bluuebunny/crossref_metadata_2025 huggingface dataset:
Retigabine holds KV7 channels open and stabilizes the resting potential
Authors: Corbin-Leftwich Aaron , Mossadeq Sayeed M. , Ha Junghoon , Ruchala Iwona , Le Audrey Han Ngoc , Villalba-Galea Carlos A.
Published: February 2016

The anticonvulsant Retigabine is a KV7 channel agonist used to treat hyperexcitability disorders in humans. Retigabine shifts the voltage dependence for activation of the heteromeric KV7.2/KV7.3 channel to more negative potentials, thus facilitating activation. Although the molecular mechanism underlying Retigabine’s action remains unknown, previous studies have identified the pore region of KV7 channels as the drug’s target. This suggested that the Retigabine-induced shift in voltage dependence likely derives from the stabilization of the pore domain in an open (conducting) conformation. Testing this idea, we show that the heteromeric KV7.2/KV7.3 channel has at least two open states, which we named O1 and O2, with O2 being more stable. The O1 state was reached after short membrane depolarizations, whereas O2 was reached after prolonged depolarization or during steady state at the typical neuronal resting potentials. We also found that activation and deactivation seem to follow distinct pathways, suggesting that the KV7.2/KV7.3 channel activity displays hysteresis. As for the action of Retigabine, we discovered that this agonist discriminates between open states, preferentially acting on the O2 state and further stabilizing it. Based on these findings, we proposed a novel mechanism for the therapeutic effect of Retigabine whereby this drug reduces excitability by enhancing the resting potential open state stability of KV7.2/KV7.3 channels. To address this hypothesis, we used a model for action potential (AP) in Xenopus laevis oocytes and found that the resting membrane potential became more negative as a function of Retigabine concentration, whereas the threshold potential for AP firing remained unaltered.
BALL-SNPgp—from genetic variants toward computational diagnostics
Authors: Mueller Sabine C. , Backes Christina , Gress Alexander , Baumgarten Nina , Kalinina Olga V. , Moll Andreas , Kohlbacher Oliver , Meese Eckart , Keller Andreas
Published: February 2016

Summary: In medical research, it is crucial to understand the functional consequences of genetic alterations, for example, non-synonymous single nucleotide variants (nsSNVs). NsSNVs are known to be causative for several human diseases. However, the genetic basis of complex disorders such as diabetes or cancer comprises multiple factors. Methods to analyze putative synergetic effects of multiple such factors, however, are limited. Here, we concentrate on nsSNVs and present BALL-SNPgp, a tool for structural and functional characterization of nsSNVs, which is aimed to improve pathogenicity assessment in computational diagnostics. Based on annotated SNV data, BALL-SNPgp creates a three-dimensional visualization of the encoded protein, collects available information from different resources concerning disease relevance and other functional annotations, performs cluster analysis, predicts putative binding pockets and provides data on known interaction sites.

Availability and implementation: BALL-SNPgp is based on the comprehensive C ++ framework Biochemical Algorithms Library (BALL) and its visualization front-end BALLView. Our tool is available at www.ccb.uni-saarland.de/BALL-SNPgp.

Contact:  ballsnp@milaman.cs.uni-saarland.de
dbDSM: a manually curated database for deleterious synonymous mutations
Authors: Wen Pengbo , Xiao Peng , Xia Junfeng
Published: February 2016

Motivation: Synonymous mutations (SMs), which changed the sequence of a gene without directly altering the amino acid sequence of the encoded protein, were thought to have no functional consequences for a long time. They are often assumed to be neutral in models of mutation and selection and were completely ignored in many studies. However, accumulating experimental evidence has demonstrated that these mutations exert their impact on gene functions via splicing accuracy, mRNA stability, translation fidelity, protein folding and expression, and some of these mutations are implicated in human diseases. To the best of our knowledge, there is still no database specially focusing on disease-related SMs.

Results: We have developed a new database called dbDSM (database of Deleterious Synonymous Mutation), a continually updated database that collects, curates and manages available human disease-related SM data obtained from published literature. In the current release, dbDSM collects 1936 SM-disease association entries, including 1289 SMs and 443 human diseases from ClinVar, GRASP, GWAS Catalog, GWASdb, PolymiRTS database, PubMed database and Web of Knowledge. Additionally, we provided users a link to download all the data in the dbDSM and a link to submit novel data into the database. We hope dbDSM will be a useful resource for investigating the roles of SMs in human disease.

Availability and implementation: dbDSM is freely available online at http://bioinfo.ahu.edu.cn:8080/dbDSM/index.jsp with all major browser supported.

Contact:  jfxia@ahu.edu.cn

Supplementary information:  Supplementary data are available at Bioinformatics online.
Histoplasmosis-Associated Hospitalizations in the United States, 2001–2012
Authors: Benedict Kaitlin , Derado Gordana , Mody Rajal K.
Published: February 2016

We examined trends in histoplasmosis-associated hospitalizations in the United States using the 2001–2012 National (Nationwide) Inpatient Sample. An estimated 50 778 hospitalizations occurred, with significant increases in hospitalizations overall and in the proportion of hospitalizations associated with transplant, diabetes, and autoimmune conditions often treated with biologic therapies; therefore, histoplasmosis remains an important opportunistic infection.
XMM-Newton and Suzaku spectroscopic studies of unidentified X-ray sources towards the Galactic bulge: 1RXS J180556.1−343818 and 1RXS J173905.2−392615
Authors: Mori Hideyuki , Maeda Yoshitomo , Ueda Yoshihiro
Published: February 2016

