bluuebunny/crossref_metadata_2025 huggingface dataset:
tRNA-derived fragments and microRNAs in the maternal-fetal interface of a mouse maternal-immune-activation autism model
Authors: Su Zhangli , Frost Elizabeth L. , Lammert Catherine R. , Przanowska Roza K. , Lukens John R. , Dutta Anindya
Published: December 2019

tRNA-derived small fragments (tRFs) and tRNA halves have emerging functions in different biological pathways, such as regulating gene expression, protein translation, retrotransposon activity, transgenerational epigenetic changes and response to environmental stress. However, small RNAs like tRFs and microRNAs in the maternal-fetal interface during gestation have not been studied extensively. Here we investigated the small RNA composition of mouse placenta/decidua, which represents the interface where the mother communicates with the fetus, to determine whether there are specific differences in tRFs and microRNAs during fetal development and in response to maternal immune activation (MIA). Global tRF expression pattern, just like microRNAs, can distinguish tissue types among placenta/decidua, fetal brain and fetal liver. In particular, 5’ tRNA halves from tRNAGly, tRNAGlu, tRNAValand tRNALysare abundantly expressed in the normal mouse placenta/decidua. Moreover, tRF and microRNA levels in the maternal-fetal-interface change dynamically over the course of embryonic development. To see if stress alters non-coding RNA expression at the maternal-fetal interface, we treated pregnant mice with a viral infection mimetic, which has been shown to promote autism-related phenotypes in the offspring. Acute changes in the levels of specific tRFs and microRNAs were observed 3-6 hours after MIA and are suppressed thereafter. A group of 5’ tRNA halves is down-regulated by MIA, whereas a group of 18-nucleotide tRF-3a is up-regulated. In conclusion, tRFs show tissue-specificity, developmental changes and acute response to environmental stress, opening the possibility of them having a role in the fetal response to MIA.
Genetic erosion reduces biomass temporal stability in wild fish populations
Authors: Prunier Jérôme G. , Chevalier Mathieu , Raffard Allan , Loot Géraldine , Poulet Nicolas , Blanchet Simon
Published: December 2019

Genetic diversity sustains species adaptation. However, it may also support key ecosystems functions and services that can be altered by the worldwide loss of genetic diversity. Here, using long-term wild fish data, we demonstrate that populations with high genetic diversity do not reach higher biomasses than populations with low genetic diversity. Nonetheless, populations with high genetic diversity have much more stable biomasses over recent decades than populations having suffered from genetic erosion, which has implications for the provision of ecosystem services and the risk of population extinction. Our results strengthen the importance of adopting prominent environmental policies to conserve this important biodiversity facet.
Alzheimer’s disease-related dysregulation of protein synthesis causes key pathological features with ageing
Authors: Ghosh Anshua , Mizuno Keiko , Tiwari Sachin S. , Proitsi Petroula , Perez-Nievas Beatriz Gomez , Glennon Elizabeth , Martinez-Nunez Rocio T. , Peter Giese K.
Published: December 2019

Alzheimer’s disease (AD) is characterised by Aβ and tau pathology as well as synaptic degeneration. Recently, it was suggested that the development of these key disease features may at least in part be due to increased protein synthesis that is regulated by fragile X mental retardation protein (FMRP) and its binding partner CYFIP2. Using an unbiased screen, we show that exposure of primary neurons to Aβ increases FMRP-regulated protein synthesis and involves a reduction of CYFIP2 levels. Modelling this CYFIP2 reduction in mice, we find Aβ accumulation, development of pre-tangle tau pathology, gliosis, loss of synapses, and deficits in memory formation with ageing. We conclude that reducing endogenous CYFIP2 expression is sufficient to cause some key features of AD in mice. We therefore propose a central role for CYFIP2 in AD as a modulator of protein synthesis, highlighting a novel direction for therapeutic targeting.
Identifying Core Operons in Metagenomic Data
Authors: Hu Xiao , Friedberg Iddo
Published: December 2019

An operon is a functional unit of DNA whose genes are co-transcribed on polycistronic mRNA, in a co-regulated fashion. Operons are a powerful mechanism of introducing functional complexity in bacteria, and are therefore of interest in microbial genetics, physiology, biochemistry, and evolution. Here we present a Pipeline for Operon Exploration in Metagenomes or POEM. At the heart of POEM lies the concept of a core operon, a functional unit enabled by a predicted operon in a metagenome. Using a series of benchmarks, we show the high accuracy of POEM, and demonstrate its use on a human gut metagenome sample. We conclude that POEM is a useful tool for analyzing metagenomes beyond the genomic level, and for identifying multi-gene functionalities and possible neofunctionalization in metagenomes. Availability:https://github.com/Rinoahu/POEM_py3k
The protective effect of club cell secretory protein (CC-16) on COPD risk and progression: a Mendelian randomisation study
Authors: Milne Stephen , Li Xuan , Cordero Ana I Hernandez , Yang Chen Xi , Cho Michael H , Beaty Terri H , Ruczinski Ingo , Hansel Nadia N , Bossé Yohan , Brandsma Corry-Anke , Sin Don D , Obeidat Ma’en
Published: December 2019

Background

There are currently no robust biomarkers of chronic obstructive pulmonary disease (COPD) risk or progression. Club cell secretory protein-16 (CC-16) is associated with the clinical expression of COPD. We aimed to determine if there is a causal effect of serum CC-16 level on COPD risk and/or progression using Mendelian randomisation (MR) analysis.

