bluuebunny/crossref_metadata_2025 huggingface dataset:
Wearing Off Effect of OnabotulinumtoxinA Near the End of Treatment Cycle for Chronic Migraine: A 4‐Year Clinical Experience
Authors: Khan Fawad A. , Mohammed Alaa E. , Poongkunran Mugilan , Chimakurthy Anilkumar , Pepper Michael
Published: November 2019

Introduction

The injection interval for onabotulinumtoxinA (BoNTA) in the management of chronic migraine (CM) is 12 weeks (78‐84 days). The aim of this study was to review patient‐reported wearing off effect (WOE) of the therapeutic benefit of BoNTA near the end of the treatment cycle. We intended to describe the demographics of patients at baseline and compare groups of patients with multiple episodes of WOE.

Methods

We conducted a retrospective review of patients with CM who received uninterrupted BoNTA therapy from January 2014 to March 2018. The data from patient‐reported WOE (worsening headache variables and neck pain) that occurred during the 4 weeks (28 days) prior to the scheduled re‐injection of BoNTA for treatment cycles with injection interval ≤13 weeks and without obvious confounding factors were reviewed.

Results

We identified 98 eligible patients and analyzed 471 treatment cycles. Forty‐three unique patients reported at least 1 occurrence of WOE. About 24/43 patients reported 1 WOE event and 19/43 patients reported ≥2 WOE events. Between the 2 groups, anxiety disorder and opioid use for headache were statistically significantly different. In the former group, the median interquartile range (IQR) dose of BoNTA was 165 (155, 175) units and the median IQR duration of the antinociceptive effect of BoNTA was 66.5 (63, 71.5) days. In the latter group, the median IQR dose of BoNTA was 167 (155, 173.3) units and the median IQR duration of the antinociceptive effect of BoNTA was 65.3 (62.5, 68.8) days. Up to 32% of these patients reported an increase in the use of abortive therapies to manage the symptoms of WOE.

Discussion

The primary goal of BoNTA in the treatment of CM is to mitigate the development of central sensitization. Since the 12‐week injection paradigm may not provide sustained antinociceptive effect in all patients, it may account for the failure of response to BoNTA. Repeated occurrences of the WOE can potentially lead to medication overuse and impact quality of life.
Development of a Prospective Real‐World Data Clinical Registry of Children and Adolescents With Migraine
Authors: Hornik Christoph P. , Gelfand Amy A. , Szperka Christina L. , Pezzuto Tara , Utevsky Amanda , Kessel Shirley , McCune Susan , Alexander John J. , Benjamin Daniel K. , Cohen‐Wolkowiez Michael
Published: November 2019

Objective

To develop a multicenter, multistakeholder, prospective clinical registry of children and adolescents with migraine to support the collection of real‐world data of sufficient quality to support regulatory submissions and provide site‐based infrastructure support for future clinical trials.

Background

As new migraine treatments come to market, pediatric efficacy and safety trials of these agents are needed. A clinical registry is an ideal regulatory strategy to provide both real‐world data and site infrastructure to execute these trials.

Design

Multicenter, multistakeholder, prospective real‐world data clinical registry of children and adolescents, 4‐17 years of age, diagnosed with migraine with or without aura. Participants will be followed for up to 12 months at 3‐month intervals, with interval recording of clinical data at study sites and self‐reported data via mobile health application, as well as biobanking. We developed electronic case report forms that incorporated routinely collected clinical data with National Institute of Neurological Disorders and Stroke Headache Common Data Elements (Version 2.0). All data are captured in a 21 CFR Part 11 – compliant electronic data capture system – augmented by a real‐time, web‐based, and customizable data visualization platform. We engaged vendors to provide ancillary biobanking, patient data entry, and data visualization services.

Results

We used an iterative and highly collaborative multistakeholder approach to design and implement a streamlined registry protocol with input from all participating US sites. At each design and implementation step, we received input from therapeutic area experts, the US Food and Drug Administration (FDA), the National Institutes of Health, patient and parent advocates, health technology partners, drug developers, and site‐based clinical investigators. The registry is governed by a multistakeholder steering committee with representation from sites, industry partners, patient advocates, and a member from the FDA (non‐voting with respect to steering committee matters). The multistakeholder and site‐driven approach to registry design and execution was highly efficient and resulted in the first patient enrolled within 6 months of concept development.

Conclusions

By ensuring regulatory compliant implementation of the registry, we created both a source of real‐world data and a multisite platform for the conduct of future clinical trials that can be submitted to regulatory authorities to support inclusion of pediatric data in approved drug labeling. A highly collaborative approach with broad stakeholder engagement at all stages of the registry development was a key to our operational success.
Narrative disclosures, firm life cycle, and audit fees
Authors: Hossain Mahmud , Hossain Mahmud , Mitra Santanu , Salama Feras
Published: November 2019

