bluuebunny/crossref_metadata_2025 huggingface dataset:
SYT1-associated neurodevelopmental disorder: a case series
Authors: Baker Kate , Gordon Sarah L , Melland Holly , Bumbak Fabian , Scott Daniel J , Jiang Tess J , Owen David , Turner Bradley J , Boyd Stewart G , Rossi Mari , Al-Raqad Mohammed , Elpeleg Orly , Peck Dawn , Mancini Grazia M S , Wilke Martina , Zollino Marcella , Marangi Giuseppe , Weigand Heike , Borggraefe Ingo , Haack Tobias , Stark Zornitza , Sadedin Simon ,   Broad Center for Mendelian Genomics, Tan Tiong Yang , Jiang Yunyun , Gibbs Richard A , Ellingwood Sara , Amaral Michelle , Kelley Whitley , Kurian Manju A , Cousin Michael A , Raymond F Lucy
Published: July 2018

Baker, Gordon et al. present the first international case series describing the neurodevelopmental disorder associated with Synaptotagmin 1 (SYT1) de novo missense mutations. Key features include movement abnormalities, severe intellectual disability, and hallmark EEG alterations. Expression of patients’ SYT1 mutations in mouse neurons disturbs presynaptic vesicle dynamics in a mutation-specific manner.
Learning to Read Increases the Informativeness of Distributed Ventral Temporal Responses
Authors: Nordt Marisa , Gomez Jesse , Natu Vaidehi , Jeska Brianna , Barnett Michael , Grill-Spector Kalanit
Published: July 2018

Becoming a proficient reader requires substantial learning over many years. However, it is unknown how learning to read affects development of distributed visual representations across human ventral temporal cortex (VTC). Using fMRI and a data-driven, computational approach, we quantified the development of distributed VTC responses to characters (pseudowords and numbers) versus other domains in children, preteens, and adults. Results reveal anatomical- and hemisphere-specific development. With development, distributed responses to words and characters became more distinctive and informative in lateral but not medial VTC, and in the left but not right hemisphere. While the development of voxels with both positive and negative preference to words affected distributed information, only development of voxels with positive preference to words (i.e., word-selective) was correlated with reading ability. These data show that developmental increases in informativeness of distributed left lateral VTC responses are related to proficient reading and have important implications for both developmental theories and for elucidating neural mechanisms of reading disabilities.
Universal Screening of Pregnant Women for Hepatitis C: The Time Is Now
Authors: Jhaveri Ravi , Broder Tina , Bhattacharya Debika , Peters Marion G , Kim Arthur Y , Jonas Maureen M
Published: July 2018

Currently, risk-based hepatitis C virus (HCV) screening is recommended for women of childbearing age and pregnant women despite a high HCV prevalence. For many reasons outlined here, the time has come for universal screening for HCV for all pregnant women.
Exchange protein activated by cyclic-adenosine monophosphate (Epac) regulates atrial fibroblast function and controls cardiac remodelling
Authors: Surinkaew Sirirat , Aflaki Mona , Takawale Abhijit , Chen Yu , Qi Xiao-Yan , Gillis Marc-Antoine , Shi Yan-Fen , Tardif Jean-Claude , Chattipakorn Nipon , Nattel Stanley
Published: July 2018

Aims

Heart failure (HF) produces left atrial (LA)-selective fibrosis and promotes atrial fibrillation. HF also causes adrenergic activation, which contributes to remodelling via a variety of signalling molecules, including the exchange protein activated by cAMP (Epac). Here, we evaluate the effects of Epac1-signalling on LA fibroblast (FB) function and its potential role in HF-related atrial remodelling.

Methods and results

HF was induced in adult male mongrel dogs by ventricular tachypacing (VTP). Epac1-expression decreased in LA-FBs within 12 h (−3.9-fold) of VTP onset. The selective Epac activator, 8-pCPT (50 µM) reduced, whereas the Epac blocker ESI-09 (1 µM) enhanced, collagen expression in LA-FBs. Norepinephrine (1 µM) decreased Epac1-expression, an effect blocked by prazosin, and increased FB collagen production. The β-adrenoceptor (AR) agonist isoproterenol increased Epac1 expression, an effect antagonized by ICI (β2-AR-blocker), but not by CGP (β1-AR-blocker). β-AR-activation with isoproterenol decreased collagen expression, an effect mimicked by the β2-AR-agonist salbutamol and blocked by the Epac1-antagonist ESI-09. Transforming growth factor-β1, known to be activated in HF, suppressed Epac1 expression, an effect blocked by the Smad3-inhibitor SIS3. To evaluate effects on atrial fibrosis in vivo, mice subjected to myocardial infarction (MI) received the Epac-activator Sp-8-pCPT or vehicle for 2 weeks post-MI; Sp-8-pCPT diminished LA fibrosis and attenuated cardiac dysfunction.

