bluuebunny/crossref_metadata_2025 huggingface dataset:
Intranasal administration of probiotic Lactobacillus rhamnosus GG prevents birch pollen‐induced allergic asthma in a murine model
Authors: Spacova I. , Petrova M. I. , Fremau A. , Pollaris L. , Vanoirbeek J. , Ceuppens J. L. , Seys S. , Lebeer S.
Published: June 2018

Background

There is an increasing interest in targeted application of probiotic bacteria for prevention and treatment of airway diseases, including allergies. Here, we investigated the beneficial effects of preventive intranasal treatment with probiotics Lactobacillus rhamnosus GG and L. rhamnosus GR‐1 in a mouse model of allergic asthma.

Methods

Lactobacillus rhamnosus was administered intranasally eight times on days 1‐4 and 8‐11 at 5 × 108 CFU/dose, followed by a 2‐week asthma induction protocol with birch pollen extract on alternating days. Effects of preventive treatment were analyzed based on serum antibody levels, bronchoalveolar lavage cell counts, lung histology, lung cytokine levels, and airway hyperreactivity. Colonization and translocation of L. rhamnosus were assessed by bacterial cell counts in nasal mucosa, fecal samples, cervical lymph nodes, and blood. Binding of fluorescent L. rhamnosus to fixed murine nasal mucosal cells and airway macrophages was visualized by fluorescence microscopy.

Results

Transient colonization of the murine upper airways by L. rhamnosus GG was demonstrated and was approximately ten times higher compared to L. rhamnosus GR‐1. Marked binding of fluorescent L. rhamnosus GG to murine nasal mucosal cells and airway macrophages was visualized. Preventive treatment with L. rhamnosus GG (but not L. rhamnosus GR‐1) resulted in a significant decrease in bronchoalveolar lavage eosinophil counts, lung interleukin‐13 and interleukin‐5 levels, and airway hyperreactivity. A tendency toward a decrease in serum Bet v 1‐specific immunoglobulin G1 was likewise observed.

Conclusion

Intranasally administered L. rhamnosus GG prevents the development of cardinal features of birch pollen‐induced allergic asthma in a strain‐specific manner.
A fast algorithm for univariate log‐concave density estimation
Authors: Liu Yu , Wang Yong
Published: June 2018

A new fast algorithm for computing the nonparametric maximum likelihood estimate of a univariate log‐concave density is proposed and studied. It is an extension of the constrained Newton method for nonparametric mixture estimation. In each iteration, the newly extended algorithm includes, if necessary, new knots that are located via a special directional derivative function. The algorithm renews the changes of slope at all knots via a quadratically convergent method and removes the knots at which the changes of slope become zero. Theoretically, the characterisation of the nonparametric maximum likelihood estimate is studied and the algorithm is guaranteed to converge to the unique maximum likelihood estimate. Numerical studies show that it outperforms other algorithms that are available in the literature. Applications to some real‐world financial data are also given.
Parental severity assessment predicts supportive care in infant bronchiolitis
Authors: Gjengstø Hunderi Jon Olav , Lødrup Carlsen Karin C. , Rolfsjord Leif Bjarte , Carlsen Kai‐Håkon , Mowinckel Petter , Skjerven Håvard Ove
Published: June 2018

Aim

In infants with acute bronchiolitis, the precision of parental disease severity assessment is unclear. We aimed to determine if parental assessment at the time of hospitalisation predicted the use of supportive care, and subsequently determine the likelihood that the infant with acute bronchiolitis would receive supportive care.

Methods

From the Bronchiolitis ALL south‐east Norway study, we included all 267, 0–12 month old, infants with acute bronchiolitis whose parents at the time of hospitalisation completed a three‐item visual analogue scale (VAS) concerning Activity, Feeding and Illness. Respiratory rate, oxygen saturation (SpO2) and use of supportive care were recorded daily. By multivariate logistic regression analyses we included significant predictors available at hospital admission to predict the use of supportive care.

Results

The parental Activity, Feeding and Illness VAS scores significantly predicted supportive care with odds ratios of 1.23, 1.26 and 1.36, respectively. The prediction algorithm included parental Feeding and Illness scores, SpO2, gender and age, with an area under the curve of 0.76 (95% CI 0.69, 0.81). A positive likelihood ratio of 2.1 gave the highest combined sensitivity of 81% and specificity of 61%.

Conclusion

Parental assessment at hospital admission moderately predicted supportive care treatment in infants with acute bronchiolitis.
Questionnaire‐based study showed that neonatal chest radiographs could be reliably interpreted using the WhatsApp messaging application
Authors: Gross Itai , Langer Yshia , Pasternak Yehonatan , Abu Ahmad Wiessam , Eventov‐Friedman Smadar , Koplewitz Benjamin Z.
Published: June 2018

Aim

We surveyed whether clinicians used the WhatsApp messaging application to view neonatal chest radiographs and asked a sub‐sample to compare them with computer screen viewings.

Methods

The study was conducted at three university‐affiliated medical centres in Israel from June–December 2016. Questionnaires on using smartphones for professional purposes were completed by 68/71 paediatric residents and 20/28 neonatologists. In addition, 11 neonatologists viewed 20 chest radiographs on a computer screen followed by a smartphone and 10 viewed the same radiographs in the opposite order, separated by a washout period of 2 months. After another 2 months, five from each group viewed the same radiographs on a computer screen. Different interpretations between viewing modes were assessed.

Results

Most respondents used WhatsApp to send chest radiographs for consultation: 82% of the paediatric residents and 80% of the neonatologists. The mean number of inconsistencies in diagnosis was 3.7/20 between two computer views and 2.9/20 between computer and smartphone views (p = 0.88) and the disease severity means were 3.7/20 and 2.85/20, respectively (p = 0.94). Neonatologists using WhatsApp only determined umbilical line placement in 80% of cases.

