bluuebunny/crossref_metadata_2025 huggingface dataset:
‘Los dos veces siete’: Baquílides y el Fedón de Platón
Authors: Flórez Flórez Alfonso
Published: September 2019

En la Oda 17 de Baquílides la expresión ‘los dos veces siete’ se usa para hacer referencia a los acompañantes de Teseo en su viaje a Creta. La misma expresión se usa en el Fedón de Platón para enumerar a los acompañantes de Sócrates en la prisión el día de su ejecución. A partir de esta repetición, se propone que la composición del Fedón toma en cuenta la oda de Baquílides. Se ofrecen argumentos para ello y se derivan las consecuencias que tiene esta línea interpretativa.
Preboundary lengthening in Japanese: To what extent do lexical pitch accent and moraic structure matter?
Authors: Seo Jungyun , Kim Sahyang , Kubozono Haruo , Cho Taehong
Published: September 2019

In this acoustic study, preboundary lengthening (PBL) in Japanese is investigated in relation to the prosodic structure in disyllabic words with different moraic and pitch accent distributions. Results showed gradient progressive PBL effects largely independent of the mora count. The domain of PBL is better explained by the syllable structure than the moraic structure. PBL, however, is attracted toward a non-final moraic nasal, showing some role of the mora. The initial pitch accent does not attract PBL directly, but it suppresses PBL of the final rime as a way of maintaining the relative prominence, showing a language-specific PBL modulation.
Fully integrated fused quartz acoustic horns for structural health monitoring
Authors: Hileman Zachary , He Jiaji , Homa Daniel , Kong Qingzhao , Wang Anbo , Pickrell Gary
Published: September 2019

Non-destructive acoustic structural sensing is an imperative technology, applicable to many different fields such as aerospace and civil engineering. To maintain a high sensitivity or to mitigate acoustic loss, it is important to increase the signal-to-noise ratio by improving coupling efficiency from acoustic sources to the object under test, such as an acoustic waveguide. Here, a fully integrated fused quartz horn design is combined with a fused quartz acoustic waveguide. The resulting system is intended to demonstrate a high accuracy low cost alternative to current sensing systems and the present article report on the viability of using a merged acoustic horn and waveguide.
A Bayesian binary algorithm for root mean squared-based acoustic signal segmentation
Authors: Hubert Paulo , Killick Rebecca , Chung Alexandra , Padovese Linilson R.
Published: September 2019

Changepoint analysis (also known as segmentation analysis) aims to analyze an ordered, one-dimensional vector in order to find locations where some characteristic of the data changes. Many models and algorithms have been studied under this theme, including models for changes in mean and/or variance, changes in linear regression parameters, etc. This work is interested in an algorithm for the segmentation of long duration acoustic signals; the segmentation is based on the change of the root-mean-square power of the signal. It investigates a Bayesian model with two possible parameterizations and proposes a binary algorithm in two versions using non-informative or informative priors. These algorithms are tested in the segmentation of annotated acoustic signals from the Alcatrazes marine preservation park in Brazil.
Simulation of nonlinear trans-skull focusing and formation of shocks in brain using a fully populated ultrasound array with aberration correction
Authors: Rosnitskiy Pavel B. , Yuldashev Petr V. , Sapozhnikov Oleg A. , Gavrilov Leonid R. , Khokhlova Vera A.
Published: September 2019

Multi-element high-intensity focused ultrasound phased arrays in the shape of hemispheres are currently used in clinics for thermal lesioning in deep brain structures. Certain side effects of overheating non-targeted tissues and skull bones have been revealed. Here, an approach is developed to mitigate these effects. A specific design of a fully populated 256-element 1-MHz array shaped as a spherical segment (F-number, F# = 1) and filled by randomly distributed equal-area polygonal elements is proposed. Capability of the array to generate high-amplitude shock fronts at the focus is tested in simulations by combining three numerical algorithms for linear and nonlinear field modeling and aberration correction. The algorithms are based on the combination of the Rayleigh integral, a linear pseudo-spectral time domain Kelvin–Voigt model, and nonlinear Westervelt model to account for the effects of inhomogeneities, aberrations, reflections, absorption, nonlinearity, and shear waves in the skull. It is shown that the proposed array can generate nonlinear waveforms with shock amplitudes >60 MPa at the focus deep inside the brain without exceeding the existing technical limitation on the intensity of 40 W/cm2 at the array elements. Such shock amplitudes are sufficient for mechanical ablation of brain tissues using the boiling histotripsy approach and implementation of other shock-based therapies.
The effect of the incoming boundary layer thickness on the aeroacoustics of finite wall-mounted square cylinders
Authors: Porteous Ric , Moreau Danielle J. , Doolan Con J.
Published: September 2019

This paper is concerned with the influence of the incoming wall boundary layer thickness on the noise produced by a square finite wall-mounted cylinder in cross-flow. Acoustic and near wake velocity measurements have been taken in an anechoic wind tunnel for a cylinder in two different near-zero-pressure gradient turbulent boundary layers with thicknesses of 130% and 370% of the cylinder width, W. The cylinders have an aspect ratio of 0.29≤L/W≤22.9 (where L is the cylinder span) and were examined at a Reynolds number, based on width, of ReW = 1.4 × 104. The results presented in this paper demonstrate that increasing the height of the boundary layer delays the production of acoustic tones to higher aspect ratios. The height of the boundary layer changes the balance between upwash and downwash across the cylinder span, resulting in a delayed onset of the shedding regimes and correspondingly, the production of acoustic tones.
Conjugated polymers optically regulate the fate of endothelial colony-forming cells
Authors: Lodola F. , Rosti V. , Tullii G. , Desii A. , Tapella L. , Catarsi P. , Lim D. , Moccia F. , Antognazza M. R.
Published: September 2019

