehiscent anther phenotypes at the late stage. These data show that high temperature at night may affect fatty acid and JA metabolism in anthers by suppressing GhACO2 and generate male sterility more strongly than high day temperature.
The matrix revolutions: towards the decoding of the plant chromatin three-dimensional reality
Authors: Huang Ying , Rodriguez-Granados Natalia Yaneth , Latrasse David , Raynaud Cecile , Benhamed Moussa , Ramirez-Prado Juan Sebastian
Published: July 2020

In recent years, we have witnessed a significant increase in studies addressing the three-dimensional (3D) chromatin organization of the plant nucleus. Important advances in chromatin conformation capture (3C)-derived and related techniques have allowed the exploration of the nuclear topology of plants with large and complex genomes, including various crops. In addition, the increase in their resolution has permitted the depiction of chromatin compartmentalization and interactions at the gene scale. These studies have revealed the highly complex mechanisms governing plant nuclear architecture and the remarkable knowledge gaps in this field. Here we discuss the state-of-the-art in plant chromosome architecture, including our knowledge of the hierarchical organization of the genome in 3D space and regarding other nuclear components. Furthermore, we highlight the existence in plants of topologically associated domain (TAD)-like structures that display striking differences from their mammalian counterparts, proposing the concept of ICONS—intergenic condensed spacers. Similarly, we explore recent advances in the study of chromatin loops and R-loops, and their implication in the regulation of gene activity. Finally, we address the impact that polyploidization has had on the chromatin topology of modern crops, and how this is related to phenomena such as subgenome dominance and biased gene retention in these organisms.
The Relationship Between Severe Visual Acuity Loss, Traumatic Brain Injuries, and Ocular Injuries in American Service Members From 2001 to 2015
Authors: Flanagan Gerald , Velez Tom , Gu Weidong , Singman Eric
Published: July 2020

Introduction

Although traumatic brain injury (TBI) is known to cause many visual problems, the correlation between the extent of severe visual acuity loss (SVAL) and severity of TBI has not been widely explored. In this retrospective analysis, combined information from Department of Defense (DoD)/Veterans Affairs ocular injury and TBI repositories were used to evaluate the relationship between chronic SVAL, TBI, ocular injuries, and associated ocular sequelae for U.S. service members serving between 2001 and 2015.

Materials and Methods

The Defense and Veterans Eye Injury and Vision Registry (DVEIVR) is an initiative led by the DoD and Veterans Affairs that consists of clinical and related data for service members serving in theater since 2001. The Defense and Veterans Brain Injury Center (DVBIC) is the DoD’s office for tracking TBI data in the military and maintains data on active-duty service members with a TBI diagnosis since 2000. Longitudinal data from these 2 resources for encounters between February 2001 and October 2015 were analyzed to understand the relation between SVAL, and TBI while adjusting for ocular covariates such as open globe injury (OGI), disorders of the anterior segment and disorders of the posterior segment in a logistic regression model. TBI cases in DVEIVR were identified using DVBIC data and classified according to International Statistical Classification of Diseases criteria established by DVBIC. Head trauma and other open head wounds (OOHW) were also included. SVAL cases in DVEIVR were identified using both International Statistical Classification of Diseases criteria for blindness and low vision as well as visual acuity test data recorded in DVEIVR.

Results

Data for a total of 25,193 unique patients with 88,996 encounters were recorded in DVEIVR from February, 2001 to November, 2015. Of these, 7,217 TBI and 1,367 low vision cases were identified, with 638 patients experiencing both. In a full logistic model, neither UTBI nor differentiated TBI (DTBI, ie, mild, moderate, severe, penetrating, or unclassified) were significant risk factors for SVAL although ocular injuries (disorders of the anterior segment, disorders of the posterior segment, and OGI) and OOHW were significant.

Conclusion

Any direct injury to the eye or head risks SVAL but the location and severity will modify that risk. After adjusting for OGIs, OOHW and their sequelae, TBI was found to not be a significant risk factor for SVAL in patients recorded in DVEIVR. Further research is needed to explore whether TBI is associated with more moderate levels of vision acuity loss.
Assessing spectra and thermal inversions due to TiO in hot Jupiter atmospheres
Authors: Piette Anjali A A , Madhusudhan Nikku , McKemmish Laura K , Gandhi Siddharth , Masseron Thomas , Welbanks Luis
Published: July 2020

Recent detections of thermal inversions in the dayside atmospheres of some hot Jupiters are motivating new avenues to understand the interplay between their temperature structures and other atmospheric conditions. In particular, TiO has long been proposed to cause thermal inversions in hot Jupiters, depending on other factors such as stellar irradiation, C/O, and vertical mixing. TiO also has spectral features in the optical and near-infrared that have been detected. However, interpretations of TiO signatures rely on the accuracy of TiO opacity used in the models. The recently reported toto TiO line list provides a new opportunity to investigate these dependences, which is the goal of this work. First, we investigate how the toto line list affects observable transmission and emission spectra of hot Jupiters at low and high resolutions. The improvement in the toto line list compared to a previous line list results in observable differences in the model spectra, particularly in the optical at high resolution. Secondly, we explore the interplay between temperature structure, irradiation, and composition with TiO as the primary source of optical opacity, using 1D self-consistent atmospheric models. Among other trends, we find that the propensity for thermal inversions due to TiO peaks at C/O ∼ 0.9, consistent with recent studies. Using these models, we further assess metrics to quantify thermal inversions due to TiO, compared to frequently used Spitzer photometry, over a range in C/O, irradiation, metallicity, gravity, and stellar type.