Conclusion

WhatsApp was reliable for preliminary interpretation of neonatal chest radiographs, but caution was needed when assessing umbilical lines.
Geographies of the ageing–migration nexus: An introduction
Authors: Sampaio Dora , King Russell , Walsh Katie
Published: June 2018

This special section builds on previous scholarship on geographies of ageing, and on relational and transnational approaches to age and migration, to assert the significance of the ageing–migration nexus in human geography. Our primary goal is to examine the intricate relationships between ageing, migration, space and place. By bringing empirical research on ageing and migration into dialogue with existing conceptual work within Geography, we also aim to critically contribute to current debates in both areas. The contributors explore a wide range of migration processes and experiences through an intersectional lens, and demonstrate the importance of a diverse set of epistemological and methodological approaches to explore the spatialities of the ageing–migration nexus. Key dimensions examined include, but are not limited to, the spaces and places of ageing and migration, the multi‐scalar nature of the geographies of the ageing–migration nexus, their (im)mobilities, fluid boundaries, and emotional geographies.
Effect of vitrification procedures on the subsequent development of in vitro matured swamp buffalo oocytes following in vitro fertilization
Authors: Liang Yuan Yuan , Parnpai Rangsun
Published: June 2018

Nowadays, the efficiency of buffalo oocytes cryopreservation is still low. The purpose of this study was to evaluate effects of two combinations of cryoprotectant agents (CPAs) and two vitrification devices for vitrification of swamp buffalo oocytes on their survival after vitrification warming, and subsequent developmental ability after in vitro fertilization. In vitro matured (IVM) oocytes were vitrified by either Cryotop (CT) or solid surface vitrification (SSV) interacting with vitrification solution A (VA) or B (VB). In the VA or VB solution exposed test, the oocytes showed similar survival rates, but decreased blastocyst rates after in vitro fertilization compared with that of untreated oocytes. After vitrification, the CT method combined with VA solution yielded a higher survival rate (91.3 ± 5.84%) of vitrified oocytes than that combined with VB solution (69.8 ± 4.19%–75.8 ± 4.55%); however, all the vitrification treatments showed lower blastocyst rates (1.1 ± 0.07%–5.2 ± 0.24%) compared with that of untreated oocytes (18.0 ± 1.09%). Our results indicated that combined vitrification treatments in this study did not improve the decreased ability of vitrified oocytes developing to the blastocyst stage.
Innate Immune System Status of Sulphur Mustard‐Poisoned Iranian Veterans Three Decades after Exposure
Authors: Riahi‐Zanjani Bamdad , Balali‐Mood Mahdi , Mahmoudi Mahmoud , Sadeghi Mahmood
Published: June 2018

Sulphur mustard (SM) is an incapacitating chemical warfare agent which causes acute and chronic toxicities in different body organs of affected individuals. The aim of this study was to investigate the innate immune status of the Iranian veterans who were exposed to SM around 30 years earlier and had more than 25% disabilities. In this regard, most functional and non‐functional parameters of innate immunity were evaluated in 35 veterans. Phagocytic activity, nitroblue tetrazolium (NBT) reduction assay and haemolytic complement activity (HCA) in addition to routine haematological parameters, serum protein electrophoresis, complements C3 and C4 levels were studied. Measures of haematological parameters, serum proteins, C3 and C4 were almost within the normal range. Functional experiments such as phagocytic activity, NBT reduction assay and HCA were normal as well. However, serum protein analysis revealed a fair decrease in percentages of α1‐globulin. Mean values of the parameters of innate immune system of the veterans three decades after SM poisoning were almost within the upper and lower normal limits. Reduced α1‐globulin – maybe subsequent to a chain of SM‐induced genetic disorders – may have been the result of α1‐antitrypsin deficiency which may result in prevalent respiratory complications among these veterans. As a supplementary study, measurement of serum α1‐antitrypsin in SM‐poisoned veterans could be beneficial. Further studies are required to prove this hypothesis. Further investigations on the evaluation of the acquired immunity parameters as the second line of defence may reveal a better understanding of SM veterans’ immune system status.
Bonus Effects of Antidiabetic Drugs: Possible Beneficial Effects on Endothelial Dysfunction, Vascular Inflammation and Atherosclerosis
Authors: Pereira Camila A. , Carneiro Fernando S. , Matsumoto Takayuki , Tostes Rita C.
Published: June 2018

Diabetes currently affects more than 400 million people worldwide. This metabolic disorder causes various micro‐ and macrovascular complications that accelerate atherosclerosis and yet trigger other cardiovascular diseases. The characteristic frame of hyperglycaemia, hyperinsulinaemia and hyperlipidaemia in diabetes increases several inflammatory mediators leading to endothelial dysfunction and pro‐atherosclerotic processes. This MiniReview summarizes evidence that antidiabetic drugs have effects beyond lowering glycaemic levels. In experimental studies, antidiabetic drugs reduce the vascular production and release of pro‐inflammatory cytokines, the recruitment, infiltration and activation of immune cells and pro‐inflammatory mediators, thus decreasing vascular inflammatory responses; they also re‐establish vascular redox homeostasis by reducing oxidative stress and balancing the release of vasoconstrictor and vasodilator factors, hence contributing to the improvement of endothelial function. These effects are associated with a reduction in vascular remodelling due to decreased matrix metalloproteinases expression/activity, reduced inflammatory processes and vascular wall fibrosis. In clinical studies, antidiabetic drugs also reduce the production and release of pro‐inflammatory, pro‐atherosclerotic and pro‐oxidative mediators and improve flow‐mediated dilatation, indicating beneficial effects on endothelial function. These bonus effects of antidiabetic drugs may delay and/or reduce the installation and development of the atherosclerotic disease, decrease cardiovascular risk and possibly impact mortality risk, life expectancy and quality.
Overcoming difficulties with equipoise to enable recruitment to a randomised controlled trial of partial ablation vs radical prostatectomy for unilateral localised prostate cancer
Authors: Elliott Daisy , Hamdy Freddie C. , Leslie Tom A. , Rosario Derek , Dudderidge Tim , Hindley Richard , Emberton Mark , Brewster Simon , Sooriakumaran Prasanna , Catto James W.F. , Emara Amr , Ahmed Hashim , Whybrow Paul , le Conte Steffi , Donovan Jenny L.
Published: June 2018

