bluuebunny/crossref_metadata_2025 huggingface dataset:
Space, time and captivity: quantifying the factors influencing the fecal microbiome of an alpine ungulate
Authors: Haworth Sarah E , White Kevin S , Côté Steeve D , Shafer Aaron B A
Published: June 2019

The community of microorganisms in the gut is affected by host species, diet and environment and is linked to normal functioning of the host organism. Although the microbiome fluctuates in response to host demands and environmental changes, there are core groups of microorganisms that remain relatively constant throughout the hosts lifetime. Ruminants are mammals that rely on highly specialized digestive and metabolic modifications, including microbiome adaptations, to persist in extreme environments. Here, we assayed the fecal microbiome of four mountain goat (Oreamnos americanus) populations in western North America. We quantified fecal microbiome diversity and composition among groups in the wild and captivity, across populations and in a single group over time. There were no differences in community evenness or diversity across groups, although we observed a decreasing diversity trend across summer months. Pairwise sample estimates grouped the captive population distinctly from the wild populations, and moderately grouped the southern wild group distinctly from the two northern wild populations. We identified 33 genera modified by captivity, with major differences in key groups associated with cellulose degradation that likely reflect differences in diet. Our findings are consistent with other ruminant studies and provide baseline microbiome data in this enigmatic species, offering valuable insights into the health of wild alpine ungulates.
The Genomic Origins of Small Mitochondrial RNAs: Are They Transcribed by the Mitochondrial DNA or by Mitochondrial Pseudogenes within the Nucleus (NUMTs)?
Authors: Pozzi Andrea , Dowling Damian K
Published: June 2019

Several studies have linked mitochondrial genetic variation to phenotypic modifications; albeit the identity of the mitochondrial polymorphisms involved remains elusive. The search for these polymorphisms led to the discovery of small noncoding RNAs, which appear to be transcribed by the mitochondrial DNA (“small mitochondrial RNAs”). This contention is, however, controversial because the nuclear genome of most animals harbors mitochondrial pseudogenes (NUMTs) of identical sequence to regions of mtDNA, which could alternatively represent the source of these RNAs. To discern the likely contributions of the mitochondrial and nuclear genome to transcribing these small mitochondrial RNAs, we leverage data from six vertebrate species exhibiting markedly different levels of NUMT sequence. We explore whether abundances of small mitochondrial RNAs are associated with levels of NUMT sequence across species, or differences in tissue-specific mtDNA content within species. Evidence for the former would support the hypothesis these RNAs are primarily transcribed by NUMT sequence, whereas evidence for the latter would provide strong evidence for the counter hypothesis that these RNAs are transcribed directly by the mtDNA. No association exists between the abundance of small mitochondrial RNAs and NUMT levels across species. Moreover, a sizable proportion of transcripts map exclusively to the mtDNA sequence, even in species with highest NUMT levels. Conversely, tissue-specific abundances of small mitochondrial RNAs are strongly associated with the mtDNA content. These results support the hypothesis that small mitochondrial RNAs are primarily transcribed by the mitochondrial genome and that this capacity is conserved across Amniota and, most likely, across most metazoan lineages.
When Will My Patient Fall? Sensor-Based In-Home Walking Speed Identifies Future Falls in Older Adults
Authors: Piau Antoine , Mattek Nora , Crissey Rachel , Beattie Zachary , Dodge Hiroko , Kaye Jeffrey
Published: June 2019

Background

Although there are known clinical measures that may be associated with risk of future falls in older adults, we are still unable to predict when the fall will happen. Our objective was to determine whether unobtrusive in-home assessment of walking speed can detect a future fall.

Method

In both ISAAC and ORCATECH Living Laboratory studies, a sensor-based monitoring system has been deployed in the homes of older adults. Longitudinal mixed-effects regression models were used to explore trajectories of sensor-based walking speed metrics in those destined to fall versus controls over time. Falls were captured during a 3-year period.

Results

We observed no major differences between those destined to fall (n = 55) and controls (n = 70) at baseline in clinical functional tests. There was a longitudinal decline in median daily walking speed over the 3 months before a fall in those destined to fall when compared with controls, p < .01 (ie, mean walking speed declined 0.1 cm s−1 per week). We also found prefall differences in sensor-based walking speed metrics in individuals who experienced a fall: walking speed variability was lower the month and the week just before the fall compared with 3 months before the fall, both p < .01.

Conclusions

While basic clinical tests were not able to differentiate who will prospectively fall, we found that significant variations in walking speed metrics before a fall were measurable. These results provide evidence of a potential sensor-based risk biomarker of prospective falls in community living older adults.
Functionalization of the TMEM175 p.M393T variant as a risk factor for Parkinson disease
Authors: Jinn Sarah , Blauwendraat Cornelis , Toolan Dawn , Gretzula Cheryl A , Drolet Robert E , Smith Sean , Nalls Mike A , Marcus Jacob , Singleton Andrew B , Stone David J
Published: June 2019