Light and semiconducting polymers induce angiogenesis in vitro.
Building and exploring libraries of atomic defects in graphene: Scanning transmission electron and scanning tunneling microscopy study
Authors: Ziatdinov Maxim , Dyck Ondrej , Li Xin , Sumpter Bobby G. , Jesse Stephen , Vasudevan Rama K. , Kalinin Sergei V.
Published: September 2019

AI-assisted construction of functional defect libraries directly from atom-resolved experimental observations.
Correlated insulating and superconducting states in twisted bilayer graphene below the magic angle
Authors: Codecido Emilio , Wang Qiyue , Koester Ryan , Che Shi , Tian Haidong , Lv Rui , Tran Son , Watanabe Kenji , Taniguchi Takashi , Zhang Fan , Bockrath Marc , Lau Chun Ning
Published: September 2019

Two graphene layers twisted at 0.93° host superconducting and correlated insulating states, expanding the “magic” range of angles.
Near-equilibrium growth from borophene edges on silver
Authors: Zhang Zhuhua , Mannix Andrew J. , Liu Xiaolong , Hu Zhili , Guisinger Nathan P. , Hersam Mark C. , Yakobson Boris I.
Published: September 2019

Borophene exhibits reconstructed edges, along which kinetic growth extends the given lattice and results in elongated hexagons.
Measurement of the cosmic ray proton spectrum from 40 GeV to 100 TeV with the DAMPE satellite
Authors:   DAMPE Collaboration, An Q. , Asfandiyarov R. , Azzarello P. , Bernardini P. , Bi X. J. , Cai M. S. , Chang J. , Chen D. Y. , Chen H. F. , Chen J. L. , Chen W. , Cui M. Y. , Cui T. S. , Dai H. T. , D’Amone A. , De Benedittis A. , De Mitri I. , Di Santo M. , Ding M. , Dong T. K. , Dong Y. F. , Dong Z. X. , Donvito G. , Droz D. , Duan J. L. , Duan K. K. , D’Urso D. , Fan R. R. , Fan Y. Z. , Fang F. , Feng C. Q. , Feng L. , Fusco P. , Gallo V. , Gan F. J. , Gao M. , Gargano F. , Gong K. , Gong Y. Z. , Guo D. Y. , Guo J. H. , Guo X. L. , Han S. X. , Hu Y. M. , Huang G. S. , Huang X. Y. , Huang Y. Y. , Ionica M. , Jiang W. , Jin X. , Kong J. , Lei S. J. , Li S. , Li W. L. , Li X. , Li X. Q. , Li Y. , Liang Y. F. , Liang Y. M. , Liao N. H. , Liu C. M. , Liu H. , Liu J. , Liu S. B. , Liu W. Q. , Liu Y. , Loparco F. , Luo C. N. , Ma M. , Ma P. X. , Ma S. Y. , Ma T. , Ma X. Y. , Marsella G. , Mazziotta M. N. , Mo D. , Niu X. Y. , Pan X. , Peng W. X. , Peng X. Y. , Qiao R. , Rao J. N. , Salinas M. M. , Shang G. Z. , Shen W. H. , Shen Z. Q. , Shen Z. T. , Song J. X. , Su H. , Su M. , Sun Z. Y. , Surdo A. , Teng X. J. , Tykhonov A. , Vitillo S. , Wang C. , Wang H. , Wang H. Y. , Wang J. Z. , Wang L. G. , Wang Q. , Wang S. , Wang X. H. , Wang X. L. , Wang Y. F. , Wang Y. P. , Wang Y. Z. , Wang Z. M. , Wei D. M. , Wei J. J. , Wei Y. F. , Wen S. C. , Wu D. , Wu J. , Wu L. B. , Wu S. S. , Wu X. , Xi K. , Xia Z. Q. , Xu H. T. , Xu Z. H. , Xu Z. L. , Xu Z. Z. , Xue G. F. , Yang H. B. , Yang P. , Yang Y. Q. , Yang Z. L. , Yao H. J. , Yu Y. H. , Yuan Q. , Yue C. , Zang J. J. , Zhang F. , Zhang J. Y. , Zhang J. Z. , Zhang P. F. , Zhang S. X. , Zhang W. Z. , Zhang Y. , Zhang Y. J. , Zhang Y. L. , Zhang Y. P. , Zhang Y. Q. , Zhang Z. , Zhang Z. Y. , Zhao H. , Zhao H. Y. , Zhao X. F. , Zhou C. Y. , Zhou Y. , Zhu X. , Zhu Y. , Zimmer S.
Published: September 2019

DAMPE satellite has directly measured the cosmic ray proton spectrum from 40 GeV to 100 TeV and revealed a new feature at about 13.6 TeV.
Manipulating optical nonlinearities of molecular polaritons by delocalization
Authors: Xiang Bo , Ribeiro Raphael F. , Li Yingmin , Dunkelberger Adam D. , Simpkins Blake B. , Yuen-Zhou Joel , Xiong Wei
Published: September 2019

The macroscopic control of optical nonlinearity is achieved in a cavity polariton due to its delocalized nature.
Synthetic networks with tunable responsiveness, biodegradation, and molecular recognition for precision medicine applications
Authors: Clegg John R. , Irani Afshan S. , Ander Eric W. , Ludolph Catherine M. , Venkataraman Abhijeet K. , Zhong Justin X. , Peppas Nicholas A.
Published: September 2019