Conclusions

HF reduces LA-FB Epac1 expression. Adrenergic activation has complex effects on FBs, with α-AR-activation suppressing Epac1-expression and increasing collagen expression, and β2-AR-activation having opposite effects. Epac1-activation reduces cardiac dysfunction and LA fibrosis post-MI. Thus, Epac1 signalling may be a novel target for the prevention of profibrillatory cardiac remodelling.
Chromosome-level reference genome of the Siamese fighting fish Betta splendens, a model species for the study of aggression
Authors: Fan Guangyi , Chan Judy , Ma Kailong , Yang Binrui , Zhang He , Yang Xianwei , Shi Chengcheng , Chun-Hin Law Henry , Ren Zhitao , Xu Qiwu , Liu Qun , Wang Jiahao , Chen Wenbin , Shao Libin , Gonçalves David , Ramos Andreia , Cardoso Sara D , Guo Min , Cai Jing , Xu Xun , Wang Jian , Yang Huanming , Liu Xin , Wang Yitao
Published: July 2018

Background

Siamese fighting fish Betta splendens are notorious for their aggressiveness and accordingly have been widely used to study aggression. However, the lack of a reference genome has, to date, limited the understanding of the genetic basis of aggression in this species. Here, we present the first reference genome assembly of the Siamese fighting fish.

Findings

Frist, we sequenced and de novo assembled a 465.24-Mb genome for the B. splendens variety Giant, with a weighted average (N50) scaffold size of 949.03 Kb and an N50 contig size of 19.01 Kb, covering 99.93% of the estimated genome size. To obtain a chromosome-level genome assembly, we constructed one Hi-C library and sequenced 75.24 Gb reads using the BGISEQ-500 platform. We anchored approximately 93% of the scaffold sequences into 21 chromosomes and evaluated the quality of our assembly using the high-contact frequency heat map and Benchmarking Universal Single-Copy Orthologs. We also performed comparative chromosome analyses between Oryzias latipes and B. splendens, revealing a chromosome conservation evolution in B. splendens. We predicted 23,981 genes assisted by RNA-sequencing data generated from brain, liver, muscle, and heart tissues of Giant and annotated 15% repetitive sequences in the genome. Additionally, we resequenced five other B. splendens varieties and detected ~3.4 M single-nucleotide variations and 27,305 insertions and deletions.

Conclusions

We provide the first chromosome-level genome for the Siamese fighting fish. The genome will lay a valuable foundation for future research on aggression in B. splendens.
Spatial and temporal dynamics of European hake (Merluccius merluccius) in the North Sea
Authors: Staby Arved , Skjæraasen Jon Egil , Geffen Audrey J , Howell Daniel
Published: July 2018

Catches of European hake (Merluccius merluccius) in the North Sea have increased substantially during the last decade, even though there is no directed commercial fishery of hake in this area. We analysed the spatial distributions of hake in the northern the parts of its range, (where it is less well-studied), using ICES international bottom trawl survey data from 1997 to 2015. We examine length-frequency distributions for (i) distinct modes enabling the assignment of fish into categories which likely corresponded to the ages 1, 2, and 3+ and (ii) patterns of seasonal spatial distribution for the different groups. Age categories 1 and 2 fish were most abundant in the northern North Sea, and appear to remain in the North Sea until 2 years of age, when they move into deeper waters. Their distribution has expanded into the western-central North Sea in the last decade. Age category 3+ fish were most abundant in the northern and central North Sea during summer, indicating a seasonal influx of large individuals into this area likely associated with spawning activity. The distribution of these older fish has gradually expanded westward in both seasons.
Topologically Nontrivial Counterexamples to Sard’s Theorem
Authors: Goldstein Paweł , Hajłasz Piotr , Pankka Pekka
Published: July 2018

We prove the following dichotomy: if $n=2,3$ and $f\in C^1(\mathbb{S}^{n+1},\mathbb{S}^n)$ is not homotopic to a constant map, then there is an open set $\Omega \subset \mathbb{S}^{n+1}$ such that $\operatorname{rank} df=n$ on $\Omega $ and $f(\Omega )$ is dense in $\mathbb{S}^n$, while for any $n\geq 4$, there is a map $f\in C^1(\mathbb{S}^{n+1},\mathbb{S}^n)$ that is not homotopic to a constant map and such that $\operatorname{rank} df<n$ everywhere. The result in the case $n\geq 4$ answers a question of Larry Guth.
Nonlinear Weakly Sequentially Continuous Embeddings Between Banach Spaces
Authors: Braga B M
Published: July 2018

In these notes, we study nonlinear embeddings between Banach spaces that are also weakly sequentially continuous. In particular, our main result implies that if a Banach space $X$ coarsely (resp. uniformly) embeds into a Banach space $Y$ by a weakly sequentially continuous map, then every spreading model $(e_n)_n$ of a normalized weakly null sequence in $X$ satisfies $$ \|e_1+\ldots+e_k\|_{\overline{\delta}_Y}\lesssim\|e_1+\ldots+e_k\|_S,$$where $\overline{\delta }_Y$ is the modulus of asymptotic uniform convexity of $Y$. Among other results, we obtain Banach spaces $X$ and $Y$ so that $X$ coarsely (resp. uniformly) embeds into $Y$, but so that $X$ cannot be mapped into $Y$ by a weakly sequentially continuous coarse (resp. uniform) embedding.
Vanishing Estimates for Fully Bubbling Solutions of SU (n + 1) Toda Systems at a Singular Source
Authors: Zhang Lei
Published: July 2018

For Gauss curvature equation (or more general Toda systems) defined on 2D spaces, the vanishing rate of certain curvature functions on blowup points is a key estimate for numerous applications. However, if these equations have singular sources, very few vanishing estimates can be found. In this article we consider a Toda system with singular sources defined on a Riemann surface and we prove a very surprising vanishing estimates and a reflection phenomenon for certain functions involving the Gauss curvature.
Almost Finiteness for General Étale Groupoids and Its Applications to Stable Rank of Crossed Products
Authors: Suzuki Yuhei
Published: July 2018