With XMM-Newton and Suzaku observations, for the first time, we acquired broad-band spectra of two unidentified X-ray sources towards the Galactic bulge: 1RXS J180556.1−343818 and 1RXS J173905.2−392615. The 1RXS J180556.1−343818 spectrum in the 0.3–7 keV band was explained by X-ray emission that originated from an optically-thin thermal plasma with temperatures of 0.5 and 1.8 keV. The estimated absorption column density of NH ∼ 4 × 1020 cm−2 was significantly smaller than the Galactic H i column density towards the source. A candidate for its optical counterpart, HD 321269, was found within 4″. In terms of the X-ray properties and the positional coincidence, it is quite conceivable that 1RXS J180556.1−343818 is an active G giant. We also found a dim X-ray source that was positionally consistent with 1RXS J173905.2−392615. Assuming that the X-ray spectrum can be reproduced with an absorbed, optically-thin thermal plasma model with kT = 1.6 keV, the X-ray flux in the 0.5–8 keV band was 8.7 × 10−14 erg s−1 cm−2, fainter by a factor of ∼7 than that of 1RXS J173905.2−392615 during the ROSAT observation. The follow-up observations we conducted revealed that these two sources would belong to the Galactic disk, rather than the Galactic bulge.
Ghost-House Busters: The Electoral Response to a Large Anti–Tax Evasion Program *
Authors: Casaburi Lorenzo , Troiano Ugo
Published: February 2016

The incentives of political agents to enforce tax collection are key determinants of the levels of compliance. We study the electoral response to the Ghost Buildings program, a nationwide anti tax evasion policy in Italy that used innovative monitoring technologies to target buildings hidden from tax authorities. The program induced monetary and non-monetary benefits for non-evaders and an increase in local government expenditures. A one standard deviation increase in town-level program intensity leads to a 4.8% increase in local incumbent reelection rates. In addition, these political returns are higher in areas with lower tax evasion tolerance and with higher efficiency of public good provision, implying complementarity among enforcement policies, the underlying tax culture, and the quality of the government.
Focus on Noncoding RNA Regulation of Plant-Microbe Interactions
Authors: Carr John P. , Whitham Steven A.
Published: February 2016

Investigations in recent years have uncovered important roles for RNA molecules that do not encode proteins (‘noncoding RNAs’) but which, nevertheless, exert powerful effects on gene expression at both transcriptional and posttranscriptional levels. Our late colleague Biao Ding, who died unexpectedly on June 25, 2015, proposed a Focus Issue on the roles in plant-microbe interactions of noncoding RNAs, whether of plant or microbial origin and including small interfering (si)RNAs, microRNAs, phased siRNAs, and long noncoding RNAs, as well as viroids and satellite RNAs. The Editorial Board of MPMI has decided to dedicate this Focus Issue to the memory of Professor Biao Ding, a valued and deeply missed colleague and friend.
Improving marine disease surveillance through sea temperature monitoring, outlooks and projections
Authors: Maynard Jeffrey , van Hooidonk Ruben , Harvell C. Drew , Eakin C. Mark , Liu Gang , Willis Bette L. , Williams Gareth J. , Groner Maya L. , Dobson Andrew , Heron Scott F. , Glenn Robert , Reardon Kathleen , Shields Jeffrey D.
Published: February 2016

To forecast marine disease outbreaks as oceans warm requires new environmental surveillance tools. We describe an iterative process for developing these tools that combines research, development and deployment for suitable systems. The first step is to identify candidate host–pathogen systems. The 24 candidate systems we identified include sponges, corals, oysters, crustaceans, sea stars, fishes and sea grasses (among others). To illustrate the other steps, we present a case study of epizootic shell disease (ESD) in the American lobster. Increasing prevalence of ESD is a contributing factor to lobster fishery collapse in southern New England (SNE), raising concerns that disease prevalence will increase in the northern Gulf of Maine under climate change. The lowest maximum bottom temperature associated with ESD prevalence in SNE is 12°C. Our seasonal outlook for 2015 and long-term projections show bottom temperatures greater than or equal to 12°C may occur in this and coming years in the coastal bays of Maine. The tools presented will allow managers to target efforts to monitor the effects of ESD on fishery sustainability and will be iteratively refined. The approach and case example highlight that temperature-based surveillance tools can inform research, monitoring and management of emerging and continuing marine disease threats.
Fishing diseased abalone to promote yield and conservation
Authors: Ben-Horin Tal , Lafferty Kevin D. , Bidegain Gorka , Lenihan Hunter S.
Published: February 2016

Past theoretical models suggest fishing disease-impacted stocks can reduce parasite transmission, but this is a good management strategy only when the exploitation required to reduce transmission does not overfish the stock. We applied this concept to a red abalone fishery so impacted by an infectious disease (withering syndrome) that stock densities plummeted and managers closed the fishery. In addition to the non-selective fishing strategy considered by past disease-fishing models, we modelled targeting (culling) infected individuals, which is plausible in red abalone because modern diagnostic tools can determine infection without harming landed abalone and the diagnostic cost is minor relative to the catch value. The non-selective abalone fishing required to eradicate parasites exceeded thresholds for abalone sustainability, but targeting infected abalone allowed the fishery to generate yield and reduce parasite prevalence while maintaining stock densities at or above the densities attainable if the population was closed to fishing. The effect was strong enough that stock and yield increased even when the catch was one-third uninfected abalone. These results could apply to other fisheries as the diagnostic costs decline relative to catch value.
Communicating about ocean health: theoretical and practical considerations
Authors: Schuldt Jonathon P. , McComas Katherine A. , Byrne Sahara E.
Published: February 2016