Modular hydrogel nanoparticles could be an enabling drug delivery technology for precision medicine applications.
Lin28b controls a neonatal to adult switch in B cell positive selection
Authors: Vanhee Stijn , Åkerstrand Hugo , Kristiansen Trine Ahn , Datta Sebak , Montano Giorgia , Vergani Stefano , Lang Stefan , Ungerbäck Jonas , Doyle Alexander , Olsson Karin , Beneventi Giulia , Jensen Christina T. , Bellodi Cristian , Soneji Shamit , Sigvardsson Mikael , Gyllenbäck Elin Jaensson , Yuan Joan
Published: September 2019

Temporally restricted expression of Lin28b promotes generation of self-reactive B-1 cells early in life.
Temperate Phages of
Staphylococcus aureus
Authors: Ingmer Hanne , Gerlach David , Wolz Christiane
Published: September 2019

Most
Staphylococcus aureus
isolates carry multiple bacteriophages in their genome, which provide the pathogen with traits important for niche adaptation. Such temperate
S. aureus
phages often encode a variety of accessory factors that influence virulence, immune evasion and host preference of the bacterial lysogen. Moreover, transducing phages are primary vehicles for horizontal gene transfer. Wall teichoic acid (WTA) acts as a common phage receptor for staphylococcal phages and structural variations of WTA govern phage-host specificity thereby shaping gene transfer across clonal lineages and even species. Thus, bacteriophages are central for the success of
S. aureus
as a human pathogen.
The glacial record in regions surrounding the Driftless Area
Authors: Carson* Eric C. , Attig John W. , Rawling III J. Elmo
Published: September 2019

The Driftless Area of southwestern Wisconsin is defined by its lack of glacial deposits; therefore, the geographic limits of the Driftless Area are delimited by glacial deposits of various ages. The northern boundary of the Driftless Area is marked by the patchy distribution of pre-Illinoian (pre–marine oxygen isotope stage [MIS] 8) deposits that contain clasts from the north and northwest. The western margin is also delimited by pre–MIS 8 sediments that extend roughly coincident with the Mississippi River. This boundary is best identified by the topographic feature of the Bridgeport moraine near the confluence of the Mississippi and Wisconsin rivers and by the presence of patchy till underlying MIS 2 loess on upland surfaces in southwesternmost Wisconsin. The southeastern margin is delimited by extensive Illinoian (MIS 6–8) deposits with eroded glacial landforms evident in modern light detection and ranging (LiDAR)–derived digital elevation models. The eastern margin is marked by well-preserved glacial landforms and sediment associated with the MIS 2 glaciation. The Green Bay Lobe of the Laurentide Ice Sheet deposited prominent moraines that dammed numerous ice-proximal lakes. The most significant of these was glacial Lake Wisconsin, which formed when the Green Bay Lobe dammed the Wisconsin River at the east end of the Baraboo Hills. The most recent episode of permafrost in the Driftless Area lasted from ca. 33 to 14 ka; a suite of permafrost-related features that formed sometime during this time period can be found throughout the Driftless Area.
Loess, eolian sand, and colluvium in the Driftless Area
Authors: Mason* Joseph A. , Jacobs Peter M. , Leigh David S.
Published: September 2019

Loess mantles upland summits across much of the Driftless Area of southwestern Wisconsin and its origin and paleoenvironmental significance has been a focus of research since the nineteenth century. Although the Driftless Area was ice free through the many glaciations of the Quaternary, long-term preservation of loess was limited by post-depositional erosion across much if not all of this highly dissected landscape, erosion that was likely accelerated under periglacial conditions during glaciations when ice sheets were nearby. Loess preserved today includes four members of the Kieler Formation and two older loesses known only from one locality. The Peoria Member, the youngest, thickest, and most extensive member of the Kieler Formation, was deposited during and just after the peak of the last glaciation. Its main sources include both the Mississippi River valley and the Iowan Erosion Surface and glacial outwash surfaces farther west in Iowa and Minnesota. More research is needed on the relative contribution from each of these sources to the Peoria Member, and on the sources of older loess units. Eolian sand, often forming dunes, covers extensive low-relief landscapes in the northern Driftless Area, the Mississippi and Wisconsin River valleys, and smaller areas elsewhere in the region, overlying sandstone bedrock, stream terraces, and the former bed of Glacial Lake Wisconsin. These sands are stabilized by vegetation today but were active during and just after the period of Peoria Member deposition. Thus, large areas of eolian sand acted as surfaces of transport where loess did not accumulate but rather was conveyed far downwind of its sources. Colluvium that is a mixture of bedrock-derived sediment and loess covers bedrock slopes throughout the Driftless Area. A variety of geochronologic, geomorphic, and stratigraphic evidence supports the hypothesis that this colluvial mantle formed mainly in the cold, periglacial environment of the last glaciation, with only limited modification during the Holocene. A new research effort, incorporating modern geochemical and geochronological techniques, could provide important insights on the processes that originally produced the colluvial mantle and those that are acting on it today.
Holocene paleohydrology and paleofloods in the Driftless Area
Authors: Daniels* J. Michael , Leigh David S. , Carson Eric C.
Published: September 2019