Objective

To describe how clinicians conceptualised equipoise in the PART (Partial prostate Ablation vs Radical prosTatectomy in intermediate‐risk unilateral clinically localised prostate cancer) feasibility study and how this affected recruitment.

Subjects and Methods

PART included a QuinteT Recruitment Intervention (QRI) to optimise recruitment. Phase I aimed to understand recruitment, and included: scrutinising recruitment data, interviewing the trial management group and recruiters (n = 13), and audio‐recording recruitment consultations (n = 64). Data were analysed using qualitative content and thematic analysis methods. In Phase II, strategies to improve recruitment were developed and delivered.

Results

Initially many recruiters found it difficult to maintain a position of equipoise and held preconceptions about which treatment was best for particular patients. They did not feel comfortable about approaching all eligible patients, and when the study was discussed, biases were conveyed through the use of terminology, poorly balanced information, and direct treatment recommendations. Individual and group feedback led to presentations to patients becoming clearer and enabled recruiters to reconsider their sense of equipoise. Although the precise impact of the QRI alone cannot be determined, recruitment increased (from a mean [range] of 1.4 [0–4] to 4.5 [0–12] patients/month) and the feasibility study reached its recruitment target.

Conclusion

Although clinicians find it challenging to recruit patients to a trial comparing different contemporary treatments for prostate cancer, training and support can enable recruiters to become more comfortable with conveying equipoise and providing clearer information to patients.
Phosphodiesterase type 5 in men with vasculogenic and post‐radical prostatectomy erectile dysfunction: is there a molecular difference?
Authors: Karakus Serkan , Musicki Biljana , Burnett Arthur L.
Published: June 2018

Objectives

To clarify the molecular basis of penile erection at the human level and distinguish the mechanisms underlying vasculogenic and post‐radical prostatectomy (RP) erectile dysfunction (ED) subtypes.

Patients and Methods

Erectile tissue was obtained from men without history of ED who underwent penile surgery for Peyronie's disease (control group, n = 5) and from men with ED who underwent penile prosthesis implantation (n = 17). ED was categorized into vasculogenic (n = 8) and post‐RP (n = 9) subtypes. Penile erectile tissue samples were collected for molecular analyses of protein expressions of neuronal and endothelial isoforms of nitric oxide synthase (nNOS and eNOS, respectively), phospho‐nNOS (Ser‐1412), phospho‐eNOS (Ser‐1177), phospho‐protein kinase B (Ser‐473), phosphodiesterase type 5 (PDE5), α‐smooth muscle actin, phospho‐myosin phosphatase target subunit 1, RhoA/Rho‐associated protein kinase (ROCK)‐α, ROCK‐β, 4‐hydroxy‐2‐nonenal, and nNOS and eNOS uncoupling by Western blot.

Results

Vasculogenic ED was characterized by decreased eNOS protein expression and eNOS and nNOS phosphorylation on their activatory sites (Ser‐1177 and Ser‐1412, respectively), uncoupled eNOS, upregulated PDE5 protein expression, increased ROCK activity, and increased oxidative stress in erectile tissue. Post‐RP ED was characterized by decreased nNOS protein expression, increased nNOS phosphorylation on its activatory site (Ser‐1412), uncoupled nNOS, downregulated PDE5 protein expression, and increased oxidative stress in erectile tissue.

Conclusion

The mechanisms of vasculogenic and post‐RP ED in the human penis involve derangements in constitutive nitric oxide synthase function, PDE5 protein expression and ROCK activity, and increased oxidative stress, which conceivably provide a molecular basis for chronically reduced nitric oxide bioavailability and increased smooth muscle contraction contributing to erectile impairment. Selective differences in PDE5 protein expression suggest distinct molecular mechanisms are in play for these ED subtypes.
Svalbard glaciers re‐advanced during the Pleistocene–Holocene transition
Authors: Farnsworth Wesley R. , Ingólfsson Ólafur , Retelle Michael , Allaart Lis , Håkansson Lena M. , Schomacker Anders
Published: June 2018

Despite warming regional conditions and our general understanding of the deglaciation, a variety of data suggest glaciers re‐advanced on Svalbard during the Lateglacial–early Holocene (LGEH). We present the first well‐dated end moraine formed during the LGEH in De Geerbukta, NE Spitsbergen. This landform was deposited by an outlet glacier re‐advancing into a fjord extending 4.4 km beyond the late Holocene (LH) maximum. Comparing the timing of the De Geerbukta glacier re‐advance to a synthesis of existing data including four palaeoclimate records and 15 other proposed glacier advances from Svalbard does not suggest any clear synchronicity in glacial and climatic events. Furthermore, we introduce six additional locations where glacier moraines have been wave‐washed or cut by postglacial raised marine shorelines, suggesting the landforms were deposited before or during high relative sea‐level stands, thus exhibiting a similar LGEH age. Contrary to current understanding, our new evidence suggests that the LGEH glaciers were more dynamic, exhibited re‐advances and extended well beyond the extensively studied LH glacial expansion. Given the widespread occurrence of the LGEH glacier deposits on Svalbard, we suggest that the culmination of the Neoglacial advances during the Little Ice Age does not mark the maximum extent of most Svalbard glaciers since deglaciation; it is just the most studied and most visible in the geological record.
Investigating the agreement between the clinician and research diagnosis of attention deficit hyperactivity disorder and how it changes over time; a clinical cohort study
Authors: Longridge Rachel , Norman Shelley , Henley William , Newlove Delgado Tamsin , Ford Tamsin
Published: June 2018