Multiple genome-wide association studies (GWAS) in Parkinson disease (PD) have identified a signal at chromosome 4p16.3; however, the causal variant has not been established for this locus. Deep investigation of the region resulted in one identified variant, the rs34311866 missense SNP (p.M393T) in TMEM175, which is 20 orders of magnitude more significant than any other SNP in the region. Because TMEM175 is a lysosomal gene that has been shown to influence α-synuclein phosphorylation and autophagy, the p.M393T variant is an attractive candidate, and we have examined its effect on TMEM175 protein and PD-related biology. After knocking down each of the genes located under the GWAS peak via multiple shRNAs, only TMEM175 was found to consistently influence accumulation of phosphorylated α-synuclein (p-α-syn). Examination of the p.M393T variant showed effects on TMEM175 function that were intermediate between the wild-type (WT) and knockout phenotypes, with reduced regulation of lysosomal pH in response to starvation and minor changes in clearance of autophagy substrates, reduced lysosomal localization, and increased accumulation of p-α-syn. Finally, overexpression of WT TMEM175 protein reduced p-α-syn, while overexpression of the p.M393T variant resulted in no change in α-synuclein phosphorylation. These results suggest that the main signal in the chromosome 4p16.3 PD risk locus is driven by the TMEM175 p.M393T variant. Modulation of TMEM175 may impact α-synuclein biology and therefore may be a rational therapeutic strategy for PD.
Developmental Stage Affects the Consequences of Transient Salinity Exposure in Toad Tadpoles
Authors: Welch Allison M , Bralley Jordan P , Reining Ashlyn Q , Infante Allison M
Published: June 2019

Development can play a critical role in how organisms respond to changes in the environment. Tolerance to environmental challenges can vary during ontogeny, with individual- and population-level impacts that are associated with the timing of exposure relative to the timing of vulnerability. In addition, the life history consequences of different stressors can vary with the timing of exposure to stress. Salinization of freshwater ecosystems is an emerging environmental concern, and habitat salinity can change rapidly due, for example, to storm surge, runoff of road deicing salts, and rainfall. Elevated salinity can increase the demands of osmoregulation in freshwater organisms, and amphibians are particularly at risk due to their permeable skin and, in many species, semi-aquatic life cycle. In three experiments, we manipulated timing and duration of exposure to elevated salinity during larval development of southern toad (Anaxyrus terrestris) tadpoles and examined effects on survival, larval growth, and timing of and size at metamorphosis. Survival was reduced only for tadpoles exposed to elevated salinity early in development, suggesting an increase in tolerance as development proceeds; however, we found no evidence of acclimation to elevated salinity. Two forms of developmental plasticity may help to ameliorate costs of transient salinity exposure. With early salinity exposure, the return to freshwater was accompanied by a period of rapid compensatory growth, and metamorphosis ultimately occurred at a similar age and size as freshwater controls. By contrast, salinity exposure later in development led to earlier metamorphosis at reduced size, indicating an acceleration of metamorphosis as a mechanism to escape salinity stress. Thus, the consequences of transient salinity exposure were complex and were mediated by developmental state. Salinity stress experienced early in development resulted in acute costs but little long-lasting effect on survivors, while exposures later in development resulted in sublethal effects that could influence success in subsequent life stages. Overall, our results suggest that elevated salinity is more likely to affect southern toad larvae when experienced early during larval development, but even brief sublethal exposure later in development can alter life history in ways that may impact fitness.
A Geometric Model for the Module Category of a Gentle Algebra
Authors: Baur Karin , Coelho Simões Raquel
Published: June 2019

In this article, gentle algebras are realised as tiling algebras, which are associated to partial triangulations of unpunctured surfaces with marked points on the boundary. This notion of tiling algebras generalise the notion of Jacobian algebras of triangulations of surfaces and the notion of surface algebras. We use this description to give a geometric model of the module category of any gentle algebra.
The Traveller’s Risk Perception (TRiP) questionnaire: pre-travel assessment and post-travel changes
Authors: Tardivo S , Zenere A , Moretti F , Marchiori F , Berti D , Migliorini M , Tomasi A , Ferrari S , Tognon F , Napoletano G , Rossanese A
Published: June 2019

Background

Travellers’ risk perception is a key component of travel risk assessment because it influences the adequate implementation of safety precautions. The aims of this study are to validate a tool to analyse travellers’ risk perception to identify which factors can influence it and how it changes upon return.

Methods

The Traveller’s Risk Perception (TRiP) questionnaire was developed and administered to outpatients before and after travel in three travel clinics. A principal component analysis (PCA) was performed to validate the questionnaire and multivariate regression analysis was used to evaluate the effect of travellers’ characteristics on the risk scores.

Results

A total of 1020 travellers completed the questionnaire. PCA identified two latent factors: ‘generic-disseminated risks’ and ‘specific-circumstantial risks’. Cronbach’s α was acceptable (0.76 and 0.70, respectively). The ‘generic-disseminated risks’ dimension scored higher than the ‘specific-circumstantial risks’ (p<0.001). The items with the highest scores were insect bites, gastrointestinal disorders and malaria. The mean scores were significantly lower after the travel for all items but one.

Conclusions

The TRiP questionnaire is a valid and reliable tool for rating travellers’ perceptions. Staff in travel clinics should be trained to systematically assess travellers’ risk perception in order to tailor the consultation according to specific information needs.
Unambivalent alignment: Japan’s China strategy, the US alliance, and the ‘hedging’ fallacy
Authors: Liff Adam P
Published: June 2019

This article examines whether the Asia-Pacific region’s geopolitical vicissitudes are causing Japan to ‘hedge’ against deepening uncertainty and risk through major strategic realignments or diversification of security and economic ties, as the original hedging literature would expect. It examines trends since 2009 in three domains fundamental to identifying whether shifts are underway in Japan’s strategic orientation vis-à-vis China: security policy (primary), trade/investment, and public opinion. Despite deepening uncertainty (and volatility), especially in ‘the Trump era’, this study finds negligible evidence of hedging behavior: e.g., realigning toward Beijing or adopting a ‘middle position’, much less developing any meaningful security ties with China. Rather, contemporary trends point in the opposite direction: Japan’s China strategy primarily centers on strengthening indigenous deterrence capabilities, bolstering the US–Japan alliance, and diversifying regional security ties beyond Beijing. Even the latter, somewhat paradoxically, aims to deepen ties with Washington and to keep it actively engaged in regional affairs.
Pre-treatment and acquired HIV drug resistance in Dar es Salaam, Tanzania in the era of tenofovir and routine viral load monitoring
Authors: Barabona Godfrey , Mahiti Macdonald , Masoud Salim , Mbelele Peter , Mgunya Amina Shaban , Minja Lilian , Sunguya Bruno , Shigemi Urara , Matsuda Masakazu , Hachiya Atsuko , Iwatani Yasumasa , Lyamuya Eligius , Ueno Takamasa
Published: June 2019

