bluuebunny/crossref_metadata_2025 huggingface dataset:
A large-scale genome-wide enrichment analysis identifies new trait-associated genes, pathways and tissues across 31 human phenotypes*
Authors: Zhu Xiang , Stephens Matthew
Published: July 2017

Genome-wide association studies (GWAS) aim to identify genetic factors that are associated with complex traits. Standard analyses test individual genetic variants, one at a time, for association with a trait. However, variant-level associations are hard to identify (because of small effects) and can be difficult to interpret biologically. “Enrichment analyses” help address both these problems by focusing onsets of biologically-related variants. Here we introduce a new model-based enrichment analysis method that requires only GWAS summary statistics, and has several advantages over existing methods. Applying this method to interrogate 3,913 biological pathways and 113 tissue-based gene sets in 31 human phenotypes identifies many previously-unreported enrichments. These include enrichments of theendochondral ossificationpathway for adult height, theNFAT-dependent transcriptionpathway for rheumatoid arthritis,brain-relatedgenes for coronary artery disease, andliver-relatedgenes for late-onset Alzheimer’s disease. A key feature of our method is that inferred enrichments automatically help identify new trait-associated genes. For example, accounting for enrichment inlipid transportgenes yields strong evidence for association betweenMTTPand low-density lipoprotein levels, whereas conventional analyses of the same data found no significant variants near this gene.
Improving Designer Glycan Production inEscherichia colithrough Model-Guided Metabolic Engineering
Authors: Wayman Joseph A. , Glasscock Cameron , Mansell Thomas J. , DeLisa Matthew P. , Varner Jeffrey D.
Published: July 2017

Asparagine-linked (N-linked) glycosylation is the most common protein modification in eukaryotes, affecting over two-thirds of the proteome. Glycosylation is also critical to the pharmacokinetic activity and immunogenicity of many therapeutic proteins currently produced in complex eukaryotic hosts. The discovery of a protein glycosylation pathway in the pathogenCampylobacter jejuniand its subsequent transfer into laboratory strains ofEscherichia colihas spurred great interest in glycoprotein production in prokaryotes. However, prokaryotic glycoprotein production has several drawbacks, including insufficient availability of non-native glycan precursors. To address this limitation, we used a constraint-based model ofE. colimetabolism in combination with heuristic optimization to design gene knockout strains that overproduced glycan precursors. First, we incorporated reactions associated withC. jejuniglycan assembly into a genome-scale model ofE. colimetabolism. We then identified gene knockout strains that coupled optimal growth to glycan synthesis. Simulations suggested that these growth-coupled glycan overproducing strains had metabolic imbalances that rerouted flux toward glycan precursor synthesis. We then validated the model-identified knockout strains experimentally by measuring glycan expression using a flow cytometric-based assay involving fluorescent labeling of cell surface-displayed glycans. Overall, this study demonstrates the promising role that metabolic modeling can play in optimizing the performance of a next-generation microbial glycosylation platform.
Translational and HIF1α-dependent metabolic reprograming underpin oncometabolome plasticity and synergy between oncogenic kinase inhibitors and biguanides
Authors: Hulea Laura , Gravel Simon-Pierre , Morita Masahiro , Cargnello Marie , Uchenunu Oro , Im Young Kyuen , McLaughlan Shannon , Larsson Ola , Ohh Michael , Ferreira Tiago , Greenwood Celia , Bridon Gaëlle , Avizonis Daina , Ursini-Siegel Josie , St-Pierre Julie , Pollak Michael , Topisirovic Ivan
Published: July 2017