We extend Matui’s notion of almost finiteness to general étale groupoids and show that the reduced groupoid C$^{\ast }$-algebras of minimal almost finite groupoids have stable rank 1. The proof follows a new strategy, which can be regarded as a local version of the large subalgebra argument. The following three are the main consequences of our result: (1) for any group of (local) subexponential growth and for any its minimal action admitting a totally disconnected free factor, the crossed product has stable rank 1; (2) any countable amenable group admits a minimal action on the Cantor set, all whose minimal extensions form the crossed product of stable rank 1; and (3) for any amenable group, the crossed product of the universal minimal action has stable rank 1.
Association Between Plasma Antibody Responses and Risk for Cryptococcus-Associated Immune Reconstitution Inflammatory Syndrome
Authors: Yoon Hyun Ah , Nakouzi Antonio , Chang Christina C , Kuniholm Mark H , Carreño Leandro J , Wang Tao , Ndung’u Thumbi , Lewin Sharon R , French Martyn A , Pirofski Liise-anne
Published: July 2018

Background

Initiation of antiretroviral therapy (ART) in human immunodeficiency virus (HIV)-infected individuals with cryptococcal meningitis places them at risk for Cryptococcus-associated immune reconstitution inflammatory syndrome (C-IRIS). The relationship between antibody immunity and C-IRIS risk has not been investigated.

Methods

We compared plasma levels of immunoglobulins, C. neoformans glucuronoxylomannan (GXM) capsule-specific and laminarin (Lam)-binding IgM and IgG, and percentages of peripheral blood total and memory B cells between 27 HIV-infected patients with CM who developed C-IRIS and 63 who did not, and evaluated associations of these parameters with risk of C-IRIS.

Results

Prior to initiation of ART, plasma IgM, Lam-binding IgM (Lam-IgM), Lam-IgG, and GXM-IgM levels were significantly lower in patients who developed C-IRIS than those who did not. Multivariate analysis revealed significant inverse associations between C-IRIS and IgM (P = .0003), Lam-IgM (P = .0005), Lam-IgG (P = .002), and GXM-IgM (P = .002) independent of age, sex, HIV viral load, CD4+ T-cell count, and cerebrospinal fluid fungal burden. There were no associations between C-IRIS and total or memory B cells.

Discussion

Antibody profiles that include plasma IgM, Lam-IgM, Lam-IgG, and/or GXM-IgM may have value in furthering our understanding of C-IRIS pathogenesis and hold promise as candidate biomarkers of C-IRIS risk.
Immunological association of inducible bronchus-associated lymphoid tissue organogenesis in Ag85B-rHPIV2 vaccine-induced anti-tuberculosis mucosal immune responses in mice
Authors: Nagatake Takahiro , Suzuki Hidehiko , Hirata So-ichiro , Matsumoto Naomi , Wada Yasuko , Morimoto Sakiko , Nasu Ayaka , Shimojou Michiko , Kawano Mitsuo , Ogami Kentaro , Tsujimura Yusuke , Kuroda Etsushi , Iijima Norifumi , Hosomi Koji , Ishii Ken J , Nosaka Tetsuya , Yasutomi Yasuhiro , Kunisawa Jun
Published: July 2018

We previously reported that Ag85B-expressing human parainfluenza type 2 virus (Ag85B-rHPIV2) was effective as a nasal vaccine against tuberculosis in mice; however, the mechanism by which it induces an immune response remains to be investigated. In the present study, we found that organogenesis of inducible bronchus-associated lymphoid tissue (iBALT) played a role in the induction of antigen-specific T cells and IgA antibody responses in the lung of mice intra-nasally administered Ag85B-rHPIV2. We found that expression of Ag85B was dispensable for the development of iBALT, suggesting that HPIV2 acted as an iBALT-inducing vector. When iBALT organogenesis was disrupted in Ag85B-rHPIV2-immunized mice, either by neutralization of the lymphotoxin pathway or depletion of CD11b+ cells, Ag85B-specific immune responses (i.e. IFN γ-producing T cells and IgA antibody) were diminished in the lung. Furthermore, we found that immunization with Ag85B-rHPIV2 induced neutrophil and eosinophil infiltration temporally after the immunization in the lung. Thus, our results show that iBALT organogenesis contributes to the induction of antigen-specific immune responses by Ag85B-rHPIV2 and that Ag85B-rHPIV2 provokes its immune responses without inducing long-lasting inflammation.
The prospects of human rights in US–China relations: a constructivist understanding
Authors: Kim Hun Joon
Published: July 2018

What are the prospects of U.S.-China relations in the area of human rights? Skeptics maintain that human rights is no longer an issue between the United States and China. A traditional understanding of U.S.–China relations ignores the role of norms, while the constructivist perspective recognizes their independent effects. This paper links the traditional understanding of power politics between the United States and China with the study of constructivist norm research. The three findings of constructivist norm theories are relevant and applied to predict the status of human rights in U.S.-China relations: the historical construction of norms, the long-term and multifaceted effects of norms, and the persistence of norms. Based on these theoretical predictions, it is expected that, although convergence is not completely impossible, the past dynamic of competition and confrontation will continue and human rights will still be a contentious issue in U.S.-China relations.
Chinese views of the United States: evidence from Weibo
Authors: Guan Yichen , Tingley Dustin , Romney David , Jamal Amaney , Keohane Robert
Published: July 2018