Objectives

We investigated the prevalence and patterns of pre-treatment and acquired HIV drug resistance mutations (DRMs) in Tanzania as a ‘treat all’ strategy, virological monitoring and the progressive increase in usage of tenofovir are being implemented in HIV treatment programmes.

Methods

Viral RNA was isolated from plasma of 60 ART-naive and 166 treated-but-viraemic (>400 copies/mL) HIV-1-infected adults attending a care and treatment clinic at Muhimbili National Hospital, Dar es Salaam, Tanzania, between June and October 2017. Viral genes encoding protease and reverse transcriptase were amplified by PCR and directly sequenced.

Results

Viral genotyping of successfully amplified samples revealed pre-treatment DRMs in 14/47 (29.8%) ART-naive subjects. Of these, 7/47 (14.9%) harboured mutations that confer high-level resistance to at least one drug of the default first-line regimen. In treated-but-viraemic subjects, DRMs were found in 100/111 (90%), where DRMs against NNRTI, NRTI and PI were observed in 95/100 (95%), 92/100 (92%) and 13/100 (13%), respectively. Tenofovir-resistance mutations K65R and K70G/E or ≥3 thymidine analogue resistance mutations including M41L and L210W were found in 18/36 (50%) subjects on a tenofovir-containing regimen at failure. Four patients harboured multiple DRMs, which can confer resistance to all available ART regimens in Tanzania.

Conclusions

Taken together, pre-treatment and acquired DRMs were highly prevalent, which represents a major risk for the efficacy of ART programmes in Tanzania. Availability of a newer generation of antiretroviral drugs with a higher genetic barrier to resistance and robust treatment monitoring is warranted for effective and sustainable HIV treatment.
Activity of cefepime/zidebactam (WCK 5222) against Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii endemic to New York City medical centres
Authors: Khan Zeb , Iregui Alejandro , Landman David , Quale John
Published: June 2019

Background

The combination of cefepime and zidebactam (WCK5222), a novel β-lactam enhancer, has demonstrated activity against a wide variety of Gram-negative pathogens and is currently under clinical evaluation.

Objectives

To examine the activity of cefepime/zidebactam against: (i) a contemporary collection of Gram-negative isolates from New York City; (ii) a collection of carbapenem-resistant clinical isolates; and (iii) a collection of isolates with characterized resistance mechanisms.

Methods

Susceptibility tests were performed using broth microdilution for cefepime, zidebactam and cefepime/zidebactam (1:1).

Results

More than 99% of a contemporary collection of Escherichia coli, Klebsiella pneumoniae and Enterobacter spp. had cefepime/zidebactam MICs ≤2 mg/L, the susceptibility breakpoint for cefepime. For K. pneumoniae, the acquisition of blaKPC resulted in increased MICs, although MICs remained ≤2 mg/L for 90% of KPC-possessing isolates. Overall for Pseudomonas aeruginosa, 98% of isolates had MICs ≤8 mg/L and MICs were affected by increased expression of ampC. For carbapenem-resistant P. aeruginosa, 78% of isolates had cefepime/zidebactam MICs ≤8 mg/L. The activity of cefepime/zidebactam against Acinetobacter baumannii was lower, with 85% of all isolates and 34% of carbapenem-resistant isolates with MICs ≤8 mg/L (cefepime interpretative criteria).

Conclusions

Cefepime/zidebactam demonstrated excellent activity against Enterobacteriaceae and P. aeruginosa, although activity was reduced in carbapenem-non-susceptible isolates. The activity against A. baumannii was reduced and studies examining the therapeutic efficacy in strains with high cefepime/zidebactam MICs are warranted.
Tolerance of Immature Black Soldier Flies (Diptera: Stratiomyidae) to Cold Temperatures Above and Below Freezing Point
Authors: Villazana Joshua , Alyokhin Andrei
Published: June 2019

Black soldier flies, Hermetia illucens (L.), consume decaying organic materials at the larval stage and can be used for recycling a variety of biogenic wastes into value-added products. Black soldier flies are normally found in subtropical and warm temperate regions. Cold temperatures may prevent their establishment in colder areas, thus alleviating a concern of their becoming an invasive species. Potentially, cold temperatures can also be used to manipulate the rate of black soldier fly development, which may be needed for timing certain life stages for mass-production needs. In the present study, immature black soldier flies were highly susceptible to freezing. Their survivorship decreased as time spent at −12°C increased from 10 to 60 min. Only ca. 2% of eggs, <1% of larvae, and no pupae survived after 60 min of exposure. Chilling at 4°C also had a significant negative effect that became more pronounced as duration of exposure increased from 24 to 72 h. Only ca. 2% of eggs and second instars and ca. 23% of pupae survived after 72 h. In the same time, >80% of third instars and >90% of fifth instars were still alive following 72 h of exposure. Chilling fifth instars resulted in smaller adults but freezing them for 48 h resulted in bigger adults. Based on these results, black soldier fly is unlikely to establish in areas with long periods of subfreezing winter temperatures. Low temperatures may be used to manipulate development of the late instars, but at a cost of higher mortality.
Virulence of Some Entomopathogenic Fungi Isolates of Beauveria bassiana (Hypocreales: Cordycipitaceae) and Metarhizium anisopliae (Hypocreales: Clavicipitaceae) to Aulacaspis tubercularis (Hemiptera: Diaspididae)and Icerya seychellarum (Hemiptera: Monophlebidae) on Mango Crop
Authors: Sayed Atef M M , Dunlap Christopher A
Published: June 2019

