bluuebunny/crossref_metadata_2025 huggingface dataset:
Noncompliance and Missing Data in Health Economic Evaluation
Authors: DiazOrdaz Karla , Grieve Richard
Published: May 2019

Health economic evaluations face the issues of noncompliance and missing data. Here, noncompliance is defined as non-adherence to a specific treatment, and occurs within randomized controlled trials (RCTs) when participants depart from their random assignment. Missing data arises if, for example, there is loss-to-follow-up, survey non-response, or the information available from routine data sources is incomplete. Appropriate statistical methods for handling noncompliance and missing data have been developed, but they have rarely been applied in health economics studies. Here, we illustrate the issues and outline some of the appropriate methods with which to handle these with application to health economic evaluation that uses data from an RCT.

In an RCT the random assignment can be used as an instrument-for-treatment receipt, to obtain consistent estimates of the complier average causal effect, provided the underlying assumptions are met. Instrumental variable methods can accommodate essential features of the health economic context such as the correlation between individuals’ costs and outcomes in cost-effectiveness studies. Methodological guidance for handling missing data encourages approaches such as multiple imputation or inverse probability weighting, which assume the data are Missing At Random, but also sensitivity analyses that recognize the data may be missing according to the true, unobserved values, that is, Missing Not at Random.

Future studies should subject the assumptions behind methods for handling noncompliance and missing data to thorough sensitivity analyses. Modern machine-learning methods can help reduce reliance on correct model specification. Further research is required to develop flexible methods for handling more complex forms of noncompliance and missing data.
The Leclerc Expedition to Saint-Domingue and the Independence of Haiti, 1802–1804
Authors: Girard Philippe
Published: May 2019

In December 1801, First Consul Napoléon Bonaparte sent a massive expedition to the French colony of Saint-Domingue (today: Haiti). His goal was to restore direct French rule and overthrow Toussaint Louverture, a former slave who, as governor general of Saint-Domingue, had been suspected of plotting independence. Bonaparte’s secondary goal may have been to reinstate slavery, which France had abolished in 1793–1794.

Bonaparte’s brother-in-law, General Victoire Leclerc, headed the expedition. After landing in Saint-Domingue in February 1802 with 20,000 troops, he managed, with great difficulty, to defeat Louverture’s army. He then deported Louverture to France, where he died in exile. In August 1802, however, resistance intensified as plantation laborers became convinced that the French intended to restore slavery. Leclerc, who lost much of his army to yellow fever, embraced increasingly murderous tactics against the black population until he died in November 1802.

For one year, Leclerc’s successor, General Donatien de Rochambeau, battled Louverture’s successor, General Jean-Jacques Dessalines, in a brutal conflict with genocidal overtones. The bravery of Dessalines’s troops, lack of support from France, epidemic disease, and the renewal of Britain’s war with France eventually doomed the French effort. After the departure of the last remnants of the Leclerc expedition, Dessalines declared the independence of Saint-Domingue, now known as Haiti, on January 1, 1804, and then put to death most of the remaining French planters.
Coca and Cocaine in Latin American History
Authors: Gootenberg Paul
Published: May 2019

Coca leaf (“chewed” by indigenous Andean peoples) and cocaine (the notorious modern illicit drug trafficked from the Andes) are deeply emblematic of South America, but neither has attracted the in-depth archival research they deserve. Their two modern histories are closely linked. Coca leaf, a part of Andean indigenous lifeways for thousands of years, is the raw ingredient for the alkaloid drug cocaine, discovered in 1860, and illicit peasant coca plots in the western Amazon of Peru, Bolivia, and Colombia have been the source for the infamous illicit cocaine “cartels” since the 1970s. The two drugs’ fates have both had surprisingly shifting trajectories and meanings across the colonial, national, and modern eras. They have also distinctively linked the Andes to the outside world and national political cultures of the three chief Andean states. Bolivia has the most continuous history with coca, related to the highland geography of its indigenous majority, though coca leaf only became a “nationalist” symbol over the past fifty years or so. Peru was home to the world’s first legal cocaine industries, starting in the 1880s, and coca and illicit cocaine have interacted in complex ways ever since. Colombia had the least coca traditions, and was the last nation to develop illicit cocaine exports in the 1970s and 1980s, although with a dramatic impact on Colombia and the world. This largely unknown and changeable history underlies the present-day crossroads of coca and cocaine: will the US-abetted Andean “drug wars” against cocaine continue, despite their long failures, and will coca’s place as a symbol of cultural and national pride in the Andes be fully restored?
Leo Tolstoy: A Very Short Introduction
Authors: Knapp Liza
Published: May 2019

War and Peace and Anna Karenina are widely recognized as two of the greatest novels ever written. Their author, Leo Tolstoy, has been honoured as the father of the modern war story, and as an innovator in psychological prose and forerunner of stream of consciousness. Leo Tolstoy: A Very Short Introduction examines the life and work of Leo Tolstoy, exploring both his celebrated novels and non-fiction writings, addressing the eternal questions of love, death, war, peace, faith, and activism found in them. It also considers Tolstoy’s different roles as a writer, thinker, and activist, highlighting those aspects of his work that are still relevant today.
1. From Ant Brothers to loving all as brothers and sisters
Authors: Knapp Liza
Published: May 2019