This study examines the relationship between narrative disclosure properties in terms of readability, optimism, and ambiguity of annual reports and audit fees, and how the relationship changes across firms' various life‐cycle stages. Using 54,883 observations for the years from 2000 to 2016, we find that these textual disclosure properties have positive audit pricing consequences. We suggest that narrative disclosure properties play an important role in estimating audit risk, and thus in audit fees. We further posit that the audit fee consequences of these disclosure characteristics vary across different phases of a client firm's corporate life cycle. Though we observe that with a decrease in readability and an increase in optimism and ambiguity of disclosure language that audit fees increase in the introduction phase, a firm's entry to the growth phase moderates the influence of these narrative disclosure features on audit fees. However, the impact of these lexical features on audit fees increases as client firms switch (1) from the growth phase to the maturity phase and (2) from the maturity phase to the decline phase. Based on these findings, we argue that, when examining the audit fee implication for management's disclosure strategies, researchers should treat client firms as dynamic evolving entities.
Preserving US microbe collections sparks future discoveries
Authors: Boundy-Mills K. , McCluskey K. , Elia P. , Glaeser J.A. , Lindner D.L. , Nobles D.R. , Normanly J. , Ochoa-Corona F.M. , Scott J.A. , Ward T.J. , Webb K.M. , Webster K. , Wertz J.E.
Published: November 2019

Collections of micro-organisms are a crucial element of life science research infrastructure but are vulnerable to loss and damage caused by natural or man-made disasters, the untimely death or retirement of personnel, or the loss of research funding. Preservation of biological collections has risen in priority due to a new appreciation for discoveries linked to preserved specimens, emerging hurdles to international collecting and decreased funding for new collecting. While many historic collections have been lost, several have been preserved, some with dramatic rescue stories. Rescued microbes have been used for discoveries in areas of health, biotechnology and basic life science. Suggestions for long-term planning for microbial stocks are listed, as well as inducements for long-term preservation.
Role of VEGFR‐1 in melanoma acquired resistance to the BRAF inhibitor vemurafenib
Authors: Atzori Maria Grazia , Ceci Claudia , Ruffini Federica , Trapani Mauro , Barbaccia Maria Luisa , Tentori Lucio , D'Atri Stefania , Lacal Pedro Miguel , Graziani Grazia
Published: November 2019

The vascular endothelial growth factor receptor‐1 (VEGFR‐1) is a tyrosine kinase receptor frequently expressed in melanoma. Its activation by VEGF‐A or placental growth factor (PlGF) promotes tumour cell survival, migration and invasiveness. Moreover, VEGFR‐1 stimulation contributes to pathological angiogenesis and induces recruitment of tumour‐associated macrophages. Since melanoma acquired resistance to BRAF inhibitors (BRAFi) has been associated with activation of pro‐angiogenic pathways, we have investigated VEGFR‐1 involvement in vemurafenib resistance. Results indicate that human melanoma cells rendered resistant to vemurafenib secrete greater amounts of VEGF‐A and express higher VEGFR‐1 levels compared with their BRAFi‐sensitive counterparts. Transient VEGFR‐1 silencing in susceptible melanoma cells delays resistance development, whereas in resistant cells it increases sensitivity to the BRAFi. Consistently, enforced VEGFR‐1 expression, by stable gene transfection in receptor‐negative melanoma cells, markedly reduces sensitivity to vemurafenib. Moreover, melanoma cells expressing VEGFR‐1 are more invasive than VEGFR‐1 deficient cells and receptor blockade by a specific monoclonal antibody (D16F7 mAb) reduces extracellular matrix invasion triggered by VEGF‐A and PlGF. These data suggest that VEGFR‐1 up‐regulation might contribute to melanoma progression and spreading after acquisition of a drug‐resistant phenotype. Thus, VEGFR‐1 inhibition with D16F7 mAb might be a suitable adjunct therapy for VEGFR‐1 positive tumours with acquired resistance to vemurafenib.
Achieving the composite end‐point of glycated hemoglobin <7.0% without weight gain or hypoglycemia with once‐weekly dulaglutide in Chinese patients with type 2 diabetes: A post‐hoc analysis
Authors: Xiao Xinhua , Wang Changjiang , Lai Xiaoyang , Zhang Bin , Gu Liqun , Hou Jianing , Zhou Zhiguang
Published: November 2019

Aims/Introduction

To assess the effect of dulaglutide (DU) 1.5/0.75 mg in comparison with glimepiride (GLIM) or insulin glargine (GLAR) on the composite end‐point in Chinese type 2 diabetes patients.

Materials and Methods

Post‐hoc analyses of two randomized phase III trials (NCT01644500 and NCT01648582) were carried out using Fisher’s exact test. The primary composite end‐point was the number of patients reaching glycated hemoglobin (HbA1c) <7.0%, without weight gain and hypoglycemia. Secondary composite end‐points included the number of patients reaching HbA1c <7.0% without weight gain and HbA1c <7.0% without hypoglycemia.

Results

Data of 1,147 Chinese type 2 diabetes patients were analyzed (NCT01644500 = 556; NCT01648582 = 591). In each analyzed trial, 40–48% of patients received DU (1.5 mg), 30–39% of patients received DU (0.75 mg) and 15–20% of patients on active comparators (GLIM/GLAR) reached the primary composite end‐point at week 26 (P < 0.001 for DU vs GLIM/GLAR). At 52 weeks, 26% of patients that received DU (1.5 mg), 23% of patients that received DU (0.75 mg) and 7% of patients that received GLAR attained the primary composite end‐point (P < 0.001 for DU vs GLAR). A similar trend of results was found for secondary composite end‐points.

Conclusions

Dulaglutide is found to be an effective therapeutic alternative for Chinese type 2 diabetes patients. Compared with GLIM/GLAR, significantly greater proportions of patients on DU attained the HbA1c target of <7.0% without weight gain or hypoglycemia.
Late recurrence of melanoma after 10 years – Is the course of the disease different from early recurrences?
Authors: Sarac E. , Wilhelmi J. , Thomas I. , Leiter U. , Keim U. , Eigentler T.K. , Garbe C. , Amaral T.
Published: November 2019

Background

It is known that melanoma can metastasize and recur many years after the first diagnosis. Although predictive and prognostic factors for melanoma are well defined, there is still insufficient information about the factors affecting the recurrence period and the effect of the recurrence time to survival.