Six fungal isolates of Beauveria bassiana (Balsamo) Vuillemin and one isolate of Metarhizium anisopliae (Metschnikoff) Sorokin were isolated and evaluated for their pathogenicity to Icerya seychellarum (Westwood) and Aulacaspis tubercularis Newstead. There is a positive correlation between the concentration of the fungal blastospore concentrations and the percentage of mortality. Bio-efficacy increased significantly after inoculation with increasing concentration of blastospores and elapsed time up to 12 d after inoculation. The mortality of nymphs exposed to fungal isolates at various concentrations varied between 2.5 and 88.8%. Probit analysis of data at 95% confidence limits of LC50 and LT50s showed significant differences in the susceptibility of nymphs of I. seychellarum and A. tubercularis to the tested fungal isolates. The fungal isolates of Egy-6 and Egy-9 were the most effective against I. seychellarum and A. tubercularis, respectively. They had the lowest LC50 (4.20 × 105 and 5.71 × 103 blastospore ml−1) and LT50 (ranged from 4.61 to 9.79 and 4.84 to 8.71 d), respectively. The current study showed that all the fungal isolates yielded moderate mortality rates of nymphs and adult female populations of both the tested insect pests. To our knowledge, this is the first report of bio-efficacy of Beauveria and Metarhizium isolates against members of the Diaspidadae and Monophlebidae family insects. These results establish that the use of these native entomopathogenic fungi isolates of B. bassiana (Egy-3, Egy-4, Egy-6, Egy-7, Egy-9, and Egy-10) and M. anisopliae (Egy-5) could be considered for further development as microbial control agents of the mealybug and scale insects as a potential biological agent for use in an IPM program.
High Court of Bombay rules against the applicability of compulsory broadcast licensing to Internet Services
Authors: Joshi Divij
Published: June 2019

Bombay High Court, Tips Industries Ltd v Wynk Music Ltd and Anr., N.M(L) 197/2018 in C.S. I.P(L) 114/2018, 23 April 2019
CJEU excludes retroactive application of reformed language of Article 7(1)(e)(iii) of the EU Trade Mark Regulation and does (not) clarify what ‘another characteristic’ means
Authors: Rosati Eleonora
Published: June 2019

CJEU, Textilis Ltd and Ozgur Keskin v Svenskt Tenn Aktiebolag, C-21/18, EU:C:2019:199, 14 March 2019
Trade mark infringement and passing off can be caused by resale of disassembled branded products
Authors: Naia Alessandra
Published: June 2019

Nomination di Antonio E Paolo Gensini SNC and Nomination SRL v Sebastian and Victoria Brealey (trading as JSC Jewellery) [2019] EWHC 599 (IPEC), 13 March 2019
Multiple lines of evidence reveal a composite of species in the plateau mouse, Peromyscus melanophrys (Rodentia, Cricetidae)
Authors: López-González Celia , García-Mendoza Diego F , López-Vidal Juan Carlos , Elizalde-Arellano Cynthia
Published: June 2019

Peromyscus melanophrys is a Mexican endemic distributed in seasonal tropical forests and semiarid lands. Molecular work based on mitochondrial and nuclear markers proposed the existence of four haplogroups within P. melanophrys. Peromyscus mekisturus (Puebla deer mouse) was included in one of these haplogroups. We tested the consistency between this hypothesis and external morphology, quantitative and qualitative cranial attributes, and ecological data for a sample of 1,155 specimens spanning the species distribution. We found ecological and morphological consistency with the phylogenetic pattern for P. melanophrys but not for P. mekisturus. We reassessed the taxonomic and nomenclatural status of the populations and type specimens formerly included in P. melanophrys. We concluded that these populations constitute four species: P. zamorae (Zamora deer mouse), distributed in the Mexican Plateau at elevations > 1,500 m; P. micropus (small-footed deer mouse), from lowland tropical deciduous forests of the San Pedro-Mezquital and Lerma-Santiago basins in western Mexico; P. melanophrys (black-eyed deer mouse) from lowland tropical deciduous forests of southeastern Mexico as far as eastern Oaxaca; and P. leucurus (Tehuantepec deer mouse), partially sympatric with P. melanophrys but reaching as far as Chiapas. Data on P. mekisturus were contradictory, and thus was kept as a valid species.