At his death in 1910, Tolstoy was known as a great writer and as a voice of protest. He was a merciless critic of institutions that perpetrated, bred, or tolerated injustice, hatred, and violence in any form. Among literary critics and rival writers, it has been a commonplace to disparage Tolstoy’s ‘thought’ while praising his ‘art’. ‘From Ant Brothers to loving all as brothers and sisters’ describes the childhood game that Tolstoy played with his siblings, which contains many hallmarks of Tolstoy’s thought and art: the yearning for universal love, the aversion to violence and war, the transformation of the everyday world through imagination, and the search for human comfort in the shadow of death.
2. Tolstoy on war and on peace
Authors: Knapp Liza
Published: May 2019

Tolstoy is often hailed as the father of the modern war story. What makes Tolstoy’s writing on war so good—and so modern—is how he seems to tell the truth about war. As he drew on his first-hand experience of warfare in the Caucasus and Crimea, Tolstoy made it clear that he was not going to repeat old lies to the effect that ‘it is sweet and fitting to die for one’s country’. ‘Tolstoy on war and on peace’ explains that Tolstoy went further in his truth-telling to reveal not just that war is hell, but that it violates the ‘law of love’ that the participants profess. It explores ‘The Raid’, the Sevastopol tales, War and Peace, and Hadji Murat.
4. Death
Authors: Knapp Liza
Published: May 2019

Death was a fact of Tolstoy’s life from the start. He lost both of his parents during childhood and then, as a young man, Tolstoy witnessed and caused death at war. Death continued to haunt him. Whether he was writing about a war zone, a pastoral landscape, a slum, or a family estate, Tolstoy’s works are set in the ‘valley of the shadow of death’. One of Tolstoy’s missions as a writer was to remind readers of their own mortality and to make them think about how to live and love in the face of death. ‘Death’ discusses Tolstoy’s treatment of dying in Childhood, Boyhood, Youth; War and Peace; Anna Karenina; and ‘The Death of Ivan Ilyich’.
5. What Tolstoy believed
Authors: Knapp Liza
Published: May 2019

As he approached the age of 50, Tolstoy experienced what is often described as a spiritual crisis. He struggled to finish Anna Karenina and then devoted the next several years to religious life. He returned to the fold of the Russian Orthodox Church, but soon doubted the Church’s doctrines, rituals, and practices. Tolstoy found faith on his own terms. Love of God and neighbour and non-violence were at the core. ‘What Tolstoy believed’ discusses the religious ideas that Tolstoy explored in his fiction and set forth more directly in works such as his Confession, Translation and Harmonization of the Gospels, The Gospel in Brief, What I Believe, and The Kingdom of God Is Within You.
6. What then must we do?
Authors: Knapp Liza
Published: May 2019

In his later years, Tolstoy occupied himself with questions of social justice. Tolstoy wrote on a number of topics, including poverty, the allocation of goods and privileges, class relations, landownership, manual labour, famine, charity, civil disobedience, non-violence, and the ethics of diet. Tolstoy had been concerned with these questions earlier, both in his fiction and in his own life. But, inspired by his newly articulated faith, he felt the need to address these social issues more directly. For Tolstoy, faith and action went hand in hand. ‘What then must we do?’ considers how Tolstoy addressed these issues in What Then Must We Do?, Resurrection, and other works.
7. Tolstoy’s art and devices
Authors: Knapp Liza
Published: May 2019

In criticism of Tolstoy’s work, many suggest that Tolstoy’s realism was at the expense of artistry or form, but ‘Tolstoy’s art and devices’ explains how Tolstoy used a variety of techniques to ‘infect’ the readers of his fiction and non-fiction with what was in his soul. It also describes the art beneath the surface of Tolstoy’s seemingly faithful rendering of Russian reality. Numerous examples from his work are given to show how Tolstoy depicted the inner life of his characters, and how he used the concept of defamiliarization, similes, the power of comparisons, and hidden symmetries.
8. Tolstoy cannot be silent
Authors: Knapp Liza
Published: May 2019

For his last thirty years, from Confession to ‘I Cannot Be Silent’, Tolstoy often spoke out in the first person, dispensing with the veil of fiction. These late works were widely disseminated. In ‘I Cannot Be Silent’, Tolstoy spoke out with the intention of inspiring and provoking everyone, from the tsar to readers around the globe. This felt more urgent to him as he approached death. ‘Tolstoy cannot be silent’ considers how in ‘I Cannot Be Silent’, Tolstoy shows—in a highly concentrated form—the devices, techniques, and subject matter that give his fiction its power. Tolstoy returned to the questions about love, death, brotherhood, and the pain of others that he had posed from the start.
2. How to learn to read (or not)
Authors: Snowling Margaret J.
Published: May 2019

‘How to learn to read (or not)’ looks at the stages through which a child must progress on the journey to literacy and the demands of learning to read. It argues that literacy builds on a foundation of spoken language and emphasizes the importance of the skills a child brings to reading. It also discusses the alphabetic principle, phoneme awareness, learning to spell, reading for meaning, and learning to read in different languages. In summary, a ‘triple foundation’ of symbol knowledge, phonological awareness, and rapid naming ability appears to underpin reading development universally. However, there are also additional predictors that are language-specific.
6. What works for dyslexia?
Authors: Snowling Margaret J.
Published: May 2019

