bluuebunny/crossref_metadata_2025 huggingface dataset:
The siRNA‐mediated downregulation of PD‐1 alone or simultaneously with CTLA‐4 shows enhanced in vitro CAR‐T‐cell functionality for further clinical development towards the potential use in immunotherapy of melanoma
Authors: Simon Bianca , Harrer Dennis C. , Schuler‐Thurner Beatrice , Schaft Niels , Schuler Gerold , Dörrie Jan , Uslu Ugur
Published: April 2018

Chimeric antigen receptor (CAR)‐T cells have been used successfully for cancer immunotherapy. While substantial tumor regression was observed in leukaemia and lymphoma, CAR therapy of solid tumors needs further improvement. A major obstacle to the efficiency of engineered T cells is posed by triggering of inhibitory receptors, for example programmed cell death protein 1 (PD‐1) and cytotoxic T lymphocyte–associated protein 4 (CTLA‐4), leading to an impaired antitumor activity. To boost CAR‐T‐cell function, we co‐electroporated T cells with both, mRNA encoding a CAR specific for chondroitin sulphate proteoglycan 4 (CSPG4) and small‐interfering RNAs (siRNAs) to downregulate PD‐1 (siPD‐1) and CTLA‐4 (siCTLA‐4). Flow cytometry revealed that activation‐induced upregulation of both PD‐1 and CTLA‐4 was suppressed when compared to CAR‐T cells electroporated with negative control siRNA. The siRNA transfection showed no influence on CAR expression of engineered T cells. Functionality assays were performed using PD‐L1‐ and CD80‐transfected melanoma cells endogenously expressing CSPG4. CAR‐T cells transfected with siPD‐1 alone showed improvement in cytokine secretion. Additionally, CAR‐T cells transfected with either siPD‐1 alone or together with siCTLA‐4 exhibited a significantly increased cytotoxicity. No or only little effects were observed when CAR‐T cells were co‐transfected with siCTLA‐4 only. Taken together, it is feasible to optimize CAR‐T cells by co‐transfection of CAR‐encoding mRNA and siRNAs to downregulate inhibitory receptors. Our in vitro data indicate an improvement of the functionality of these CAR‐T cells, suggesting that this strategy could represent a novel method to enhance CAR‐T‐cell immunotherapy of cancer.
Neuraminidase A from Streptococcus pneumoniae has a modular organization of catalytic and lectin domains separated by a flexible linker
Authors: Sharapova Yana , Suplatov Dmitry , Švedas Vytas
Published: April 2018

Neuraminidase A (NanA) of the pathogen Streptococcus pneumoniae cleaves receptors of the human respiratory epithelial surface during bacterial colonization. The full‐size structure of NanA that contains one lectin and one catalytic domain within a single polypeptide chain remains unresolved. Both domains are crucial for the microorganism's virulence and considered as promising antimicrobial targets. Methods of bioinformatics and molecular dynamics have been implemented to model NanA's structure and study interaction between the lectin and catalytic domains in three neuraminidases NanA, NanB, and NanC from Streptococcus pneumoniae. A significant difference in spatial organization of these homologous enzymes has been revealed. The lectin and catalytic domains of NanB and NanC form rigid globules stabilized by multiple interdomain interactions, whereas in NanA, the two domains are separated by a 16 amino acids long flexible linker – a characteristic of proteins that require conformational flexibility for their functioning. The biological role of this structural adaptation of NanA as a key virulence enzyme is discussed.
External cervical resorption‐part 1: histopathology, distribution and presentation
Authors: Patel S. , Mavridou A. M. , Lambrechts P. , Saberi N.
Published: April 2018

External cervical resorption (ECR) is the loss of dental hard tissue as a result of odontoclastic action. It is a dynamic process that involves periodontal, dental and in later stages pulpal tissues. Over the last two decades, ECR has attracted increased interest; this is in part due to novel micro‐CT and histopathological techniques for its assessment and also improved radiographic detection using CBCT. This literature review will cover the aetiology, potential predisposing factors, histopathology and diagnosis of ECR. Part 2 will cover the management of ECR.
Association of manual or engine‐driven glide path preparation with canal centring and apical transportation: a systematic review
Authors: Hartmann R. C. , Peters O. A. , de Figueiredo J. A. P. , Rossi‐Fedele G.
Published: April 2018

The role and effect of glide path preparation in root canal treatment remain controversial. This systematic review aims to compare apical transportation and canal centring of different glide path preparation techniques, with or without subsequent engine‐driven root canal preparation. A database search in PubMed, PubMed Central, Embase, Scopus, EBSCO Dentistry & Oral Sciences Source and Virtual Health Library was conducted, using appropriate key words to identify the effect of glide path preparation (or its absence) on apical transportation and canal centring. An assessment for the risk of bias in included studies was carried out. Amongst 2146 studies, 18 satisfied the inclusion criteria. Nine studies assessed glide path preparation per se, comparing apical transportation and canal centring of rotary systems and/or manual files; eleven further investigations examined the efficacy of the glide path prior to final canal preparation with different engine‐driven systems. Risk of bias and other study design features with potential influence on study outcomes and clinical implications were assessed. Based on the available evidence, and within the limitation of the studies included, preparation of a glide path using rotary sequences performs similarly (in most of the component studies) or significantly better than manual preparation when assessing apical transportation or canal centring. When compared to the absence of a glide path, canal shaping following glide path preparation was of similar, or significantly better quality, in regard to apical transportation or canal centring.
Colocating an accredited practising dietitian to an adult community mental health service: An exploratory study
Authors: Furness Trentham , Wallace Elizabeth , McElhinney Jo , McKenna Brian , Cuzzillo Celeste , Foster Kim
Published: April 2018