Peromyscus melanophrys es un roedor endémico de México, distribuido en bosques tropicales caducifolios y regiones semiáridas. Datos moleculares usando marcadores mitocondriales y nucleares indicaron la existencia de cuatro haplogrupos dentro de P. melanophrys. Peromyscus mekisturus (ratón de Puebla) se incluyó dentro de uno de éstos. Con base en una muestra de 1,155 ejemplares de toda la distribución de la especie, se examinó si esta hipótesis era consistente con datos de morfología externa y craneal, morfometría e información ecológica. Se encontró coincidencia para P. melanophrys pero no para P. mekisturus. Estos resultados hicieron necesaria la reevaluación del estado taxonómico y nomenclatural de las poblaciones incluidas en P. melanophrys. Se concluye que existen cuatro especies dentro de lo que se conocía como P. melanophrys: P. zamorae (ratón de Zamora) distribuido en el Altiplano Mexicano a elevaciones ≥ 1,500 m; P. micropus (ratón de pata pequeña) distribuido en los bosques tropicales caducifolios de las cuencas San Pedro-Mezquital y Lerma-Santiago en el occidente de México; P. melanophrys (ratón de ojo oscuro) de los bosques y matorrales tropicales caducifolios del sureste de México, al menos hasta el este de Oaxaca, y P. leucurus (ratón de Tehuantepec) parcialmente simpátrico con P. melanophrys pero llegando hasta el estado de Chiapas. La información disponible no permitió asignar a P. mekisturus a ninguno de los grupos y por tanto se sigue considerando como especie válida.
Rheb promotes brown fat thermogenesis by Notch-dependent activation of the PKA signaling pathway
Authors: Meng Wen , Liang Xiuci , Xiao Ting , Wang Jing , Wen Jie , Luo Hairong , Teng Jianhui , Fei Yanquan , Zhang Qinghai , Liu Bilian , Hu Fang , Bai Juli , Liu Meilian , Zhou Zhiguang , Liu Feng
Published: June 2019

Increasing brown and beige fat thermogenesis have an anti-obesity effect and thus great metabolic benefits. However, the molecular mechanisms regulating brown and beige fat thermogenesis remain to be further elucidated. We recently found that fat-specific knockout of Rheb promoted beige fat thermogenesis. In the current study, we show that Rheb has distinct effects on thermogenic gene expression in brown and beige fat. Fat-specific knockout of Rheb decreased protein kinase A (PKA) activity and thermogenic gene expression in brown adipose tissue of high-fat diet-fed mice. On the other hand, overexpression of Rheb activated PKA and increased uncoupling protein 1 expression in brown adipocytes. Mechanistically, Rheb overexpression in brown adipocytes increased Notch expression, leading to disassociation of the regulatory subunit from the catalytic subunit of PKA and subsequent PKA activation. Our study demonstrates that Rheb, by selectively modulating thermogenic gene expression in brown and beige adipose tissues, plays an important role in regulating energy homeostasis.
A Review of Perspectives on the Use of Randomization in Phase II Oncology Trials
Authors: Grayling Michael J , Dimairo Munyaradzi , Mander Adrian P , Jaki Thomas F
Published: June 2019

Historically, phase II oncology trials assessed a treatment’s efficacy by examining its tumor response rate in a single-arm trial. Then, approximately 25 years ago, certain statistical and pharmacological considerations ignited a debate around whether randomized designs should be used instead. Here, based on an extensive literature review, we review the arguments on either side of this debate. In particular, we describe the numerous factors that relate to the reliance of single-arm trials on historical control data and detail the trial scenarios in which there was general agreement on preferential utilization of single-arm or randomized design frameworks, such as the use of single-arm designs when investigating treatments for rare cancers. We then summarize the latest figures on phase II oncology trial design, contrasting current design choices against historical recommendations on best practice. Ultimately, we find several ways in which the design of recently completed phase II trials does not appear to align with said recommendations. For example, despite advice to the contrary, only 66.2% of the assessed trials that employed progression-free survival as a primary or coprimary outcome used a randomized comparative design. In addition, we identify that just 28.2% of the considered randomized comparative trials came to a positive conclusion as opposed to 72.7% of the single-arm trials. We conclude by describing a selection of important issues influencing contemporary design, framing this discourse in light of current trends in phase II, such as the increased use of biomarkers and recent interest in novel adaptive designs.
Incidence of health problems in travelers to Southeast Asia: a prospective cohort study
Authors: Pisutsan Phimphan , Soonthornworasiri Ngamphol , Matsee Wasin , Phumratanaprapin Weerapong , Punrin Suda , Leowattana Wattana , Mansanguan Chayasin , Leshem Eyal , Piyaphanee Watcharapong
Published: June 2019

Background

There are few studies of the incidence of health problems among travelers to Southeast Asia. The current study sought to determine the incidence of self-reported health problems among travelers visiting the region.

Methods

A prospective questionnaire-based study was conducted among travelers from high-income countries who visited Southeast Asia. Participants were enrolled at time of their pre-travel visit at Mahidol University, Bangkok, Thailand. Travelers were prospectively followed by self-administered questionnaires 2 weeks after arrival, upon return to their home country and 2 weeks after return.

Results

During January 2018–February 2019, 359 travelers were enrolled in Bangkok, Thailand, and the first questionnaire was administered. Follow-up questionnaires were returned by 191, 96 and 64 participants 2 weeks later, at the end of the trip and 2 weeks after return, respectively. A total of 6094 travel days were included in the final analysis. The incidence of acute diarrhea per month per 1000 travelers was 217 [95% confidence interval (CI), 189–248] episodes; skin problems, 197 (95% CI, 170–227); respiratory symptoms, 133 (95% CI, 111–158); fever, 49 (95% CI, 36–65); and potential rabies exposure, 34 (95% CI, 24–48). The incidence of acute diarrhea episodes per month per 1000 travelers was significantly higher during the first 2 weeks of travel compared with subsequent weeks of travel: 325 (95% CI, 291–362) vs 132 (95% CI, 110–1157) (P < 0.05). The incidence of outpatient visits and hospitalizations per month per 1000 travelers was 49 (95% CI, 36–65) and 5 (95% CI, 2–10), respectively.