Background

Attention Deficit Hyperactivity Disorder (ADHD) is a common reason for referral to Child and Adolescent Mental Health Services (CAMHS), but families experience long delays between first professional contact and diagnosis, which risks development of secondary impairments. This study explores the agreement between clinician and research diagnoses of ADHD among children attending CAMHS, and their access to interventions. From the limited literature, we anticipated fluctuation and delays, but no other study has focused prospectively on ADHD diagnoses.

Methods

This was a secondary analysis of a cohort of children attending two CAMHS between 2006 and 2009. The sample included 288 consecutive referrals of children aged between 5 and 11 years. Parents and teachers completed the Development and Well‐Being Assessment (DAWBA) when the child was recruited to the study, which provided the research diagnosis of ADHD from the baseline. Clinicians reported no, possible, or definite diagnosis of ADHD and interventions provided at 6‐monthly intervals for up to 2 years while the child attended CAMHS. We assessed agreement between the diagnoses using Kendall's Tau‐B.

Results

Of the 101 children with a research diagnosis of ADHD, 26 received a definite clinician diagnosis during 2‐year follow‐up, and 47 received a possible clinician diagnosis. The chance‐corrected agreement was poor at all time points (Kendall's Tau‐B 0.14–0.48). Clinician diagnoses were unstable, particularly if possible ADHD was recorded at the initial assessment. Of those with a research diagnosis, 15 were prescribed medication and 11 were offered parent training.

Conclusions

The use of standardised diagnostic assessments could reduce diagnostic uncertainty and increase access to evidence‐based interventions.
Tumor necrosis factor superfamily 15 promotes lymphatic metastasis via upregulation of vascular endothelial growth factor‐C in a mouse model of lung cancer
Authors: Qin Tingting , Huang Dingzhi , Liu Zhujun , Zhang Xiaoling , Jia Yanan , Xian Cory J. , Li Kai
Published: June 2018

Lymphatic metastasis is facilitated by lymphangiogenic growth factor vascular endothelial growth factor‐C (VEGFC) that is secreted by some primary tumors. We previously identified tumor necrosis factor superfamily 15 (TNFSF15), a blood vascular endothelium‐derived cytokine, in lymphatic endothelial cells, as a key molecular modulator during lymphangiogenesis. However, the effect of TNFSF15 on tumor lymphatic metastasis and the underlying molecular mechanisms remain unclear. We report here that TNFSF15, which is known to inhibit primary tumor growth by suppressing angiogenesis, can promote lymphatic metastasis through facilitating lymphangiogenesis in tumors. Mice bearing tumors induced by A549 cells stably overexpressing TNFSF15 exhibited a significant increase in densities of lymphatic vessels and a marked enhancement of A549 tumor cells in newly formed lymphatic vessels in the primary tumors as well as in lymph nodes. Treatment of A549 cells with TNFSF15 results in upregulation of VEGFC expression, which can be inhibited by siRNA gene silencing of death domain‐containing receptor‐3 (DR3), a cell surface receptor for TNFSF15. In addition, TNFSF15/DR3 signaling pathways in A549 cells include activation of NF‐κB during tumor lymphangiogenesis. Our data indicate that TNFSF15, a cytokine mainly produced by blood endothelial cells, facilitates tumor lymphangiogenesis by upregulating VEGFC expression in A549 cells, contributing to lymphatic metastasis in tumor‐bearing mice. This finding also suggests that TNFSF15 may have potential as an indicator for prognosis evaluation.
High‐affinity PD‐1 molecules deliver improved interaction with PD‐L1 and PD‐L2
Authors: Li Yanyan , Liang Zhaoduan , Tian Ye , Cai Wenxuan , Weng Zhiming , Chen Lin , Zhang Huanling , Bao Yifeng , Zheng Hongjun , Zeng Sihai , Bei Chunhua , Li Yi
Published: June 2018

The inhibitory checkpoint molecule programmed death (PD)‐1 plays a vital role in maintaining immune homeostasis upon binding to its ligands, PD‐L1 and PD‐L2. Several recent studies have demonstrated that soluble PD‐1 (sPD‐1) can block the interaction between membrane PD‐1 and PD‐L1 to enhance the antitumor capability of T cells. However, the affinity of natural sPD‐1 binding to PD‐L1 is too low to permit therapeutic applications. Here, a PD‐1 variant with approximately 3000‐fold and 70‐fold affinity increase to bind PD‐L1 and PD‐L2, respectively, was generated through directed molecular evolution and phage display technology. Structural analysis showed that mutations at amino acid positions 124 and 132 of PD‐1 played major roles in enhancing the affinity of PD‐1 binding to its ligands. The high‐affinity PD‐1 mutant could compete with the binding of antibodies specific to PD‐L1 or PD‐L2 on cancer cells or dendritic cells, and it could enhance the proliferation and IFN‐γ release of activated lymphocytes. These features potentially qualify the high‐affinity PD‐1 variant as a unique candidate for the development of a new class of PD‐1 immune‐checkpoint blockade therapeutics.
Socioeconomic and ethnic inequalities in oral health among children and adolescents living in England, Wales and Northern Ireland
Authors: Rouxel Patrick , Chandola Tarani
Published: June 2018

Objectives

Although adolescence is a sensitive developmental period in oral health, the social equalization hypothesis that suggests health inequalities attenuate in adolescence has not been examined. This study analyses whether the socioeconomic gap and ethnic disadvantage in oral health among children aged 5 reduces among adolescents aged 15.