Methods

We performed a genome-wide association meta-analysis for serum CC-16 in two COPD cohorts (Lung Health Study [LHS], n=3,850 and ECLIPSE, n=1,702). We then used the CC-16-associated single-nucleotide polymorphisms (SNPs) in MR analysis to estimate the causal effect of serum CC-16 on COPD risk (International COPD Genetics Consortium/UK-Biobank dataset; n=35,735 cases, n=222,076 controls) and progression (change in forced expiratory volume in 1 s [FEV1] in LHS and ECLIPSE). We also determined the associations between SNPs associated with CC-16 and gene expression using n=1,111 lung tissue samples from the Lung eQTL Study.

Results

We identified 7 SNPs independently associated (p<5×10−8) with serum CC-16 levels; 6 of these were novel. MR analysis suggested a protective causal effect of increased serum CC-16 on COPD risk (p=0.008) and progression (LHS only, p=0.02). Five of the SNPs were also associated with gene expression in lung tissue, including that of the CC-16-encoding geneSCGB1A1(false discovery rate<0.1).

Conclusion

We have identified several novel genetic variants associated with serum CC-16 level in COPD cohorts. These genetic associations suggest a potential causal effect of serum CC-16 on COPD risk and progression. Further investigation of CC-16 as a biomarker or therapeutic target in COPD is warranted.

KEY MESSAGES

What is the key question?

Can genetics help uncover a causal effect of serum CC-16 level on COPD risk and/or progression?

What is the bottom line?

There is a protective effect of genetically-increased serum CC-16 on both COPD risk and progression (as measured by change in FEV1over time), which may be due to increased expression of the CC-16-encoding geneSCGB1A1in the lung.

Why read on?

This is the first study to demonstrate a possible causal effect of serum CC-16 in people with COPD, and highlights the potential for CC-16 as a biomarker or therapeutic target.
Optimal maturation of the SIV-specific CD8+T-cell response after primary infection is associated with natural control of SIV. ANRS SIC study
Authors: Passaes Caroline , Millet Antoine , Madelain Vincent , Monceaux Valérie , David Annie , Versmisse Pierre , Sylla Naya , Gostick Emma , Price David A. , Blancher Antoine , Dereuddre-Bosquet Nathalie , Pancino Gianfranco , Grand Roger Le , Lambotte Olivier , Müller-Trutwin Michaela , Rouzioux Christine , Guedj Jeremie , Avettand-Fenoel Veronique , Vaslin Bruno , Sáez-Cirión Asier
Published: December 2019

Highly efficient virus-specific CD8+T-cells are associated with immune control of HIV infection, but it remains unclear how these cells are generated and maintained over time. We used a macaque model of spontaneous control of SIVmac251 infection to monitor the development and evolution of potent antiviral CD8+T-cell responses. SIV-specific CD8+T-cells emerged during primary infection in all animals. However, the ability of CD8+T cells to suppress SIV replication was low in early stages but increased after a period of maturation, temporally linked with the establishment of sustained low-level viremia in controller macaques. SIV-specific CD8+T-cells with a central memory phenotype expressed higher levels of survival markers in controllersversusnon-controllers. In contrast, a persistently skewed differentiation phenotype was observed among central memory SIV-specific CD8+T-cells in non-controllers since primary infection, typified by relatively high expression levels of T-bet.

Collectively, these data show that the phenotype of SIV-specific CD8+T-cells defined early after SIV infection favor the gain of antiviral potency as a function of time in controllers, whereas SIV-specific CD8+T-cell responses in non-controllers fail to gain antiviral potency due to early defects imprinted in the central memory pool.
Chlorotoxin Conjugated with Saporin Reduces Viability of ML-1 Thyroid Cancer Cells In Vitro
Authors: Rizvanovic Husref , Pinheiro A Daniel , Kim Kyoungtae , Thomas Johnson
Published: December 2019

Background

Although differentiated thyroid cancer has good prognosis, radioactive iodine (RAI) resistant thyroid cancer is difficult to treat. Current therapies for progressive RAI resistant thyroid cancer are not very effective. There is an unmet need for better therapeutic agents in this scenario. Studies have shown that aggressive thyroid cancers express matrix metalloproteinase −2 (MMP-2). Chlorotoxin is a selective MMP-2 agonist. Given that Saporin is a well-known ribosome-inactivating protein used for anti-cancer treatment, we hypothesized that Chlorotoxin-conjugated Saporin (CTX-SAP) would inhibit the growth of aggressive thyroid cancer cell lines expressing MMP-2.

Methods

The ML-1 thyroid cancer cell line was used for this study because it is known to express MMP-2. ML-1 cells were treated with a toxin consisting of biotinylated Chlorotoxin bonded with a secondary conjugate of Streptavidin-ZAP containing Saporin (CTX-SAP) from 0 to 600 nM for 72 hours. Then, cell viability was measured via XTT assay at an absorbance of A450-630. Control experiments were set up using Chlorotoxin and Saporin individually at the same varying concentrations.

Results

After 7 hours of incubation, there was a statistically significant reduction in cell viability with increasing concentrations of the CTX-SAP conjugate (F=4.286, p=0.0057). In particular, the cell viability of ML-1 cells was decreased by 49.77% with the treatment of 600 nM of CTX-SAP (F=44.24), and the reduction in cell viability was statistically significant (Dunnett’s test p<0.0001). In contrast, individual Chlorotoxin or Saporin in increasing concentrations had no significant effect on cell viability using similar assay.