We study Chinese attitudes toward the United States, and secondarily toward Japan, Russia, and Vietnam, by analyzing social media discourse on the Chinese social media site, Weibo. We focus separately on a general analysis of attitudes and on Chinese responses to specific international events involving the United States. In general, we find that Chinese netizens are much more interested in US politics than US society. Their views of the United States are characterized by deep ambivalence; they have remarkably favorable attitudes toward many aspects of US influence, whether economic, political, intellectual, or cultural. Attitudes toward the United States become negative when the focus turns to US foreign policy – actions that Chinese netizens view as antithetical to Chinese interests. On the contrary, attitudes toward Japan, Russia, and Vietnam vary a great deal from one another. The contrast between these differentiated Chinese views toward the United States and other countries, on the one hand, and the predominant anti-Americanism in the Middle East, on the other, is striking.
A case study evaluating the portability of an executable computable phenotype algorithm across multiple institutions and electronic health record environments
Authors: Pacheco Jennifer A , Rasmussen Luke V , Kiefer Richard C , Campion Thomas R , Speltz Peter , Carroll Robert J , Stallings Sarah C , Mo Huan , Ahuja Monika , Jiang Guoqian , LaRose Eric R , Peissig Peggy L , Shang Ning , Benoit Barbara , Gainer Vivian S , Borthwick Kenneth , Jackson Kathryn L , Sharma Ambrish , Wu Andy Yizhou , Kho Abel N , Roden Dan M , Pathak Jyotishman , Denny Joshua C , Thompson William K
Published: July 2018

Electronic health record (EHR) algorithms for defining patient cohorts are commonly shared as free-text descriptions that require human intervention both to interpret and implement. We developed the Phenotype Execution and Modeling Architecture (PhEMA, http://projectphema.org) to author and execute standardized computable phenotype algorithms. With PhEMA, we converted an algorithm for benign prostatic hyperplasia, developed for the electronic Medical Records and Genomics network (eMERGE), into a standards-based computable format. Eight sites (7 within eMERGE) received the computable algorithm, and 6 successfully executed it against local data warehouses and/or i2b2 instances. Blinded random chart review of cases selected by the computable algorithm shows PPV ≥90%, and 3 out of 5 sites had >90% overlap of selected cases when comparing the computable algorithm to their original eMERGE implementation. This case study demonstrates potential use of PhEMA computable representations to automate phenotyping across different EHR systems, but also highlights some ongoing challenges.
Exploring app features with outcomes in mHealth studies involving chronic respiratory diseases, diabetes, and hypertension: a targeted exploration of the literature
Authors: Donevant Sara Belle , Estrada Robin Dawson , Culley Joan Marie , Habing Brian , Adams Swann Arp
Published: July 2018

Objectives

Limited data are available on the correlation of mHealth features and statistically significant outcomes. We sought to identify and analyze: types and categories of features; frequency and number of features; and relationship of statistically significant outcomes by type, frequency, and number of features.

Materials and Methods

This search included primary articles focused on app-based interventions in managing chronic respiratory diseases, diabetes, and hypertension. The initial search yielded 3622 studies with 70 studies meeting the inclusion criteria. We used thematic analysis to identify 9 features within the studies.

Results

Employing existing terminology, we classified the 9 features as passive or interactive. Passive features included: 1) one-way communication; 2) mobile diary; 3) Bluetooth technology; and 4) reminders. Interactive features included: 1) interactive prompts; 2) upload of biometric measurements; 3) action treatment plan/personalized health goals; 4) 2-way communication; and 5) clinical decision support system.

Discussion

Each feature was included in only one-third of the studies with a mean of 2.6 mHealth features per study. Studies with statistically significant outcomes used a higher combination of passive and interactive features (69%). In contrast, studies without statistically significant outcomes exclusively used a higher frequency of passive features (46%). Inclusion of behavior change features (ie, plan/goals and mobile diary) were correlated with a higher incident of statistically significant outcomes (100%, 77%).

Conclusion

This exploration is the first step in identifying how types and categories of features impact outcomes. While the findings are inconclusive due to lack of homogeneity, this provides a foundation for future feature analysis.
The Opioid Epidemic: Moving Toward an Integrated, Holistic Analytical Response
Authors: Morrow Jayne B , Ropero-Miller Jeri D , Catlin Megan L , Winokur Agnes D , Cadwallader Amy B , Staymates Jessica L , Williams Shannan R , McGrath Jonathan G , Logan Barry K , McCormick Michael M , Nolte Kurt B , Gilson Thomas P , Menendez M J , Goldberger Bruce A
Published: July 2018