There is no ‘quick fix’ or cure for dyslexia; it is a lifelong condition. Nevertheless, there are ways of helping to improve reading and spelling as well as ways to get around some of the problems that come with dyslexia. In addition, early intervention can set a child on to the right track to developing adequate literacy skills. ‘What works for dyslexia?’ discusses the importance of evidence-based approaches in order to provide advice as to what works. Screening in the mainstream classroom can be used to identify children with potential problems and tiers of intervention can then be put in place. It also considers what parents, schools, and employers can do to help.
A Cross-Sectional Analysis of Telomere Length and Sleep in the Women’s Health Initiative
Authors: Grieshober Laurie , Wactawski-Wende Jean , Hageman Blair Rachael , Mu Lina , Liu Jingmin , Nie Jing , Carty Cara L , Hale Lauren , Kroenke Candyce H , LaCroix Andrea Z , Reiner Alex P , Ochs-Balcom Heather M
Published: May 2019

Telomere length is a heritable marker of cellular age that is associated with morbidity and mortality. Poor sleep behaviors, which are also associated with adverse health events, may be related to leukocyte telomere length (LTL). We studied a subpopulation of 3,145 postmenopausal women (1,796 European-American (EA) and 1,349 African-American (AA)) enrolled in the Women’s Health Initiative in 1993–1998 with data on Southern blot-measured LTL and self-reported usual sleep duration and sleep disturbance. LTL-sleep associations were analyzed separately for duration and disturbance using weighted and confounder-adjusted linear regression models in the entire sample (AAs + EAs; adjusted for race/ethnicity) and in racial/ethnic strata, since LTL differs by ancestry. After adjustment for covariates, each additional daily hour of sleep beyond 5 hours, approximately, was associated with a 27-base-pair (95% confidence interval (CI): 6, 48) longer LTL in the entire sample. Associations between sleep duration and LTL were strongest among AAs (adjusted β = 37, 95% CI: 4, 70); a similar, nonsignificant association was observed for EAs (adjusted β = 20, 95% CI: −7, 48). Sleep disturbance was not associated with LTL in our study. Our models did not show departure from linearity (quadratic sleep terms: P ≥ 0.55). Our results suggest that longer sleep duration is associated with longer LTL in postmenopausal women.
Deep fusion of contextual and object-based representations for delineation of multiple nuclear phenotypes
Authors: Khoshdeli Mina , Winkelmaier Garrett , Parvin Bahram
Published: May 2019

Motivation

Nuclear delineation and phenotypic profiling are important steps in the automated analysis of histology sections. However, these are challenging problems due to (i) technical variations (e.g. fixation, staining) that originate as a result of sample preparation; (ii) biological heterogeneity (e.g. vesicular versus high chromatin phenotypes, nuclear atypia) and (iii) overlapping nuclei. This Application-Note couples contextual information about the cellular organization with the individual signature of nuclei to improve performance. As a result, routine delineation of nuclei in H&E stained histology sections is enabled for either computer-aided pathology or integration with genome-wide molecular data.

Results

The method has been evaluated on two independent datasets. One dataset originates from our lab and includes H&E stained sections of brain and breast samples. The second dataset is publicly available through IEEE with a focus on gland-based tissue architecture. We report an approximate AJI of 0.592 and an F1-score 0.93 on both datasets.

Availability and implementation

The code-base, modified dataset and results are publicly available.

Supplementary information

Supplementary data are available at Bioinformatics online.
CNet: a multi-omics approach to detecting clinically associated, combinatory genomic signatures
Authors: Jia Peilin , Pei Guangsheng , Zhao Zhongming
Published: May 2019

Motivation

Genome-wide multi-omics profiling of complex diseases provides valuable resources and opportunities to discover associations between various measures of genes and diseases. Currently, a pressing challenge is how to effectively detect functional genes associated with or causing phenotypic outcomes. We developed CNet to identify groups of genomic signatures whose combinatory effect is significantly associated with clinical and phenotypical outcomes.

Results

CNet builds on a generalized sequential feedforward method, augmented by a down-sampling bootstrap strategy to reduce random hitchhiking signatures. It further applies a dynamic trimming procedure to remove relatively less informative signatures at every step. CNet can manage heterogeneous genomic signature profiles simultaneously and select the best signature to represent a specific gene. To deal with various forms of clinical and phenotypical measurements, we introduced four models to deal with continuous, categorical and censored data. We tested CNet using drug-response data, multidimensional cancer genomics data and genome-wide association study data for multiple traits. Our results demonstrated that in various scenarios, CNet could effectively identify signatures that are associated with the outcomes. In addition, we applied CNet to identify likely disease-causing chains involving somatic mutations, pathway activities and patient outcomes. With appropriate setting, CNet can be applied in many biological conditions.

Availability and implementation

CNet can be downloaded at https://github.com/bsml320/CNet.