Conclusion

Thisin vitrostudy demonstrated the efficacy of a CTX-SAP conjugate in reducing the viability of ML-1 thyroid cancer cells in a dose dependent manner. Further studies are needed to delineate the effectiveness of CTX-SAP in the treatment of aggressive thyroid cancer. Our study points towards MMP-2 as a potential target for RAI-resistant thyroid cancer.
Micrografting device for testing environmental conditions for grafting and systemic signaling in Arabidopsis
Authors: Tsutsui Hiroki , Yanagisawa Naoki , Kawakatsu Yaichi , Ikematsu Shuka , Sawai Yu , Tabata Ryo , Arata Hideyuki , Higashiyama Tetsuya , Notaguchi Michitaka
Published: December 2019

Grafting techniques have been applied in studies of systemic, long-distance signaling in several model plants. Seedling grafting in Arabidopsis, known as micrografting, enables investigation of the molecular mechanisms of systemic signaling between shoots and roots. However, conventional micrografting requires a high level of skill, limiting its use. Thus, an easier user-friendly method is needed. Here, we developed a silicone microscaled device, the micrografting chip, to obviate the need for training and to generate less stressed and more uniformly grafted seedlings. The chip has tandemly arrayed units, each of which consists of a seed pocket for seed germination and a micro-path with pairs of pillars for hypocotyl holding. Grafting, including seed germination, micrografting manipulation, and establishment of tissue reunion, is performed on the chip. Using the micrografting chip, we evaluated the effect of temperature and the carbon source on grafting and showed that a temperature of 27°C and a sucrose concentration of 0.5% were optimal. We also used the chip to investigate the mechanism of systemic signaling of iron status using a quadruple nicotianamine synthase (nas) mutant. The constitutive iron-deficiency response in thenasmutant because of aberrant partitioning was significantly rescued by grafting of wild-type shoots or roots, suggesting that shoot-and root-ward translocation of nicotianamine–iron complexes is essential for iron mobilization. Thus, our micrografting chip will promote studies of long-distance signaling in plants.

Significance Statement

A number of micrografting studies on systemic, long-distance signaling have been performed, but the technique is not yet used widely. Here, we developed a silicone-based micrografting chip to improve the ease-of-use, efficiency, and success rate of micrografting, even for untrained users.
Log Transformation Improves Dating of Phylogenies
Authors: Mai Uyen , Mirarab Siavash
Published: December 2019

Phylogenetic trees inferred from sequence data often have branch lengths measured in the expected number of substitutions and therefore, do not have divergence times estimated. These trees give an incomplete view of evolutionary histories since many applications of phylogenies require time trees. Many methods have been developed to convert the inferred branch lengths from substitution unit to time unit using calibration points, but none is universally accepted as they are challenged in both scalability and accuracy under complex models. Here, we introduce a new method that formulates dating as a non-convex optimization problem where the variance of log-transformed rate multipliers are minimized across the tree. On simulated and real data, we show that our method, wLogDate, is often more accurate than alternatives and is more robust to various model assumptions.
Resource abundance, financial crisis and economic growth: did resource‐rich countries fare better during the global financial crisis?
Authors: Bashar Omar H. M. N. , Bashar Omar K. M. R.
Published: December 2019

This study examines the role of resource abundance in the cross‐country differences in the impacts of the global financial crisis (GFC) of 2008–2009. Using forecasts from the unobserved components model and exponential smoothing technique, we estimate the output levels a country would reach in 2009 and 2013 in the absence of the GFC, and compare these with the realised output levels. We find large variations in the output losses across 72 countries. The mineral‐rich countries have been found to be in a strong position to survive any adverse shocks stemming from the GFC. Income per capita, trade openness, and institutional quality and government effectiveness are also found to be key factors determining the differences in output loss in the post‐crisis period. These findings have strong implications for resource‐rich countries such as Australia and are expected to shed new light on alternative policy designs and appropriate strategies to deal with any future economic crisis.
Risk of preterm birth in a twin pregnancy after an early‐term birth in the preceding singleton pregnancy: a retrospective cohort study
Authors: Berveiller P , Rousseau A , Rousseau M , Bitumba I , Goffinet F , Rozenberg P
Published: December 2019

Objective

To evaluate whether a history of spontaneous early‐term birth (37+0–38+6 weeks of gestation) in the previous singleton pregnancy is a risk factor for preterm birth (PTB) in a subsequent twin pregnancy.

Design

Retrospective cohort study.

Settings

Two French university hospitals (2006–2016).

Population

All women who delivered twins from 24+0 weeks after a preceding singleton pregnancy birth at 37+0 to 41+6 weeks.

Methods

Multivariate logistic regression analysis of association between twin PTB and a previous spontaneous singleton early‐term birth.

Main outcome measures

Twin PTB rate before 37, 34 and 32 weeks of gestation.

Results

Among 618 twin pregnancies, 270 were born preterm, 92 of them with a preceding spontaneous singleton early‐term birth. The univariate analysis showed a significantly higher risk of twin PTB before 37, 34 and 32 weeks among those 92 women compared with those with a full‐ or late‐term birth in their previous singleton pregnancy. This association remained significant after logistic regression (odds ratio [OR] between 2.42 and 3.88). The secondary analysis, restricted to the twin pregnancies with spontaneous PTB found similar results, with a risk of PTB before 37, 34 and 32 weeks significantly higher among women with a previous spontaneous singleton early‐term birth, including after logistic regression analysis (OR between 3.51 and 3.56).

Conclusion

A preceding spontaneous singleton early‐term birth is a strong and easily identified risk factor for PTB in twin pregnancies.