For people with severe mental illness, accredited practising dietitians may assist with a nutrition care plan that considers the medical, psychiatric, psychological, social, spiritual, and pharmacological aspects of their care. However, consumers’ access to care has been limited by difficulties attending appointments and suboptimal interface between nutritional and mental health services. Therefore, the objectives of this exploratory study were to describe access to, and key stakeholder perspectives of, the accredited practising dietitian role colocated in a community mental health service. A total of 16 key stakeholders participated in one‐to‐one interviews. Two main themes with subthemes were derived from analysis of interviews: (i) ‘building empowerment and collaboration’ and included the subthemes, (a) nutrition awareness and education and (b) healthy lifestyle changes, and (ii) ‘overcoming challenges to optimal nutrition and effective health care’. In addition, improved access to the role was demonstrated with 124 (79%) consumers attending at least one appointment with an accredited practising dietitian. A total of 15 (12%) consumers attended more than 10 appointments during their outpatient admission to the community mental health service. Colocating an accredited practising dietitian was perceived to build empowerment and collaboration, and overcome challenges to optimal nutrition and effective health care for consumers, carers, and clinicians. The colocation of a dietitian can empower consumers’ to make health‐informed decisions and support their willingness to engage with physical healthcare provision when it is prioritized alongside mental healthcare provision.
Twenty‐first‐century skin findings response
Authors: Reese V. , Croley J.A. , Ryan M.P. , Wagner R.F.
Published: April 2018

Linked article: This article is commentary on by Y. Ishida et al., p. e425 in this issue. To view this article visithttps://doi.org/10.1111/jdv.15013
The role of interleukins in vitiligo: a systematic review
Authors: Gomes I.A. , de Carvalho F.O. , de Menezes A.F. , Almeida F.M. , Shanmugam S. , de Souza Siqueira Quintans J. , Quintans‐Júnior L.J. , de Moura T.R. , Oliveira P.D. , de Souza Araújo A.A.
Published: April 2018

Vitiligo is a disorder of the skin that causes depigmentation and asymptomatic macules whose exact cause is still unclear. Although its aetiology is not fully elucidated, the main theory of its pathomechanism is that it is associated with the autoimmune process. There is few summarized information about the role of inflammatory mediators, as interleukins, in vitiligo, so our aim was to present a systematic review of the role of interleukins in vitiligo, focusing on interleukins. In this review, we included all studies assessing interleukin levels in vitiligo patients conducted up to June 2017. Quality assessment of these studies was performed using the Newcastle‐Ottawa Scale (NOS). The interleukins mainly involved were IL‐2, IL‐4, IL‐6, IL‐10 and IL‐17. The studies highlight the crucial role of IL‐17 in the onset and progression of the disease, and its synergistic action with IL‐2, IL‐6 and IL‐33. Dysregulated levels of the interleukins were also correlated with the stage of disease, the affected skin surface area, and indicated as the main factor for lymphocyte infiltration found in depigmented regions. These findings illustrate the growing need for new therapies targeting vitiligo and further research into the role of interleukins as an area of particular interest.
Relations between a standardized experimental stressor and cutaneous sensory function in patients with chronic pruritus and healthy controls: an experimental case–control study
Authors: Schneider G. , Stumpf A. , Burgmer M. , Volmering L. , Broecker P. , Ständer S.
Published: April 2018

Background

While chronic pruritus (CP) is a frequent symptom, many aspects of its underlying pathophysiological mechanisms still need elucidation. Research on sensory cutaneous function and on the influence of stress has been conducted mainly in patients with atopic dermatitis but is lacking for patients withCP.

Objective

To assess whether a standardized social stressor influences cutaneous sensory function in patients withCPin comparison with healthy controls (HC).

Methods

Case–control study; 33CPand 30HCwere submitted to the standardized quantitative sensory testing protocol before and after the Trier Social Stress Test and 1 h later. Intraepidermal nerve fibre density (IENFD) was determined.

Results

Mechanical pain sensitivity and mechanical detection thresholds were significantly higher inCPthan inHC, and mechanical detection thresholds increased more inCPthan inHCover the three measurements. In both groups, cold pain threshold increased and heat pain threshold decreased from before to after the stress test and remained constant 1 h later. Only inCP, almost allQSTtests induced at least a small amount of pruritus, which was not significantly altered by the stress test.IENFDin pruritic skin was significantly reduced inCPwhen compared to healthy controls.

Conclusion

Peripheral thermal sensory function was not altered inCPdespite reducedIENFDin lesional skin, but we could demonstrate central sensitization processes specifically inCPand influences of an acute stressor inducing more sensitivity to thermal pain in both groups.
The smart approach: feasibility of lentigo maligna superficial margin assessment with hand‐held reflectance confocal microscopy technology
Authors: Pellacani G. , De Carvalho N. , Ciardo S. , Ferrari B. , Cesinaro A.M. , Farnetani F. , Bassoli S. , Guitera P. , Star P. , Rawson R. , Rossi E. , Magnoni C. , Gualdi G. , Longo C. , Scope A.
Published: April 2018

Background

Lentigo maligna may be challenging to clear surgically.

Objective

To evaluate feasibility of using superficial skin cuts as RCM imaging anchors for attaining negative surgical margins in lentigo maligna.