Supplementary information

Supplementary data are available at Bioinformatics online.
White matter hyperintensities: relationship to amyloid and tau burden
Authors: Graff-Radford Jonathan , Arenaza-Urquijo Eider M , Knopman David S , Schwarz Christopher G , Brown Robert D , Rabinstein Alejandro A , Gunter Jeffrey L , Senjem Matthew L , Przybelski Scott A , Lesnick Timothy , Ward Chadwick , Mielke Michelle M , Lowe Val J , Petersen Ronald C , Kremers Walter K , Kantarci Kejal , Jack Clifford R , Vemuri Prashanthi
Published: May 2019

Although white matter hyperintensities have traditionally been viewed as a marker of vascular disease, recent pathology studies have found an association between white matter hyperintensities and Alzheimer’s disease pathologies. The objectives of this study were to investigate the topographic patterns of white matter hyperintensities associated with Alzheimer’s disease biomarkers measured using PET. From the population-based Mayo Clinic Study of Aging, 434 participants without dementia (55% male) with FLAIR and gradient recall echo MRI, tau-PET (AV-1451) and amyloid-PET scans were identified. A subset had cerebral microbleeds detected on T2* gradient recall echo scans. White matter hyperintensities were semi-automatically segmented using FLAIR MRI in participant space and normalized to a custom template. We used statistical parametric mapping 12-based, voxel-wise, multiple-regression analyses to detect white matter hyperintense regions associated with Alzheimer’s biomarkers (global amyloid from amyloid-PET and meta-regions of interest tau uptake from tau-PET) after adjusting for age, sex and hypertension. For amyloid associations, we additionally adjusted for tau and vice versa. Topographic patterns of amyloid-associated white matter hyperintensities included periventricular white matter hyperintensities (frontal and parietal lobes). White matter hyperintense volumes in the detected topographic pattern correlated strongly with lobar cerebral microbleeds (P < 0.001, age and sex adjusted Cohen’s d = 0.703). In contrast, there were no white matter hyperintense regions significantly associated with increased tau burden using voxel-based analysis or region-specific analysis. Among non-demented elderly, amyloid load correlated with a topographic pattern of white matter hyperintensities. Further, the amyloid-associated, white matter hyperintense regions strongly correlated with lobar cerebral microbleeds suggesting that cerebral amyloid angiopathy contributes to the relationship between amyloid and white matter hyperintensities. The study did not support an association between increased tau burden and white matter hyperintense burden.
TSC22D2 identified as a candidate susceptibility gene of multi-cancer pedigree using genome-wide linkage analysis and whole-exome sequencing
Authors: Xiao Lan , Wei Fang , Liang Fang , Li Qiao , Deng Hao , Tan Shiming , Chen Shuai , Xiong Fang , Guo Can , Liao Qianjin , Li Xiayu , Zhang Wenling , Wu Minghua , Zhou Yanhong , Xiang Bo , Zhou Ming , Li Xiaoling , Xiong Wei , Zeng Zhaoyang , Li Guiyuan
Published: May 2019

Cancer is a complex disease, which may involve multiple tumor susceptibility genes that mediate the occurrence and development of tumor molecular events. This study aimed to identify new genetic loci using genome-wide linkage analysis and whole-exome sequencing in a rare, large multi-cancer pedigree recently found in China. We performed high-throughput single-nucleotide polymorphism (SNP) array and linkage analyses of 24 core members of this pedigree and found that the disease susceptibility locus in the multi-cancer pedigree was mapped to chromosome 3q24-26. We also used microsatellites to further validate the results of the SNP locus linkage analysis. Furthermore, we sequenced the whole exome of three members in this pedigree and identified a novel mutant of transforming growth factor β stimulated clone 22 domain family, member 2 (TSC22D2, c.-91T-C) cosegregated with the cancer phenotype. This change was at a highly conserved position, and the exome results were validated using linkage analysis. Moreover, we found the histone H4 transcription factor (HINFP) binds to the promoter region of TSC22D2 and may regulate its transcription. In conclusion, our findings are of great significance to the early pathogenesis of tumors and contribute to the search for molecular targets for the early prevention and treatment of tumors.
Reduced Segregation Between Cognitive and Emotional Processes in Cannabis Dependence
Authors: Manza Peter , Shokri-Kojori Ehsan , Volkow Nora D
Published: May 2019