Tweetable abstract

Spontaneous ‘early‐term’ birth of a singleton is a significant risk factor for future preterm births in twin pregnancies.
Renal transplantation in HLA sensitized patients: Traversing the immunological barrier
Authors: Pandey Prashant , Setya Divya , Sinha Vijay , Bhatt Anil , Devra Amit , Pande Amit , Kumar Praveen , Ranjan Shweta
Published: December 2019

Successful renal transplantation across HLA barrier in sensitized individuals has been on the rise during the past decade, primarily due to improved desensitization regimes. The aim of this study was to share outcome of desensitization in renal transplant recipients with donor‐specific anti‐HLA antibodies (DSA). This was a retrospective analysis of all HLA immunized individuals who were prospective renal transplant recipients. All such patients underwent preconditioning as per the institutional desensitization protocol. Complement‐dependent cytoxicity‐based crossmatch (CDC‐XM), luminex‐based crossmatch (LM‐XM) and flowcytometry‐based crossmatch (FC‐XM) were done in all cases. If any of these tests turned out positive, single antigen bead assay (SAB) was performed. Desensitization for DSA was performed in 55 patients and all patients were followed‐up for 1 year to assess graft function and patient outcome. CDC‐XM being a less sensitive assay, could not detect incompatibility in 29 (52.73%) cases. After desensitization, even though SAB and LM‐XM results revealed an MFI within acceptable range, FC‐XM being an extremely sensitive assay, continued to give a positive result in eight (14.55%) cases. The mean ± SD number of pretransplant TPE were 3.44 ± 0.98 (2‐11). Out of 55, there were 10 patients who were lost to follow up. Patient and graft survival of 45 patients at 1 year was found to be 100%. Preconditioning for renal transplants in the form of immunosuppression with TPE is an extremely useful auxiliary for transplantation in HLA sensitized renal transplant recipients.
Quantitative analysis for modified Schall's classification by stimulation test with dynamic scintigraphy in Sjögren's syndrome
Authors: Zhu Guang‐wen , Gao Zhou , Feng Hong‐bo , Qiu Juan‐juan
Published: December 2019

Objectives

To update Schall's classification for Sjögren's syndrome (SS) by the new quantitative stimulation test with dynamic salivary glands scintigraphy (qsDSGS) and to standardize quantitative salivary gland scintigraphy.

Methods

The histopathology, oral, ocular, serological examination and qsDSGS of 268 consecutive patients with suggestive SS were evaluated in this retrospective cohort study. The serological examination included 15 autoantibodies, antinuclear antibodies (ANA) and so on. The diagnostic thresholds of the functional parameters were set by the quantitative method, and the modified Schall's classification is well established and verified.

Results

Based on the quantitative analysis of qsDSGS, the peak uptake level (PUL) and stimulation excretion fraction (sEF) of each parotid gland were determined as the key imaging features, which had good diagnostic performance for SS. By the modified Schall's classification, all patients were classified into: Class 1 (normal; n = 44), Class 2 (mild to moderate involvement; n = 130), Class 3 (severe involvement; n = 56) and Class 4 (very severe involvement, non‐function; n = 38). Using the threshold PUL ≤ 10 counts per sec/pixel as positivity, the modified Schall's classification could provide better diagnostic performance with 88.4% specificity, 71.3% sensitivity, 96.14% positive predictive value and 43.20% negative predictive value for SS (likelihood ratio 6.15). The trends of serologically positive frequencies against SSA/Ro, anti‐SSB/La and ANA were significantly increased with the new classification.

Conclusion

The modified Schall's classification by the new stimulation test with dynamic scintigraphy is eligible to standardize quantitative salivary gland scintigraphy for SS, and may be more convenient and suitable in daily practice for clinical research and management of SS.
Alleviating the Thucydides' Trap through Welfare State Dependence: How the Funding Needs of the Western Welfare State Can Influence Multilateral Relations with China
Authors: Avgouleas Emilios , Trigkas Vasilis
Published: December 2019

The dual threat of a US–China confrontation and the rise of populism in the West due, in part, to the gradual decay of the welfare state, paint an ominous picture for the future of the post‐war status quo of ever‐expanding prosperity. Hegemonic competition between the incumbent superpower (the USA) and the challenger (China) framed as the Thucydides' Trap and adverse demographic and financial trends are the main causes behind both crises. In this paper, we argue that amidst deteriorating demographics, the sustainability of the Western welfare state could be significantly enhanced by positioning Western institutional investments in the regions across India and South East Asia – areas with strong modernization dynamics and the world's nascent most populous middle class. Such a policy could generate long‐term higher risk‐adjusted returns for Western pension funds, especially if Western investors look for complementarities with China's Belt and Road Initiative (BRI). The proposed geographical calibration in Western institutional investments could lead to a relationship of strong reciprocal dependence between economic and social growth in the target regions, exports of Chinese construction and financial capacity, and Western welfare state viability. We call the suggested policy the ‘welfare state dependence’ hypothesis. The key objective of the hypothesis is the promotion of peaceful economic and geopolitical co‐existence in Eurasia through rational re‐alignment of the incentives of Western polities with Eurasian growth. But to make this new approach feasible, a number of BRI policy reforms that support its multilateralization are required.
Understanding volume kinetics
Authors: Hahn Robert G.
Published: December 2019