The study of Holocene paleohydrology and paleofloods represents one of James C. Knox’s most enduring contributions to our understanding of the geology and physical geography of the Driftless Area. His work on these subjects resulted in over 20 journal articles, refereed book chapters, field-trip guidebooks, and unpublished reports over a period of 40 years. By systematically amassing a wealth of radiocarbon-dated morphologic, stratigraphic, and sedimentologic observations, he was able to quantitatively document changing hydrologic conditions in the region over the past 11.7 ka. He extended these empirical results to establish a broadly applicable theoretical perspective about the profound hydrologic and geomorphologic impacts of even modest changes in climate. This theory, grounded in field-derived data collection, detailed sedimentological analysis, statistical methods, and contextual analysis of supplementary paleoenvironmental evidence, has important implications for our understanding of changing flood magnitudes and frequencies in response to ongoing climate change. Knox pioneered novel methods for reconstructing past hydrologic variability. His work on the cross-sectional geometry of paleomeanders provides a direct proxy for estimation of high-frequency, low-magnitude bankfull floods. His analysis of overbank gravels facilitates reconstruction of an early through late Holocene time-series of large, infrequent floods. His attention to sandy beds occurring within uninterrupted, fine-grained, overbank depositional sequences enables continuous magnitude and frequency analysis of floods to be extended hundreds, even thousands, of years beyond the modern gaging record. We demonstrate this with statistical correlation of a gaging record to >0.25 mm sand contents at one of Knox’s former sites. By quantifying hydrologic change in the Driftless Area over millennial timescales, Knox’s work demonstrates conclusively the non-stationarity of flood magnitudes and frequencies, a result that has significance for fluvial geomorphology, paleohydrology, water resource management, and flood mitigation. The scientific and societal value of these results continues to increase in relevance for the future.
Quality of investigations into unexpected deaths of infants and young children in England after implementation of national child death review procedures in 2008: a retrospective assessment
Authors: Fleming Peter , Pease Anna , Ingram Jenny , Sidebotham Peter , Cohen Marta C , Coombs Robert C , Ewer Andrew K , Ward Platt Martin , Fox John , Marshall David , Lewis Anne , Evason-Coombe Carol , Blair Peter
Published: September 2019

Objectives

In 2008, new statutory national procedures for responding to unexpected child deaths were introduced throughout England. There has, to date, been no national audit of these procedures.

Study design

Families bereaved by the unexpected death of a child under 4 years of age since 2008 were invited to participate. Factors contributing to the death and investigations after the death were explored. Telephone interviews were conducted, and coroners’ documents were obtained. The nature and quality of investigations was compared with the required procedures; information on each case was reviewed by a multiagency panel; and the death was categorised using the Avon clinicopathological classification.

Results

Data were obtained from 91 bereaved families (64 infant deaths and 27 children aged 1–3 years); 85 remained unexplained after postmortem examination. Documentation of multiagency assessments was poorly recorded. Most (88%) families received a home visit from the police, but few (37%) received joint visits by police and healthcare professionals. Postmortem examinations closely followed national guidance; 94% involved paediatric pathologists; 61% of families had a final meeting with a paediatrician to explain the investigation outcome. There was no improvement in frequency of home visits by health professionals or final meetings with paediatricians between 2008–2013 and 2014–2017 and no improvement in parental satisfaction with the process.

Conclusions

Statutory procedures need to be followed more closely. The implementation of a national child mortality database from 2019 will allow continuing audit of the quality of investigations after unexpected child deaths. An important area amenable to improvement is increased involvement by paediatricians.
Identifying central serous chorioretinopathy biomarkers in coexisting diabetic retinopathy: a multimodal imaging study
Authors: Dhurandhar Deven Sushil , Singh Sumit Randhir , Sahoo Niroj Kumar , Goud Abhilash , Lupidi Marco , Chhablani Jay
Published: September 2019

Background

To describe clinical and imaging characteristics of patients presenting with diabetic retinopathy (DR) with coexisting acute or chronic central serous chorioretinopathy (CSCR).

Methods

This was a cross-sectional study which included 54 eyes of 27 patients with coexisting DR and CSCR. Demographic details, prior history of laser, best-corrected visual acuity (BCVA), central macular thickness (CMT), height of neurosensory detachment (NSD), subfoveal choroidal thickness (SFCT), subfoveal large choroidal vessel layer thickness (SF-LCVT), fluorescein angiography and indocyanine green angiography features were recorded. Subanalysis was done for patients with unilateral CSCR. Data was evaluated using Student t-test for quantitative data and χ2 test for qualitative data. CSCR between different grades of DR was analysed using analysis of variance.

Results

Prevalence of coexistent CSCR in eyes with DR was 0.4%. Mean age was 53.96±8.79 years, with 25 males. Mean CMT was 349.2±258 μm. Mean SFCT and SF- LCVT of 38 eyes were 376.40±86 μm and 178.80±62.8 μm, respectively. Fifteen eyes had centre involving diabetic macular oedema. Subanalysis of patients with unilateral CSCR showed that the loss of inner segment-outer segment (IS-OS) integrity (p=0.001), photoreceptor footplates at the NSD roof (p=0.001) on optical coherence tomography and dilated choroidal vessels (p=0.05) on indocyanine green angiography were found more often in the CSCR eyes compared with their fellow eyes. Features of CSCR among the different grades of DR were not significantly different between the groups.

Conclusion

Our study describes features of a unique subset of patients presenting with coexistent DR and CSCR. Such coexistent nature needs special attention by the clinicians as this may change the treatment approach and alter outcomes.
Classifying juvenile onset primary open angle glaucoma using cluster analysis
Authors: Birla Shweta , Gupta Dinesh , Somarajan Bindu I , Gupta Shikha , Chaurasia Abadh Kishore , Kishan Azmira , Gupta Viney
Published: September 2019

Aim

To classify unrelated patients with juvenile onset primary open angle glaucoma (JOAG) into clinically useful phenotypes using cluster analysis.