There is heightened interest to devise therapies that target the oncometabolome. We show that kinase inhibitors (KIs) and biguanides synergistically target melanoma, leukemia, and breast, colon and renal cancer cells, but not non-transformed cells. Metabolic profiling confirmed opposing effects of KIs and biguanides on glycolysis, but this was insufficient to explain the observed synergy between the drugs. Rather, we define a critical role for the synthesis of non-essential amino acids (NEAA) aspartate, asparagine and serine as well as reductive glutamine metabolism, in determining the sensitivity of cancer cells to KI - biguanide combinations. The mTORC1/4E-BP axis regulates aspartate, asparagine and serine synthesis by modulating translation of mRNAs encoding PC, ASNS, PHGDH and PSAT1. Ablation of 4E-BP1 and 2 results in a dramatic increase in serine, aspartate and asparagine levels and a substantial decrease in sensitivity of breast cancer and melanoma cells to KI - biguanide combinations. In turn, efficacy of KI – biguanide combinations is impeded by HIF1α and sustained reductive glutamine metabolism. These findings identify hitherto unappreciated translational reprograming of NEAA synthesis and HIF1α-dependent stimulation of reductive glutamine metabolism as critical metabolic vulnerabilities of cancer that underpin synergy between KIs and biguanides.
A random-matrix theory of the number sense
Authors: Hannagan T. , Nieder A. , Viswanathan P. , Dehaene S.
Published: July 2017

Number sense, a spontaneous ability to process approximate numbers, has been documented in human adults, infants and newborns, and many other animals. Species as distant as monkeys and crows exhibit number-selective neuronal activity. How number sense can emerge in the absence of learning or fine tuning is currently unknown. We introduce a random matrix theory of self-organised neural states where numbers are coded by vectors of activation across multiple units, and where the vector codes for successive integers are obtained through multiplication by a fixed but random matrix. This cortical implementation of the “von Mises” algorithm explains many otherwise disconnected observations ranging from neural tuning curves in monkeys to looking times in neonates and cortical numerotopy in adults. The theory clarifies the origin of Weber-Fechner’s law and yields a novel and empirically validated prediction of multi-peak number neurons. Random matrices constitute a novel mechanism for the emergence of brain states coding for quantity.
Nucleosomes and DNA methylation shape meiotic DSB frequency in Arabidopsis transposons and gene regulatory regions
Authors: Choi Kyuha , Zhao Xiaohui , Lambing Christophe , Underwood Charles J. , Hardcastle Thomas J. , Serra Heïdi , Tock Andrew J. , Ziolkowski Piotr A. , Yelina Nataliya E. , Martienssen Robert A. , Henderson Ian R.
Published: July 2017

Meiotic recombination initiates via DNA double strand breaks (DSBs) generated by SPO11 topoisomerase-like complexes. Recombination frequency varies extensively along eukaryotic chromosomes, with hotspots controlled by chromatin and DNA sequence. To map meiotic DSBs throughout a plant genome, we purified and sequenced Arabidopsis SPO11-1-oligonucleotides. DSB hotspots occurred in gene promoters, terminators and introns, driven by AT-sequence richness, which excludes nucleosomes and allows SPO11-1 access. A strong positive relationship was observed between SPO11-1 DSBs and final crossover levels. Euchromatic marks promote recombination in fungi and mammals, and consistently we observe H3K4me3enrichment in proximity to DSB hotspots at gene 5’-ends. Repetitive transposons are thought to be recombination-silenced during meiosis, in order to prevent non-allelic interactions and genome instability. Unexpectedly, we found strong DSB hotspots in nucleosome-depleted Helitron/Pogo/Tc1/Mariner DNA transposons, whereas retrotransposons were coldspots. Hotspot transposons are enriched within gene regulatory regions and in proximity to immunity genes, suggesting a role as recombination-enhancers. As transposon mobility in plant genomes is restricted by DNA methylation, we used themet1DNA methyltransferase mutant to investigate the role of heterochromatin on the DSB landscape. Epigenetic activation of transposon meiotic DSBs occurred inmet1mutants, coincident with reduced nucleosome occupancy, gain of transcription and H3K4me3. Increasedmet1SPO11-1 DSBs occurred most strongly within centromeres and Gypsy and CACTA/EnSpm coldspot transposons. Together, our work reveals complex interactions between chromatin and meiotic DSBs within genes and transposons, with significance for the diversity and evolution of plant genomes.
Epigenetic activation of meiotic recombination in Arabidopsis centromeres via loss of H3K9me2 and non-CG DNA methylation
Authors: Underwood Charles J. , Choi Kyuha , Lambing Christophe , Zhao Xiaohui , Serra Heïdi , Borges Filipe , Simorowski Joe , Ernst Evan , Jacob Yannick , Henderson Ian R. , Martienssen Robert A.
Published: July 2017