The distribution and elimination kinetics of the water volume in infusion fluids can be studied by volume kinetics. The approach is a modification of drug pharmacokinetics and uses repeated measurements of blood hemoglobin and urinary excretion as input variables in (usually) a two‐compartment model with expandable walls. Study results show that crystalloid fluid has a distribution phase that gives these fluids a plasma volume expansion amounting to 50%‐60% of the infused volume as long as the infusion lasts, while the fraction is reduced to 15%‐20% within 30 minutes after the infusion ends. Small volumes of crystalloid barely distribute to the interstitium, whereas rapid infusions tend to cause edema. Fluid elimination is very slow during general anesthesia due to the vasodilatation‐induced reduction of the arterial pressure, whereas elimination is less affected by hemorrhage. The half‐life is twice as long for saline than for Ringer solutions. Elimination is slower in conscious males than conscious females, and high red blood cell and thrombocyte counts retard both distribution and re‐distribution. Children have faster turnover than adults. Plasma volume expansions are similar for glucose solutions and Ringer's, but the expansion duration is shorter for glucose. Concentrated urine before and during infusion slows down the elimination of crystalloid fluid. Colloid fluids have no distribution phase, an intravascular persistence half‐life of 2‐3 hours, and—at least for hydroxyethyl starch—the ability to reduce the effect of subsequently infused crystalloids. Accelerated distribution due to degradation of the endothelial glycocalyx layer has not yet been demonstrated.
Vital pulp therapy of mature permanent teeth with irreversible pulpitis from the perspective of pulp biology
Authors: Lin Louis M. , Ricucci Domenico , Saoud Tarek M. , Sigurdsson Asgeir , Kahler Bill
Published: December 2019

The American Association of Endodontists (AAE) Consensus Conference Recommended Diagnostic Terminology states that mature permanent teeth clinically diagnosed with irreversible pulpitis are treated with pulpectomy and root canal filling because inflamed vital pulp is not capable of healing. Histological studies have demonstrated that clinically diagnosed irreversible pulpitis does not involve the entire pulp. A recent International Endodontic Journal Editorial suggested clinical diagnosis of pulp disease should be reassessed because of the poor correlation between clinical symptoms and pulp sensibility testing and the actual histological status of the pulp. This review identified studies in a PubMed search that provide evidence for vital pulp therapy (VPT) of mature permanent teeth with irreversible pulpitis is predictable if correctly diagnosed and properly treated. A narrative review was undertaken to outline the correlation between the clinical symptoms/signs and pulp sensibility testing and the histological findings of the pulp. Treatment procedures for permanent teeth are outlined.
Identity as Dependent Variable: How Americans Shift Their Identities to Align with Their Politics
Authors: Egan Patrick J.
Published: December 2019

Political science generally treats identities such as ethnicity, religion, and sexuality as “unmoved movers” in the chain of causality. I hypothesize that the growing salience of partisanship and ideology as social identities in the United States, combined with the increasing demographic distinctiveness of the nation's two political coalitions, is leading some Americans to engage in a self‐categorization and depersonalization process in which they shift their identities toward the demographic prototypes of their political groups. Analyses of a representative panel data set that tracks identities and political affiliations over a 4‐year span confirm that small but significant shares of Americans engage in identity switching regarding ethnicity, religion, sexual orientation, and class that is predicted by partisanship and ideology in their pasts, bringing their identities into alignment with their politics. These findings enrich and complicate our understanding of the relationship between identity and politics and suggest caution in treating identities as unchanging phenomena.
Fast and approximate exhaustive variable selection for generalised linear models with APES
Authors: Wang Kevin YX , Tarr Garth , Yang Jean YH , Mueller Samuel
Published: December 2019

We present APproximated Exhaustive Search (APES), which enables fast and approximated exhaustive variable selection in Generalised Linear Models (GLMs). While exhaustive variable selection remains as the gold standard in many model selection contexts, traditional exhaustive variable selection suffers from computational feasibility issues. More precisely, there is often a high cost associated with computing maximum likelihood estimates (MLE) for all subsets of GLMs. Efficient algorithms for exhaustive searches exist for linear models, most notably the leaps‐and‐bound algorithm and, more recently, the mixed integer optimisation (MIO) algorithm. The APES method learns from observational weights in a generalised linear regression super‐model and reformulates the GLM problem as a linear regression problem. In this way, APES can approximate a true exhaustive search in the original GLM space. Where exhaustive variable selection is not computationally feasible, we propose a best‐subset search, which also closely approximates a true exhaustive search. APES is made available in both as a standaloneRpackage as well as part of the already existingmplotpackage.
Risk factors for failed induction of labor among pregnant women with Class III obesity
Authors: Kerbage Yohan , Senat Marie V. , Drumez Elodie , Subtil Damien , Vayssiere Christophe , Deruelle Philippe
Published: December 2019

Introduction

Our aim was to identify risk factors for failed induction in morbidly obese patients undergoing the induction of labor at term.

Material and methods

This was a retrospective multicenter study on a cohort of 235 patients with a body mass index greater than 40 kg/m2 and giving birth to a singleton in cephalic presentation, who had an induction of labor from 38 weeks of amenorrhea. Scheduled cesareans and spontaneous vaginal deliveries were excluded. Maternal, peri‐partum and neonatal characteristics were analyzed according to the delivery route.