Methods

Out of the 527 unrelated patients with JOAG, the study included 414 patients who had all the phenotypic characteristics required for the study. A cluster analysis was performed to classify the patients based on their iris and angle morphology, age of onset, highest untreated intraocular pressure (IOP), worst mean deviation and greatest vertical cup disc ratio of the worst eye. The iris features were broadly classified into three groups: those with normal iris crypts (NIC), those with prominent iris crypts (PIC) and those with absence of iris crypts. The gonio photographs were graded as normal appearing angle or those with angle dysgenesis in the form of a featureless angle, one with a high iris insertion and an angle with prominent iris processes. Using a hierarchical clustering model and a two-way cluster analysis, the distribution of clusters of JOAG was analysed to obtain a classification of JOAG subtypes.

Results

The four major clusters identified were: Cluster 1 with NIC and normal angles had the lowest untreated IOP and higher age of onset among all clusters. Cluster 2 with NIC and featureless angle was found to be associated with earliest age of onset. Cluster 3 had NIC and either a high iris insertion or prominent iris processes. Cluster 4 was a heterogeneous cluster with maximum number of patients in a group comprising of those with PIC and high iris insertion.

Conclusions

Cluster analysis extracted four subgroups of the JOAG phenotype that have clinical and prognostic significance and can potentially be helpful while evaluating these patients in the clinics.
Effect of posterior vitreous detachment on treat-and-extend versus monthly ranibizumab for neovascular age-related macular degeneration
Authors: Waldstein Sebastian M , Coulibaly Leonard , Riedl Sophie , Sadeghipour Amir , Gerendas Bianca S , Schmidt-Erfurth Ursula Margarethe
Published: September 2019

Aims

To investigate the impact of posterior vitreous detachment (PVD) on the efficacy of treat-and-extend (T&E) ranibizumab in neovascular age-related macular degeneration.

Methods

In a post hoc analysis of a randomised controlled clinical trial, spectral-domain optical coherence tomography images of treatment-naïve patients randomised to receive T&E (n=265) or monthly (n=264) ranibizumab for 12 months were included. Certified, masked graders diagnosed the presence or the absence of complete PVD. The main outcome measures were the mean change in best-corrected visual acuity (BCVA) and central retinal thickness (CRT) at month 12, the number of administered ranibizumab injections and the proportion of patients extended to more than 8 weeks.

Results

At baseline, complete PVD was present in 51% and 56% of patients in the monthly and T&E arms, respectively. Mean change in BCVA at month 12 was +9.0 (PVD) vs +9.5 letters (no PVD, p=0.78) in monthly treated eyes, and +6.0 (PVD) vs +7.5 letters (no PVD, p=0.42) in T&E treated eyes. Conversely, mean change in CRT at month 12 was −174 (PVD) vs −173 µm (no PVD, p=0.98) in the monthly arm, and −175 (PVD) vs −164 µm (no PVD, p=0.58) in the T&E arm. In T&E treated patients, the median number of injections was eight vs nine (p=0.035). 71% of PVD eyes were extended successfully, compared with 55% of eyes without PVD (p=0.005).

Conclusion

PVD was not found to impact functional and anatomical outcomes of T&E ranibizumab therapy. However, patients without a complete PVD required more retreatments and were significantly less likely to be successfully extended.

Trial registration number

NCT01948830
Adverse events of exercise therapy in randomised controlled trials: a systematic review and meta-analysis
Authors: Niemeijer Andre , Lund Hans , Stafne Signe Nilssen , Ipsen Thomas , Goldschmidt Cathrine Luhaäär , Jørgensen Claus Thomas , Juhl Carsten B
Published: September 2019

Objective

To evaluate the relative risk (RR) of serious and non-serious adverse events in patients treated with exercise therapy compared with those in a non-exercising control group.

Design

Systematic review and meta-analysis.

Data sources

Primary studies were identified based on The Cochrane Database of Systematic Reviews investigating the effect of exercise therapy.

Eligibility criteria

At least two of the authors independently evaluated all identified reviews and primary studies. Randomised controlled trials were included if they compared any exercise therapy intervention with a non-exercising control. Two authors independently extracted data. The RR of serious and non-serious adverse events was estimated separately.

Results

180 Cochrane reviews were included and from these, 773 primary studies were identified. Of these, 378 studies (n=38 368 participants) reported serious adverse events and 375 studies (n=38 517 participants) reported non-serious adverse events. We found no increase in risk of serious adverse events (RR=0.96 (95%CI 0.90 to 1.02, I2: 0.0%) due to exercise therapy. There was, however, an increase in non-serious adverse events (RR=1.19 (95%CI 1.09 to 1.30, I2: 0.0%). The number needed to treat for an additional harmful outcome for non-serious adverse events was 6 [95%CI 4 to 11).

Conclusion

Participating in an exercise intervention increased the relative risk of non-serious adverse events, but not of serious adverse events. Exercise therapy may therefore be recommended as a relatively safe intervention.