Addiction is characterized by an erosion of cognitive control toward drug taking that is accentuated by negative emotional states. Here we tested the hypothesis that enhanced interference on cognitive control reflects a loss of segregation between cognition and emotion in addiction. We analyzed Human Connectome Project data from 1206 young adults, including 89 with cannabis dependence (CD). Two composite factors, one for cognition and one for emotion, were derived using principal component (PC) analyses. Component scores for these PCs were significantly associated in the CD group, such that negative emotionality correlated with poor cognition. However, the corresponding component scores were uncorrelated in matched controls and nondependent recreational cannabis users (n = 87). In CD, but not controls or recreational users, functional magnetic resonance imaging activations to emotional stimuli (angry/fearful faces > shapes) correlated with activations to cognitive demand (working memory; 2-back > 0-back). Canonical correlation analyses linked individual differences in cognitive and emotional component scores with brain activations. In CD, there was substantial overlap between cognitive and emotional brain–behavior associations, but in controls, associations were more restricted to the cognitive domain. These findings support our hypothesis of impaired segregation between cognitive and emotional processes in CD that might contribute to poor cognitive control under conditions of increased emotional demand.
Predicting Hemolytic Uremic Syndrome and Renal Replacement Therapy in Shiga Toxin–producing Escherichia coli–infected Children
Authors: McKee Ryan S , Schnadower David , Tarr Phillip I , Xie Jianling , Finkelstein Yaron , Desai Neil , Lane Roni D , Bergmann Kelly R , Kaplan Ron L , Hariharan Selena , Cruz Andrea T , Cohen Daniel M , Dixon Andrew , Ramgopal Sriram , Rominger Annie , Powell Elizabeth C , Kilgar Jennifer , Michelson Kenneth A , Beer Darcy , Bitzan Martin , Pruitt Christopher M , Yen Kenneth , Meckler Garth D , Plint Amy C , Bradin Stuart , Abramo Thomas J , Gouin Serge , Kam April J , Schuh Abigail , Balamuth Fran , Hunley Tracy E , Kanegaye John T , Jones Nicholas E , Avva Usha , Porter Robert , Fein Daniel M , Louie Jeffrey P , Freedman Stephen B
Published: May 2019

Background

Shiga toxin–producing Escherichia coli (STEC) infections are leading causes of pediatric acute renal failure. Identifying hemolytic uremic syndrome (HUS) risk factors is needed to guide care.

Methods

We conducted a multicenter, historical cohort study to identify features associated with development of HUS (primary outcome) and need for renal replacement therapy (RRT) (secondary outcome) in STEC-infected children without HUS at initial presentation. Children aged <18 years who submitted STEC-positive specimens between January 2011 and December 2015 at a participating study institution were eligible.

Results

Of 927 STEC-infected children, 41 (4.4%) had HUS at presentation; of the remaining 886, 126 (14.2%) developed HUS. Predictors (all shown as odds ratio [OR] with 95% confidence interval [CI]) of HUS included younger age (0.77 [.69–.85] per year), leukocyte count ≥13.0 × 103/μL (2.54 [1.42–4.54]), higher hematocrit (1.83 [1.21–2.77] per 5% increase) and serum creatinine (10.82 [1.49–78.69] per 1 mg/dL increase), platelet count <250 × 103/μL (1.92 [1.02–3.60]), lower serum sodium (1.12 [1.02–1.23 per 1 mmol/L decrease), and intravenous fluid administration initiated ≥4 days following diarrhea onset (2.50 [1.14–5.46]). A longer interval from diarrhea onset to index visit was associated with reduced HUS risk (OR, 0.70 [95% CI, .54–.90]). RRT predictors (all shown as OR [95% CI]) included female sex (2.27 [1.14–4.50]), younger age (0.83 [.74–.92] per year), lower serum sodium (1.15 [1.04–1.27] per mmol/L decrease), higher leukocyte count ≥13.0 × 103/μL (2.35 [1.17–4.72]) and creatinine (7.75 [1.20–50.16] per 1 mg/dL increase) concentrations, and initial intravenous fluid administration ≥4 days following diarrhea onset (2.71 [1.18–6.21]).

Conclusions

The complex nature of STEC infection renders predicting its course a challenge. Risk factors we identified highlight the importance of avoiding dehydration and performing close clinical and laboratory monitoring.
A novel therapeutic peptide targeting myocardial reperfusion injury
Authors: Boisguérin Prisca , Covinhes Aurélie , Gallot Laura , Barrère Christian , Vincent Anne , Busson Muriel , Piot Christophe , Nargeot Joël , Lebleu Bernard , Barrère-Lemaire Stéphanie
Published: May 2019

Aims

Regulated cell death is a main contributor of myocardial ischaemia-reperfusion (IR) injury during acute myocardial infarction. In this context, targeting apoptosis could be a potent therapeutical strategy. In a previous study, we showed that DAXX (death-associated protein) was essential for transducing the FAS-dependent apoptotic signal during IR injury. The present study aims at evaluating the cardioprotective effects of a synthetic peptide inhibiting FAS:DAXX interaction.

Methods and results

An interfering peptide was engineered and then coupled to the Tat cell penetrating peptide (Tat-DAXXp). Its internalization and anti-apoptotic properties were demonstrated in primary cardiomyocytes. Importantly, an intravenous bolus injection of Tat-DAXXp (1 mg/kg) 5 min before reperfusion in a murine myocardial IR model decreased infarct size by 48% after 24 h of reperfusion. In addition, Tat-DAXXp was still efficient after a 30-min delayed administration, and was completely degraded and eliminated within 24 h thereby reducing risks of potential side effects. Importantly, Tat-DAXXp reduced mouse early post-infarction mortality by 67%. Mechanistically, cardioprotection was supported by both anti-apoptotic and pro-survival effects, and an improvement of myocardial functional recovery as evidenced in ex vivo experiments.