As anthropogenic stressors threaten the health of marine ecosystems, there is a need to better understand how the public processes and responds to information about ocean health. Recent studies of public perceptions about ocean issues report high concern but limited knowledge, prompting calls for information campaigns to mobilize public support for ocean restoration policy. Drawing on the literature from communication, psychology and related social science disciplines, we consider a set of social-cognitive challenges that researchers and advocates are likely to encounter when communicating with the public about ocean health and emerging marine diseases—namely, the
psychological distance
at which ocean issues are construed, the
unfamiliarity
of aquatic systems to many members of the public and the potential for marine health issues to be interpreted through
politicized
schemas that encourage motivated reasoning over the dispassionate consideration of scientific evidence. We offer theory-based strategies to help public outreach efforts address these challenges and present data from a recent experiment exploring the role of message framing (emphasizing the public health or environmental consequences of marine disease) in shaping public support for environmental policy.
The hidden complexity of Mendelian traits across yeast natural populations
Authors: Hou Jing , Sigwalt Anastasie , Pflieger David , Peter Jackson , de Montigny Jacky , Dunham Maitreya , Schacherer Joseph
Published: February 2016

Mendelian traits are considered as the lower end of the complexity spectrum of heritable phenotypes. However, more than a century after the rediscovery of Mendel’s law, the global landscape of monogenic variants as well as their effects and inheritance patterns within natural populations is still not well understood. Using the yeast Saccharomyces cerevisiae, we performed a species-wide survey of Mendelian traits across a large population of isolates. We generated offspring from 41 unique parental pairs, and analyzed 1,105 cross/trait combinations. We found that 8.9% of the cases were Mendelian. Most were caused by common variants showing stable inheritances in a natural population. However, we also found that a rare monogenic variant related to drug resistance displayed a significant and variable expressivity across different genetic backgrounds, leading to modified inheritances ranging from intermediate to high complexities. Our results illustrate for the first time the continuum of the hidden complexity of a monogenic mutation, where genotype is hardly predictive of phenotype.
Muscleblind-like 1 suppresses breast cancer metastatic colonization and stabilizes metastasis suppressor transcripts
Authors: Fish Lisa , Pencheva Nora , Goodarzi Hani , Tran Hien , Yoshida Mitsukuni , Tavazoie Sohail F.
Published: February 2016

Post-transcriptional deregulation is a defining feature of metastatic cancer. While many microRNAs have been implicated as regulators of metastatic progression, less is known about the roles and mechanisms of RNA-binding proteins in this process. We identified muscleblind-like 1 (MBNL1), a gene implicated in myotonic dystrophy, as a robust suppressor of multiorgan breast cancer metastasis. MBNL1 binds the 3′ untranslated regions (UTRs) of DBNL (drebrin-like protein) and TACC1 (transforming acidic coiled-coil containing protein 1)—two genes that we implicate as metastasis suppressors. By enhancing the stability of these genes’ transcripts, MBNL1 suppresses cell invasiveness. Consistent with these findings, elevated MBNL1 expression in human breast tumors is associated with reduced metastatic relapse likelihood. Our findings delineate a post-transcriptional network that governs breast cancer metastasis through RNA-binding protein-mediated transcript stabilization.
Initiation of stem cell differentiation involves cell cycle-dependent regulation of developmental genes by Cyclin D
Authors: Pauklin Siim , Madrigal Pedro , Bertero Alessandro , Vallier Ludovic
Published: February 2016

Coordination of differentiation and cell cycle progression represents an essential process for embryonic development and adult tissue homeostasis. These mechanisms ultimately determine the quantities of specific cell types that are generated. Despite their importance, the precise molecular interplays between cell cycle machinery and master regulators of cell fate choice remain to be fully uncovered. Here, we demonstrate that cell cycle regulators Cyclin D1–3 control cell fate decisions in human pluripotent stem cells by recruiting transcriptional corepressors and coactivator complexes onto neuroectoderm, mesoderm, and endoderm genes. This activity results in blocking the core transcriptional network necessary for endoderm specification while promoting neuroectoderm factors. The genomic location of Cyclin Ds is determined by their interactions with the transcription factors SP1 and E2Fs, which result in the assembly of cell cycle-controlled transcriptional complexes. These results reveal how the cell cycle orchestrates transcriptional networks and epigenetic modifiers to instruct cell fate decisions.
A MED13-dependent skeletal muscle gene program controls systemic glucose homeostasis and hepatic metabolism
Authors: Amoasii Leonela , Holland William , Sanchez-Ortiz Efrain , Baskin Kedryn K. , Pearson Mackenzie , Burgess Shawn C. , Nelson Benjamin R. , Bassel-Duby Rhonda , Olson Eric N.
Published: February 2016