Eukaryotic centromeres contain the kinetochore, which connects chromosomes to the spindle allowing segregation. During meiosis centromeres are suppressed for crossovers, as recombination in these regions can cause chromosome mis-segregation. Plant centromeres are surrounded by repetitive, transposon-dense heterochromatin that is epigenetically silenced by histone 3 lysine 9 dimethylation (H3K9me2), and DNA methylation in CG and non-CG sequence contexts. Here we show that disruption of Arabidopsis H3K9me2 and non-CG DNA methylation pathways increases meiotic DNA double strand breaks (DSBs) within centromeres, whereas crossovers increase within pericentromeric heterochromatin. Increased pericentromeric crossovers in H3K9me2/non-CG mutants occurs in both inbred and hybrid backgrounds, and involves the interfering crossover repair pathway. Epigenetic activation of recombination may also account for the curious tendency of maize transposonDsto disruptCHROMOMETHYLASE3when launched from proximal loci. Thus H3K9me2 and non-CG DNA methylation exert differential control of meiotic DSB and crossover formation in centromeric and pericentromeric heterochromatin.
Pan-cancer analysis reveals complex tumor-specific alternative polyadenylation
Authors: Xue Zhuyi , Warren René L , Gibb Ewan A , MacMillan Daniel , Wong Johnathan , Chiu Readman , Hammond S Austin , Ennis Catherine A , Hahn Abigail , Reynolds Sheila , Birol Inanc
Published: July 2017

Alternative polyadenylation (APA) of 3’ untranslated regions (3’ UTRs) has been implicated in cancer development. Earlier reports on APA in cancer primarily focused on 3’ UTR length modifications, and the conventional wisdom is that tumor cells preferentially express transcripts with shorter 3’ UTRs. Here, we analyzed the APA patterns of 114 genes, a select list of oncogenes and tumor suppressors, in 9,939 tumor and 729 normal tissue samples across 33 cancer types using RNA-Seq data from The Cancer Genome Atlas, and we found that the APA regulation machinery is much more complicated than what was previously thought. We report 77 cases (gene-cancer type pairs) of differential 3’ UTR cleavage patterns between normal and tumor tissues, involving 33 genes in 13 cancer types. For 15 genes, the tumor-specific cleavage patterns are recurrent across multiple cancer types. While the cleavage patterns in certain genes indicate apparent trends of 3’ UTR shortening in tumor samples, over half of the 77 cases imply 3’ UTR length change trends in cancer that are more complex than simple shortening or lengthening. This work extends the current understanding of APA regulation in cancer, and demonstrates how large volumes of RNA-seq data generated for characterizing cancer cohorts can be mined to investigate this process.
No cause for pause: new analyses of ramping and stepping dynamics in LIP (Rebuttal to Response to Reply to Comment on Latimer et al 2015)
Authors: Latimer Kenneth W. , Huk Alexander C. , Pillow Jonathan W.
Published: July 2017