In many jurisdictions, public safety and public health entities are working together to enhance the timeliness and accuracy of the analytical characterization and toxicology testing of novel synthetic opioids. The improved sharing and early detection of these analytical data are intended to inform surveillance, interdiction efforts, patient intervention and treatment, all of which are critical to curbing the opioid epidemic. Forensic practitioners working to identify novel synthetic opioids struggle to provide timely results when encountering new or unknown substances, such as the fentanyl analogs. These compounds, which mimic heroin in pharmacologic effect but can be far more potent, are inconsistently present in chemical identification libraries, and are currently largely unavailable as reference materials for analytical comparison. Additionally, federal, state and local governments as well as nongovernmental organizations require potency, toxicity and potential-for-abuse data to evaluate the potential health risks of emerging drug threats. Subsequent scheduling efforts and criminal prosecutions also require these thorough drug characterization studies. Pilot programs have demonstrated that early communication of real-time drug toxicity and analytical data significantly impacts the successful response to emerging opioids. High-quality, real-time, national-level data on chemical composition, toxicological test data, drug toxicity and overdoses, and analysis of seized materials by law enforcement are needed to track drug trends. However, the USA still lacks a national system to coordinate and communicate toxicology, medical and medical examiner and coroner data with the broader medical and law enforcement communities. Opportunities to address these gaps as well as recent advancements collected through interagency efforts and technical workshops in the toxicology and analytical chemistry communities are presented here. Opportunities for partnership, increased communication and expanding best practices to move toward an integrated, holistic analytical response are also explored.
‘What cannot often be obtainable’: the Revd Greville John Chester and the Bodleian genizah collection
Authors: Jefferson Rebecca J W
Published: July 2018

The following article examines the Revd Greville John Chester’s activities in the Egyptian antiquities trade from 1889 to 1892, specifically his involvement in discovering and distributing Hebrew manuscripts from the now famous Cairo Genizah. Based on letters written by Chester to the Bodleian Librarian, E.W.B. Nicholson, as well as other supporting documentary evidence, this investigation provides insights into the early history of the Cairo Genizah manuscripts before Solomon Schechter’s celebrated ‘discovery’ of them in 1896/97. Overall, this article shows that the provenance story of ‘the Cairo Genizah’ is multi-faceted and needs to be subjected to much greater scrutiny.
Pseudo-True SDFs in Conditional Asset Pricing Models*
Authors: Antoine Bertille , Proulx Kevin , Renault Eric
Published: July 2018

This article is motivated by the need to bridge some gap between modern asset pricing theory and recent developments in econometric methodology. While asset pricing theory enhances the use of conditional pricing models, econometric inference of conditional models can be challenging due to misspecification or weak identification. To tackle the case of misspecification, we utilize the conditional Hansen and Jagannathan (1997) (HJ) distance as studied by Gagliardini and Ronchetti (2016), but we set the focus on interpretation and estimation of the pseudo-true value defined as the argument of the minimum of this distance. While efficient Generalized Method of Moments (GMM) has no meaning for estimation of a pseudo-true value, the HJ-distance not only delivers a meaningful loss function, but also features an additional advantage for the interpretation and estimation of managed portfolios whose exact pricing characterizes the pseudo-true pricing kernel (stochastic discount factor (SDF)). For conditionally affine pricing kernels, we can display some managed portfolios which are well-defined independently of the pseudo-true value of the parameters, although their exact pricing is achieved by the pseudo-true SDF. For the general case of nonlinear SDFs, we propose a smooth minimum distance (SMD) estimator (Lavergne and Patilea, 2013) that avoids a focus on specific directions as in the case of managed portfolios. Albeit based on kernel smoothing, the SMD approach avoids instabilities and the resulting need of trimming strategies displayed by classical local GMM estimators when the density function of the conditioning variables may take arbitrarily small values. In addition, the fact that SMD may allow fixed bandwidth asymptotics is helpful regarding the curse of dimensionality. In contrast with the true unknown value for a well-specified model, the estimated pseudo-true value, albeit defined in a time-invariant (unconditional) way, may actually depend on the choice of the state variables that define fundamental factors and their scaling weights. Therefore, we may not want to be overly parsimonious about the set of explanatory variables. Finally, following Antoine and Lavergne (2014), we show how SMD can be further robustified to deal with weaker identification contexts. Since SMD can be seen as a local extension of the method of jackknife GMM (Newey and Windmeijer, 2009), we characterize the Gaussian asymptotic distribution of the estimator of the pseudo-true value using classical U-statistic theorems.
Effect Sizes Hypothesized and Observed in Contemporary Phase III Trials of Targeted and Immunological Therapies for Advanced Cancer
Authors: Lawrence Nicola Jane , Roncolato Felicia , Martin Andrew , Simes Robert John , Stockler Martin R
Published: July 2018

Background

We sought to compare the effect sizes hypothesized in the trial design, observed in the trial results, and considered clinically meaningful by the American Society of Clinical Oncology (ASCO) 2014 recommendations, in phase III trials of targeted and immunological therapies.

Methods

We studied phase III, superiority trials of targeted and immunological therapies in advanced cancers published from 2005 to 2015. We recorded the characteristics, design parameters, and observed results for the primary endpoint of each trial. The effect sizes hypothesized in the trial design were compared with the ASCO 2014 recommendation that phase III trials be designed to detect overall survival (OS) benefits that are clinically meaningful (hazard ratio ≤0.8).

Results

All critical elements of the trial design (effect sizes hypothesized, estimated survival in the control group, power, and significance level) were identified in 165 of 213 included trials (77%). Of trials with a statistically significant result for the primary endpoint, 16 of 30 (53%) with a primary endpoint of OS and 20 of 53 (38%) with a primary endpoint of progression free survival (PFS) had an observed effect size less extreme than hypothesized; and 7 of 30 trials (23%) reported an observed effect size for OS that was statistically significant but not clinically meaningful (HR > 0.80) according to the ASCO 2014 recommendations.