Methods

Included patients presented with lentigo maligna near cosmetically sensitive facial structures. We evaluated, with hand‐held‐RCM, microscopic clearance of melanoma beyond its dermoscopically detected edges. Evaluated margins were annotated using shallow skin cuts. If a margin was positive at ‘first‐step’ RCM evaluation, we sequentially advanced the margin radially outward at that segment by 2‐mm intervals until an RCM‐negative margin was identified. Prior to final surgical excision, we placed sutures at the outmost skin cuts to allow comparison of RCM and histopathological margin assessments. Primary outcome measure was histopathological verification that RCM‐negative margins were clear of melanoma.

Results

The study included 126 first‐step margin evaluations in 23 patients, median age 70 years (range: 43–91). Seventeen patients (74%) had primary in‐situ melanoma and six (26%) invasive melanoma, mean thickness 0.3 mm (range 0.2–0.4 mm). Six cases (26%) showed complete negative RCM margins on ‘first‐step’, 11 (48%) were negative at ‘second‐step’, and four (17%) at ‘third‐step’. In two additional cases (9%), margins clearance could not be determined via RCM due to widespread dendritic cells proliferation. The RCM‐negative margins in all 21 cases proved clear of melanoma on histopathology. Of the 15 cases that returned at 1‐year follow‐up, none showed any residual melanoma on dermoscopic and RCM examinations. Interobserver reproducibility showed fair agreement between bedside RCM reader and blinded remote‐site reader, with Spearman's rho of 0.48 and Cohen's kappa of 0.43; using bedside reader as reference, the remote reader's sensitivity was 92% and specificity 57% in positive margin detection.

Conclusions

Margin mapping of lentigo maligna with hand‐held‐RCM, using superficial skin cuts, appears feasible. This approach needs validation by larger studies.
The early exhumation history of the Western TianshanUHPmetamorphic belt, China: New constraints from titanite U–Pb geochronology and thermobarometry
Authors: Zhang Lijuan , Chu Xu , Zhang Lifei , Fu Bin , Bader Thomas , Du Jinxue , Li Xiaoli
Published: April 2018

The Chinese Western Tianshan terrane is a well‐known ultrahigh‐pressure (UHP) metamorphic belt that mainly consists of subducted oceanic crustal materials. While two uplift stages have been recognized, the early exhumation history has not been fully constrained. We conducted U–Th–Pb and trace element microanalysis of titanite as well as zircon fromUHPeclogites. Apart from several inclusions in garnet, three types of retrograde titanite have been identified based on their petrographic occurrences: (a) in matrix enclosing relict rutile; (b) as coarse‐grained coronas around garnet; and (c) in veins coexisting with epidote and/or apatite. The three types of titanite are homogeneous in chemical composition, low in Al, enriched in middle rare earth elements (REEs), and depleted in lightREEs and heavyREEs, suggesting their growth during retrograde decompression. Sensitive high‐resolution ion microprobe (SHRIMP) andLA‐ICP‐MSU–Pb dating of titanite from four samples, regardless of their textural occurrences, gave consistent ages ofc. 306 Ma. Phase equilibria modelling and Zr‐in‐titanite thermometry indicate that titanite replaced rutile at ~14 kbar and ~570°C, following a nearly isothermal decompression from theUHPpeak conditions of 30 kbar and 550–570°C.SHRIMPzircon U–Pb dating yields two age groups:c. 320 Ma andc. 305 Ma. The former is generally interpreted to be the age ofUHPstage. The latter, overlapping the titanite ages, represents the timing of titanite growth during exhumation. Thus, we estimate that the near‐isothermal exhumation from theUHPpeak conditions to the epidote–amphibolite facies retrogression (14 kbar) lastedc. 15 Ma, corresponding to an average exhumation rate of 3.4 ± 2.5 mm/yr (2σ). This exhumation rate lies within the range of oceanicLT‐HPbelts in the absence of continental subduction, suggesting a similar slab exhumation mechanism that operates in theUHPregime. The consistent retrograde metamorphic ages recorded by titanite from different localities, and the general agreement amongP–Tpaths in the adjacent area, suggest that theUHPunit of Western Tianshan metamorphic belt was likely exhumed as a coherent unit.
Substitution of sodium chloride by salt microspheres in dough: Effect on dough rheological properties
Authors: Král Martin , Pospiech Matej , Běhalová Hana , Dordevic Dani , Ošťádalová Martina , Tremlová Bohuslava , Florkiewicz Adam
Published: April 2018

This research aimed to evaluate the impact of different salts on dough rheology parameters and gas cell development during dough preparation. Three types of salts in four concentrations each were used in dough preparation and following analyses were conducted: sodium content, salt structure analysis, dough hardness, dough stickiness and dough image analysis. The research showed how significantly (p < .05) the measured properties of dough can be influenced by the used type of salt, salt concentrations and fermentation time. The emphasis is put on salt substitutes of hollow microsphere salt (Hs) substitutes due to its special physical characteristics. The uniqueness of Hs physical characteristics was confirmed by electron microscope photomicrographs. The gained results are indicating that even low changes in salt concentration (0.40; 0.30; 0.25; and 0.15) make noticeable changes in dough characteristics. The usage of salt substitutes in food industry has been constantly growing and it makes the research a valuable source of information for further application of this salts.