We recently presented a statistical comparison between two models of latent dynamics in macaque lateral intraparietal (LIP) area spike trains—a continuous ‘ramping’ (diffusion-to-bound) model, and a discrete ‘stepping’ model—and found that a substantial fraction of neurons (recorded in two different studies) were better supported by the stepping model (Latimer et al., 2015). Here, we respond to a recent challenge to the validity of these findings that focuses primarily on the possibility of a lower bound on LIP firing rates (Zylberberg & Shadlen, 2016). The paper in question proposed alternate formulations of the ramping model, and argued (via indirect analyses) that half the neurons in the population were better explained by the new model; if correct, this would lead to an even split in the number of neurons better explained by each model. These analyses, while interesting, do not alter the conclusions of our original paper. Here, we review the criticisms raised by Zylberberg & Shadlen and report several new analyses using models with lower bounds. First, we show that the stepping model continued to provide a better description of LIP spike trains when fit using only an early period of each trial. Second, we performed a direct model comparison between our stepping model and a ramping-with-baseline model proposed by Zylberberg & Shadlen; we found that (in a pleasing moment of agreement) roughly half the neurons were better explained by each model. Interestingly, inspection of the cells that switched classifications revealed that many did not strictly exhibit the classical ramping PSTHs that motivated these analyses in the first place. We also examined two other issues raised in recent discussions of LIP: (1) We show that a non-integrating model is consistent with some core aspects of behavioral data previously offered as evidence for continuous integration; and (2) We examine analyses based on the response covariance (“CorCE”), and show that it does not reliably distinguish ramping and stepping dynamics for our dataset. Taken together, these discussions highlight the value of data-driven characterizations of both neural and behavioral dynamics with appropriate statistical tools.
SMELL-S and SMELL-R: olfactory tests not influenced by odor-specific insensitivity or prior olfactory experience
Authors: Hsieh Julien W. , Keller Andreas , Wong Michele , Jiang Rong-San , Vosshall Leslie B.
Published: July 2017

Smell dysfunction is a common and underdiagnosed medical condition that can have serious consequences. It is also an early biomarker of Alzheimer’s disease that precedes detectable memory loss. Clinical tests that evaluate the sense of smell face two major challenges. First, human sensitivity to individual odorants varies significantly, leading to potential misdiagnosis of people with an otherwise normal sense of smell but insensitivity to the test odorant. Second, prior familiarity with odor stimuli can bias smell test performance. We have developed new non- semantic tests for olfactory sensitivity (SMELL-S) and olfactory resolution (SMELL-R) that overcome these challenges by using mixtures of odorants that have unfamiliar smells. The tests can be self-administered with minimal training and showed high test-retest reliability. Because SMELL-S uses odor mixtures rather than a single molecule, odor-specific insensitivity is averaged out. Indeed, SMELL-S accurately distinguished people with normal and dysfunctional smell. SMELL-R is a discrimination test in which the difference between two stimulus mixtures can be altered stepwise. This is an advance over current discrimination tests, which ask subjects to discriminate monomolecular odorants whose difference cannot be objectively calculated. SMELL-R showed significantly less bias in scores between North American and Taiwanese subjects than conventional semantically-based smell tests that need to be adapted and translated to different populations. We predict that SMELL-S and SMELL-R will be broadly effective in diagnosing smell dysfunction, including that associated with the earliest signs of memory loss in Alzheimer’s disease.

Significance statement

Currently available smell testing methods can misdiagnose subjects with lack of prior experience or insensitivity to the odorants used in the test. This introduces a source of bias into clinical tests aimed at detecting patients with olfactory dysfunction. We have developed smell tests that use mixtures of 30 molecules that average out the variability in sensitivity to individual molecules. Because these mixtures have unfamiliar odors, and the tests are non-semantic, their use eliminates differences in test performance due to the familiarity with the smells or the words used to describe them. The SMELL-S and SMELL-R tests facilitate smell testing of diverse populations, without the need to adapt the test stimuli.
A positive feedback-based mechanism for constriction rate acceleration during cytokinesis inC. elegans
Authors: Khaliullin Renat N. , Green Rebecca A. , Shi Linda Z. , Gomez-Cavazos J. Sebastian , Berns Michael W. , Desai Arshad , Oegema Karen
Published: July 2017