Conclusion

Many trials were designed such that an observed benefit in OS or PFS that was not clinically meaningful would be statistically significant. Phase III trials should be designed to provide results that are statistically significant for observed effects that are clinically meaningful but not for observed results that are of dubious clinical importance.
Prevention and Control of Youth Camp–Associated Acute Gastroenteritis Outbreaks
Authors: Kambhampati Anita K , Marsh Zachary A , Hlavsa Michele C , Roberts Virginia A , Vieira Antonio R , Yoder Jonathan S , Hall Aron J
Published: July 2018

Background

Approximately 14 million children attend more than 14000 US camps every year. Shared accommodations and activities can facilitate acute gastroenteritis (AGE) outbreaks.

Methods

We analyzed data from the National Outbreak Reporting System on US youth camp–associated AGE outbreaks that occurred between 2009 and 2016. We also conducted a systematic literature search of youth camp–associated AGE outbreaks that have occurred around the world and a gray literature search for existing recommendations on outbreak prevention and control at camps worldwide.

Results

Thirty-nine US jurisdictions reported a total of 229 youth camp–associated AGE outbreaks to the National Outbreak Reporting System. Of the 226 outbreaks included in our analyses, 120 (53%) were reported to have resulted from person-to-person transmission, 42 (19%) from an unknown transmission mode, 38 (17%) from foodborne transmission, 19 (8%) from waterborne transmission, 5 (2%) from animal contact, and 2 (<1%) from environmental contamination. Among 170 (75%) outbreaks with a single suspected or confirmed etiology, norovirus (107 [63%] outbreaks), Salmonella spp (16 [9%]), and Shiga-toxin producing Escherichia coli (12 [7%]) were implicated most frequently. We identified 43 additional youth camp–associated AGE outbreaks in the literature that occurred in various countries between 1938 and 2014. Control measures identified through the literature search included camp closure, separation of ill campers, environmental disinfection, and education on food preparation and hand hygiene.

Conclusions

Youth camp–associated AGE outbreaks are caused by numerous pathogens every year. These outbreaks are facilitated by factors that include improper food preparation, inadequate cleaning and disinfection, shared accommodations, and contact with animals. Health education focused on proper hygiene and preventing disease transmission could help control or prevent these outbreaks.
The Effects of Sampling Frame Designs on Nonresponse and Coverage Error: Evidence from the Netherlands
Authors: Kölln Ann-Kristin , Ongena Yfke P , Aarts Kees
Published: July 2018

Survey researchers sometimes face several options to formally define and draw random probability samples from their target population of individuals. Relatively little is known about the consequences for the quality of survey estimates when different sampling frames are used, for example frames that list addresses versus individuals While the initial choice for a sampling frame design may be based on diverse criteria, we argue that any decision has consequences for the quality of survey estimates. We hypothesize that knowing respondents’ names upfront decreases nonresponse and coverage error. This can be accomplished by either using person-based sampling frames or augmenting nonperson-based sampling frames with names. We systematically compare sampling frame designs in the context of face-to-face surveys in connection with the European Social Survey (ESS) with the help of three quasi-experimental datasets from a single country. Even the most conservative measures support our hypothesis that the presence of names in the sampling frames could improve response rates, noncontact rates, cooperation rates, and ineligibility rates by between 2.5 and 6 percentage points. Additionally, the accuracy of population estimates could increase. These results suggest that survey researchers collecting individual-level data would be best advised to use well-maintained sampling frame designs (augmented) with person-specific information.
Growth factors and uncontrolled proliferation
Authors: Liu Shujuan , Ashour Ahmed Ahmed
Published: July 2018

A mandatory requirement of normal growth and development is the tight spatial and temporal synchronization of cellular proliferation within a specific tissue type and between tissue types that make up an organ, a process that is governed by intrinsic and extrinsic regulatory pathways. For a cell to synchronize its growth with that of other cells it requires a network of proteins that can sense external cues, send internal messages, and produce extracellular messengers that feed back information to neighbouring cells. Growth factors act as cellular messengers to feed back regulatory signals that modulate the cell’s own behaviour (autocrine signals) and that of other adjacent cells (paracrine signals). These proteins regulate a myriad of other cellular activities. In this chapter we discuss how different growth factors relay messages to cells and describe how their deregulation contributes to the development of uncontrolled proliferation and cancer.
Cancer, immunity, and inflammation
Authors: Roxburgh Campbell S.D. , McMillan Donald C.
Published: July 2018

The chapter focuses on the role of immunity and inflammation in established cancer. From the evidence reviewed it is clear that immune and inflammatory responses, innate, humoral and adaptive, local and systemic, are intimately linked to the tumour and themselves and impact on cancer survival. It is also possible to identify key mediators that may be targeted in the cancer patient. However, further work is required to elucidate the mechanisms by which these immune and inflammatory responses are activated, maintained, and interact. Therapeutic intervention using non-selective anti-inflammatory agents is widely advocated and likely to become part of routine clinical practice in the near future. Selective therapeutic intervention directed at the immune and inflammatory responses in cancer is in its infancy. Therefore, it would appear that, at least in non-hereditary disease, immune and inflammatory responses are of key, if not of prime, importance in tumour progression and dissemination.
Familial cancer syndromes
Authors: Snyder Carrie L. , Hampel Heather , Lynch Henry T.
Published: July 2018