The Mediator complex governs gene expression by linking upstream signaling pathways with the basal transcriptional machinery. However, how individual Mediator subunits may function in different tissues remains to be investigated. Through skeletal muscle-specific deletion of the Mediator subunit MED13 in mice, we discovered a gene regulatory mechanism by which skeletal muscle modulates the response of the liver to a high-fat diet. Skeletal muscle-specific deletion of MED13 in mice conferred resistance to hepatic steatosis by activating a metabolic gene program that enhances muscle glucose uptake and storage as glycogen. The consequent insulin-sensitizing effect within skeletal muscle lowered systemic glucose and insulin levels independently of weight gain and adiposity and prevented hepatic lipid accumulation. MED13 suppressed the expression of genes involved in glucose uptake and metabolism in skeletal muscle by inhibiting the nuclear receptor NURR1 and the MEF2 transcription factor. These findings reveal a fundamental molecular mechanism for the governance of glucose metabolism and the control of hepatic lipid accumulation by skeletal muscle. Intriguingly, MED13 exerts opposing metabolic actions in skeletal muscle and the heart, highlighting the customized, tissue-specific functions of the Mediator complex.
Genetics and biology of pancreatic ductal adenocarcinoma
Authors: Ying Haoqiang , Dey Prasenjit , Yao Wantong , Kimmelman Alec C. , Draetta Giulio F. , Maitra Anirban , DePinho Ronald A.
Published: February 2016

With 5-year survival rates remaining constant at 6% and rising incidences associated with an epidemic in obesity and metabolic syndrome, pancreatic ductal adenocarcinoma (PDAC) is on track to become the second most common cause of cancer-related deaths by 2030. The high mortality rate of PDAC stems primarily from the lack of early diagnosis and ineffective treatment for advanced tumors. During the past decade, the comprehensive atlas of genomic alterations, the prominence of specific pathways, the preclinical validation of such emerging targets, sophisticated preclinical model systems, and the molecular classification of PDAC into specific disease subtypes have all converged to illuminate drug discovery programs with clearer clinical path hypotheses. A deeper understanding of cancer cell biology, particularly altered cancer cell metabolism and impaired DNA repair processes, is providing novel therapeutic strategies that show strong preclinical activity. Elucidation of tumor biology principles, most notably a deeper understanding of the complexity of immune regulation in the tumor microenvironment, has provided an exciting framework to reawaken the immune system to attack PDAC cancer cells. While the long road of translation lies ahead, the path to meaningful clinical progress has never been clearer to improve PDAC patient survival.
Plant functional constraints guide macroevolutionary trade‐offs in competitive and conservative growth responses to nitrogen
Authors: Wooliver Rachel , Pfennigwerth Alix A. , Bailey Joseph K. , Schweitzer Jennifer A.
Published: February 2016

Decades of research show that plants vary in their growth responses to increasing soil nitrogen (N), supporting theory on evolutionary trade‐offs between competitive and conservative growth strategies. However, we lack an explicit examination of the evolutionary processes guiding trade‐offs in competitive and conservative growth responses to N addition (GRN), processes which should include selection across environmental gradients and constraint within certain plant functional types.

To determine current variation in GRN across plants, we collected previously published data on total biomass responses of 125 terrestrial plant species to N fertilization, relative to control soil N conditions. We calculated phylogenetic signal of GRN to assess the influence of shared evolutionary history on variation in N use capacities. To determine whether this variation is consistent with stabilizing selection towards unique N use capacities across environmental gradients and plant functional types, we compared the fit (second‐order Akaike Information Criterion) of species’ GRN data to models that approximate evolution according to genetic drift with and without stabilizing selection across plant functional types, biomes, latitude, mean annual temperature and annual precipitation.

More than one in four species in our analysis responded negatively or neutrally to increasing soil N and responses ranged from a 60% decrease to an 1800% increase in biomass with added N. We identified a significant phylogenetic signal for GRN, and evolutionary models incorporating stabilizing selection plus genetic drift explained more variation in GRN than models incorporating genetic drift alone. Parameter estimates from selection‐based models indicate that plant functional types have experienced selection towards GRN values (i.e. evolutionary optima) that differ more than among biomes or across climatic gradients.

Overall, our results suggest that phylogenetic relatedness and stabilizing selection associated with functional constraints are two aspects of past evolution that govern whether species will be winners or losers in global soil N addition scenarios.
Party patronage in contemporary democracies: Results from an expert survey in 22 countries from five regions
Authors: KOPECKÝ PETR , MEYER SAHLING JAN‐HINRIK , PANIZZA FRANCISCO , SCHERLIS GERARDO , SCHUSTER CHRISTIAN , SPIROVA MARIA
Published: February 2016

This Research Note presents a new dataset of party patronage in 22 countries from five regions. The data was collected using the same methodology to compare patterns of patronage within countries, across countries and across world regions that are usually studied separately. The Note addresses three research questions that are at the centre of debates on party patronage, which is understood as the power of political parties to make appointments to the public and semi‐public sector: the scope of patronage, the underlying motivations and the criteria on the basis of which appointees are selected. The exploration of the dataset shows that party patronage is, to a different degree, widespread across all regions. The data further shows differences between policy areas, types of institutions such as government ministries, agencies and state‐owned enterprises, and higher, middle and lower ranks of the bureaucracy. It is demonstrated that the political control of policy making and implementation is the most common motivation for making political appointments. However, in countries with a large scope of patronage, appointments serve the purpose of both political control and rewarding supporters in exchange for votes and services. Finally, the data shows that parties prefer to select appointees who are characterised by political and personal loyalty as well as professional competence.
The pelican slaughter of 1911: a history of competing values, killing and private property from the Coorong, South Australia
Authors: O'Gorman Emily
Published: February 2016