Results

In all, 235 patients were included. Of these, 62.5% patients delivered vaginally and 37.5% by cesarean section. The frequency of nulliparity was greater in patients who had a cesarean section (56 [interquartile range, IQR, 38.1] vs 56 [IQR 63.6], P < .001). In multivariate analysis, nulliparity (odds ratio [OR] 2.81, 95% confidence interval [CI] 1.58‐4.97], P < .001), low Bishop’s score (OR .794, 95% CI .70‐.90, P < .001) and weight gain (OR 1.04, 95% CI 1.01‐1.08, P = .033) were independent risk factors for failed induction. Umbilical cord pH at birth lower than 7 (0 vs 7 [IQR 8.0], P < .001) and lower than 7.20 (36 [IQR 24.5] vs 35 [IQR 39.8], P = .014) as well as the Apgar at 1 minute (14 [IQR 9.5] vs 17 [IQR 19.3], P = .032) was significantly higher in infants born by cesarean section.

Conclusions

In this cohort, 63% of women with Class III obesity had successful inductions of labor; risk factors for failed induction include nulliparity and unfavorable Bishop score.
Effectiveness of interventions on the appropriate use of opioids for noncancer pain among hospital inpatients: A systematic review
Authors: Liu Shania , Gnjidic Danijela , Nguyen Jessica , Penm Jonathan
Published: December 2019

Aims

To summarise the effectiveness of interventions on appropriate opioid use for noncancer pain among hospital inpatients.

Methods

Two reviewers independently searched 6 databases up to March 2018 original research articles reporting on quantitative outcomes of interventions on appropriate opioid use among hospital inpatients. Appropriate opioid use was measured by changes in prescribing, such as the lowest effective opioid dose and duration, or clinical outcomes such as adequate pain control. Quality and intervention complexity assessments were performed by 2 independent reviewers. The full methodological approach was published on PROSPERO (ID: CRD42019145947).

Results

Of 398 full‐text articles assessed for eligibility, 37 articles were included in the review. Most articles had a moderate or high risk of bias (27 of 37 studies). Thirty‐one articles primarily addressed appropriate opioid use and 6 articles targeted opioid safety as a secondary outcome. A multifaceted approach was the most common primary intervention (16 studies) and adequate pain control was the main outcome measured (14 studies). Health provider education, reinforced by hard‐copy material and feedback, was associated with a 13.0 to 29.5% increase in the proportion of opioid prescriptions written in concordance with local guidelines and reduced pain scores ranging from 7.0 to 34.5%. Interventions to improve opioid safety in patient‐controlled analgesia reduced medication errors by up to 89.1%.

Conclusion

Interventions involving academic detailing and education, especially when reinforced by feedback, show positive effects on appropriate opioid use among hospital inpatients. Future studies investigating the impact of administrative interventions on opioid use and related outcomes are warranted.
How to address second and therapy‐related acute myelogenous leukaemia
Authors: Oliai Caspian , Schiller Gary
Published: December 2019

Secondary acute myelogenous leukaemia (AML), as compared to de novo AML, occurs in the more elderly population, is independently more resistant to cytotoxic chemotherapy, has a higher relapse rate, and a worse prognosis. Secondary AML (sAML) is a heterogeneous disease, both biologically and clinically, even within the World Health Organization subgroups of sAML. Outcomes are the poorest in subgroups with sAML arising from an antecedent haematologic disorder which has been previously treated (ts‐AML), and sAML in patients <55 years of age. This review describes the suboptimal outcomes of contemporary therapy, to support the notion of an unmet need for innovative treatment strategies in sAML. Despite the recent approval of CPX‐351, long‐term outcomes for this high‐risk disease remain dismal. Resistance mechanisms to intensive chemotherapy contribute to relapse. Targeted immune therapy may avoid multidrug resistance mechanisms, but are unlikely to provide long‐term remission due to a complex and rapidly evolving clonal disease profile. Advances for sAML will likely be accomplished by CAR T cell therapy or bispecific antibodies providing a bridge to allogeneic stem cell transplantation. Therefore, focus should be placed on novel strategies that can augment the untargeted effector function of allogeneic grafts.
Salvage radical prostatectomy following focal therapy: functional and oncological outcomes
Authors: Herrera‐Caceres Jaime O. , Nason Gregory J. , Salgado‐Sanmamed Noelia , Goldberg Hanan , Woon Dixon T.S. , Chandrasekar Thenappen , Ajib Khaled , Tan Guan Hee , Alhunaidi Omar , van der Kwast Theodorus , Finelli Antonio , Zlotta Alexandre R. , Hamilton Robert J. , Berlin Alejandro , Perlis Nathan , Fleshner Neil E.
Published: December 2019

Objectives

To report the oncological and functional outcomes of salvage radical prostatectomy (sRP) after focal therapy (FT).

Patients and Methods

A retrospective review of all patients who underwent sRP after FT was performed. Clinical and pathological outcomes focussed on surgical complications, oncological, and functional outcomes.

Results

In all, 34 patients were identified. The median (interquartile range [IQR]) age was 61 (8.25) years. FT modalities included high‐intensity focussed ultrasound (19 patients), laser ablation (13), focal brachytherapy (one) and cryotherapy (one). The median (IQR) time from FT to recurrence was 10.9 (17.6) months. There were no rectal or ureteric injuries. Two (5.9%) patients had iatrogenic cystotomies and four (11.8%) developed bladder neck contractures. The mean (sd) hospital stay was 2.5 (2.1) days. The T‐stage was pT2 in 14 (41.2%) patients, pT3a in 16 (47.1%), and pT3b in four (11.8%). In all, 13 (38%) patients had positive surgical margins (PSMs). Six (17.6%) patients received adjuvant radiotherapy (RT). At a mean follow‐up of 4.3 years, seven (20.6%) patients developed biochemical recurrence (BCR), and of these, six (17.6%) patients required salvage RT. PSMs were associated with worse BCR‐free survival (hazard ratio 6.624, 95% confidence interval 2.243–19.563; P < 0.001). The median (IQR) preoperative International Prostate Symptom Score and International Index of Erectile Function score was 7 (4.5–9.5) and 23.5 (15.75–25) respectively, while in the final follow‐up the median (IQR) values were 7 (3.5–11) and 6 (5–12.25), respectively (P = 0.088 and P < 0.001). At last follow‐up, 31 (91.2%) patients were continent, two (5.9%) had moderate (>1 pad/day) incontinence, and one (2.9%) required an artificial urinary sphincter.