Practical applications

The different salt types (table—Ts, sea—Ss and hollow microsphere—Hs) which were studied in our work differ just slightly. However, an important issue in choosing salt should also be the nutritive perspective, in particular low sodium content as a preventive measure against cardio‐vascular diseases. Hs and Ss are therefore suitable alternatives to typical Ts.
Prognostic importance of plasma total magnesium in a cohort of cats with azotemic chronic kidney disease
Authors: van den Broek D. Hendrik N. , Chang Yu‐Mei , Elliott Jonathan , Jepson Rosanne E.
Published: April 2018

Background

Hypomagnesemia is associated with increased mortality and renal function decline in humans with chronic kidney disease (CKD). Magnesium is furthermore inversely associated with fibroblast growth factor 23 (FGF23), an important prognostic factor in CKD in cats. However, the prognostic significance of plasma magnesium in cats with CKD is unknown.

Objectives

To explore associations of plasma total magnesium concentration (tMg) with plasma FGF23 concentration, all‐cause mortality, and disease progression in cats with azotemic CKD.

Animals

Records of 174 client‐owned cats with IRIS stage 2‐4 CKD.

Methods

Cohort study. Cats with azotemic CKD were identified from the records of two London‐based first opinion practices (1999–2013). Possible associations of baseline plasma tMg with FGF23 concentration and risks of death and progression were explored using, respectively, linear, Cox, and logistic regression.

Results

Plasma tMg (reference interval, 1.73–2.57 mg/dL) was inversely associated with plasma FGF23 when controlling for plasma creatinine and phosphate concentrations (partial correlation coefficient, −0.50;P < .001). Hypomagnesemia was observed in 12% (20/174) of cats, and independently associated with increased risk of death (adjusted hazard ratio, 2.74; 95% confidence interval [CI], 1.35–5.55;P = .005). The unadjusted associations of hypermagnesemia (prevalence, 6%; 11/174 cats) with survival (hazard ratio, 2.88; 95% CI, 1.54–5.38;P = .001), and hypomagnesemia with progressive CKD (odds ratio, 17.7; 95% CI, 2.04–154;P = .009) lost significance in multivariable analysis.

Conclusions and Clinical Importance

Hypomagnesemia was associated with higher plasma FGF23 concentrations and increased risk of death. Measurement of plasma tMg augments prognostic information in cats with CKD, but whether these observations are associations or causations warrants further investigation.
Accumulation of 24 nucleotide transgene‐derived siRNAs is associated with crinivirus immunity in transgenic plants
Authors: Qiao Wenjie , Zarzyńska‐Nowak Aleksandra , Nerva Luca , Kuo Yen‐Wen , Falk Bryce W.
Published: April 2018

RNA silencing is a conserved antiviral defence mechanism that has been used to develop robust resistance against plant virus infections. Previous efforts have been made to develop RNA silencing‐mediated resistance to criniviruses, yet none have given immunity. In this study, transgenic Nicotiana benthamiana plants harbouring a hairpin construct of the Lettuce infectious yellows virus (LIYV) RNA‐dependent RNA polymerase (RdRp) sequence exhibited immunity to systemic LIYV infection. Deep sequencing analysis was performed to characterize virus‐derived small interfering RNAs (vsiRNAs) generated on systemic LIYV infection in non‐transgenic N. benthamiana plants as well as transgene‐derived siRNAs (t‐siRNAs) derived from the immune‐transgenic plants before and after LIYV inoculation. Interestingly, a similar sequence distribution pattern was obtained with t‐siRNAs and vsiRNAs mapped to the transgene region in both immune and susceptible plants, except for a significant increase in t‐siRNAs of 24 nucleotides in length, which was consistent with small RNA northern blot results that showed the abundance of t‐siRNAs of 21, 22 and 24 nucleotides in length. The accumulated 24‐nucleotide sequences have not yet been reported in transgenic plants partially resistant to criniviruses, and thus may indicate their correlation with crinivirus immunity. To further test this hypothesis, we developed transgenic melon (Cucumis melo) plants immune to systemic infection of another crinivirus, Cucurbit yellow stunting disorder virus (CYSDV). As predicted, the accumulation of 24‐nucleotide t‐siRNAs was detected in transgenic melon plants by northern blot. Together with our findings and previous studies on crinivirus resistance, we propose that the accumulation of 24‐nucleotide t‐siRNAs is associated with crinivirus immunity in transgenic plants.
Xanthomonas oryzae pv. oryzae TALE proteins recruit OsTFIIAγ1 to compensate for the absence of OsTFIIAγ5 in bacterial blight in rice
Authors: Ma Wenxiu , Zou Lifang , Zhiyuan JI , Xiameng XU , Zhengyin XU , Yang Yangyang , Alfano James R. , Chen Gongyou
Published: April 2018

Xanthomonas oryzae pv. oryzae (Xoo), the causal agent of bacterial blight (BB) of rice, uses transcription activator‐like effectors (TALEs) to interact with the basal transcription factor gamma subunit OsTFIIAγ5 (Xa5) and activates the transcription of host genes. However, how OsTFIIAγ1, the other OsTFIIAγ protein, functions in the presence of TALEs remains unclear. In this study, we show that OsTFIIAγ1 plays a compensatory role in the absence of Xa5. The expression of OsTFIIAγ1, which is activated by TALE PthXo7, increases the expression of host genes targeted by avirulent and virulent TALEs. Defective OsTFIIAγ1 rice lines show reduced expression of the TALE‐targeted susceptibility (S) genes, OsSWEET11 and OsSWEET14, which results in increased BB resistance. Selected TALEs (PthXo1, AvrXa7 and AvrXa27) were evaluated for interactions with OsTFIIAγ1, Xa5 and xa5 (naturally occurring mutant form of Xa5) using biomolecular fluorescence complementation (BiFC) and microscale thermophoresis (MST). BiFC and MST demonstrated that the three TALEs bind Xa5 and OsTFIIAγ1 with a stronger affinity than xa5. These results provide insights into the complex roles of OsTFIIAγ1 and OsTFIIAγ5 in TALE‐mediated host gene transcription.
Do UV‐A radiation and blue light during growth prime leaves to cope with acute high light in photoreceptor mutants ofArabidopsis thaliana?
Authors: Brelsford Craig C. , Morales Luis O. , Nezval Jakub , Kotilainen Titta K. , Hartikainen Saara M. , Aphalo Pedro J. , Robson T. Matthew
Published: April 2018