Objectives

This study investigates the course of melanoma to show prognostic factors comparing early and late recurrence patients. The main objective is to uncover the effect of the recurrence time on the progression of the disease.

Methods

In this retrospective study, late recurrence (LR) was defined as melanoma recurrence 10 years after the first diagnosis and early recurrence (ER) was defined as recurrence within 10 years. Gender, age, localization of primary tumour, time to first metastasis, survival rates, histological subtype, stage, tumour thickness, invasion level, ulceration and regression of the primary melanoma were documented. Survival curves were evaluated using the Kaplan–Meier and compared with the log‐rank test. Multivariate Cox proportional hazard models were used to identify significant independent prognostic factors for melanoma‐specific survival (MSS).

Results

A total of 1537 melanoma patients were analysed. Early metastasis was developed in 1438 patients (93.6%), and 99 patients (6.4%) developed late metastasis. Late recurrence patients were younger (P < 0.001) and had fewer ulcerated (P = 0.005), fewer head/neck localized (P = 0.009) and thinner (P < 0.001) melanomas than ER patients. The MSS time (mean ± SD) was nearly identical for LR (31 ± 4.4 months 95% CI [22.3–39.7]) and ER (32 ± 1.9 months [28.3–35.7]). Multivariate regression analysis revealed male gender (hazard ratio [HR = 1.4, P < 0.001), truncal tumour localization (HR = 1.7, P < 0.001), tumour thickness (HR = 1.4, P < 0.045) and ulceration (HR = 1.3, P < 0.008) as significant independent prognostic factors for MSS.

Conclusion

Although ER and LR patients are found to have different clinicopathologic features, the time of the first recurrence after diagnosis do not seem to have an effect on the survival.
Intravenous lipid emulsion modifies synaptic transmission in hippocampal CA1 pyramidal neurons after bupivacaine‐induced central nervous system toxicity
Authors: Nie Hao , Bai Zhixia , Li Zhenzhou , Yan Li , Chen Xue‐Xin
Published: November 2019

Local anesthetics can cause severe toxicity when absorbed systemically. Rapid intravenous administration of lipid emulsion (LE) is the standard of care for severe local anesthetic systemic toxicity which can cause cardiovascular and central nervous system (CNS) injury. The biological mechanism by which LE alleviates CNS toxicity remains unknown and understudied. Previous research has suggested that local anesthetics cause an imbalance of excitatory and inhibitory transmission in the brain. Therefore, this study aimed to observe the effect of LE on glutamate‐ and GABA‐induced currents in CA1 pyramidal neurons after bupivacaine‐induced CNS toxicity. We further characterized post‐synaptic modifications in these cells to try to elucidate the mechanism by which LE mediates bupivacaine‐induced CNS toxicity. Sprague–Dawley rats received intravenous bupivacaine (1 mg kg−1 min−1) in either normal saline or LE (or LE without bupivacaine) for 5 min. An acute brain slice preparation and a combination of whole‐cell patch clamp techniques and whole‐cell recordings were used to characterize action potential properties, miniature excitatory, and inhibitory post‐synaptic currents, and post‐synaptic modifications of excitatory and inhibitory transmission in CA1 hippocampal pyramidal neurons. The expression level of GABAA receptors were assessed with western blotting, whereas H&E and TUNEL staining were used to assess cytoarchitecture and apoptosis levels respectively. Bupivacaine treatment significantly increased the number of observed action potentials, whereas significantly decreasing rheobase, the first interspike interval (ISI), and hyperpolarization‐activated cation currents (Ih) in CA1 pyramidal neurons. LE treatment significantly reduced the frequency of miniature inhibitory post‐synaptic currents and enhanced GABA‐induced paired pulse ratio with 50 ms interval stimulation in bupivacaine‐treated rats. Regulation of GABAA levels is a promising mechanism by which LE may ameliorate CNS toxicity after systemic absorption of bupivacaine.

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Insulin‐induced hypoglycaemia suppresses pulsatile luteinising hormone secretion and arcuate Kiss1 cell activation in female mice
Authors: McCosh Richard B. , Kreisman Michael J. , Tian Katherine , Ho Bryan S. , Thackray Varykina G. , Breen Kellie M.
Published: November 2019