Methods

Data from the cross‐sectional Children's Dental Health Survey 2013 were analysed, comprising of 8541 children aged 5, 8, 12 and 15 attending schools in England, Wales and Northern Ireland. Oral health indicators included decayed and filled teeth, plaque, gingivitis and periodontal health. Ethnicity was measured using the 2011 UK census ethnic categories. Socioeconomic position was measured by family, school and residential deprivation. Negative binomial and probit regression models estimated the levels of oral health by ethnicity and socioeconomic position, adjusted for demographic and tooth characteristics.

Results

The predicted rate of decayed teeth for White British/Irish children aged 5 was 1.54 (95%CI 1.30‐1.77). In contrast, the predicted rate for Indian and Pakistani children was about 2‐2.5 times higher. At age 15, ethnic differences had reduced considerably. Family deprivation was associated with higher levels of tooth decay among younger children but not among adolescents aged 15. The influence of residential deprivation on the rate of tooth decay and filled teeth was similar among younger and older children. Moreover, inequalities in poor periodontal health by residential deprivation was significantly greater among 15‐year‐old children compared to younger children.

Conclusions

This study found some evidence of smaller ethnic and family socioeconomic differences in oral health among British adolescents compared to younger children. However, substantial differences in oral health by residential deprivation remain among adolescents. Community levels of deprivation may be particularly important for the health of adolescents.
Topical axitinib is a potent inhibitor of corneal neovascularization
Authors: Lledó Riquelme Mariola , Campos‐Mollo Ezequiel , Fernández‐Sánchez Laura
Published: June 2018

Background

This study evaluated the effects of topically applied axitinib, a tyrosine kinase inhibitor, in an experimental model of corneal neovascularization (CNV).

Methods

A total of 48 New Zealand rabbits were used. CNV was induced by placing five silk sutures in the upper cornea of one eye per rabbit. Rabbits were randomized into four groups (12 rabbits each): 0.9% saline (control group), 0.02 mg/mL axitinib, 0.35 mg/mL axitinib and 0.5 mg/mL axitinib groups. All treatments were administered three times daily for 14 days. Photographs were taken using a slit lamp on days 7 and 14. The area of neovascularization was measured in mm2, as the percentage of total corneal area and as the percentage of corneal surface covered by sutures (SCS).

Results

On day 14, the CNV area in the control group (31.50 ± 7.47 mm2; 115.00 ± 22.55% of the corneal SCS) was larger than that in the 0.02 mg/mL axitinib group (19.20 ± 8.92 mm2; 73.89 ± 34.98%), the 0.35 mg/mL axitinib group (8.83 ± 3.92 mm2; 31.90 ± 13.59%) and the 0.5 mg/mL axitinib group (5.12 ± 3.97 mm2; 18.38 ± 13.65%). Compared with saline, CNV was inhibited 39.04% by 0.02 mg/mL axitinib, 71.96% by 0.35 mg/mL axitinib and 84.73% by 0.5 mg/mL axitinib.

Conclusion

Topical administration of the three axitinib concentrations inhibited CNV in rabbits, blocking both vascular endothelial growth factor and platelet‐derived growth factor pathways. Axitinib at 0.5 mg/mL induced profound inhibition of corneal angiogenesis.
Genotype‐phenotype correlations of low‐frequency variants in the complement system in renal disease and age‐related macular degeneration
Authors: Geerlings M.J. , Volokhina E.B. , de Jong E.K. , van de Kar N. , Pauper M. , Hoyng C.B. , van den Heuvel L.P. , den Hollander A.I.
Published: June 2018

Genetic alterations in the complement system have been linked to a variety of diseases, including atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy (C3G), and age‐related macular degeneration (AMD). We performed sequence analysis of the complement genes complement factor H (CFH), complement factor I (CFI), and complement C3 (C3) in 866 aHUS/C3G and 697 AMD patients. In total, we identified 505 low‐frequency alleles, representing 121 unique variants, of which 51 are novel. CFH contained the largest number of unique low‐frequency variants (n = 64; 53%), followed by C3 (n = 32; 26%) and CFI (n = 25; 21%). A substantial number of variants were found in both patients groups (n = 48; 40%), while 41 (34%) variants were found only in aHUS/C3G and 32 (26%) variants were AMD specific. Genotype‐phenotype correlations between the disease groups identified a higher frequency of protein altering alleles in short consensus repeat 20 (SCR20) of factor H (FH), and in the serine protease domain of factor I (FI) in aHUS/C3G patients. In AMD, a higher frequency of protein‐altering alleles was observed in SCR3, SCR5, and SCR7 of FH, the SRCR domain of FI, and in the MG3 domain of C3. In conclusion, we observed a substantial overlap of variants between aHUS/C3G and AMD; however, there is a distinct clustering of variants within specific domains.
Clinical characteristics and outcomes of PTLD following intestinal transplantation
Authors: Wozniak Laura J. , Mauer Tian L. , Venick Robert S. , Said Jonathan W. , Kao Roy L. , Kempert Pamela , Marcus Elizabeth A. , Hwang Vilayphone , Cheng Elaine Y. , Busuttil Ronald W. , McDiarmid Sue V. , Farmer Douglas G.
Published: June 2018