Conclusions

Our study demonstrates that a single dose of Tat-DAXXp injected intravenously at the onset of reperfusion leads to a strong cardioprotection in vivo by inhibiting IR injury validating Tat-DAXXp as a promising candidate for therapeutic application.
Supplementary Nutrition of Eucryptorrhynchus brandti (Coleoptera: Curculionidae: Cryptorrhychinae): Effect of Ailanthus altissima Host Tissues on Ovary Maturation and Oviposition
Authors: Guo Wenjuan , Yang Kailang , Zhang Ganyu , Wen Junbao
Published: May 2019

Eucryptorrhynchus brandti is a trunk-boring pest that causes severe damage to its single host, Ailanthus altissima in China. Eucryptorrhynchus brandti adults require supplementary nutrition to achieve sexual maturity. Adults feed on petioles, shoots, 2- to 3-yr-old branches, and stems of A. altissima, but prefer to feed on stems. The effects of different host plant tissues on ovary development and oviposition in E. brandti are unclear. Thus, we examined the effects of the consumption of A. altissima petioles, shoots, branches, and stems on ovary development of E. brandti. Using ovaries of different ages, we also evaluated the differentiation of ovarioles, presence and appearance of follicular relics, number of eggs, cuticle hardness, and fat body quantity over time. We found the reproductive system was composed of two ovaries, lateral oviducts, a common oviduct, and spermatheca. The physiological age of ovaries was divided into three nulliparous and three parous stages. Females fed on stems had mature ovaries and successfully oviposited; females fed on other tree tissues or water had no functional ovaries and did not lay eggs. We found virgin females must obtain sufficient nutrition, as evidenced by the immature ovaries in females fed the water. We also found that only stems of A. altissima contribute to egg development; however, the other tree tissues do not contribute to egg development. These findings improve our understanding of the feeding preference of E. brandti from the perspective of ovary development as well as optimal host tissues for ovary development.
Minimally invasive surgical approaches to left main and left anterior descending coronary artery revascularization are superior compared to first- and second-generation drug-eluting stents: a network meta-analysis
Authors: Indja Ben , Woldendorp Kei , Black Deborah , Bannon Paul G , Wilson Michael K , Vallely Michael P
Published: May 2019

OBJECTIVES

There are a number of minimally invasive approaches to revascularization of coronary artery disease that involve the left main or proximal left anterior descending artery; however, studies to date provide mixed results.

METHODS

A Bayesian network meta-analysis was performed to compare early and late postoperative outcomes between percutaneous coronary intervention with first- and second-generation drug-eluting stents (DESs), off-pump coronary artery bypass and minimally invasive direct coronary artery bypass (MIDCAB) in patients with involvement of left main or left anterior descending disease.

RESULTS

A total of 37 studies with 31 728 patients were included in the analysis. There were no significant differences in early mortality rates, strokes or myocardial infarctions (MIs). The long-term all-cause mortality rate was equivalent between the groups. Patients who had off-pump coronary artery bypass had fewer late MI compared with those who had first-generation DES (DES1) [odds ratio (OR) 0.38, 95% confidence interval (CI) 0.20–0.72] and MIDCAB (OR 0.41, 95% CI 0.17–0.97) and reduced late target vessel revascularization compared with DES1 (OR 0.17, 95% CI 0.09–0.32) and second-generation DES (DES2) (OR 0.32, 95% CI 0.14–0.72). The rate of late major adverse cardiac events was lower with off-pump coronary artery bypass compared with that with DES1 (OR 0.33, 95% CI 0.26–0.43) and DES2 (OR 0.62, 95% CI 0.45–0.90). The rate of late major adverse cardiac events with MIDCAB was lower than that with DES1 (OR 0.43, 95% CI 0.31–0.62) as was that with DES2 compared with DES1 (OR 0.53, 95% CI 0.39–0.70).

CONCLUSIONS

Surgical approaches to left main or proximal left anterior descending disease remain superior to first- or second-generation DES in terms of long-term freedom from MI and target vessel revascularization as well as improved overall long-term survival. Conflicting rates of late MI and target vessel revascularization in patients who underwent MIDCAB suggest disease in alternate vessels that may best be approached via hybrid techniques.
Implications of N-terminal pro-B-type natriuretic peptide in patients with three-vessel disease
Authors: Zhang Ce , Jiang Lin , Xu Lianjun , Tian Jian , Liu Junhao , Zhao Xueyan , Feng Xinxing , Wang Dong , Zhang Yin , Sun Kai , Xu Bo , Zhao Wei , Hui Rutai , Gao Runlin , Yuan Jinqing , Song Lei
Published: May 2019

Aims

Risk assessment and treatment stratification for three-vessel disease (3VD) remain challenging. N-terminal pro-B-type natriuretic peptide (NT-proBNP) is an established biomarker for prognostication and treatment in heart failure. The present study aimed to evaluate the prognostic value of NT-proBNP beyond the SYNTAX score II (SSII), and its association with long-term outcome after three strategies [percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG), and medical therapy (MT)] in a cohort of patients with 3VD.