Conclusions

In this prospective cohort study we observed substantial burden of acute diarrhea and skin and respiratory symptoms among travelers to Southeast Asia. The higher incidence of diarrhea in the first 2 weeks of travel should be further investigated.
The rise in travel-associated measles infections—GeoSentinel, 2015–2019
Authors: Angelo Kristina M , Libman Michael , Gautret Philippe , Barnett Elizabeth , Grobusch Martin P , Hagmann Stefan H F , Gobbi Federico , Schwartz Eli , van Genderen Perry J J , Asgeirsson Hilmir , Hamer Davidson H ,   GeoSentinel Surveillance Network, Larsen Carsten Schade , Wejse Christian , Goorhuis Bram , Piyaphanee Watcharapong , Silachamroon Udomsak , Kuhn Susan , Perez Cecilia Perret , Weitzel Thomas , Mendelson Marc , Parker Salim , Piper-Jenks Nancy , Kerr Christine , Lachish Tamar , Pandey Prativa , Murphy Holly , Menendez Marta , Esteban Elena , Leder Karin , Torresi Joe , Mavunda Kunjana , Rothe Camilla , von Sonnenburg Frank , Javelle Emilie , Ward Brian , Jensenius Mogens , Caumes Eric , Lim Poh Lian , Glans Hedvig , Yoshimura Yukihiro , Tachikawa Natsuo
Published: June 2019

The global threat of measles in recent years affects international travelers, and is acquired in both endemic and outbreak settings. The number of measles cases reported to GeoSentinel has risen each year since 2015 and demonstrates a high median age, short travel duration, and low measles vaccination coverage.
Transportable nuclear power plants: an enigma of international nuclear liability law
Authors: Handrlica Jakub
Published: June 2019

On 28th April 2018, the world’s only transportable nuclear power plant (TNPP) ‘Academic Lomonosov’ has left St Petersburg and headed to its base in Chukotka. These developments again triggered the attention of the legal community to various legal aspects of the TNPPs. In this context, different opinions concerning the applicability of the existing nuclear liability conventions vis-á-vis TNPPs were expressed. According to one line of interpretation, the existing nuclear liability conventions do apply also to a TNPP anchored at a coast to deliver electricity to the grid. This article questions such opinion. It argues, that a TNPP cannot be considered a ‘nuclear installation’ in the sense of the existing nuclear liability conventions, when anchored at the coast. In this respect, the article identifies bilateral agreements between the licensing State and the host State to only viable option to address the liability issues arising from a TNPP entering foreign waters to deliver electricity to the domestic grid there.
Evidence for the absorption of crystalline silicates at 11.1 $\mu$m in the spectra of the nucleus of the Circinus galaxy
Authors: Do Duy Tho , Lawson Warrick A
Published: June 2019

Several mid-infrared spectra of the Circinus galaxy nucleus taken with T-ReCS on Gemini South and MIDI on VLTI have consistently shown an inflection centred around 11 $\mu$m. We ascribe this feature to the absorption of crystalline silicate, based on their similarity in profile shape and improvement in fitting quality using a partially crystalline silicate model, compared to entirely amorphous models. Spectral fits reveal a fraction of 0.6–2.0 per cent of crystalline forsterite in the nucleus of the Circinus galaxy, which is similar to the values obtained for the interstellar medium (ISM) of the Milky Way. This is probably the first detection of crystalline silicate absorption in the nucleus of this Seyfert 2 galaxy. In addition, the presence of large grain-size amorphous silicates, together with the similarity in profile shape of the optical depth of Circinus with those of young stellar objects in the Milky Way, implies that most of the contribution to the spectra of Circinus comes from dust in the star formation regions near the centre of the nucleus or along the line of sight to the Earth, rather than in the ISM of Circinus. We also compare our optical depths of Circinus with those in previous studies.
Dural Ectasia in Neurofibromatosis 1: Case Series, Management, and Review
Authors: Polster Sean P , Dougherty Mark C , Zeineddine Hussein A , Lyne Seán B , Smith Heather L , MacKenzie Cynthia , Pytel Peter , Yang Carina W , Tonsgard James H , Warnke Peter C , Frim David M
Published: June 2019

BACKGROUND

The natural history and management of dural ectasia in Neurofibromatosis 1 (NF1) is still largely unknown. Dural ectasias are one of the common clinical manifestations of NF1; however, the treatment options for dural ectasias remain unstudied.

OBJECTIVE

To investigate the natural history, diagnosis, management, and outcome of the largest case series of patients with NF1-associated dural ectasia to date.

METHODS

Records from our NF1 clinic were reviewed to identify NF1 patients with computed tomography or magnetic resonance imaging evidence of dural ectasia(s) to determine their clinical course. Demographics, symptoms, radiographic and histopathologic findings, treatment, and clinical course were assessed.

RESULTS

Thirty-four of 37 patients were managed without surgery. Of the 18 initially asymptomatic patients, 5 (27.8%) progressed to symptoms attributable to a dural ectasia (onset of 2.7% per patient-year). Three patients required surgical intervention because of extraspinal mass effect. All 3 initially improved but had symptom recurrence within 2 yr. Reoperation involved shunt placement for cerebrospinal fluid (CSF) diversion. On imaging review, 26 (76.5%) of the nonsurgical patients harbored an associated nearby plexiform neurofibroma. Pathology of one surgical case revealed dural infiltration by diffuse neurofibroma.