Stress suppresses pulsatile luteinising hormone (LH) secretion in a variety of species, although the mechanism underlying this inhibition of reproductive function remains unclear. Metabolic stress, particularly hypoglycaemia, is a clinically‐relevant stress type that is modelled with bolus insulin injection (insulin‐induced hypoglycaemia). The present study utilised ovariectomised C57BL/6 mice to test the hypothesis that acute hypoglycaemia suppresses pulsatile LH secretion via central mechanisms. Pulsatile LH secretion was measured in 90‐minute sampling periods immediately prior to and following i.p. injection of saline or insulin. The secretion of LH was not altered over time in fed animals or acutely fasted (5 hours) animals following an i.p. saline injection. By contrast, insulin elicited a robust suppression of pulsatile LH secretion in fasted animals, preventing LH pulses in five of six mice. To identify the neuroendocrine site of impairment, a kisspeptin challenge was performed in saline or insulin pre‐treated animals in a cross‐over design. LH secretion in response to exogenous kisspeptin was not different between animals pre‐treated with saline or insulin, indicating normal gonadotrophin‐releasing hormone cell and pituitary responses during acute hypoglycaemia. Based on this finding, the effect of insulin‐induced hypoglycaemia on arcuate kisspeptin (Kiss1) cell function was determined using c‐Fos as a marker of neuronal activation. Insulin caused a significant suppression in the percentage of Kiss1 cells in the arcuate nucleus that contained c‐Fos compared to saline‐injected controls. Taken together, these data support the hypothesis that insulin‐induced hypoglycaemia suppresses pulsatile LH secretion in the female mouse via predominantly central mechanisms, which culminates in the suppression of the arcuate Kiss1 population.
Perinatal compromise contributes to programming of GABAergic and glutamatergic systems leading to long‐term effects on offspring behaviour
Authors: Shaw Julia C. , Crombie Gabrielle K. , Zakar Tamas , Palliser Hannah K. , Hirst Jonathan J.
Published: November 2019

Extensive evidence now shows that adversity during the perinatal period is a significant risk factor for the development of neurodevelopmental disorders long after the causative event. Despite stemming from a variety of causes, perinatal compromise appears to have similar effects on the developing brain, thereby resulting in behavioural disorders of a similar nature. These behavioural disorders occur in a sex‐dependent manner, with males affected more by externalising behaviours such as attention deficit hyperactivity disorder (ADHD) and females by internalising behaviours such as anxiety. Regardless of the causative event or the sex of the offspring, these disorders may begin in childhood or adolescence but extend into adulthood. A mechanism by which adverse events in the perinatal period impact later in life behaviour has been shown to be the changing epigenetic landscape. Methylation of the GAD1/GAD67 gene, which encodes the key glutamate‐to‐GABA‐synthesising enzyme glutamate decarboxylase 1, resulting in increased levels of glutamate, is one epigenetic mechanism that may account for a tendency towards excitation in disorders such as ADHD. Exposure of the fetus or the neonate to high levels of cortisol may be the mediator between perinatal compromise and poor behavioural outcomes because evidence suggests that increased glucocorticoid exposure triggers widespread changes in the epigenetic landscape. This review summarises the current evidence and recent literature about the impact of various perinatal insults on the epigenome and the common mechanisms that may explain the similarity of behavioural outcomes occurring following diverse perinatal compromise.
Effects of diisopentyl phthalate exposure during gestation and lactation on hormone‐dependent behaviours and hormone receptor expression in rats
Authors: Neubert da Silva Gabriela , Zauer Curi Tatiana , Lima Tolouei Sara Emília , Tapias Passoni Marcella , Sari Hey Giovanna Beatriz , Marino Romano Renata , Martino‐Andrade Anderson Joel , Dalsenter Paulo Roberto
Published: November 2019

Phthalates are found in different plastic materials, such as packaging, toys and medical devices. Some of these compounds are endocrine disruptors, comprising substances that are able to induce multiple hormonal disturbances and downstream developmental effects, including the disruption of androgen‐dependent differentiation of the male reproductive tract and changes in pathways that regulate hormone‐dependent behaviours. In a previous study, metabolites of diisopentyl phthalate (DiPeP), a potent anti‐androgenic phthalate, were found in the urine of Brazilian pregnant women. Therefore, the present study aimed to evaluate the effects of DiPeP exposure during critical developmental periods on behaviours controlled by sex hormones in rats. Pregnant Wistar rats were treated with DiPeP (1, 10 or 100 mg kg day‐1) or canola oil by oral gavage between gestational day 10 and post‐natal day (PND) 21. Male offspring were tested in a behavioural battery, including the elevated plus maze task, play behaviour, partner preference and sexual behaviour. After the behavioural tests, the hypothalamus and pituitary of these animals were removed on PND 60‐65 and PND 145‐160 to quantify gene expression for aromatase, androgen receptor (Ar) and oestrogen receptors α (Esr1) and β (Esr2). Male rats exposed to 1 and 10 mg kg day‐1 DiPeP displayed no preference for the female stimulus rat in the partner preference test and 1 mg kg day‐1 DiPeP rats also showed a significant increase in mount and penetration latencies when mated with receptive females. A decrease in pituitary Esr1 expression was observed in all DiPeP treated groups regardless of age. A reduction in hypothalamic Esr1 expression in rats exposed to 10 mg kg day‐1 DiPeP was also observed. No significant changes were found with respect to Ar, Esr2 and aromatase expression in the hypothalamus. These results suggest that DiPeP exposure during critical windows of development in rats may induce changes in behaviours related to mating and the sexual motivation of males.
What Is a Patent Worth? Evidence from the U.S. Patent “Lottery”
Authors: FARRE‐MENSA JOAN , HEGDE DEEPAK , LJUNGQVIST ALEXANDER
Published: November 2019

We provide evidence on the value of patents to startups by leveraging the quasi‐random assignment of applications to examiners with different propensities to grant patents. Using unique data on all first‐time applications filed at the U.S. Patent Office since 2001, we find that startups that win the patent “lottery” by drawing lenient examiners have, on average, 55% higher employment growth and 80% higher sales growth five years later. Patent winners also pursue more, and higher quality, follow‐on innovation. Winning a first patent boosts a startup’s subsequent growth and innovation by facilitating access to funding from venture capitalists, banks, and public investors.
Cultural self‐goals influence how much is remembered from early childhood events
Authors: Aydin Cagla , Conway Martin A.
Published: November 2019

Objective

Prior work examining the role of cultural self‐goals on the retrieval of early memories treated the presence of self‐goals; such as autonomy and relatedness, as a binary category which has led to overlooking within‐group nuances. Here, based on the idea that these goals co‐exist in varying degrees in individuals, we explore the relative contributions of self‐goals on age‐at‐event and the level of detail in positive and negative early memories.