Methods and results

A total of 6597 patients with available baseline NT-proBNP data were included in the study. Baseline, procedural, and follow-up data were collected. The primary endpoint was all-cause death. Secondary endpoints included cardiac death and major adverse cardiac and cerebrovascular events (MACCE), a composite of death, myocardial infarction, and stroke. During a median follow-up of 7.0 years, higher NT-proBNP levels were strongly associated with increased risks of all-cause death, cardiac death, and MACCE (all adjusted P < 0.01). Moreover, NT-proBNP significantly improved discrimination and reclassification of the SSII. Notably, there was a significant interaction between NT-proBNP quartiles and treatment strategies for MACCE (P = 0.004). Revascularization was associated with lower risks of MACCE than MT, except for patients in the lowest quartile wherein no such association was observed. Among patients in the highest quartile, PCI was associated with an increased risk of MACCE compared with CABG (hazard ratio 1.43, 95% confidence interval 1.09–1.87).

Conclusion

N-terminal pro-BNP is a potential biomarker for risk stratification and therapeutic decision-making in patients with 3VD. Further randomized studies are needed to confirm these findings.
Biomarkers to predict the response to cardiac resynchronization therapy
Authors: Heggermont Ward , Auricchio Angelo , Vanderheyden Marc
Published: May 2019

Cardiac resynchronization therapy (CRT) is an established non-pharmacological treatment for selected heart failure patients with wide QRS duration. However, there is a persistent number of non-responders throughout. The prediction of the CRT response is paramount to adequately select the correct patients for CRT. One of the expanding fields of research is the development of biomarkers that predict the response to CRT. A review of the available literature on biomarkers in CRT patients has been performed to formulate a critical appraisal of the available data. The main conclusion of our review is that biomarker research in this patient population is very fragmented and broad. This results in the use of non-uniform endpoints to define the CRT response, which precludes an in-depth comparison of the available data. To improve research development in this field, a uniform definition of the CRT response and relevant endpoints is necessary to better predict the CRT response.
Recent Secondary Contacts, Linked Selection, and Variable Recombination Rates Shape Genomic Diversity in the Model Species Anolis carolinensis
Authors: Bourgeois Yann , Ruggiero Robert P , Manthey Joseph D , Boissinot Stéphane
Published: May 2019

Gaining a better understanding on how selection and neutral processes affect genomic diversity is essential to gain better insights into the mechanisms driving adaptation and speciation. However, the evolutionary processes affecting variation at a genomic scale have not been investigated in most vertebrate lineages. Here, we present the first population genomics survey using whole genome resequencing in the green anole (Anolis carolinensis). Anoles have been intensively studied to understand mechanisms underlying adaptation and speciation. The green anole in particular is an important model to study genome evolution. We quantified how demography, recombination, and selection have led to the current genetic diversity of the green anole by using whole-genome resequencing of five genetic clusters covering the entire species range. The differentiation of green anole’s populations is consistent with a northward expansion from South Florida followed by genetic isolation and subsequent gene flow among adjacent genetic clusters. Dispersal out-of-Florida was accompanied by a drastic population bottleneck followed by a rapid population expansion. This event was accompanied by male-biased dispersal and/or selective sweeps on the X chromosome. We show that the interaction between linked selection and recombination is the main contributor to the genomic landscape of differentiation in the anole genome.
Changing Impact of Obesity on Active Life Expectancy of Older Americans
Authors: Zhang Yuan S , Saito Yasuhiko , Crimmins Eileen M
Published: May 2019

Background

The rise in the number and earlier age of onset of obese persons has raised critical concerns about consequences of obesity; however, recent evidence suggests that the impact of obesity on health outcomes may have changed. This study aims to assess the change of the impact of obesity on active life expectancy among Americans aged 70 years and older over almost two decades, 1993–1998 to 2010–2014.

Methods

For each period, we use three waves of data from the Health and Retirement Study to estimate age-specific transition probabilities between health states. The average number of years active and disabled is calculated with Interpolated Markov Chain software based on estimated transition probabilities.

Results

Overall obesity and severe obesity increased markedly over time yet active life expectancy expanded for all individuals and the increases are greater among the obese and women. Increases in total and active life expectancy occurred because of the changing association of obesity with disability and mortality.

Conclusions

Individuals at age 70 years in the later period in each weight group could expect to live a smaller proportion of remaining life with activities of daily living disability than those in the earlier period. High levels of obesity continue to have significant adverse effects on the quality of life. The increasing prevalence of severe obesity and the growing number of older persons may result in substantial additional health care needs and costs. Continued effort to improve cardiovascular health is required to control the burden of obesity in later life in an era of rising obesity.
Ibuprofen enhances synaptic function and neural progenitors proliferation markers and improves neuropathology and motor coordination in Machado–Joseph disease models
Authors: Mendonça Liliana S , Nóbrega Clévio , Tavino Silvia , Brinkhaus Maximilian , Matos Carlos , Tomé Sandra , Moreira Ricardo , Henriques Daniel , Kaspar Brian K , Pereira de Almeida Luís
Published: May 2019

Machado–Joseph disease or spinocerebellar ataxia type 3 is an inherited neurodegenerative disease associated with an abnormal glutamine over-repetition within the ataxin-3 protein. This mutant ataxin-3 protein affects several cellular pathways, leading to neuroinflammation and neuronal death in specific brain regions resulting in severe clinical manifestations. Presently, there is no therapy able to modify the disease progression. Nevertheless, anti-inflammatory pharmacological intervention has been associated with positive outcomes in other neurodegenerative diseases. Thus, the present work aimed at investigating whether ibuprofen treatment would alleviate Machado–Joseph disease.