CONCLUSION

Using the largest NF1-associated dural ectasia group to date, we report the first symptom-onset rate for nonsurgical patients. In the few cases requiring surgery for decompression, primary resection, and patching of ectasias failed, subsequently requiring CSF shunting. We demonstrate imaging evidence of nearby plexiform neurofibroma in a majority of cases, which, when combined with histopathology, provides a novel explanation for the formation of dural ectasias.
Mechanical Thrombectomy in Acute Ischemic Stroke: A Meta-Analysis of Stent Retrievers vs Direct Aspiration vs a Combined Approach
Authors: Texakalidis Pavlos , Giannopoulos Stefanos , Karasavvidis Theofilos , Rangel-Castilla Leonardo , Rivet Dennis J , Reavey-Cantwell John
Published: June 2019

BACKGROUND

Recent randomized control trials (RCTs) established that mechanical thrombectomy is superior to medical therapy for patients with stroke due to a large vessel occlusion.

OBJECTIVE

To compare the safety and efficacy profile of the different mechanical thrombectomy strategies.

METHODS

A random-effects meta-analysis was performed and the I2 statistic was used to assess heterogeneity according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines.

RESULTS

Nineteen studies with a total of 2449 patients were included. No differences were identified between the stent retrieval and direct aspiration groups in terms of modified Thrombolysis in Cerebral Infarction (mTICI) 2b/3 and mTICI 3 recanalization rates, and favorable outcomes (modified Rankin Scale [mRS] ≤ 2). Adverse event rates, including 90-d mortality, symptomatic intracerebral hemorrhage (sICH), and subarachnoid hemorrhage (SAH), were similar between the stent retrieval and direct aspiration groups. The use of the stent retrieval was associated with a higher risk of vasospasm (odds ratio [OR]: 2.98; 95% confidence interval [CI]: 1.10-8.09; I2: 0%) compared to direct aspiration. When compared with the direct aspiration group, the subgroup of patients who underwent thrombectomy with the combined approach as a first-line strategy had a higher likelihood of successful mTICI 2b/3 (OR: 1.47; 95% CI: 1.02-2.12; I2: 0%) and mTICI 3 recanalization (OR: 3.65; 95% CI: 1.56-8.54), although with a higher risk of SAH (OR: 4.33; 95% CI: 1.15-16.32).

CONCLUSION

Stent retrieval thrombectomy and direct aspiration did not show significant differences. Current available evidence is not sufficient to draw conclusions on the best surgical approach. The combined use of a stent retriever and aspiration as a first-line strategy was associated with higher mTICI 2b/3 and mTICI 3 recanalization rates, although with a higher risk of 24-h SAH, when compared with direct aspiration.
Re-Evaluation of the Size Limitation in Single-Session Stereotactic Radiosurgery for Brain Arteriovenous Malformations: Detailed Analyses on the Outcomes with Focusing on Radiosurgical Doses
Authors: Hasegawa Hirotaka , Hanakita Shunya , Shin Masahiro , Sugiyama Takehiro , Kawashima Mariko , Takahashi Wataru , Ishikawa Osamu , Nakatomi Hirofumi , Saito Nobuhito
Published: June 2019

BACKGROUND

Single-session stereotactic radiosurgery (SRS) for large arteriovenous malformations (AVMs) ≥10 mL remains controversial, which is considered as the current size limitation.

OBJECTIVE

To reconsider the size limitation of SRS for AVMs by profoundly analyzing dose-volume relationship.

METHODS

Data on 610 consecutive patients with AVM treated with SRS using regular (18-22 Gy) or low (<18 Gy) prescription doses were retrospectively analyzed. AVMs were classified into 4 groups: small (<5 mL), medium (≥5 and <10 mL), medium-large (≥10 and <15 mL), and large (≥15 mL). The maximum volumes were 22.5 mL (regular-dose group) and 23.5 mL (low-dose group).

RESULTS

When treated with regular doses, the cumulative 6-yr obliteration rates for each of the 4 AVM groups were 86%, 80%, 87%, and 79%, respectively; the cumulative 10-yr significant neurological event (SNE) rates were 2.6%, 3.9%, 6.8%, and 5.3%, respectively. Regarding large AVMs, regular-dose SRS resulted in marginally better obliteration rate (6-yr cumulative rate, 79% vs 48%, P = .111) and significantly lower SNE (5-yr cumulative rate, 5% vs 31%, P = .038) and post-SRS hemorrhage rate (8-yr cumulative rate, 0% vs 54%, P = .002) compared to low-dose SRS. Multivariate analyses revealed that regular-dose SRS significantly contributed to increase in the obliteration rate and decrease in SNEs and hemorrhage.

CONCLUSION

The outcomes for large AVMs were generally favorable when treated with ablative doses. Single-session SRS could be acceptable for AVMs up to ≈20 mL if treated with ablative doses.
Trace elements in schizophrenia: a systematic review and meta-analysis of 39 studies (N = 5151 participants)
Authors: Saghazadeh Amene , Mahmoudi Maryam , Shahrokhi Shayan , Mojarrad Maryam , Dastmardi Maedeh , Mirbeyk Mona , Rezaei Nima
Published: June 2019

Context

The pathogenesis of schizophrenia appears to be multifaceted.

Objective

The aim of this meta-analysis of studies that investigated blood and hair concentrations of trace elements in people diagnosed with schizophrenia was to determine whether levels of trace elements in patients with schizophrenia differ from those in healthy individuals.

Data Sources

The PubMed, Scopus, and Web of Science databases were searched to January 2018.

Study Selection

Studies that compared concentrations of trace elements in patients with schizophrenia with those in healthy controls, in patients with schizophrenia under different treatment regimens, or in patients with schizophrenia at different stages of disease were included.

Data Extraction

Data on study and sample characteristics and measures of trace elements were extracted.