Method

Participants (N = 119) recalled and dated two earliest positive and negative memories that they were highly confident were memories, and answered a set of questions about event‐specific details. They also completed a self‐construal scale.

Results

For positive memories, Autonomous‐Related Self scores predicted both the age‐at‐event and the amount of detail in early memories, while. no such relationship was observed for negative memories.

Conclusions

Together these findings indicate that cultural self‐goals operate on the accessibility of early memories not only at the level of the boundaries of childhood amnesia but also on how much is recalled from early experiences.
Born migrators: Historical biogeography of the cosmopolitan family Cannabaceae
Authors: Jin Jian‐Jun , Yang Mei‐Qing , Fritsch Peter W. , van Velzen Robin , Li De‐Zhu , Yi Ting‐Shuang
Published: November 2019

Dispersal scenarios have been favored over tectonic vicariance as an explanation for disjunct distributions in many plant taxa during the last two decades. However, this argument has been insufficiently addressed in cosmopolitan groups showing disjunct patterns in both the temperate and tropical regions. In this study, we used the Cannabaceae, an angiosperm family distributed in tropical and temperate regions of both the New World and the Old World, to explore the role of dispersal in shaping disjunct patterns and species diversification of cosmopolitan plants. We reconstructed the phylogenetic relationships of all 10 genera and 75 species of Cannabaceae (ca. 64.1% of recognized species) based on eight DNA regions. Based on fossil calibrations, we estimated the divergence times and net diversification rates. We further inferred the ancestral geographical ranges with several models and compared the fitness of different models. The Cannabaceae and most genera were strongly supported as monophyletic except for the Parasponia being embedded within the Trema. The Celtis were resolved into two strongly supported clades primarily corresponding to temperate and tropical regions. We inferred that the Cannabaceae originated at ca. 93 Ma, and that subsequent rampant and widespread dispersals shaped the intercontinentally disjunct distribution of the Cannabaceae. Dispersal coincides with adaptation to drier and colder climate in the Northern Hemisphere, or humid and warm climate in the tropical regions, followed by rapid species diversification. This study advances our understanding as to the formation of distribution patterns and species diversification of a plant family with tropical to temperate disjunct distributions.
Hepatic NK cells attenuate fibrosis progression of non‐alcoholic steatohepatitis in dependent of CXCL10‐mediated recruitment
Authors: Fan Yuting , Zhang Wendi , Wei Haiming , Sun Rui , Tian Zhigang , Chen Yongyan
Published: November 2019

Background & Aims

Non‐alcoholic steatohepatitis (NASH) is a major cause of chronic liver disease. The precise role of NK cells in the progression of NASH has yet to be elucidated.

Methods

Using methionine‐ and choline‐deficient diets (MCD)‐induced NASH model, the role of NK cells was identified in WT mice compared with conventional NK cell–deficient Nfil3−/− mice.

Results

After 8 weeks of MCD treatment, NASH was induced as shown by the significant macrovesicular steatosis, necro‐inflammation and fibrosis in the liver of WT B6 mice. In MCD‐treated WT B6 mice, the number of NK cells was markedly increased in the liver, but decreased in the spleen. Intrahepatic NK cells exhibited high levels of activation, as evidenced by the expression of CD107a and cytokine production of IFN‐γ, TGF‐β and IL‐10. Lower expression levels of Ki67 indicated a reduction in the proliferation of intrahepatic NK cells after MCD treatment. Increased expression of CXCL10 in the liver early after MCD treatment led to the increased recruitment of CXCR3+ NK cells into the liver. The MCD‐treated Nfil3−/− mice showed similar levels of TG and macrovesicular steatosis, thus more inflammatory infiltration and increased collagen deposition in the liver. Furthermore, the depletion of NK cells during MCD‐induced NASH caused a significant increase in the infiltration of monocyte‐derived macrophages (MoMFs) particularly Ly6Clo subsets towards M2.

Conclusions

Intrahepatic NK cells, recruited through CXCL10‐CXCR3 interaction, play a protective role against the fibrosis progression in NASH, which provide us with a better understanding of the immunopathogenesis of NASH.
Effects of sofosbuvir/ledipasvir therapy on chronic hepatitis C virus genotype 4, infected children of 3‐6 years of age
Authors: Kamal Enas M. , El‐Shabrawi Mortada , El‐Khayat Hisham , Yakoot Mostafa , Sameh Yehia , Fouad Yasser , Attia Dina
Published: November 2019

Background & Aims

Treatment of children aged 3‐6 genotype 4 is still limited by the interferon side effects. We aimed in this study to evaluate the effectiveness and safety of sofosbuvir/ledipasvir in children (3‐6 years) genotype 4 chronic HCV‐infected patients.

Methods

In total, 22 consecutive chronic HCV‐infected patients (mean age 4.8 ± 0.9years, 19 males) were included in this prospective study. All patients received sofosbuvir 200 mg/ledipasvir 45 mg in a single oral daily dose. Patients were randomly subdivided into two groups according the duration of treatment into 8 and 12 weeks. All the clinical and laboratory data were collected. All the side effects were recorded from the patients or their parents. Follow‐up were made at Week 4, 8 and 12 and 12 weeks after the end of treatment (SVR12).