Post‐transplant lymphoproliferative disease (PTLD) has the highest incidence following intestinal transplantation (ITx). Our center has seen a recent increase in PTLD. Our aim was to review a single‐center PTLD experience with a focus on clinical characteristics and outcomes. We completed a retrospective review of biopsy‐proven PTLD cases using a prospectively maintained database of 115 ITx recipients transplanted between 1991 and 2014. Nineteen (17%) ITx recipients developed 25 PTLD cases during a median follow‐up time of 6.4 (1.6‐14.6) years. The incidence of early PTLD was 6% (n = 7). There was a trend toward increased risk of PTLD in children compared with adults (P = .11) and a significantly increased risk of PTLD in re‐ITx compared with primary ITx recipients (P = .03). Most PTLD cases were diagnosed between 2010 and 2014 (n = 14). All early PTLD cases were EBV+ on in situ hybridization. Overall graft and patient survival are 68% and 74%, respectively. Second episodes of PTLD were diagnosed in 43% of surviving pediatric patients. Our program has a low incidence of early PTLD with overall excellent graft and patient survival following diagnosis. However, we have also seen a rising incidence of late PTLD. The cause of the increase is unknown as no major changes in immunosuppression protocols have occurred since 1999.
Homicides with direct and indirect links to the night‐time economy
Authors: Tomsen Stephen
Published: June 2018

Introduction and Aims

Alcohol use and homicide are a wide community concern with particular interest in understanding and preventing attacks (e.g. ‘one punch’ male on male attacks) in commercial nightlife settings with high levels of collective drinking. There is insufficient knowledge of the long‐term patterns in this violence or the relationship between public drinking and flow on violence in other social settings.

Design and Methods

Alcohol‐related homicides were those in which alcohol consumption was a contributing factor. Those also linked to purchase or consumption in locations where alcohol is sold after dark were classified as night‐time economy related. The study comprised a first‐hand analysis of files in the archive of the Australian National Homicide Monitoring Program in 2 years with a decade gap (1998/1999–2007/2008), and it classified 73 of all 238 alcohol‐related incidents by direct or indirect relation to public nightlife settings.

Results

Related homicides in these years were not highly concentrated in developed night‐time economies, but more spread outside major nightlife zones. Indirectly related killings were even more dispersed and included more women victims killed in domestic settings.

Discussion and Conclusions

There is a consistent though dispersed relationship between heavy public drinking at night and homicide. Concerns about homicide and night‐time drinking leisure with mostly male victims attacked in well‐known areas of busy city nightlife, must also consider the broader gendered patterns of ‘flow on’ nightlife‐related incidents, including fatal semi‐private and domestic violence that is indirectly but importantly related to drinking and alcohol purchase in public commercial nightlife.
Community violence exposure in early adolescence: Longitudinal associations with hippocampal and amygdala volume and resting state connectivity
Authors: Saxbe Darby , Khoddam Hannah , Piero Larissa Del , Stoycos Sarah A. , Gimbel Sarah I. , Margolin Gayla , Kaplan Jonas T.
Published: June 2018

Community violence exposure is a common stressor, known to compromise youth cognitive and emotional development. In a diverse, urban sample of 22 adolescents, participants reported on community violence exposure (witnessing a beating or illegal drug use, hearing gun shots, or other forms of community violence) in early adolescence (average age 12.99), and underwent a neuroimaging scan 3–5 years later (average age 16.92). Community violence exposure in early adolescence predicted smaller manually traced left and right hippocampal and amygdala volumes in a model controlling for age, gender, and concurrent community violence exposure, measured in late adolescence. Community violence continued to predict hippocampus (but not amygdala) volumes after we also controlled for family aggression exposure in early adolescence. Community violence exposure was also associated with stronger resting state connectivity between the right hippocampus (using the manually traced structure as a seed region) and bilateral frontotemporal regions including the superior temporal gyrus and insula. These resting state connectivity results held after controlling for concurrent community violence exposure, SES, and family aggression. Although this is the first study focusing on community violence in conjunction with brain structure and function, these results dovetail with other research linking childhood adversity with smaller subcortical volumes in adolescence and adulthood, and with altered frontolimbic resting state connectivity. Our findings suggest that even community‐level exposure to neighborhood violence can have detectable neural correlates in adolescents.
Improved glycaemic control and treatment satisfaction with a simple wearable 3‐day insulin delivery device among people with Type 2 diabetes
Authors: Mader J. K. , Lilly L. C. , Aberer F. , Poettler T. , Johns D. , Trautmann M. , Warner J. L. , Pieber T. R.
Published: June 2018

Aim

To evaluate the PAQ® (CeQur SA, Horw, Switzerland), a wearable 3‐day insulin delivery device that provides set basal rates and bolus insulin on demand, in people with Type 2 diabetes.

Method

Adults with Type 2 diabetes with HbA1c concentrations ≥53 and ≤97 mmol/mol (7.0 and 11.0%) while treated with ≥2 insulin injections/day were enrolled in two single‐arm studies comprising three periods: a baseline (insulin injections), a transition and a PAQ treatment period (12 weeks). Endpoints included HbA1c, seven‐point self‐monitored blood glucose, total daily dose of insulin and body weight. Safety was assessed according to examination, hypoglycaemic episodes and adverse device effects.

Results

A total of 28 adults were enrolled (age 63 ± 7 years, 86% men, BMI 32.3 ± 4.3kg/m2, Type 2 diabetes duration 17 ± 8 years, HbA1c 70 ± 12 mmol/mol (8.6 ± 1.1%), total daily insulin dose 58.7 ± 20.7 U), of whom 24 completed the studies. When transitioned to PAQ, 75% of participants continued on the first basal rate selected. After 12 weeks of PAQ wear, significant improvements from baseline were seen [HbA1c –16 ± 9 mmol/mol (95% CI –20, –12) or –1.5 ± 0.9% (95% CI –1.8, –1.1) P<0.0001], and at all seven self‐monitored blood glucose readings time points (P ≤0.03). Total daily insulin dose increased by 12.1 ± 19.5 U (95% CI 3.9, 20.4; P=0.0058), the number of meal time boluses increased by 0.9 ± 1.5/day (95% CI 0.3, 1.5; P=0.0081) and body weight remained stable. Six participants had mild to moderate catheter site reactions and one mild skin irritation occurred. No participant experienced severe hypoglycaemia.