Results

Thirty-nine studies with a total of 5151 participants were included. Meta-analysis of combined plasma and serum data showed higher levels of copper, lower levels of iron, and lower levels of zinc among patients with schizophrenia vs controls without schizophrenia. Subgroup analyses confirmed the following: higher levels of copper in plasma, in users of typical antipsychotic drugs, and in males; lower levels of zinc in serum, in patients in Asia, in drug-naive/drug-free patients, and in inpatients; lower levels of iron in serum, in patients in Asia, in drug-naive/drug-free patients, in patients on antipsychotic drugs, in inpatients, in patients with acute or newly diagnosed schizophrenia, in patients with chronic or previously diagnosed schizophrenia, and in males; and lower levels of manganese in plasma and in patients with chronic or previously diagnosed schizophrenia.

Conclusions

This meta-analysis provides evidence of an excess of copper, along with deficiencies of zinc, iron, and manganese, in patients with schizophrenia.
Return to work after kidney transplant: a systematic review
Authors: D’Egidio V , Mannocci A , Ciaccio D , Sestili C , Cocchiara R A , Del Cimmuto A , La Torre G
Published: June 2019

Background

Renal transplant is the gold standard treatment for patients with end-stage renal disease. Employment after transplant is an important marker of recovery and a key component of general well-being with important social implications.

Aims

To evaluate employment status after renal transplant and to investigate facilitators of and barriers to return to work for renal transplant patients.

Methods

We searched PubMed, Scopus and the Cochrane Library in March 2019 using the following algorithms: ‘return to work’ AND kidney AND transplant. Eligible studies were selected by two independent researchers. Quality assessment was performed using the following tools: International Narrative Systematic Assessment (INSA) and Newcastle–Ottawa Scale (NOS) for cross-sectional and cohort studies.

Results

The review included 18 papers: 10 cross-sectional studies, 6 cohort studies and 2 narrative reviews. The weighted mean percentage for return to work within 1 year was 39.4% (95% CI 39.3–39.6%). Employment status was influenced by modifiable and non-modifiable factors, such as pre-transplant employment, sociodemographic characteristics, clinical conditions and comorbidities, operative technique (invasive or not), type of transplants (living donor or cadaver), pre-transplant dialysis, psychosocial support, educational level and participation in education programmes.

Conclusion

Return to work after kidney transplant is a dynamic process influenced by numerous factors. It is vital to implement multidimensional interventions focused on rehabilitation and influencing modifiable factors to improve return to work after kidney transplant. This systematic review updates knowledge in the field of transplant and of disability management.
Next generation sequencing panel in undifferentiated autoinflammatory diseases identifies patients with colchicine-responder recurrent fevers
Authors: Papa Riccardo , Rusmini Marta , Volpi Stefano , Caorsi Roberta , Picco Paolo , Grossi Alice , Caroli Francesco , Bovis Francesca , Musso Valeria , Obici Laura , Castana Cinzia , Ravelli Angelo , Van Gijn Marielle E , Ceccherini Isabella , Gattorno Marco
Published: June 2019

Objectives

The number of innate immune system disorders classified as systemic autoinflammatory diseases (SAID) has increased in recent years. More than 70% of patients with clinical manifestations of SAID did not receive a molecular diagnosis, thus being classed as so-called undifferentiated or undefined SAID (uSAID). The aim of the present study was to evaluate a next-generation sequencing (NGS)-based clinically oriented protocol in patients with uSAID.

Methods

We designed a NGS panel that included 41 genes clustered in seven subpanels. Patients with uSAID were classified into different groups according to their clinical features and sequenced for the coding portions of the 41 genes.

Results

Fifty patients were enrolled in the study. Thirty-four patients (72%) displayed recurrent fevers not consistent with a PFAPA phenotype. Sixteen patients displayed a chronic inflammatory disease course. A total of 100 gene variants were found (mean 2 per patient; range 0–6), a quarter of which affected suspected genes. Mutations with a definitive diagnostic impact were detected in two patients. Patients with genetically negative recurrent fevers displayed a prevalent gastrointestinal, skin and articular involvement. Patients responded to steroids on demands (94%) and colchicine, with a response rate of 78%.

Conclusion

Even with a low molecular diagnostic rate, a NGS-based approach is able to provide a final diagnosis in a proportion of uSAID patients with evident cost-effectiveness. It also allows the identification of a subgroup of genetically negative patients with recurrent fever responding to steroid on demand and colchicine.
Diversity of Eocene Ripiphoridae with descriptions of the first species of Pelecotominae and larva of Ripidiinae (Coleoptera)
Authors: Batelka Jan , Perkovsky Evgeny E , Prokop Jakub
Published: June 2019

The Eocene records of the beetle family Ripiphoridae are evaluated and summarized. A new species of Pelecotominae belonging to the genus Clinops, C. svachaisp. nov. from Baltic amber, is described and figured. The female holotype of C. svachai is the first Palaeogene member of this subfamily to be identified. In addition, a male of a different unidentified genus of Pelecotominae, preserved as an inclusion in Baltic amber, is documented. The first Palaeogene primary larva of Ripiphoridae is described from Sakhalin amber and is compared with all other primary larvae of this family. The larva is attributed to Ripidius (Ripidiinae) and bears some unique characters absent in larvae of this extant genus. A putative record of Ripiphorus (Ripiphorinae) in the Berendt collection is identified as a member of Ripidius. Distribution of Eocene species are compared with those of their closest extant relatives and mapped. Based on the fossil record and the distribution of extant South African species of Clinops, this genus is tentatively thought to be an example of an Eocene relict, while the extant pelecotomine genus Scotoscopus from the East Mediterranean is considered to be an Oligocene–Miocene relict as its distribution corresponds with the geological history of the Aegais landmass.