We studied how plants acclimated to growing conditions that included combinations of blue light (BL) and ultraviolet (UV)‐A radiation, and whether their growing environment affected their photosynthetic capacity during and after a brief period of acute high light (as might happen during an under‐canopy sunfleck).Arabidopsis thalianaLandsbergerectawild‐type were compared with mutants lacking functional blue light and UV photoreceptors: phototropin 1, cryptochromes (CRY1 and CRY2) and UV RESISTANT LOCUS 8 (uvr8). This was achieved using light‐emitting‐diode (LED) lamps in a controlled environment to create treatments with or without BL, in a split‐plot design with or without UV‐A radiation. We compared the accumulation of phenolic compounds under growth conditions and after exposure to 30 min of high light at the end of the experiment (46 days), and likewise measured the operational efficiency of photosystem II (ϕPSII, a proxy for photosynthetic performance) and dark‐adapted maximum quantum yield (Fv/Fmto assessPSIIdamage). Our results indicate that cryptochromes are the main photoreceptors regulating phenolic compound accumulation in response to BL and UV‐A radiation, and a lack of functional cryptochromes impairs photosynthetic performance under high light. Our findings also reveal a role for UVR8 in accumulating flavonoids in response to a low UV‐A dose. Interestingly, phototropin 1 partially mediated constitutive accumulation of phenolic compounds in the absence of BL. Low‐irradiance BL and UV‐A did not improve ϕPSIIandFv/Fmupon our acute high‐light treatment; however, CRYs played an important role in ameliorating high‐light stress.
MaBZR1/2 act as transcriptional repressors of ethylene biosynthetic genes in banana fruit
Authors: Guo Yu‐fan , Shan Wei , Liang Shu‐min , Wu Chao‐jie , Wei Wei , Chen Jian‐ye , Lu Wang‐jin , Kuang Jian‐fei
Published: April 2018

Banana fruit (Musa acuminate L.) ripening is a complex genetical process affected by multiple phytohormones and expression of various genes. However, whether plant hormone brassinosteroid (BR) is involved in this process remains obscure. In this work, three genes that encode BR core signaling components brassinazole resistant (BZR) proteins, namely MaBZR1 to MaBZR3, were characterized from banana fruit. MaBZR1‐MaBZR3 exhibited both nuclear and cytoplasmic localization and behaved as transcription inhibitors. Expression analysis showed that MaBZR1/2/3 were continuously decreased as fruit ripening proceeded, indicating their negative roles in banana ripening. Moreover, gel shift and transient expression assays demonstrated that MaBZR1/2 could suppress the transcription of ethylene biosynthetic genes, including MaACS1, MaACO13 and MaACO14, which increased gradually during the banana ripening, via specifically binding to CGTGT/CG sequence in their promoters. Importantly, exogenous application of BRs promotes banana ripening, which is presumably due to the accelerated expression of MaACS1 and MaACO13/14, and consequently the ethylene production. Our study indicates that MaBZR1/2 act as transcriptional repressors of ethylene biosynthetic genes during banana fruit ripening.
Methods for Preferential Sampling in Geostatistics
Authors: Dinsdale Daniel , Salibian-Barrera Matias
Published: April 2018

Preferential sampling in geostatistics occurs when the locations at which observations are made may depend on the spatial process that underlines the correlation structure of the measurements. We show that previously proposed Monte Carlo estimates for the likelihood function may not be approximating the desired function. Furthermore, we argue that, for preferential sampling of moderate complexity, alternative and widely available numerical methods to approximate the likelihood function produce better results than Monte Carlo methods. We illustrate our findings on the Galicia data set analysed previously in the literature.
Distribution of exogenous complement factor H in mice in vivo
Authors: Koskinen A. R. , Cheng Z.‐Z. , Pickering M. C. , Kairemo K. , Meri T. , Cook H. T. , Meri S. , Jokiranta T. S.
Published: April 2018

Factor H is an important regulator of complement activation in plasma and on cell surfaces in both humans and mice. If FH function is compromised, inappropriate complement activation on self‐surfaces can have disastrous effects as seen in the kidney diseases atypical haemolytic uremic syndrome (aHUS) and C3 glomerulopathy. As FH constructs have been proposed to be used in treatment for these diseases, we studied the distribution of exogenous FH fragments in mice. Full‐length mFH, mFH1‐5 and mFH18‐20 fragments were radiolabelled, and their distribution was examined in WT, FH−/− and FH−/−C3−/− mice in vivo. Whole body scintigraphy revealed accumulation of radioactivity in the abdominal part of the mice, but also to the thyroid gland and urinary bladder. At organ level in WT mice, some full‐length FH accumulated in internal organs, but most of it remained in the circulation. Both of the mFH fragments accumulated in the kidneys and were excreted in urine. For mFH1‐5, urinary secretion is the likely cause for the accumulation. Concentration of mFH18‐20 to kidneys was slower, and at tissue level, mFH18‐20 was localized at the proximal tubuli in WT and FH−/−C3−/− mice. No C3‐independent binding to glomeruli was detected. In conclusion, these results show that glomerular glycosaminoglycans and sialic acids alone do not collect FH in kidneys. Deposition of C3 fragments is also needed, which implies that in aHUS, the problem is in simultaneous recognition of C3 fragments and glycosaminoglycans or sialic acids by FH, not just the inability of FH to recognize glomerular endothelium as such.
‘Was it meant to be mean?’ Young children's hostile attributional bias and intent attribution skills
Authors: van Dijk Anouk , de Castro Bram Orobio , Thomaes Sander , Poorthuis Astrid M. G.
Published: April 2018