In 1911, approximately 2000 pelicans were slaughtered on a group of islands within the Coorong lagoon in South Australia. The islands were a favoured nesting site, and a group of people had waited until the eggs hatched to kill both adult and young birds in order to collect the maximum payout from a 1 penny bounty that had been put on the head of each pelican by the South Australian Fisheries Department. The killings prompted advocates of bird protection, particularly ornithologists, to seek security for the rookeries against future raids by leasing the islands. A range of other interests became entangled in this decision, as some ornithologists also sought to prevent local Aboriginal people from harvesting bird eggs in the area. Examining these events and their consequences, this article has two related goals. The first goal is to show the role of animals and their environments in co‐shaping legal geographies. The second is to examine the contours and histories of competing ideas about protection, killing, and private property that shaped the legal geography of the Coorong.
Effectiveness of a universal internet‐based prevention program for ecstasy and new psychoactive substances: a cluster randomized controlled trial
Authors: Champion Katrina E. , Newton Nicola C. , Stapinski Lexine A. , Teesson Maree
Published: February 2016

Aim

To evaluate the effectiveness of an online school‐based prevention program for ecstasy (MDMA) and new psychoactive substances (NPS).

Design

Cluster randomized controlled trial with two groups (intervention and control).

Setting

Eleven secondary schools in Australia.

Participants

A total of 1126 students (mean age: 14.9 years).

Intervention

The internet‐based Climate Schools: Ecstasy and Emerging Drugs module uses cartoon storylines to convey information about harmful drug use. It was delivered once weekly, during a 4‐week period, during health education classes. Control schools received health education as usual.

Measurement

Primary outcomes were self‐reported intentions to use ecstasy and NPS at 12 months. Secondary outcomes were ecstasy and NPS knowledge and life‐time use of ecstasy and NPS. Surveys were administered at baseline, post‐intervention and 6 and 12 month post‐baseline.

Findings

At 12 months, the proportion of students likely to use NPS was significantly greater in the control group (1.8%) than the intervention group [0.5%; odds ratio (OR) = 10.17, 95% confidence interval (CI) = 1.31–78.91]. However, students' intentions to use ecstasy did not differ significantly between groups (control = 2.1%, intervention = 1.6%; OR = 5.91, 95% CI = 1.01–34.73). There was a significant group difference in the change from baseline to post‐test for NPS knowledge (β = −0.42, 95% CI = −0.62 to −0.21, Cohen's d = 0.77), with controls [mean = 2.78, standard deviation (SD = 1.48] scoring lower than intervention students (mean = 3.85, SD = 1.49). There was also evidence of a significant group difference in ecstasy knowledge at post‐test (control: mean = 9.57, SD = 3.31; intervention: mean = 11.57, SD = 3.61; β = −0.54, 95% CI = −0.97 to −0.12, P = 0.01, d = 0.73).

Conclusions

The Climate Schools: Ecstasy and Emerging Drugs module, a universal online school‐based prevention program, appeared to reduce students' intentions to use new psychoactive substances and increased knowledge about ecstasy and new psychoactive substances in the short term.
A successful high‐visibility enforcement intervention targeting underage drinking drivers
Authors: Johnson Mark B.
Published: February 2016

Aims

To measure the effectiveness of a high‐visibility enforcement campaign to reduce rates of underage drinking and driving.

Design

Mixed‐model analysis compares rates of drinking and driving (1) between the baseline and intervention period and (2) between the baseline and follow‐up period. The impact of the intervention was evaluated using roadside surveys and web surveys.

Setting

Two college‐town communities in the mid‐Atlantic region of the United States.

Participants

Study participants consisted of 6825 drivers stopped, interviewed and breathalyzed on weekend nights. Web survey data were collected from 2061 students from large state universities in each community.

Intervention

Increased high‐visibility enforcement of drinking and driving laws, featuring the use of passive alcohol sensors by police, along with a coordinated publicity campaign.

Measures

Roadside surveys measured breath alcohol concentrations (BrAC) of drivers. The web surveys measured self‐reported drinking.

Findings

Mixed‐model analysis revealed a statistically significant reduction in drivers with BrACs ≥ 0.08 g/dl during the intervention and follow‐up periods, F(2, 5744) = 6.5, P < 0.01. The web‐survey revealed that students under age 21 also reported significantly less driving after drinking during the intervention and follow‐up periods, F(2, 1767) = 4.6, P < 0.01.

Conclusions

A high‐visibility enforcement campaign targeting underage drinking and driving appeared to reduce both underage driving after drinking among US college students as well as drunk driving (breath alcohol concentration ≥ 0.08 g/dl) at any age..
A randomized trial of a pain management intervention for adults receiving substance use disorder treatment
Authors: Ilgen Mark A. , Bohnert Amy S. B. , Chermack Stephen , Conran Carly , Jannausch Mary , Trafton Jodie , Blow Frederic C.
Published: February 2016

Background and Aims

Chronic pain is difficult to treat in individuals with substance use disorders and, when not resolved, can have a negative impact on substance use disorder treatment outcomes. This study tested the efficacy of a psychosocial pain management intervention, ImPAT (improving pain during addiction treatment), that combines pain management with content related to managing pain without substance use.

Design

Single‐site, parallel‐groups randomized controlled trial comparing ImPAT to a supportive psychoeducational control (SPC) condition; follow‐up assessments occurred at 3, 6 and 12 months.

Setting

The Ann Arbor VA Substance Use Disorder treatment program, USA.