Conclusions

sRP should be considered as an option for patients who have persistent clinically significant prostate cancer or recurrence after FT. PSMs should be recognised as a risk for recurrent disease after sRP.
Japanese version of The Cancer Genome Atlas, JCGA, established using fresh frozen tumors obtained from 5143 cancer patients
Authors: Nagashima Takeshi , Yamaguchi Ken , Urakami Kenichi , Shimoda Yuji , Ohnami Sumiko , Ohshima Keiichi , Tanabe Tomoe , Naruoka Akane , Kamada Fukumi , Serizawa Masakuni , Hatakeyama Keiichi , Matsumura Kenya , Ohnami Shumpei , Maruyama Koji , Mochizuki Tohru , Kusuhara Masatoshi , Shiomi Akio , Ohde Yasuhisa , Terashima Masanori , Uesaka Katsuhiko , Onitsuka Tetsuro , Nishimura Seiichiro , Hirashima Yasuyuki , Hayashi Nakamasa , Kiyohara Yoshio , Tsubosa Yasuhiro , Katagiri Hirohisa , Niwakawa Masashi , Takahashi Kaoru , Kashiwagi Hiroya , Nakagawa Masahiro , Ishida Yuji , Sugino Takashi , Takahashi Mitsuru , Akiyama Yasuto
Published: December 2019

This study aimed to establish the Japanese Cancer Genome Atlas (JCGA) using data from fresh frozen tumor tissues obtained from 5143 Japanese cancer patients, including those with colorectal cancer (31.6%), lung cancer (16.5%), gastric cancer (10.8%) and other cancers (41.1%). The results are part of a single‐center study called “High‐tech Omics‐based Patient Evaluation” or “Project HOPE” conducted at the Shizuoka Cancer Center, Japan. All DNA samples and most RNA samples were analyzed using whole‐exome sequencing, cancer gene panel sequencing, fusion gene panel sequencing and microarray gene expression profiling, and the results were annotated using an analysis pipeline termed “Shizuoka Multi‐omics Analysis Protocol” developed in‐house. Somatic driver alterations were identified in 72.2% of samples in 362 genes (average, 2.3 driver events per sample). Actionable information on drugs that is applicable in the current clinical setting was associated with 11.3% of samples. When including those drugs that are used for investigative purposes, actionable information was assigned to 55.0% of samples. Germline analysis revealed pathogenic mutations in hereditary cancer genes in 9.2% of samples, among which 12.2% were confirmed as pathogenic mutations by confirmatory test. Pathogenic mutations associated with non–cancerous hereditary diseases were detected in 0.4% of samples. Tumor mutation burden (TMB) analysis revealed 5.4% of samples as having the hypermutator phenotype (TMB ≥ 20). Clonal hematopoiesis was observed in 8.4% of samples. Thus, the JCGA dataset and the analytical procedures constitute a fundamental resource for genomic medicine for Japanese cancer patients.
Dentate nNOS accounts for stress‐induced 5‐HT1A receptor deficiency: Implication in anxiety behaviors
Authors: Zhu Li‐Juan , Xu Chu , Ren Jie , Chang Lei , Zhu Xian‐Hui , Sun Nan , Meng Guo‐liang , Liu Meng‐Ying , Zhang Jing , Li Yuan‐Yuan , Tang Yu‐Lin , Zhou Qi‐Gang
Published: December 2019

Background

Anxiety is a common disorder with high social burden worldwide. Dysfunction of serotonin‐1A receptor (5‐HT1A receptor) in the dentate gyrus (DG) of the hippocampus has been predominantly implicated in the anxiety behavior. However, the molecular mechanism underlying the deficiency of postsynaptic 5‐HT1A receptor in regulating anxiety behavior remains unclear.

Methods

Using pharmacological and genetic methods, we investigated the role of detate nNOS in 5‐HT1A receptor decline and anxiety behavior induced by chronic mild stress (CMS) in mice.

Results

Here we showed that local elevation of glucocorticoids in the DG accounted for chronic stress‐induced anxiety behavior. Neuronal nitric oxide synthase (nNOS) mediated chronic stress‐induced downregulation of 5‐HT1A receptor in the DG through peroxynitrite anion (ONOO•) pathway but not cyclic guanosine monophosphate (cGMP) pathway. By using pharmacological tool drugs and nNOS knockout mice, we found that nNOS in the DG played a key role in chronic stress‐induced anxiety behavior.