Conclusions

Adults with Type 2 diabetes were safely transitioned from insulin injections to the PAQ and had significantly improved glycaemic control and treatment satisfaction with insulin therapy.

(ClinicalTrials.gov identifiers: NCT02158078 & NCT02419859)
Efficacy and safety of dapagliflozin in patients with type 2 diabetes and moderate renal impairment (chronic kidney disease stage 3A): The DERIVE Study
Authors: Fioretto Paola , Del Prato Stefano , Buse John B. , Goldenberg Ronald , Giorgino Francesco , Reyner Daniel , Langkilde Anna Maria , Sjöström C. David , Sartipy Peter ,   On Behalf of the DERIVE Study Investigators
Published: June 2018

Aims

Dapagliflozin is a selective inhibitor of sodium glucose co‐transporter 2 (SGLT2). This study assessed the efficacy and safety of dapagliflozin 10 mg vs placebo in patients with type 2 diabetes (T2D) and moderate renal impairment (estimated glomerular filtration rate [eGFR], 45–59 mL/min/1.73 m2; chronic kidney disease [CKD] stage 3A).

Materials and methods

In this double‐blind, parallel group, Phase 3 study (NCT02413398, clinicaltrials.gov) patients with inadequately controlled T2D (HbA1c 7.0%‐11.0%) were randomized (1:1) to dapagliflozin 10 mg once daily (N = 160) or matching placebo (N = 161) for 24 weeks. Randomization was stratified by pre‐enrolment glucose‐lowering therapy. The primary endpoint was change from baseline in HbA1c at Week 24.

Results

At Week 24, compared with placebo, dapagliflozin significantly decreased HbA1c (difference [95% CI], −0.34% [−0.53, −0.15]; P < 0.001), body weight (difference [95% CI], −1.25 kg [−1.90, −0.59]; P < 0.001), fasting plasma glucose (difference [95% CI], −0.9 mmol/L [−1.5, −0.4]; P = 0.001) and systolic blood pressure (difference [95% CI], −3.1 mm Hg [−6.3, 0.0]; P < 0.05). Decreases from baseline in eGFR were greater with dapagliflozin than placebo at Week 24 (−2.49 mL/min/1.73 m2 [−4.96, −0.02]), however, eGFR returned to baseline levels at Week 27 (3 weeks post‐treatment) (0.61 mL/min/1.73 m2 [−1.59, 2.81]). No increase in adverse events (AEs; 41.9% vs 47.8%) or serious AEs (5.6% vs 8.7%) were reported with dapagliflozin versus placebo. No AEs of bone fractures, amputations or DKA were reported.

Conclusions

The findings of this study (NCT02413398, clinicaltrials.gov) support the positive benefit/risk profile of dapagliflozin for the treatment of patients with T2D and CKD 3A.
Glycaemic control, hypoglycaemia, and weight change with insulin glargine 300 U/mL versus insulin glargine 100 U/mL in Japanese adults with type 2 diabetes: A 12‐month comparison by concomitant sulphonylurea and/or glinide use
Authors: Terauchi Yasuo , Riddle Matthew C. , Hirose Takahisa , Koyama Masayoshi , Cheng Xi , Takahashi Yoshinori , Bolli Geremia B.
Published: June 2018

Aim

To explore if clinical effects and hypoglycaemia risks associated with insulin glargine 300 U/mL (Gla‐300) and 100 U/mL (Gla‐100) differed by sulphonylurea and/or glinide (SU/G) treatment.

Methods

A post hoc subgroup analysis of 12‐month treatment data from the EDITION Japan 2 trial, a randomized, open‐label, phase 3 study of Japanese people with type 2 diabetes receiving once‐daily Gla‐300/Gla‐100 + oral antihyperglycaemic drugs. Participants previously receiving SU/G (+SU/G) were compared with those not taking SU/G (‐SU/G). Endpoints included HbA1c, hypoglycaemia and body weight.

Results

For +SU/G (n = 152, 63%), HbA1c was reduced from baseline to month 12 for Gla‐300 (8.1% to 7.6%) and Gla‐100 (8.2% to 7.8%). For ‐SU/G (n = 89, 37%), reductions were 7.8% to 7.4%, and 7.9% to 7.5% for Gla‐300 and Gla‐100, respectively. A lower annualized rate of hypoglycaemia with Gla‐300 versus Gla‐100 was observed at night (00:00–05:59 hours; p = 0.0001) and any time of day (24 hour; p = 0.0015). Irrespective of the insulin used, the incidence and rate of confirmed (≤3.9 mmol/L [≤70 mg/dL]) or severe hypoglycaemia appeared higher in +SU/G versus ‐SU/G; overall, a reduced incidence of nocturnal hypoglycaemia, and rate of hypoglycaemia at any time, was observed in ‐SU/G versus +SU/G. In the ‐SU/G subgroup, body weight gain differences were observed between Gla‐300 and Gla‐100 (p < 0.0001).