Thanks to the veritably logarithmic advances in the molecular genetics of many emerging hereditary cancer syndromes, genetic counselling has become of paramount importance. It is a key element of the emerging concepts for patient education and management, which have become the clinical bedrock for diagnosis and management of hereditary cancer. Genetic counsellors have become proficient in the understanding of the complexities of molecular genetics in relation to hereditary cancer syndromes, demonstrating their ability both to supplement and replace the customary physician’s role in this overall process. We have used colorectal cancer, in particular Lynch syndrome, as a clinical genetic model based on the authors’ experience with diagnosis, DNA testing, and counselling of thousands of families for over four decades. Undoubtedly, the surface of the proverbial iceberg has barely been grazed in regard to the developments for the genetic counseling discipline.
Pancreatic cancer
Authors: Weitz Jürgen , Büchler Markus W. , Sykes Paul D. , Neoptolemos John P. , Costello Eithne , Halloran Christopher M. , Hackert Thilo , Bergmann Frank , Schirmacher Peter , Bork Ulrich , Fritz Stefan , Werner Jens , Brunner Thomas B. , Smyth Elizabeth , Cunningham David , Untch Brian R. , Allen Peter J.
Published: July 2018

Pancreatic cancer comprises of several different exocrine and endocrine malignant diseases. The most common form is pancreatic adenocarcinoma, the tenth most common solid cancer in most of Western countries, which is discussed in this chapter. The lifetime risk of developing such a disease is 1.5%, with a mean age of diagnosis in the seventh decade. Unfortunately, no specific symptoms of this disease exist. Typically, patients present with unspecific abdominal discomfort, weight loss, and early satiety. More specific symptoms are painless jaundice and signs of endocrine or exocrine pancreatic insufficiency. Management of pancreatic cancer is complex and should best be performed by a multidisciplinary team. The individual components of such an approach are described in this chapter.
Smoking
Authors: Pisinger Charlotta , Tonstad Serena
Published: July 2018

Smoking causes all forms of cardiovascular disease (CVD): there is no safe level of smoking. The health benefits of quitting smoking are immediate. In patients with coronary heart disease smoking cessation results in a dramatic decline in future cardiovascular events and reduces cardiovascular death; it is the most effective and cheapest treatment for preventing new or recurrent CVD. Tobacco dependence should be regarded as a chronic disease with a lifelong risk of relapse. Making treatment readily available and reducing barriers to treatment increase the likelihood that smokers will accept treatment. Medication and follow-up should be arranged for all smokers upon hospital discharge and in outpatient settings. High priority should be given to identification and documentation of the smoking status of all patients, and systematic provision of cessation support. Clinicians should also ask about exposure to second-hand smoke and should play an active role in advocating for stronger tobacco controls.
Coagulation and thrombosis
Authors: Huber Kurt , Morais Joao
Published: July 2018

Antithrombotic therapy consisting of antiplatelet agents and/or anticoagulants is an important way to avoid atherothrombotic complications, especially in secondary prevention. Primary prevention by antithrombotic measures usually refers to the prevention of stroke in patients with atrial fibrillation and an increased risk for stroke or peripheral thromboembolic events by the use of anticoagulants. In certain situations a combination of anticoagulants and antiplatelet agents is mandatory. This chapter provides the pathophysiological background of coagulation and thrombosis, reports on the epidemiology of antithrombotic treatment, and describes the efficacy and safety of preventive antithrombotic measures in different cardiovascular indications. A short paragraph summarizes the current discussion of skipping aspirin in order to reduce the rate and severity of bleeding events.
Psychosocial factors in the prevention of cardiovascular disease
Authors: Theorell Töres , Brisson Chantal , Vézina Michel , Milot Alain , Gilbert-Ouimet Mahée
Published: July 2018

The chapter starts with a theoretical sociological, psychological, and physiological framework for the relationships between psychosocial factors and coronary heart disease (CHD). This is followed by a review of the scientific evidence supporting such an association. Individual behaviours and coping mechanisms as well as environmental conditions of relevance for CHD are described. In particular, type A and D behaviour, depressive states, covert coping, social support and social network, socioeconomic conditions, as well as theoretical work environment models of relevance for CHD (job strain, effort-reward imbalance, organizational justice and leadership) are discussed. The remaining part of the chapter surveys the results from controlled studies of the effects of psychosocial interventions. There is accumulating evidence from such controlled studies that risk factors for CHD can be favourably influenced.
Cardioprotective drugs
Authors: Sutter Johan De , Mendes Miguel , Franco Oscar H.
Published: July 2018

Cardioprotective drugs are important in the treatment of patients at risk for or with documented cardiovascular disease. Beta-blockers are indicated after acute coronary syndromes, stable coronary artery disease, heart failure, and arrhythmias. Angiotensin-converting enzyme inhibitors (ACEi) are important in congestive heart failure, stable angina, post-acute myocardial infarction, and secondary prevention after any event or revascularization. Angiotensin receptor blockers are mainly alternative drugs for the same indications in case of intolerance to ACEi. Calcium channel blockers are first line medication for patients with isolated systolic hypertension, black people, and during pregnancy, in the presence of intermittent claudication, asymptomatic atherosclerosis, or metabolic syndrome. A polypill is a combination pill in which multiple medications effective in the prevention of cardiovascular disease (for example statins, antihypertensives, and aspirin) are put together in a single pill.
The influence of age on neurorehabilitation
Authors: Wirz Markus , Rutz-LaPitz Louise
Published: July 2018