PROSPERO registration number

CRD42014014819.
Towards better evidence-informed global action: lessons learnt from the Lancet series and recent developments in physical activity and public health
Authors: Ding Ding , Ramirez Varela Andrea , Bauman Adrian E , Ekelund Ulf , Lee I-Min , Heath Gregory , Katzmarzyk Peter T , Reis Rodrigo , Pratt Michael
Published: September 2019

In the past few decades, the field of physical activity has grown and evolved in scope, depth, visibility and impact around the world. Global progress has been observed in research and practice in physical activity regarding surveillance, health outcomes, correlates/determinants, interventions, translation and policy. The 2012 and 2016Lancetseries on physical activity provide some of the most comprehensive global analysis on various topics within physical activity. Based on theLancetseries and other key developments in the field, literature searches, and expert group meetings and consultation, we provide a global summary on the progress of, gaps in and future directions for physical activity research in the following areas: (1) surveillance and trends, (2) correlates and determinants, (3) health outcomes and (4) interventions, programmes and policies. Besides lessons learnt within each specific area, several recommendations are shared across areas of research, including improvement in measurement, applying a global perspective with a growing emphasis on low-income and middle-income countries, improving inclusiveness and equity in research, making translation an integral part of research for real-world impact, taking an ‘upstream’ public health approach, and working across disciplines and sectors to co-design research and co-create solutions. We have summarised lessons learnt and recommendations for future research as ‘roadmaps’ in progress to encourage moving the field of physical activity towards achieving population-level impact globally.
Subclinical ochronosis features in alkaptonuria: a cross-sectional study
Authors: Cox Trevor , Psarelli Eftychia Eirini , Taylor Sophie , Shepherd Hannah Rose , Robinson Mark , Barton Gabor , Mistry Alpesh , Genovese Federica , Braconi Daniela , Giustarini Daniela , Rossi Ranieri , Santucci Annalisa , Khedr Milad , Hughes Andrew , Milan Anna , Taylor Leah Frances , West Elizabeth , Sireau Nicolas , Dillon Jane Patricia , Rhodes Nicholas , Gallagher James Anthony , Ranganath Lakshminarayan
Published: September 2019

Background

Alkaptonuria (AKU) is present from birth, yet clinical effects are considered to appear later in life. Morbidity of AKU, considered irreversible, is secondary to ochronosis. Age of ochronosis onset is not clearly known. Nitisinone profoundly lowers homogentisic acid (HGA), the metabolic defect in AKU. Nitisinone also arrests ochronosis and slows progression of AKU. However, tyrosinaemia post-nitisinone has been associated with corneal keratopathy, rash and cognitive impairment in HT 1. The optimal time to start nitisinone in AKU is unknown.

Methods

In an open, cross-sectional, single-site study, 32 patients with AKU were to be recruited. The primary outcome was presence of ochronosis in an ear biopsy. Secondary outcomes included analysis of photographs of eyes/ears, serum/urine HGA, markers of tissue damage/inflammation/oxidation, MRI imaging, gait, quality of life and Alkaptonuria Severity Score Index (qAKUSSI).

Results

Thirty patients, with mean age (SD) 38 (14) years, were recruited. Percentage pigmentation within ear biopsies increased with age. Ear pigmentation was detected in a 20-year-old woman implying ochronosis can start in patients before the age of 20. Gait and qAKUSSI were outside the normal range in all the patients with AKU.

Conclusions

Ochronosis can be present before age 20 years.
Age, cancer site and gender associations with symptoms and problems in specialised palliative care: a large, nationwide, register-based study
Authors: Hansen Maiken Bang , Ross Lone , Petersen Morten Aagaard , Groenvold Mogens
Published: September 2019

Background

Patients referred to specialised palliative care are troubled by symptoms/problems, but more knowledge is needed on the level and frequency of symptoms/problems. It is also uncertain how gender, age and cancer diagnosis, respectively, are associated with symptoms/problems.

Aims

To describe symptoms/problems in patients with cancer at the start of specialised palliative care, and to study how age, gender and cancer diagnosis were associated with symptoms/problems.

Design

A register-based study including data from the Danish Palliative Care Database.

Setting/Participants

Patients with cancer who reported their symptoms/problems using the European Organisation for Research and Treatment of Cancer Quality of Life Questionaire-Core-15-Palliative Care (EORTC QLQ-C15-PAL) at the start of specialised palliative care were included. Ordinal logistic regression was performed to test if gender, age and cancer diagnosis were associated with each symptom/problem.

Results

31 771 patients with cancer were included in the study. The most prevalent and severe symptoms/problems were pain, appetite loss, fatigue, poor physical function and poor quality of life. Gender, age and cancer diagnosis were significantly associated with most symptoms/problems. The strongest associations between symptoms/problems and gender and age, respectively, were increased risk of nausea in women, as well as increased risk of poor physical function and reduced risk of sleeplessness and pain with increasing age. Patients with brain/central nervous system cancer had the lowest risk of symptoms but the highest risk of poor physical function.

Conclusion

At the start of specialised palliative care, patients with cancer experience severe levels of symptoms, poor physical function and poor quality of life. Age, gender and diagnosis were significantly associated with most symptoms/problems, but the strength and direction of the associations differed across symptoms/problems.
Norepinephrine pressor infusion withdrawal in a National Health Service hospice
Authors: Woods Elizabeth , Baker Lisa , Hindmarsh Jonathan
Published: September 2019

Norepinephrine (NE) is a peripheral vasoconstrictor used as an emergency measure to restore blood pressure secondary to acute hypotension. NE must be administered centrally as a continuous infusion and requires intensive monitoring. Consequently, its use is restricted to critical care environments. We discuss the withdrawal of NE in a hospice for a patient with advanced malignancy and profound hypotension from sepsis. The patient was admitted to intensive care but chose to stop active treatment and insisted on being discharged. Due to concerns about withdrawing NE in the community, he was transferred to a local hospice. We describe various challenges, including the administration and monitoring of NE outside of intensive care, the withdrawal process and concerns that profound hypotension might compromise subcutaneous medications absorption.
How to perform a meta-analysis with R: a practical tutorial
Authors: Balduzzi Sara , Rücker Gerta , Schwarzer Guido
Published: September 2019

Objective

Meta-analysis is of fundamental importance to obtain an unbiased assessment of the available evidence. In general, the use of meta-analysis has been increasing over the last three decades with mental health as a major research topic. It is then essential to well understand its methodology and interpret its results. In this publication, we describe how to perform a meta-analysis with the freely available statistical software environment R, using a working example taken from the field of mental health.