Results

The overall SVR12 rate was 100%. At Week 4, 9/11 patients in the 12‐week group (81.8%; 95% CI: 52.3%‐94.7%) achieved virologic negativity, vs 10/11 (90.9%; 95% CI: 62.3%‐98.4%) in the 8‐week group. At Week 8, 10/11 (90.8%; 95% CI: 62.3%‐98.4%) in the 12‐week group vs 11/11 (100%; 95% CI: 74.1%‐100%) in the 8‐week group were virologically negative. The reported side effects were cough, abdominal pain, nausea, vomiting and diarrhoea especially early in the treatment. The main complaint was difficulty in swallowing the tablets in the youngest patient at the beginning of the course of treatment. All patients were compliant to treatment.

Conclusion

Sofosbuvir/ledipasvir combination is safe and tolerable in the chronic infected HCV genotype 4 infected children (3‐6 years). The 8‐week treatment duration is similarly effective as the 12‐week duration.
Cohabitation and roommate bias of symbiotic bacteria in insect hosts
Authors: Zytynska Sharon E.
Published: November 2019

Symbiotic interactions between insects and bacteria have long fascinated ecologists. Aphids have emerged as the model system on which to study the effect of endosymbiotic bacteria on their hosts. Aphid‐symbiont interactions are ecologically interesting as aphids host multiple secondary symbionts that can provide broad benefits, such as protection against heat stress or specialist natural enemies (parasitic wasps and entomopathogenic fungi). There are nine common aphid secondary symbionts and individual aphids host on average 1–2 symbionts. A cost‐benefit trade‐off for hosting symbionts is thought to explain why not all aphids host every possible symbiont in a population. Both positive and negative associations between various symbionts occur, and this could happen due to increased costs when cohosting certain combinations or as a consequence of competitive interactions between the symbionts within a host. In this issue of Molecular Ecology, Mathé‐Hubert, Kaech, Hertaeg, Jaenike, and Vorburger (2019) use data on the symbiont status of field‐collected aphids to inform a model on the evolution of symbiont co‐occurrence. They vary the effective female population size as well as the rate of horizontal and maternal transmission to infer the relative impact of symbiont‐symbiont interactions versus random drift. Additional data analysis revisits an association between two symbionts in a fruit fly species using a long‐term data set to highlight that such interactions are not limited to aphids.
Spatiotemporal landscape genetics: Investigating ecology and evolution through space and time
Authors: Fenderson Lindsey E. , Kovach Adrienne I. , Llamas Bastien
Published: November 2019

Genetic time‐series data from historical samples greatly facilitate inference of past population dynamics and species evolution. Yet, although climate and landscape change are often touted as post‐hoc explanations of biological change, our understanding of past climate and landscape change influences on evolutionary processes is severely hindered by the limited application of methods that directly relate environmental change to species dynamics through time. Increased integration of spatiotemporal environmental and genetic data will revolutionize the interpretation of environmental influences on past population processes and the quantification of recent anthropogenic impacts on species, and vastly improve prediction of species responses under future climate change scenarios, yielding widespread revelations across evolutionary biology, landscape ecology and conservation genetics. This review encourages greater use of spatiotemporal landscape genetic analyses that explicitly link landscape, climate and genetic data through time by providing an overview of analytical approaches for integrating historical genetic and environmental data in five key research areas: population genetic structure, demography, phylogeography, metapopulation connectivity and adaptation. We also include a tabular summary of key methodological information, suggest approaches for mitigating the particular difficulties in applying these techniques to ancient DNA and palaeoclimate data, and highlight areas for future methodological development.
Thermoelastic finite element model updating with application to monumental buildings
Authors: Ceravolo Rosario , De Lucia Giulia , Miraglia Gaetano , Pecorelli Marica L.
Published: November 2019

A reliable and predictive model of an existing structure entails the use of model updating techniques, which are usually performed on the basis of operational modal analysis campaigns. In this paper, a new model calibration strategy is proposed that adopts a multiphysics approach to exploit data collected by both static and dynamic monitoring systems. More specifically, mechanical and temperature data are assimilated into the model through a thermoelastic updating. The proposed scheme is validated with numerical simulations and applied on the Sanctuary of Vicoforte, a complex historical building that is subjected to both static and dynamic monitoring.
Hospitalisations for mycoses as an indicator of socio‐environmental vulnerability in the Brazilian Amazon‐Savanna transition region
Authors: da Silva Letícia Chagas , de Oliveira Lorena Vívien Neves , Silva Fabrício Brito , Santos Jessflan Rafael Nascimento , de Araújo Mayara Lucyanne Santos , Mendes Amanda Graziela Gonçalves , Miranda Rita de Cássia Mendonça de , Santos Daniel Assis , Holanda Rodrigo Assuncao , Santos Julliana Ribeiro Alves
Published: November 2019

Background

The infections caused by fungi represent a global concern and an important cause of hospital admissions in endemic areas. The influence of socio‐environmental factors in infectious diseases has been documented; however, this phenomenon remains unclear regarding mycoses.

Objectives

This study aimed to analyse the spatio‐temporal dynamics of hospitalisations for mycoses (HM) and the association with socio‐economic and climate data in the Amazon‐Savanna Transition Region in the state of Maranhão, Brazil.