This chapter addresses issues related to neurorehabilitation of elderly patients. As society is growing older the age of patients referred to rehabilitation is also increasing. This is evident in patients with spinal cord injury, which was classically a condition affecting young individuals. The stroke population is typically older. However, the age at the occurrence of stroke is also increasing. There is no clear criterion when a patient is considered old. Defining age exclusively by means of years of one’s life is insufficient. Nowadays, seniors can be healthy, active, and fit. In principle, there is no specific rehabilitation strategy for the aged. However, there are a number of age-related conditions that have to be accounted for during rehabilitation. It is the challenge of the rehabilitation team to uncover and reinforce resources while considering age-related impairments and limitations to return the person to their home, possibly for further rehabilitation, as soon as possible.
Enhancement of neuroplasticity by drug therapy
Authors: Ziemann Ulf
Published: July 2018

This chapter reviews effects of CNS active drugs specifically on activity-dependent plasticity and learning. The rationale for choosing this focus is the existing evidence that CNS active drugs have an impact on rehabilitation success after stroke to a relevant extent only if coupled with task-specific practice. This chapter reviews pharmacological modulation of stimulation induced long-term potentiation (LTP) in animal and human studies because synaptic plasticity in the form of LTP is a basic mechanism of learning and memory processes. Next, the chapter reviews the evidence of CNS active drugs on learning in animal and human studies. In the third part, the impact of CNS active drugs on neurorehabilitation of stroke patients is surveyed and the translational cascade from basic research to clinical studies is described. Finally, limitations of the current studies, open questions and future directions are discussed. This chapter demonstrates significant impact of neuropharmacology on activity-dependent plasticity and learning.
Acquired disorders of language and their treatment
Authors: Leff Alex , Crinion Jenny
Published: July 2018

This chapter covers the classification of acquired aphasic syndromes. It illustrates some of the speech errors aphasic stroke patients make with videos of a patient describing a picture and attempting to repeat words. The main part of the chapter assesses the evidencebase for speech and language therapy (SALT) and answers the following questions: Does SALT work? What is the correct dose and intensity? And is it ever too late for SALT intervention? We then discuss two main adjuvants to SALT:one old—drug therapy; one new—non-invasive brain stimulation. Finally, we examine the role for e-rehabilitation and augmentative aids before asking what the future might hold for aphasia therapy, and wondering if it might already be here.
Technology to enhance arm and hand function
Authors: Prochazka Arthur
Published: July 2018

About 2% of people have weak or paralysed upper limbs (ULs) due to stroke or spinal cord injury (SCI). Physiotherapy involving exercise can improve motor function in many such cases. This chapter reviews conventional and robotic exercise therapy, FES and passive exercise devices that enhance engagement in the UL rehabilitation with computer gaming, which can restore neuromuscular control and improve motivation by making exercise therapy enjoyable. Over the last 10 years many devices have been developed and tested. For example, neuroprostheses that activate hand muscles with functional electrical stimulation (FES). Exercise therapy performed with robotic devices has been one of the most active areas of research and development. It is suggested that important developments in the next few years will include the widespread availability and adoption of affordable FES and in-home exercise devices, and the provision of tele-coaching over the Internet.
Low testosterone is associated with frailty, muscle wasting and physical dysfunction among men receiving hemodialysis: a longitudinal analysis
Authors: Chiang Janet M , Kaysen George A , Segal Mark , Chertow Glenn M , Delgado Cynthia , Johansen Kirsten L
Published: July 2018

Background

Despite the high prevalence of frailty among patients receiving hemodialysis, few preventable or treatable contributing causes have been identified. Hypogonadism is also common in this population and low serum testosterone concentrations share several clinical phenotypes with frailty. We hypothesized that low serum testosterone concentrations would be associated with frailty and several of its individual components.

Methods

We used data from 440 men from A Cohort Study To Investigate the Value of Exercise in ESRD/Analysis Designed to Investigate the Paradox of Obesity and Survival in ESRD, a longitudinal study that recruited participants from 14 dialysis centers in Atlanta, GA and the San Francisco, CA Bay Area from 2009 to 2011. We assessed frailty using the Fried Frailty Phenotype. We examined the association between free testosterone (as a continuous and dichotomous variable) and frailty, individual frailty components, sarcopenia, lower extremity function and muscle mass estimation by creatinine and body impedance spectroscopy over 12 months using generalized estimating equations.

Results

The mean age was 56.1 ± 14.2 years and 27% were white. A 50% lower concentration of free testosterone was associated with 1.40-fold higher odds of being frail [95% confidence interval (CI) 1.05–1.53] and 1.40-fold higher odds of becoming frail over 12 months (95% CI 1.07–1.73). This association was mainly due to an association with two components of frailty: grip strength and gait speed. In addition, 50% lower free testosterone concentration was associated with a 1.55-fold higher odds of having sarcopenia (95% CI 1.09–2.02) and 1.72-fold higher odds for developing sarcopenia (95% CI 1.13–2.33) as well as with lower muscle mass and a decrease in muscle mass over 12 months as estimated by serum creatinine and by bioelectrical impedance spectroscopy.

Conclusion

Serum free testosterone concentration was associated with frailty, physical function, sarcopenia and muscle mass as well as with changes in these outcomes over 12 months. Testosterone replacement may be a feasible therapeutic target toward prevention of frailty, although clinical trials are needed to test this possibility.