We found that ibuprofen-treated mouse models presented a significant reduction in the neuroinflammation markers, namely Il1b and TNFa mRNA and IKB-α protein phosphorylation levels. Moreover, these mice exhibited neuronal preservation, cerebellar atrophy reduction, smaller mutant ataxin-3 inclusions and motor performance improvement. Additionally, neural cultures of Machado–Joseph disease patients’ induced pluripotent stem cells-derived neural stem cells incubated with ibuprofen showed increased levels of neural progenitors proliferation and synaptic markers such as MSI1, NOTCH1 and SYP. These findings were further confirmed in ibuprofen-treated mice that display increased neural progenitor numbers (Ki67 positive) in the subventricular zone. Furthermore, interestingly, ibuprofen treatment enhanced neurite total length and synaptic function of human neurons. Therefore, our results indicate that ibuprofen reduces neuroinflammation and induces neuroprotection, alleviating Machado–Joseph disease-associated neuropathology and motor impairments. Thus, our findings demonstrate that ibuprofen treatment has the potential to be used as a neuroprotective therapeutic approach in Machado–Joseph disease.
Learning impairments and molecular changes in the brain caused by β-catenin loss
Authors: Wickham Robert J , Alexander Jonathan M , Eden Lillian W , Valencia-Yang Mabel , Llamas Josué , Aubrey John R , Jacob Michele H
Published: May 2019

Intellectual disability (ID), defined as IQ<70, occurs in 2.5% of individuals. Elucidating the underlying molecular mechanisms is essential for developing therapeutic strategies. Several of the identified genes that link to ID in humans are predicted to cause malfunction of β-catenin pathways, including mutations in CTNNB1 (β-catenin) itself. To identify pathological changes caused by β-catenin loss in the brain, we have generated a new β-catenin conditional knockout mouse (β-cat cKO) with targeted depletion of β-catenin in forebrain neurons during the period of major synaptogenesis, a critical window for brain development and function. Compared with control littermates, β-cat cKO mice display severe cognitive impairments. We tested for changes in two β-catenin pathways essential for normal brain function, cadherin-based synaptic adhesion complexes and canonical Wnt (Wingless-related integration site) signal transduction. Relative to control littermates, β-cat cKOs exhibit reduced levels of key synaptic adhesion and scaffold binding partners of β-catenin, including N-cadherin, α-N-catenin, p120ctn and S-SCAM/Magi2. Unexpectedly, the expression levels of several canonical Wnt target genes were not altered in β-cat cKOs. This lack of change led us to find that β-catenin loss leads to upregulation of γ-catenin (plakoglobin), a partial functional homolog, whose neural-specific role is poorly defined. We show that γ-catenin interacts with several β-catenin binding partners in neurons but is not able to fully substitute for β-catenin loss, likely due to differences in the N-and C-termini between the catenins. Our findings identify severe learning impairments, upregulation of γ-catenin and reductions in synaptic adhesion and scaffold proteins as major consequences of β-catenin loss.
Taking a Stab at Quantifying the Energetics of Biological Puncture
Authors: Anderson Philip S L , Crofts Stephanie B , Kim Jin-Tae , Chamorro Leonardo P
Published: May 2019

An organism’s ability to control the timing and direction of energy flow both within its body and out to the surrounding environment is vital to maintaining proper function. When physically interacting with an external target, the mechanical energy applied by the organism can be transferred to the target as several types of output energy, such as target deformation, target fracture, or as a transfer of momentum. The particular function being performed will dictate which of these results is most adaptive to the organism. Chewing food favors fracture, whereas running favors the transfer of momentum from the appendages to the ground. Here, we explore the relationship between deformation, fracture, and momentum transfer in biological puncture systems. Puncture is a widespread behavior in biology requiring energy transfer into a target to allow fracture and subsequent insertion of the tool. Existing correlations between both tool shape and tool dynamics with puncture success do not account for what energy may be lost due to deformation and momentum transfer in biological systems. Using a combination of pendulum tests and particle tracking velocimetry (PTV), we explored the contributions of fracture, deformation and momentum to puncture events using a gaboon viper fang. Results on unrestrained targets illustrate that momentum transfer between tool and target, controlled by the relative masses of the two, can influence the extent of fracture achieved during high-speed puncture. PTV allowed us to quantify deformation throughout the target during puncture and tease apart how input energy is partitioned between deformation and fracture. The relationship between input energy, target deformation and target fracture is non-linear; increasing impact speed from 2.0 to 2.5 m/s created no further fracture, but did increase deformation while increasing speed to 3.0 m/s allowed an equivalent amount of fracture to be achieved for less overall deformation. These results point to a new framework for examining puncture systems, where the relative resistances to deformation, fracture and target movement dictate where energy flows during impact. Further developing these methods will allow researchers to quantify the energetics of puncture systems in a way that is comparable across a broad range of organisms and connect energy flow within an organism to how that energy is eventually transferred to the environment.