Conclusions

Participants with prior and continued SU/G use had similar therapeutic responses with basal insulin but greater risk of hypoglycaemia than those not using SU/G; hypoglycaemia risk was lower with Gla‐300 than Gla‐100 in both subgroups.
Body mass index impacts the choice of lipid‐lowering treatment with no correlation to blood cholesterol – Findings from 52 916 patients in the Dyslipidemia International Study (DYSIS)
Authors: Ferrières Jean , Lautsch Dominik , Gitt Anselm K. , De Ferrari Gaetano , Toplak Hermann , Elisaf Moses , Drexel Heinz , Horack Martin , Baxter Carl , Ambegaonkar Baishali , Brudi Philippe , Toth Peter P.
Published: June 2018

A high body mass index (BMI) is associated with increased cardiovascular risk. We sought to identify whether BMI influences the choice of lipid‐lowering treatment in a large, real‐world cohort of 52 916 patients treated with statins. The Dyslipidemia International Study (DYSIS) is a cross‐sectional, observational, multicentre study in statin‐treated patients ≥45 years of age from 30 countries; 1.1% were underweight (BMI < 18.5 kg/m2), 33.1% had normal weight (BMI 18.5‐24.9 kg/m2), 41.5% were overweight (BMI 25‐29.9 kg/m2), 17.1% had class I obesity (BMI 30.0‐34.9 kg/m2), 5.0% had class II obesity (BMI 35‐39.9 kg/m2), and 2.1% had class III obesity (≥40 kg/m2). BMI correlated with high‐density lipoprotein cholesterol (HDL‐C) and triglycerides (Spearman's ρ: −0.147 and 0.170, respectively; P < 0.0001 for both); however, there was no correlation with low‐density lipoprotein cholesterol (LDL‐C; ρ: 0.003; P = 0.51). Statin intensity increased with increasing BMI (ρ: 0.13; P < 0.001), an association that held after adjustment for comorbidities (OR: 2.4; 95% CI: 2.0‐3.0) on BMI ≥ 30 kg/m2 for atorvastatin equivalent ≥40 mg/d.
Destigmatizing psychosis: Investigating the effectiveness of a school‐based programme in Hong Kong secondary school students
Authors: Hui Christy L.M. , Leung Whitty W.T. , Wong Andreas K.H. , Loong Ka Yan , Kok Joy , Hwang Amanda , Lee Edwin H.M. , Chan Sherry K.W. , Chang Wing Chung , Chen Eric Y.H.
Published: June 2018

Aim

Although the reasons behind the stigmatization of psychosis are manifold, poor mental health literacy among the general public is likely to be a major factor. In Hong Kong, the Early Psychosis Foundation (EPISO) was established in 2007 to tackle this issue by providing educational and mental health promotional activities, among other aims and services. The current study evaluated the effectiveness of a school‐based interventional programme, the School Tour, developed by EPISO.

Methods

The School Tour differentiates itself from other interventional programmes by supplementing a traditional psychoeducational talk with 2 additional elements: an engaging drama performance and exercise demonstrations. Twelve secondary schools, with a total of 4520 students, participated in the study. Knowledge and attitudes towards psychosis were evaluated before and after the school programme.

Results

The School Tour was found to improve both students' knowledge of psychosis (P < .001) and their attitude (P < .001) towards the illness.

Conclusions

Its effectiveness in reducing the stigma towards psychosis validates the use of novel strategies like drama performances to engage adolescent students, and urges the government to support increased student participation in the programme by providing funding to the relevant organizations.
Distress‐dependent temporal variability of regions encoding domain‐specific and domain‐general behavioral manifestations of phantom percepts
Authors: Mohan Anusha , De Ridder Dirk , Idiculla Rajith , DSouza Clisha , Vanneste Sven
Published: June 2018

Tinnitus is the perception of a phantom sound characterized behaviorally by a loudness and a distress component. Although a wealth of information is available about the relationship between these behavioral correlates and changes in static functional connectivity, its relationship with dynamic changes in network connectivity is yet unexplored. The aim of this study was thus to investigate changes in the flexibility and stability of temporal variability in tinnitus and its relation to loudness and distress using continuous resting‐state EEG. We observe an increase in temporal variability at the whole‐brain level in tinnitus, which is spatiotemporally distributed at the nodal level. Behaviorally, we observe changes in the relationship between temporal variability and loudness and distress depending on the amount of distress experienced. In patients with low distress, there is no relationship between temporal variability and loudness or distress, demonstrating a resilience in dynamic connectivity of the brain. However, patients with high distress exhibit a direct relationship with increasing loudness in the primary auditory cortex and parahippocampus, and an inverse relationship with increasing distress in the parahippocampus. In tinnitus, the specific sensory (loudness) component related to increased temporal variability possibly reflects a Bayesian search for updating deafferentation‐based missing information. On the other hand, the decreased temporal variability related to the nonspecific distress component possibly reflects a more hard‐wired or less adaptive contextual processing. Therefore, our findings may reveal a way to understand the changes in network dynamics not just in tinnitus, but also in other brain disorders.
Electrocorticography reveals continuous auditory and visual speech tracking in temporal and occipital cortex
Authors: Micheli Cristiano , Schepers Inga M. , Ozker Müge , Yoshor Daniel , Beauchamp Michael S. , Rieger Jochem W.
Published: June 2018

During natural speech perception, humans must parse temporally continuous auditory and visual speech signals into sequences of words. However, most studies of speech perception present only single words or syllables. We used electrocorticography (subdural electrodes implanted on the brains of epileptic patients) to investigate the neural mechanisms for processing continuous audiovisual speech signals consisting of individual sentences. Using partial correlation analysis, we found that posterior superior temporal gyrus (pSTG) and medial occipital cortex tracked both the auditory and the visual speech envelopes. These same regions, as well as inferior temporal cortex, responded more strongly to a dynamic video of a talking face compared to auditory speech paired with a static face. Occipital cortex and pSTG carry temporal information about both auditory and visual speech dynamics. Visual speech tracking in pSTG may be a mechanism for enhancing perception of degraded auditory speech.