Methods

R package meta is used to conduct standard meta-analysis. Sensitivity analyses for missing binary outcome data and potential selection bias are conducted with R package metasens. All essential R commands are provided and clearly described to conduct and report analyses.

Results

The working example considers a binary outcome: we show how to conduct a fixed effect and random effects meta-analysis and subgroup analysis, produce a forest and funnel plot and to test and adjust for funnel plot asymmetry. All these steps work similar for other outcome types.

Conclusions

R represents a powerful and flexible tool to conduct meta-analyses. This publication gives a brief glimpse into the topic and provides directions to more advanced meta-analysis methods available in R.
Exploiting differential Wnt target gene expression to generate a molecular biomarker for colorectal cancer stratification
Authors: Kleeman Sam O , Koelzer Viktor H , Jones Helen JS , Vazquez Ester Gil , Davis Hayley , East James E , Arnold Roland , Koppens Martijn AJ , Blake Andrew , Domingo Enric , Cunningham Chris , Beggs Andrew D , Pestinger Valerie , Loughrey Maurice B , Wang Lai-Mun , Lannagan Tamsin RM , Woods Susan L , Worthley Daniel , Tomlinson Ian , Dunne Philip D , Maughan Timothy , Leedham Simon J
Published: September 2019

Objective

Pathological Wnt pathway activation is a conserved hallmark of colorectal cancer. Wnt-activating mutations can be divided into: i) ligand-independent (LI) alterations in intracellular signal transduction proteins (Adenomatous polyposis coli, β-catenin), causing constitutive pathway activation and ii) ligand-dependent (LD) mutations affecting the synergistic R-Spondin axis (RNF43,RSPO-fusions) acting through amplification of endogenous Wnt signal transmembrane transduction. Our aim was to exploit differential Wnt target gene expression to generate a mutation-agnostic biomarker for LD tumours.

Design

We undertook harmonised multi-omic analysis of discovery (n=684) and validation cohorts (n=578) of colorectal tumours collated from publicly available data and the Stratification in Colorectal Cancer Consortium. We used mutation data to establish molecular ground truth and subdivide lesions into LI/LD tumour subsets. We contrasted transcriptional, methylation, morphological and clinical characteristics between groups.

Results

Wnt disrupting mutations were mutually exclusive. Desmoplastic stromal upregulation ofRSPOmay compensate for absence of epithelial mutation in a subset of stromal-rich tumours. Key Wnt negative regulator genes were differentially expressed between LD/LI tumours, with targeted hypermethylation of some genes (AXIN2,NKD1) occurring even in CIMP-negative LD cancers.AXIN2mRNA expression was used as a discriminatory molecular biomarker to distinguish LD/LI tumours (area under the curve >0.93).

Conclusions

Epigenetic suppression of appropriate Wnt negative feedback loops is selectively advantageous in LD tumours and differentialAXIN2expression in LD/LI lesions can be exploited as a molecular biomarker. Distinguishing between LD/LI tumour types is important; patients with LD tumours retain sensitivity to Wnt ligand inhibition and may be stratified at diagnosis to clinical trials of Porcupine inhibitors.
Multiplex fluorescence in situ hybridisation to detect anaplastic lymphoma kinase and ROS proto-oncogene 1 receptor tyrosine kinase rearrangements in lung cancer cytological samples
Authors: Zito Marino Federica , Rossi Giulio , Cozzolino Immacolata , Montella Marco , Micheli Mariacarolina , Bogina Giuseppe , Munari Enrico , Brunelli Matteo , Franco Renato
Published: September 2019

Aims

Several predictive biomarkers of response to specific inhibitors have become mandatory for the therapeutic choice in non-small-cell lung cancer (NSCLC). In most lung cancer patients, the biological materials available to morphological and molecular diagnosis are exclusively cytological samples and minimum tumour wastage is necessary. Multiplex fluorescence in situ hybridisation (mFISH) to detect simultaneouslyALK-rearrangement andROS1-rearrangement on a single slide could be useful in clinical practice to save cytological samples for further molecular analysis. In this study, we aim to validate diagnostic performance of multiplex ALK/ROS1 fluorescence in situ hybridisation (FISH) approach in lung adenocarcinoma cytological series compared with classic single break apart probes.

Methods

We collected a series of 61 lung adenocarcinoma cytological specimens enriched in tumours harbouringALK-rearrangement andROS1-rearrangement.ALKandROS1status were previously assessed by classic FISH test using single break apart probes and immunohistochemistry. Study population was composed of 6ALK-positive, 2ROS1-positive and 53ALK/ROS1-wild type. All specimens were analysed by multiplex FISH assay using FlexISH ALK/ROS1 DistinguISH Probe Zytovision.

Results

The dual ALK/ROS1 FISH probe test results were fully concordant with the results of previous single ALK and ROS1 FISH tests on two different slides. 6ALK-positive and 2ROS1-positive were confirmed through multiplex FISH test, without false-positive and false-negative results. Multiplex ALK/ROS1 FISH test results agreed with immunohistochemistry assay staining results.