Participants

Veterans Health Administration patients {n = 129; mean [standard deviation (SD)], age = 51.7 (9.5); 115 of 129 (89%) male; ImPAT (n = 65); SPC (n = 64)}.

Intervention

ImPAT combines principles of cognitive–behavioral therapy and acceptance‐based approaches to pain management with content related to avoiding the use of substances as a coping mechanism for pain. The SPC used a psychoeducational attention control treatment for alcoholism modified to cover other substances in addition to alcohol.

Measurements

Primary: Pain intensity over 12 months; secondary: pain‐related functioning, frequency of alcohol and drug use over 12 months.

Findings

Primary: randomization to the ImPAT intervention versus SPC predicted significantly lower pain intensity {β [standard error (SE)] = −0.71 (0.29); 95% confidence interval (CI) = −1.29, −0.12}; secondary: relative to the SPC condition, those who received ImPAT also reported improved pain‐related functioning [β (SE) = 0.27 (0.11); 95% CI = 0.05, 0.49] and lower frequency of alcohol consumption [β (SE) = −0.77; 95% CI = −1.34, −0.20]. No differences were found between conditions on frequency of drug use over follow‐up.

Conclusions

For adults with pain who are enrolled in addictions treatment, receipt of a psychological pain management intervention (improving pain during addiction treatment) reduced pain and alcohol use and improves pain‐related functioning over 12 months relative to a matched‐attention control condition.
The Genetic History of Peruvian Quechua‐Lamistas and Chankas: Uniparental DNA Patterns among Autochthonous Amazonian and Andean Populations
Authors: Sandoval José R. , Lacerda Daniela R. , Acosta Oscar , Jota Marilza S. , Robles‐Ruiz Paulo , Salazar‐Granara Alberto , Vieira Pedro Paulo R. , Paz‐y‐Miño César , Fujita Ricardo , Santos Fabricio R. ,   The Genographic Project Consortium
Published: February 2016

This study focuses on the genetic history of the Quechua‐Lamistas, inhabitants of the Lamas Province in the San Martin Department, Peru, who speak their own distinct variety of the Quechua family of languages. It has been suggested that different pre‐Columbian ethnic groups from the Peruvian Amazonia, like the Motilones or “shaven heads”, assimilated the Quechua language and then formed the current native population of Lamas. However, many Quechua‐Lamistas claim to be direct descendants of the Chankas, a famous pre‐Columbian indigenous group that escaped from Inca rule in the Andes. To investigate the Quechua‐Lamistas and Chankas’ ancestries, we compared uniparental genetic profiles (17 STRs of Q‐M3 Y‐chromosome and mtDNA complete control region haplotypes) among autochthonous Amazonian and Andean populations from Peru, Bolivia and Ecuador. The phylogeographic and population genetic analyses indicate a fairly heterogeneous ancestry for the Quechua‐Lamistas, while they are closely related to their neighbours who speak Amazonian languages, presenting no direct relationships with populations from the region where the ancient Chankas lived. On the other hand, the genetic profiles of self‐identified Chanka descendants living in Andahuaylas (located in the Apurimac Department, Peru, in the Central Andes) were closely related to those living in Huancavelica and the assumed Chanka Confederation area before the Inca expansion.
Pain in children and adolescents with cerebral palsy: a population‐based registry study
Authors: Alriksson‐Schmidt Ann , Hägglund Gunnar
Published: February 2016

Aim

We assessed prevalence and location of pain in a total population of children and adolescents with cerebral palsy (CP) based on the Gross Motor Function Classification System (GMFCS), age and gender.

Methods

This cross‐sectional study was based on the last assessment of children aged 1–14 years in the combined Swedish follow‐up programme and national quality register programme for CP. All were born 2001–2012 and reported to the registry in 2013–2014. Logistic regression was used to regress age, gender and the GMFCS level on the presence of pain. We also assessed pain sites among GMFCS groups.

Results

We included 2777 children (57% boys) at a median age of 7 years; 32.4% reported pain, with significantly more girls than boys experiencing pain and significantly more children at GMFCS levels III and V than GMFCS I. Pain frequency increased with age and differences among GMFCS levels were found in the lower extremities and abdomen. Pain in the abdomen and hips was most frequent at GMFCS V, knee pain at level III and foot pain at level I.

Conclusion

Our results showed that although a lower prevalence than in many other studies, pain constituted a significant problem in children and adolescents with CP.
High melphalan exposure is associated with improved overall survival in myeloma patients receiving high dose melphalan and autologous transplantation
Authors: Nath Christa E. , Trotman Judith , Tiley Campbell , Presgrave Peter , Joshua Douglas , Kerridge Ian , Kwan Yiu Lam , Gurney Howard , McLachlan Andrew J. , Earl John W. , Nivison‐Smith Ian , Zeng Lihua , Shaw Peter J.
Published: February 2016

Aim

High dose melphalan (HDM) and autologous stem cell transplantation (ASCT) retains a central role in the treatment of myeloma. The aim of this study was to determine whether HDM exposure (area under the concentration vs. time curve, AUC), is significantly associated with transplant outcomes.

Methods

Melphalan concentrations were measured in six to 11 plasma samples collected after HDM (median 192 mg m–2) to determine melphalan AUC for a total of 114 patients. Binary logistic regression was used to assess whether melphalan AUC was associated with severe (≥ grade 3) oral mucositis. Multivariate Cox regression was used to assess whether melphalan AUC was significantly associated with time to progression, progression‐free survival and overall survival (OS).