Methods

In this study, Spearman's correlation was applied to determine the correlation between HM, socio‐economic and climatic data obtained from national databases in the period from 1998 to 2016. Hospitalisations for mycoses data were spatialised and analysed using the local Moran's index.

Results

Our data revealed a negative and significant correlation between HM and socio‐economic data regarding population, demographic density, human development index, health facilities and sanitary sewage. Significant correlations were observed between HM and precipitation, maximum temperature and minimum temperature. The main modulating climatic variable was the minimum temperature. The spatial autocorrelation analysis showed the dynamics of HM in municipalities belonging to the different regions of the state influenced by socio‐economic conditions. We observed the presence of municipalities with high incidence of HM surrounded by others with low HM cases and vice versa.

Conclusions

Our results indicate that hospitalisations for mycoses represent an important indicator of socio‐environmental vulnerability in the Amazon‐Savanna transition region in Brazil. We encourage the adoption of measures to mitigate social and environmental impact on these diseases, especially in municipalities with low socio‐economic status.
Diffuse gliomas in patients aged 55 years or over: A suggestion for IDH mutation testing
Authors: Barresi Valeria , Eccher Albino , Simbolo Michele , Cappellini Rekha , Ricciardi Giuseppe K. , Calabria Francesca , Cancedda Marco , Mazzarotto Renzo , Bonetti Bruno , Pinna Giampietro , Sala Francesco , Ghimenton Claudio , Scarpa Aldo
Published: November 2019

Diffuse gliomas are defined on the isocitrate dehydrogenase (IDH) gene (IDH) mutational mutational status. The most frequent IDH mutation is IDH1 R132H, which is detectable by immunohistochemistry; other IDH mutations are rare (10%). IDH mutant gliomas have better prognosis. Further, IDH wild‐type low‐grade (II/III) gliomas have clinical behaviors similar to those of glioblastoma (GBM) and it was suggested that they are submitted to similar post‐surgical treatment. The incidence of IDH mutant gliomas (2%) and that of GBMs with non‐canonical IDH mutations (< 1%) are very low in patients ≥ 55 years. For this reason, it was suggested that immunohistochemistry against IDH1 R132H is sufficient to classify GBM as IDH wild‐type in this age group. However, no indication was provided for IDH mutational testing in low‐grade diffuse gliomas. To address this issue, 273 diffuse gliomas were tested for IDH1 R132H immunohistochemistry. 2/4 diffuse astrocytomas (DAs), 4/9 anaplastic astrocytomas (AAs), 2/256 GBMs, and 4/4 oligodendrogliomas had positive staining. No other IDH mutations were found in immuno‐negative low‐grade cases by DNA sequencing. To validate our findings, we considered 311 diffuse gliomas in patients ≥ 55 years in The Cancer Genome Atlas database. Fifty‐five out of 311 gliomas had IDH R132H mutations (9/16 DAs; 8/48 AAs; 3/211 GBMs; 35/36 oligodendrogliomas), one DA, and one oligodendroglioma had other IDH mutations. IDH mutant gliomas had significantly higher frequency of O‐6‐methylguanine‐DNA methyltransferase promoter methylation (P = 0.0008) and longer overall survival (P < 0.0001). In conclusion, low‐grade gliomas are a minor part of gliomas (117/584) in patients ≥ 55 years, albeit they represent most IDH mutant gliomas in this age group (64/69 cases). IDH non‐canonical mutations can be found in immunonegative low‐grade gliomas (2/54). In view of its significance for prognosis and therapeutic management, our results suggest that IDH mutational status is assessed in all diffuse gliomas in patients ≥ 55 years by immunohistochemistry, followed by IDH sequencing in low‐grade immunonegative cases.
Plastic transport systems of rice for mineral elements in response to diverse soil environmental changes
Authors: Wang Peitong , Yamaji Naoki , Inoue Komaki , Mochida Keiich , Ma Jian Feng
Published: November 2019

Climate change will increase frequency of drought and flooding, which threaten global crop productivity and food security. Rice (Oryza sativa) is unique in that it is able to grow in both flooded and upland conditions, which have large differences in the concentrations and chemical forms of mineral elements available to plants.

To comprehensively understand the mechanisms of rice for coping with different water status, we performed ionomics and transcriptomics analysis of the roots, nodes and leaves of rice grown in flooded and upland conditions.

Focusing the analysis on genes encoding proteins involved in transport functions for mineral elements, it was found that, although rice plants maintained similar levels of each element in the shoots for optimal growth, different transporters for mineral elements were utilised for nitrogen, iron, copper and zinc to deal with different soil water conditions. For example, under flooded conditions, rice roots take up nitrogen using transporters for both ammonium (OsAMT1/2) and nitrate (OsNPF2.4, OsNRT1.1A and OsNRT2.3), whereas under upland conditions, nitrogen uptake is mediated by different nitrate transporters (OsNRT1.1B and OsNRT1.5A).

This study shows that rice possesses plastic transport systems for mineral elements in response to different water conditions (upland and flooding).
Correlation between prognostic nutritional index and occlusal status in gastric cancer
Authors: Abe Atsushi , Kurita Kenichi , Hayashi Hiroki , Ishihama Takanori , Ueda Akane
Published: November 2019

Objective

Systemic inflammatory responses in cancer patients are important factors for nutrition and prognosis. This study evaluates the association between tooth loss, occlusal status, and prognostic nutritional index (PNI).