Two studies investigated whether young children's hostile attributional bias (i.e., the tendency to assume that others have hostile intentions) may be explained by a lack of intent attribution skills (i.e., the ability to correctly infer others’ intentions). We also investigated whether these intent attribution skills depend on children's false‐belief understanding. Children who lack false‐belief understanding may base their attributions on the observable outcomes of others’ behavior, rather than on others’ intentions. These hypotheses were tested by assessing intent attributions made by children ages 3–7 years. We systematically varied intent and outcome information in vignettes (Study 1, N = 151) and staged interactions with puppets (Study 2, N = 85). Results replicated across studies. Children who understood false belief (vs. those who did not) based their attributions more on intent information. However, these intent attribution skills did not affect children's hostile attributional bias. Exploratory analyses showed that children with higher levels of hostile attributional bias, more than others, based their attributions on outcome information. Thus, the findings from this research do not support the assumption that young children with a hostile attributional bias lack intent attribution skills; instead, the findings suggest that these children have a heightened sensitivity for negative outcomes.
HLA‐DQB1*03:01:40, an HLA‐DQB1*03:01 variant, identified in a Taiwanese individual
Authors: Yang K. L. , Lin P. Y.
Published: April 2018

One nucleotide substitution at codon 106 of HLA‐DQB1*03:01:01:01 results in a new allele, HLA‐DQB1*03:01:40.
Spatial analysis of reported new cases and local risk of leprosy in hyper‐endemic situation in Northeastern Brazil
Authors: Barbosa Celivane Cavalcanti , Bonfim Cristine Vieira do , de Brito Cintia Michele Gondim , Ferreira Andrea Torres , Gregório Vera Rejane do Nascimento , de Oliveira André Luiz Sá , Portugal José Luiz , de Medeiros Zulma Maria
Published: April 2018

Objective

To analyse the spatial distribution of the incidence of leprosy and identify areas at risk for occurrences of hyper‐endemic disease in Northeastern Brazil.

Methods

Ecological study using municipalities as the analysis unit. Data on new cases of leprosy came from the Health Hazard Notification System (SINAN). This study focused on Pernambuco and covered the years 2005 to 2014. Indicators for monitoring were calculated per 100 000 inhabitants. The local empirical Bayes method was used to minimise rate variance, and spatial autocorrelation maps were used for spatial pattern analysis (box maps and Moran maps).

Results

A total of 28 895 new cases were registered in the study period. The average incidence was 21.88/100 000; the global Moran's I index was 0.36 (P < 0.01), thus indicating the existence of spatial dependence; and the Moran map identified 20 municipalities with high priority for attention. The average incidence rate among individuals under 15 years of age was 8.78/100 000; the global Moran's I index showed the presence of positive spatial autocorrelation (0.43; P < 0.01), and the Moran map showed a main cluster of 15 hyper‐endemic municipalities. The average rate of grade 2 physical disability at the time of diagnosis was 1.12/100 000; the global Moran index presented a positive spatial association (0.17; P < 0.01); and the Moran map located clusters of municipalities (high‐high) in three mesoregions.

Conclusion

Application of different spatial analysis methods made it possible to locate areas that would not have been identified by epidemiological indicators alone.
The effect of ischaemic preconditioning on central and peripheral fatiguing mechanisms in humans following sustained maximal isometric exercise
Authors: Halley Samuel L. , Marshall Paul , Siegler Jason C.
Published: April 2018

New Findings

What is the central question of this study?

Does ischaemic preconditioning (IPC) influence central and peripheral fatiguing mechanisms during sustained maximal isometric exercise?

What is the main finding and its importance?

Voluntary activation and pre‐ to postexercise reductions in resting twitch torque values were unchanged by IPC. However, an effect on tissue oxygenation was observed within the IPC trials, where greater concentrations of deoxyhaemoglobin were recorded with concurrent upward trends of total haemoglobin concentrations. Using a direct assessment of neural drive, we found that IPC had no influence on either central or peripheral fatiguing pathways after maximal isometric exercise.