Results

Melphalan AUC ranged from 4.9 to 24.6 mg l–1 h, median 12.84 mg l–1 h. Melphalan AUC above the median was a risk factor for severe mucositis (HR 1.21, 95% CI 1.06, 1.38, P = 0.004) but was also associated with significantly improved overall survival (OS) (HR 0.40, 95% CI 0.20, 0.81, P = 0.001), with an estimated median survival of 8.50 years vs. 5.38 years for high vs. low AUC groups. Multivariate analysis did not identify melphalan AUC as being significantly associated with time to progression or progression‐free survival.

Conclusions

This large scale pharmacodynamic analysis of HDM demonstrates that high melphalan exposure is associated with improved survival, with an acceptable increase in transplant toxicity. These results suggest studies targeting a higher AUC are warranted in patients undergoing HDM and ASCT for myeloma.
Initial experience of an algorithm‐based protocol for the community follow‐up of men with prostate cancer
Authors: Goodall Philip P. , Little Jessica , Robinson Eleanor , Trimble Ian , Cole Owen J. , Walton Thomas J.
Published: February 2016

Objective

To evaluate the implementation of a novel algorithm‐based discharge programme for the community follow‐up of men with prostate cancer.

Patients and Methods

Men with prostate cancer considered suitable for discharge were identified from consultant‐led and clinical nurse‐specialist telephone clinics at Nottingham University Hospitals National Health Service Trust. Patients were discharged on to one of four discharge pathways: watchful waiting, androgen‐deprivation therapy (ADT), post‐prostatectomy, and post‐radiotherapy. Primary care providers were asked to adhere to specific surveillance measures and refer patients back to secondary care after breach of pre‐defined prostate‐specific antigen (PSA) level threshold criteria. Reasons for non‐compliance, re‐referral, and cause of death were determined for all discharged men.

Results

In all, 573 men were discharged across all four pathways; 169 on the watchful‐waiting pathway, 229 on the ADT pathway, 95 on the post‐prostatectomy pathway, and 80 on the post‐radiotherapy pathway. All patients had ≥12 months of follow‐up. In all, 48 of 54 (88.9%) men were re‐referred promptly after a PSA‐threshold breach. Of the remaining six patients there were three refusals, one unrelated death before referral, and two late referrals at 4 months. Three patients were lost to follow‐up due to database non‐registration and were subsequently recalled, none of whom had a PSA‐threshold breach. There were three unexpected deaths attributed to prostate cancer: two were community deaths with no biochemical or clinical evidence of prostate cancer progression, while one was due to a likely progressive PSA non‐secreting tumour.

Conclusion

Initial results suggest the algorithm‐based protocol is a viable, effective, and oncologically safe method for the controlled discharge of men from secondary to primary care. Longer‐term follow‐up, patient satisfaction and cost‐effectiveness data are required to assess the true impact of the initiative.
Target the Source: Optimal Spatiotemporal Resource Allocation for Invasive Species Control
Authors: Baker Christopher M.
Published: February 2016

Determining how to cost‐effectively allocate resources for managing invasive species is a notoriously difficult problem. Invasive species control problems are always spatiotemporal, but much of the current theory about control strategies is either spatial or temporal. This article uses a deterministic spatiotemporal model of invasive species dynamics and identifies the optimal management strategy across a range of situations. The optimal solution points a principle of targeting the source of the population, which in many cases is the region of the landscape where the invader is most abundant. The analysis presented here is the first capable of solving for optimal strategies for invasive species over large and irregular environments. Thus, it is an important step forward for both the understanding of control strategies and the application to management scenarios.
Lactic acidosis: relationship between metformin levels, lactate concentration and mortality
Authors: Boucaud‐Maitre D. , Ropers J. , Porokhov B. , Altman J.‐J. , Bouhanick B. , Doucet J. , Girardin E. , Kaloustian E. , Lassmann Vague V. , Emmerich J.
Published: February 2016

Aim

The role of metformin in lactic acidosis is regularly questioned. Arguments against a causal role for metformin in lactic acidosis occurrence are the lack of correlation between plasma metformin and lactate levels, as well as between metformin plasma levels and mortality. We aim to analyse these correlations in a large series of lactic acidosis cases recorded in the French nationwide pharmacovigilance database.

Methods

All cases of lactic acidosis spontaneously reported between 1985 and October 2013 associated with metformin exposure were extracted from the pharmacovigilance database. We assessed the statistical correlations between prescribed daily doses of metformin, plasma concentrations of metformin and lactate, pH and plasma creatinine, as well as the relationship between mortality and these variables.

Results

Seven hundred and twenty‐seven cases of lactic acidosis were reported during the period. Metformin plasma concentration was documented for 260 patients, lactate plasma concentration for 556 patients, pH for 502 patients, creatinine for 397 patients and the vital outcome for 713 patients. Metformin plasma concentration, lactate concentration, pH and plasma creatinine were all correlated (P < 0.001). There were significant differences between surviving and deceased patients in terms of metformin plasma levels (25.2 vs. 37.4 mg/l, P = 0.002) and lactate concentrations (10.8 vs. 16.3 mmol/l, P < 0.001). Thirty per cent of patients died when metformin concentration was > 5 mg/l compared with 11% for patients with concentration < 5 mg/l (P = 0.003).