Conclusion

Multiplex ALK/ROS1 FISH probe test is a useful tool to detect simultaneouslyALK-rearrangement andROS1-rearrangement on a single slide in cytological specimens with a small amount of biomaterial.
Onset of type 1 diabetes mellitus in rural areas of the USA
Authors: Rogers Mary A M
Published: September 2019

Background

In the USA, the epidemiologic features of type 1 diabetes are not well-defined across all 50 states. However, the advent of large nationwide insurance databases enables the investigation of where type 1 diabetes cases occur throughout the country.

Methods

An integrated database from a large nationwide health insurer in the USA (Clinformatics Data Mart Database) was used, from 2001 to 2017. The database contained longitudinal information on approximately 77 million people.

Results

The incidence of type 1 diabetes was greatest in areas of low population density across the 50 states. Individuals in the lowest population density areas had rates that were 2.28 times (95% CI 2.08 to 2.50) that of persons living in high-density areas. This association was consistent across various measures of rural status (p<0.001 for population density; p<0.001 for per cent rural as defined by the US Census Bureau; p=0.026 for farmland). The association between rural areas and the incidence of type 1 diabetes was evident across all four general regions of the USA.

Conclusions

The predilection of type 1 diabetes in rural areas provides clues to potential factors associated with the onset of this autoimmune disease.
Undiagnosed and untreated chronic kidney disease and its impact on renal outcomes in the Japanese middle-aged general population
Authors: Yamada Yukari , Ikenoue Tatsuyoshi , Saito Yoshiyuki , Fukuma Shingo
Published: September 2019

Background

The effectiveness of identifying and monitoring early-stage chronic kidney disease (CKD) is not fully recognised. This study quantified people with undiagnosed CKD among the middle-aged Japanese population and clarified potential risks of untreated CKD.

Methods

We included 71 233 individuals who underwent annual health check-ups (AHC) in 2014 for both baseline and follow-up proteinuria and serum creatine measurements. CKD was identified by AHC data as proteinuria or estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. We differentiated undiagnosed from diagnosed CKD using the medical claims database. In undiagnosed CKD, we assessed risk differences for disease progression, defined as an eGFR decline slope >3 mL/min/1.73 m2/year or proteinuria incidence over 3 years, between those who visited a physician for CKD treatment within 6 months after AHC and those who did not.

Results

CKD prevalence was 5.7% (5.2% undiagnosed and 0.5% diagnosed). Only 2.1% of the patients with undiagnosed CKD visited a physician for CKD treatment within 6 months after AHC. Between-group risk differences in instrumental variable adjustment models showed that those left untreated progressed to kidney diseases 16.3% more often than those who visited physicians for CKD treatment.

Conclusion

CKD was undiagnosed in 5.2% of the middle-aged general population. Only a few people visited physicians for CKD treatment. Visiting physicians for CKD treatment during the first 6 months after screening may be associated with a lower risk of kidney disease progression.
THUR 072 A service evaluation of patients attending A&E with seizures
Authors: Navindi Fernandopulle , Mahinda Yogarajah
Published: September 2019

Background

Epilepsy is the most common, chronic neurological condition with a prevalence of 0.5% and an incidence of 3 to 5%. Despite anticonvulsant use, there are approximately 60,000 A&E attendances and 40,000 hospital admissions.

Method

Using A&E triage records a list of all patients attending St George’s Hospital A&E department with a seizure within a six month period was derived. By referring to clinical records, management in A&E and beyond was audited according to NICE guidelines.

Results

382 adults with seizures were identified. 33% attended A&E in the previous 12 months with a seizure. Of those with epilepsy (n=187), 9% were on no drug. In all seizure cases, documentation was often incomplete and a collateral history was only obtained in 44% cases. 44% of patients were admitted, and of these, 15% were unnecessary according to criteria outlined by Iyer et al. Only 8% were asked if they were a driver and alcohol intake was not documented in 44%. Only 37% were referred to a neurologist or epilepsy specialist.

Conclusion

Seeing as a third of the patients attended A&E in the previous 12 months, it is clear that thorough history taking and better management in the community is necessary.
THUR 038 Encephalopathy with MRI cortical ribbon and reversible white matter hyperintensities
Authors: Morrison Hamish , Morgan Dafydd , Smith Matthew , Mclauchlan Duncan , Johnston Ann
Published: September 2019

We present an unusual case of encephalopathy with profound MR white matter and cortical abnormalities secondary to, and responsive to treatment for, hepatic encephalopathy alone.

A 52-year-old man with known alcohol related liver disease (now abstinent), previous intravenous drug abuse and treated Hepatitis C presented over 18 months with discrete episodes of fluctuating confusion, and altered consciousness progressing to coma.

Neuroimaging demonstrated symmetrical confluent white matter T2/ FLAIR hyperintensities in the posterior frontal and parietal lobes with symmetrical dWI cortical ribboning in the precentral gyrus. Due to his clinical state and the unusual neuroimaging findings he was transferred for further neurological investigation and management.

On admission a serum ammonia was 111 µmol/L (normal range 16 – 60 µmol/L). Further to this a detailed systemic blood, imaging and CSF analysis did not yield an alternative diagnosis. Electroencephalography revealed generalised slowing.

Serial imaging showed persistent, fluctuating, confluent, and symmetrical white matter T2/ FLAIR hyperintensities. Fluctuations in his clinical state correlated with serum ammonia levels, bowel motions, neuroimaging and the EEG findings. He was treated for hepatic encephalopathy alone, on one occasion in intensive care, with lactulose, phosphate enemas and diuretics. He was discharged home independently after a period of sustained clinical improvement.