Ischaemic preconditioning (IPC) is thought to inhibit neural feedback from metabolically sensitive muscle afferents during exercise. It was hypothesized that IPC could affect mechanisms associated with centrally mediated fatigue after a maximally fatiguing protocol. Eleven resistance‐trained men completed three 2 min maximal voluntary contractions (MVCs) via an isometric leg extension preceded by treatments of IPC (three bouts of 5 min bilateral leg occlusions at 220 mmHg), SHAM (three bouts of 5 min at 20 mmHg) or CON (30 min passive rest). Femoral nerve stimulation was used to explore central and peripheral fatigue pathways. These pathways were profiled at baseline (BL), before the 2 min MVC (Pre) and 10 s afterwards (Post). Tissue oxygenation was measured throughout the 2 min MVCs via near‐infrared spectroscopy. The Pre to Post MVC (−71 ± 56 Nm; d = 1.33 ± 0.51, P < 0.01) and twitch torque (−51 ± 20 Nm; d = 3.76 ± 0.84, P < 0.01) levels declined without differences between conditions (MVC, P = 0.67; twitch torque, P = 0.39). Voluntary activation was also unaffected by condition (P = 0.80). Peak deoxyhaemoglobin concentrations were elevated in the IPC trials relative to CON (3.7 ± 3.0 μmol l−1; d = 1.02 ± 0.46, P < 0.01) and SHAM (3.0 ± 3.7 μmol l−1; d = 0.82 ± 0.57, P < 0.05). These findings demonstrate that IPC does not affect central or peripherally mediated mechanisms of fatigue during a sustained 2 min maximal effort isometric leg‐extension task.
Physical Education and Leisure-Time Physical Activity in Youth Are Both Important for Adulthood Activity, Physical Performance, and Health
Authors: Ekblom-Bak Elin , Ekblom Örjan , Andersson Gunnar , Wallin Peter , Ekblom Björn
Published: April 2018

Background: The importance of youth physical activity (PA) for adulthood PA, performance, and health was retrospectively evaluated. Methods: A total of 258,146 participants (49% women), aged 19–70, with a first-time health-profile assessment between 1982 and 2015, provided self-reported data on current perceived health, PA, lifestyle, and physical education class participation, and PA outside school hours before age 20. Data on anthropometrics, blood pressure, and estimated maximal oxygen consumption (VO2max) were obtained. Results: Women participating in physical education class, compared with those who did not, had significantly lower OR (range: 0.81–0.87) for perceiving poor overall health, general obesity, and high diastolic blood pressure after adjustment for potential confounders, and increased OR (range: 1.17–1.23) for exercising regularly and a normal/high VO2max in adulthood. For men, the ORs were significantly lower (range: 0.66–0.86) for poor perceived overall health, general, and abdominal obesity. These associations were seen for participants up to 70 years. Increased PA outside school hours revealed even stronger beneficial associations. In joint analyses, both youth and current PA were important for lower OR of poor health and being obese in adulthood. Conclusions: Physical education class participation and additional PA after school hours were both important for perceived health, PA, VO2max, and metabolic health in adulthood up to 70 years.
Does screening for congenital cytomegalovirus at birth improve longer term hearing outcomes?
Authors: Hilditch Cathie , Liersch Bianca , Spurrier Nicola , Callander Emily J , Cooper Celia , Keir Amy K
Published: April 2018

Currently, the diagnosis of congenital cytomegalovirus (cCMV) infection in most highly resourced countries is based on clinical suspicion alone. This means only a small proportion of cCMV infections are diagnosed. Identification, through either universal or targeted screening of asymptomatic newborns with cCMV, who would previously have gone undiagnosed, would allow for potential early treatment with antiviral therapy, ongoing audiological surveillance and early intervention if sensorineural hearing loss (SNHL) is identified. This paper systematically reviews published papers examining the potential benefits of targeted and universal screening for newborn infants with cCMV. We found that the treatment of these infants with antiviral therapy remains controversial, and clinical trials are currently underway to provide further answers. The potential benefit of earlier identification and intervention (eg, amplification and speech therapy) of children at risk of later-onset SNHL identified through universal screening is, however, clearer.
Development of a screening tool to predict the risk of chronic pain and disability following musculoskeletal trauma: protocol for a prospective observational study in the United Kingdom
Authors: Rushton Alison B , Evans David W , Middlebrook Nicola , Heneghan Nicola R , Small Charlotte , Lord Janet , Patel Jaimin M , Falla Deborah
Published: April 2018

Introduction

Pain is an expected and appropriate experience following traumatic musculoskeletal injury. By contrast, chronic pain and disability are unhelpful yet common sequelae of trauma-related injuries. Presently, the mechanisms that underlie the transition from acute to chronic disabling post-traumatic pain are not fully understood. Such knowledge would facilitate the development and implementation of precision rehabilitation approaches that match interventions to projected risk of recovery, with the aim of preventing poor long-term outcomes. The aim of this study is to identify a set of predictive factors to identify patients at risk of developing ongoing post-traumatic pain and disability following acute musculoskeletal trauma. To achieve this, we will use a unique and comprehensive combination of patient-reported outcome measures, psychophysical testing and biomarkers.

Methods and analysis

A prospective observational study will recruit two temporally staggered cohorts (n=250 each cohort; at least 10 cases per candidate predictor) of consecutive patients with acute musculoskeletal trauma aged ≥16 years, who are emergency admissions into a Major Trauma Centre in the United Kingdom, with an episode inception defined as the traumatic event. The first cohort will identify candidate predictors to develop a screening tool to predict development of chronic and disabling pain, and the second will allow evaluation of the predictive performance of the tool (validation). The outcome being predicted is an individual’s absolute risk of poor outcome measured at a 6-month follow-up using the Chronic Pain Grade Scale (poor outcome ≥grade II). Candidate predictors encompass the four primary mechanisms of pain:nociceptive(eg, injury location),neuropathic(eg, painDETECT),inflammatory(biomarkers) andnociplastic(eg, quantitative sensory testing). Concurrently, patient-reported outcome measures will assess general health and psychosocial factors (eg, pain self-efficacy). Risk of poor outcome will be calculated using multiple variable regression analysis.