Conclusions

Our data suggest that metformin accumulation contributes to the pathogenesis and prognosis of lactic acidosis.
Soluble galectin‐3 is associated with premature myocardial infarction
Authors: Winter Max‐Paul , Wiesbauer Franz , Alimohammadi Arman , Blessberger Hermann , Pavo Noemi , Schillinger Martin , Huber Kurt , Wojta Johann , Lang Irene M. , Maurer Gerald , Goliasch Georg
Published: February 2016

Background

Inflammatory responses are pivotal in the initiation and development of premature atherosclerotic lesions. Galectin‐3 represents a valuable biomarker for both progression and destabilization of atherosclerotic lesions. This study aims to assess the involvement of galectin‐3 in premature myocardial infarction.

Design

In this multicentre case–control study, we assessed circulating galectin‐3 levels in 144 patients comprising 72 consecutive survivors of acute myocardial infarction (≤ 40 years) and 72 hospital controls frequency matched for age, gender and centre.

Results

Patients with acute myocardial infarction showed significantly higher galectin‐3 levels as compared to controls in the acute phase of acute myocardial infarction (2552 ± 1992 vs. 1666 ± 829 pg/mL; P < 0·001) as well as in the stable phase 1 year after the index event (3692 ± 1774 vs. 1666 ± 829 pg/mL; P < 0·001). Circulating galectin‐3 was significantly and independently associated with premature myocardial infarction in the logistic regression analysis (acute phase: adj. OR per 1‐SD change 2·03, 95% CI 1·30−3·19; P = 0·002; stable phase: adj. OR of 6·54 (95% CI 2·56−16·68; P < 0·001). Moreover, we observed a significant correlation between circulating galectin‐3 and leucocyte count (r = 0·35, P < 0·001), non‐HDL cholesterol (r = 0·23, P = 0·014) and HDL cholesterol (r = −0·29, P = 0·002).

Conclusion

We demonstrated that elevated levels of circulating galectin‐3 are strongly associated with premature myocardial infarction. Galectin‐3 might serve as link between dyslipidaemia as driving force of plaque formation with inflammation as initiator of plaque rupture in patients with premature acute myocardial infarction.
The interrelationships of birthweight, inflammation and body composition in healthy adults
Authors: Kofler Thomas , Bossard Matthias , Aeschbacher Stefanie , Tabord Alexandra , Ruperti Repilado Francisco Javier , van der Lely Stéphanie , Berger Sebastian , Risch Martin , Risch Lorenz , Conen David
Published: February 2016

Background

Lower birthweight is associated with an increased risk of cardiovascular diseases and diabetes. We hypothesized that inflammation and body fat may be potential mediators for these inverse relationships.

Materials and methods

Healthy adults aged 25–41 years were enrolled in a prospective population‐based cohort study in the Principality of Liechtenstein. Main exclusion criteria were diabetes, overt cardiovascular disease or a body mass index > 35 kg/m2. Birthweight was self‐reported by the study participants. White blood cell (WBC) count and high‐sensitivity C‐reactive protein (hs‐CRP) levels were assayed from fresh blood samples. Body composition was determined by bioelectrical impedance analysis. Multivariable linear regression models were constructed to assess the relationships between birthweight, inflammation and body composition.

Results

Our sample consisted of 1774 participants (53·4% females) with a median age of 37 years. Median birthweight was 3355 g. In multivariable models, we found an inverse relationship of birthweight with hs‐CRP levels (β −0·010 (95% CI −0·02; −0·002), P = 0·01) and WBC count (β −0·002 (95% CI −0·004; −0·0002), P = 0·03). Additional adjustment for body fat mass attenuated these relationships (β −0·008 (95% CI −0·02; 0·0003), P = 0·06 for hs‐CRP levels and (β −0·002 (95% CI −0·004; 0·0006), P = 0·16 for WBC count. Body fat mass itself was strongly associated with birthweight (β −0·06 (95% CI −0·10; −0·03), P < 0·0001).

Conclusion

Birthweight is inversely associated with inflammation in adulthood. This relationship may be mediated by an elevated body fat mass among individuals with lower birthweight.
SURPRISE ME IF YOU CAN: THE INFLUENCE OF NEWSPAPER ENDORSEMENTS IN U.S. PRESIDENTIAL ELECTIONS
Authors: Casas Agustin , Fawaz Yarine , Trindade Andre
Published: February 2016

We here evaluate the heterogeneous effects of newspaper endorsements of U.S. Presidential candidates in the 100 days preceding the 2008 and 2012 elections on the probability that they win the election. Our identification strategy relies on daily variations in the winning probabilities (obtained from the Intrade prediction market) and the fact that newspapers decide their endorsements weeks before their announcement. Endorsements that are classified as surprising and consistent have the largest effect. An endorsement is surprising when the newspaper has not traditionally endorsed the candidate's party. An endorsement is inconsistent when the newspaper leans ideologically to one party but endorses a candidate from another party. (JEL L82, D7)
ARE PROMISES MEANINGLESS IN AN UNCERTAIN CROWDFUNDING ENVIRONMENT?
Authors: Hauge Janice A. , Chimahusky Stanley
Published: February 2016

We use a prominent crowdfunding organization, Kickstarter, to analyze the factors that determine timeliness of delivery of rewards to financial backers. We seek to determine the extent to which promised rewards are delivered on time and to characterize projects that have stronger likelihood of timely delivery of rewards. We find that lateness commonly occurs, yet cannot be explained universally with any given set of project characteristics, implying that the uncertainty of rewards involved with crowdfunding entities is difficult to overcome. (JEL D71, D83, L82)