Conclusions

These findings uncovered an important role of nNOS‐5‐HT1A receptor pathway in the DG of the hippocampus in chronic stress‐induced anxiety. Accordingly, we developed a “dentate nNOS‐5‐HT1A receptor closed‐loop” theory (stress‐glucocorticoids‐nNOS‐Nitric oxide‐ONOO•‐5‐HT1A receptor ‐nNOS) of stress‐related anxiety.
Identification of Potential Therapeutic Gene Markers in Nasopharyngeal Carcinoma Based on Bioinformatics Analysis
Authors: Xue Kai , Cao Jinfeng , Wang Yinan , Zhao Xue , Yu Dan , Jin Chunshun , Xu Chengbi
Published: December 2019

Nasopharyngeal carcinoma (NPC) is a common cancer found in the nasopharynx with high metastatic and invasive nature. Increasing evidences have identified the critical role of gene therapy in NPC treatment. Hence, this study was designed to identify specific gene markers that affected NPC progression through gene expression profile analysis. NPC‐related gene expression data set gene set enrichment (GSE)53819 were retrieved and analyzed to screen out differentially expressed genes (DEGs), followed by determination of their expression in noncancerous tissues and NPC specimens. Next, weighted gene co‐expression network analysis (WGCNA) was conducted on DEGs to obtain tumor‐associated gene modules. Genes in those modules were intersected with DEGs for gene ontology and Kyoto Encyclopedia of Genes and Genomes functional enrichment analysis. Then protein‐protein interaction network of tumor‐associated genes was constructed to select genes most closely linked to NPC. Afterward, expression of chromosome 9 open reading frame 24 (c9orf24), primary ciliary dyskinesia protein 1 (PCDP1), and leucine‐rich repeat‐containing protein 46 (LRRC46) was detected in GSE53819 and further verified in GSE12452 and GSE64634. Differential analysis on GSE53819 found that 2,173 genes were aberrantly expressed in NPC, among which 917 genes are upregulated and 1,256 genes are downregulated. WGCNA showed that genes were enriched in 17 modules and 727 genes exhibited ectopic expression in NPC and enriched in cytokine‐cytokine receptor interaction, cytochrome P450, and chemical carcinogenesis signaling pathways, among which c9orf24, PCDP1, and LRRC46 were poorly expressed in NPC. Therefore, c9orf24, PCDP1, and LRRC46 might serve as prominent diagnostic markers for NPC, which presents new insights for NPC therapy.
Contingency management treatment for methamphetamine use disorder in South Africa
Authors: Okafor Chukwuemeka N. , Stein Dan J. , Dannatt Lisa , Ipser Jonathan , van Nunen Lara J. , Lake Marilyn T. , Krishnamurti Tamar , London Edythe D. , Shoptaw Steve
Published: December 2019

Introduction and Aims

As South Africa, especially the Western Cape Province, faces an epidemic of methamphetamine use disorder, therapeutic approaches suited to the South African context are needed. This secondary analysis assessed retention and methamphetamine abstinence outcomes in response to an 8‐week pilot contingency management (CM) intervention trial of neural correlates of methamphetamine abstinence, exploring sociodemographic and clinical differences between responders and non‐responders.

Design and Methods

Research participants provided thrice‐weekly monitored urine samples, which were analysed by qualitative radioimmunoassay. The primary outcome for this analysis was therapeutic response, defined as abstinence from methamphetamine (≥23 of 24 possible methamphetamine‐negative urine samples).

Results

Data from 30 adults living in Cape Town, South Africa (34 ± 6.1 years of age, mean age ± SD, 21 men) were included. Sixty‐three percent (12 men) were responders. In bivariate comparisons, baseline measurements showed fewer responders reported monthly household income ≥25 000+ South African Rand (ZAR; ~USD $1880; vs. ZAR < 25 000) than non‐responders (15.8% vs. 63.6%;P= 0.007). Furthermore, responders had higher median years of education (12 vs. 10; Kruskal–Wallis χ2= 4.25, DF = 1,P= 0.039) and lower median body mass index than non‐responders (19 vs. 24; Kruskal–Wallis χ2= 6.84,P= 0.008).

Discussion and Conclusions

Therapeutic response in this study were comparable to those obtained with CM for methamphetamine use disorder in North America and Europe. Our findings suggest that CM may be a useful component of treatment strategies to boost retention and continuous abstinence from methamphetamine in Cape Town, South Africa. Larger efficacy studies are needed in this setting.
Neural recruitment related to threat perception differs as a function of adolescent sleep
Authors: Tashjian Sarah M. , Galván Adriana
Published: December 2019

Detecting threat cues in the environment is an important aspect of social functioning. This is particularly true for adolescents as social threats become more salient and they navigate increasingly complex relationships outside of the family. Sleep relates to socioemotional processing throughout development, but the neurobiological relevance of sleep for threat perceptions in adolescence remains unknown. In the present study, 46 human adolescents (aged 14–18 years; 26 female) made judgments while undergoing a brain scan about whether unfamiliar, affectively neutral, computer‐generated faces were threatening. Prior to the scan, several indices of sleep were assessed nightly for two‐weeks using actigraphy. Sleep duration and poor sleep quality (defined as less efficiency, more awakenings, longer awakenings), factors influenced by biological and psychosocial changes during adolescence, elicited distinct neural activation patterns. Sleep duration was positively associated with activation in visual and face processing regions (occipital cortex, occipital fusiform gyrus), and this activation was linked to increased threat detection during the threat perception task. Sleep quality was negatively related to dorsolateral prefrontal cortex activation, which moderated the relation between reaction time (RT) and exposure to faces. Findings suggest reduced threat perception for adolescents with shorter sleep durations and more impulsive responding (as evinced by less consistent RT) for adolescents experiencing worse quality sleep. This study identifies an association between sleep and neural functioning relevant for socioemotional decision making during adolescence, a time when these systems undergo significant development.