Ethics and dissemination

Approved by the NHS Research Ethics Committee (17/WA/0421).
Novel augmented reality solution for improving health literacy around antihypertensives in people living with type 2 diabetes mellitus: protocol of a technology evaluation study
Authors: Ahmadvand Alireza , Drennan Judy , Burgess Jean , Clark Michele , Kavanagh David , Burns Kara , Howard Sarah , Kelly Fleur , Campbell Chris , Nissen Lisa
Published: April 2018

Introduction

Low health literacy is common in people with type 2 diabetes mellitus (T2DM) (up to 40%), associated with decreased self-efficacy in managing T2DM and its important complications, mainly hypertension. This study introduces, for the first time, an easy-to-use solution based on augmented reality (AR) on smartphones, to enhance health literacy around antihypertensive medicines. It assesses the feasibility of the solution for improving health literacy, oriented specifically to angiotensin II receptor blockers; embedding the health literacy improvement into the use cycle of angiotensin II receptor blockers and providing continuous access to information as a form of patient engagement.

Methods and analysis

This is a technology evaluation study with one technology group (AR plus usual care) and one non-technology group (usual care). Both groups receive face-to-face communications with community pharmacists regarding angiotensin II receptor blockers; the technology group receive additional AR-enhanced digital consumer medicine information throughout the use of their medications. The primary outcome is the change in health literacy and the hypothesis is that the proportions of people who show high health literacy will be larger in the technology group. Mixed effects models will be used to analyse solution effectiveness on outcomes. Multiple regression models will be used to find additional variables that might affect the relationship between health literacy and the AR solution.

Ethics and dissemination

Queensland University of Technology (QUT) Human Research Ethics Committee has approved the study as a low-risk technology evaluation study (approval number: 1700000275). Findings will be disseminated via attending scientific conferences and publishing in peer-reviewed journals. Facilitated by QUT, two press releases have been published in public media and two presentations have been made in university classrooms.
Identification and initial response to children’s exposure to intimate partner violence: a qualitative synthesis of the perspectives of children, mothers and professionals
Authors: Lewis Natalia V , Feder Gene S , Howarth Emma , Szilassy Eszter , McTavish Jill R , MacMillan Harriet L , Wathen Nadine
Published: April 2018

Objectives

To synthesise evidence on the acceptable identification and initial response to children’s exposure to intimate partner violence (IPV) from the perspectives of providers and recipients of healthcare and social services.

Design

We conducted a thematic synthesis of qualitative research, appraised the included studies with the modified Critical Appraisal Skills Programme checklist and undertook a sensitivity analysis of the studies scored above 15.

Data sources

We searched eight electronic databases, checked references and citations and contacted authors of the included studies.

Eligibility criteria

We included qualitative studies with children, parents and providers of healthcare or social services about their experiences of identification or initial responses to children’s exposure to IPV. Papers that have not been peer-reviewed were excluded as well as non-English papers.

Results

Searches identified 2039 records; 11 studies met inclusion criteria. Integrated perspectives of 42 children, 212 mothers and 251 professionals showed that sufficient training and support for professionals, good patient-professional relationship and supportive environment for patient/clients need to be in place before enquiry/disclosure of children’s exposure to IPV should occur. Providers and recipients of care favour a phased enquiry about IPV initiated by healthcare professionals, which focuses on ‘safety at home’ and is integrated into the context of the consultation or visit. Participants agreed that an acceptable initial response prioritises child safety and includes emotional support, education about IPV and signposting to IPV services. Participants had conflicting perspectives on what constitutes acceptable engagement with children and management of safety. Sensitivity analysis produced similar results.

Conclusions

Healthcare and social service professionals should receive sufficient training and ongoing individual and system-level support to provide acceptable identification of and initial response to children’s exposure to IPV. Ideal identification and responses should use a phased approach to enquiry and the WHO Listen, Inquire about needs and concerns, Validate, Enhance safety and Support principles integrated into a trauma-informed and violence-informed model of care.
Education, job position, income or multidimensional indices? Associations between different socioeconomic status indicators and chronic low back pain in a German sample: a longitudinal field study
Authors: Fliesser Michael , De Witt Huberts Jessie , Wippert Pia-Maria
Published: April 2018

Objective

To investigate associations between socioeconomic status (SES) indicators (education, job position, income, multidimensional index) and the genesis of chronic low back pain (CLBP).

Design

Longitudinal field study (baseline and 6-month follow-up).

Setting

Four medical clinics across Germany.

Participants

352 people were included according to the following criteria: (1) between 18 and 65 years of age, (2) intermittent pain and (3) an understanding of the study and the ability to answer a questionnaire without help. Exclusion criteria were: (1) pregnancy, (2) inability to stand upright, (3) inability to give sick leave information, (4) signs of serious spinal pathology, (5) acute pain in the past 7 days or (6) an incomplete SES indicators questionnaire.

Outcome measures

Subjective intensity and disability of CLBP.

Results

Analysis showed that job position was the best single predictor of CLBP intensity, followed by a multidimensional index. Education and income had no significant association with intensity. Subjective disability was best predicted by job position, succeeded by the multidimensional index and education, while income again had no significant association.

Conclusion

The results showed that SES indicators have different strong associations with the genesis of CLBP and should therefore not be used interchangeably. Job position was found to be the single most important indicator. These results could be helpful in the planning of back pain care programmes, but in general, more research on the relationship between SES and health outcomes is needed.