Methods

A total of 93 patients with gastric cancer were included. These parameters were investigated the following: stage, body mass index (BMI), total lymphocyte count, C‐reactive protein (CRP), PNI, and albumin (ALB). Patients were divided into three groups by Eichner classification (group A had contact in four support zones; group B had in one to three zones or in anterior region; and group C had no contact). PNI assumed 40 or less undernutrition. Multiple regression analysis was performed (PNI, dependent variable; Eichner index, main independent variable), using four independent variables (sex, age, BMI, and CRP) as adjustment factors.

Results

The mean ± SD PNI in groups A, B, and C was 43.0 ± 4.7, 41.7 ± 5.2, and 36.7 ± 7.7, respectively. A significant positive correlation was found between the number of teeth, both ALB, and PNI. ALB and PNI differed significantly between groups A and C (ALB, p = .0003; PNI, p = .005).

Conclusion

We recommend a preoperative dental evaluation for assessing the nutritional status of patients with gastric cancer.
Lower vitamin D levels in the breast milk is associated with atopic dermatitis in early infancy
Authors: Wang Li‐Chieh , Chiang Bor‐Luen , Huang Yen‐Ming , Shen Pei‐Ting , Huang Hsun‐Yi , Lin Bi‐Fong
Published: November 2019

Background

Our previous study showed that the discontinuation of breastfeeding could improve atopic dermatitis (AD) symptoms in exclusively breastfed infants. As vitamins A and D are influential on the immune system, we aimed to analyze the association of vitamin A and D levels in breast milk (BM) with AD.

Methods

We enrolled two‐ to four‐month‐old exclusively breastfed infants. The objective SCORing Atopic Dermatitis (objSCORAD) was evaluated. The lipid layer of BM was extracted and analyzed by liquid chromatography for vitamin A and D levels. Medical charts were reviewed for the clinical course of AD.

Results

Forty‐five AD patients and 45 healthy controls were enrolled. The objSCORAD was 20.54 ± 1.73 (shown as mean ± SEM) in the AD group. The sex, parental atopy history, nutrient intake of mothers, and vitamin A levels in BM were not significantly different between the two groups. The 25‐(OH) D3 level in BM was significantly lower in the AD group than in the control group (1.72 ± 0.30 and 3.95 ± 0.64 ng/mL, respectively; P = .001). The 25‐(OH) D3 level negatively correlated with objSCORAD (P = .003). The only factor that is significantly associated with persistent AD is the objSCORAD in infancy (P = .003) after adjusting for age, sex, parental atopy history, and 25‐(OH) D3 level by multiple regression.

Conclusion

Vitamin D levels in BM for exclusively breastfed infants were negatively associated with objSCORAD. Lower vitamin D levels in BM might be a risk factor for infantile AD.
A polerovirus, Potato leafroll virus, alters plant–vector interactions using three viral proteins
Authors: Patton MacKenzie F. , Bak Aurélie , Sayre Jordan M. , Heck Michelle L. , Casteel Clare L.
Published: November 2019

Potato leafroll virus (PLRV), genus Polerovirus, family Luteoviridae, is a major pathogen of potato worldwide. PLRV is transmitted among host plants by aphids in a circulative–nonpropagative manner. Previous studies have demonstrated that PLRV infection increases aphid fecundity on, and attraction to, infected plants as compared to controls. However, the molecular mechanisms mediating this relationship are still poorly understood. In this study, we measured the impact of PLRV infection on plant–aphid interactions and plant chemistry in two hosts: Solanum tuberosum and Nicotiana benthamiana. Our study demonstrates that PLRV infection attenuates the induction of aphid‐induced jasmonic acid and ethylene in S. tuberosum and N. benthamiana. Using transient expression experiments, insect bioassays and chemical analysis, we show that expression of three PLRV proteins (P0, P1, and P7) mediate changes in plant–aphid interactions and inhibition of aphid‐induced jasmonic acid and ethylene in N. benthamiana. This study enhances our understanding of the plant‐vector‐pathogen interface by elucidating new mechanisms by which plant viruses transmitted in a circulative manner can manipulate plant hosts.
Water and vapor transport in algal‐fungal lichen: Modeling constrained by laboratory experiments, an application forFlavoparmelia caperata
Authors: Potkay Aaron , ten Veldhuis Marie‐Claire , Fan Ying , Mattos Caio R. C. , Ananyev Gennady , Dismukes G. Charles
Published: November 2019

Algal‐fungal symbionts share water, nutrients, and gases via an architecture unique to lichens. Because lichen activity is controlled by moisture dynamics, understanding water transport is prerequisite to understand their fundamental biology. We propose a model of water distributions within foliose lichens governed by laws of fluid motion. Our model differentiates between water stored in symbionts, on extracellular surfaces, and in distinct morphological layers. We parameterize our model with hydraulic properties inverted from laboratory measurements ofFlavoparmelia caperataand validate for wetting and drying. We ask: (1) Where is the bottleneck to water transport? (2) How do hydration and dehydration dynamics differ? and (3) What causes these differences? Resistance to vapor flow is concentrated at thallus surfaces and acts as the bottleneck for equilibrium, while internal resistances are small. The model captures hysteresis in hydration and desiccation, which are shown to be controlled by nonlinearities in hydraulic capacitance. Muting existing nonlinearities slowed drying and accelerated wetting, while exaggerating nonlinearities accelerated drying and slowed wetting. The hydraulic nonlinearity ofF. caperatais considerable, which may reflect its preference for humid and stable environments. The model establishes the physical foundation for future investigations of transport of water, gas, and sugar between symbionts.