During cytokinesis, an equatorial actomyosin contractile ring constricts at a relatively constant overall rate despite its progressively decreasing size. Thus, the per-unit-length rate of ring closure increases as ring perimeter decreases. To understand this acceleration, we monitored cortical surface and ring component dynamics during the first division of theC. elegansembryo. We show that the polar cortex expands during ring constriction to provide the cortical surface area required for division. Polar expansion also allows ring myosin to compress cortical surface along the pole-to-pole axis, leading to a continuous flow of cortical surface into the ring. We propose that feedback between ring myosin and compression-driven cortical flow drives an exponential increase in the amount of ring myosin that maintains the high overall closure rate as ring perimeter decreases. We further show that an analytical mathematical formulation of the proposed feedback, called the Compression Feedback model, recapitulates the experimental observations.

IMPACT STATEMENT

During cytokinesis, positive feedback between myosin motors in the contractile ring and compression-driven cortical flow along the axis perpendicular to the ring drives constriction rate acceleration to ensure timely cell separation.

MAJOR SUBJECT AREAS

Cell biology, Computational and Systems Biology
Cyanobacterial Growth on Municipal Wastewater Requires Low Temperatures
Authors: Korosh Travis C. , Dutcher Andrew , Pfleger Brian F. , McMahon Katherine D.
Published: July 2017

Side-streams in wastewater treatment plants can serve as concentrated sources of nutrients (i.e. nitrogen and phosphorus) to support the growth of photosynthetic organisms that ultimately serve as feedstock for production of fuels and chemicals. However, other chemical characteristics of these streams may inhibit growth in unanticipated ways. Here, we evaluated the use of liquid recovered from municipal anaerobic digesters via gravity belt filtration as a nutrient source for growing the cyanobacteriumSynechococcussp. strain PCC 7002. The gravity belt filtrate (GBF) contained high levels of complex dissolved organic matter (DOM), which seemed to negatively influence cells. We investigated the impact of GBF on physiological parameters such as growth rate, membrane integrity, membrane composition, photosystem composition, and oxygen evolution from photosystem II. At 37°C, we observed an inverse correlation between GBF concentration and membrane integrity. Radical production was also detected upon exposure to GBF at 37°C. However, at 27°C the dose dependent relationship between GBF concentration and lack of membrane integrity was abolished. Immediate resuspension of strains in high doses of GBF showed markedly reduced oxygen evolution rates relative to the control. Together, this suggests that one mechanism responsible for GBF toxicity toSynechococcusis the interruption of photosynthetic electron flow and subsequent phenomena. We hypothesize this is likely due to the presence of phenolic compounds within the DOM.

IMPORTANCE

Cyanobacteria are viewed as promising platforms to produce fuels and/or high-value chemicals as part of so-called “bio-refineries”. Their integration into wastewater treatment systems is particularly interesting because removal of the nitrogen and phosphorus in many wastewater streams is an expensive but necessary part of wastewater treatment. In this study, we evaluated strategies for cultivatingSynechococcusstrain PCC 7002 on media comprised of two wastewater streams; treated secondary effluent supplemented with the liquid fraction extracted from sludge following anaerobic digestion. This strain is commonly used for metabolic engineering to produce a variety of valuable chemical products and product precursors (e.g. lactate). However, initial attempts to grow PCC 7002 under otherwise standard conditions of light and temperature failed. We thus systematically evaluated alternative cultivation conditions and then used multiple methods to dissect the apparent toxicity of the media under standard cultivation conditions.
Psychotropic polypharmacy in Australia, 2006 to 2015: a descriptive cohort study
Authors: Brett Jonathan , Daniels Benjamin , Karanges Emily A. , Buckley Nicholas A. , Schneider Carl , Nassir Atheer , McLachlan Andrew J. , Pearson Sallie‐Anne
Published: July 2017

Aims

To describe psychotropic polypharmacy in Australia between 2006 and 2015.

Methods

We used pharmaceutical claims from a national 10% sample of people with complete dispensing histories to estimate the annual prevalence of the combined use (overlap of >60 days exposure) of ≥2 psychotropics overall and within the same class or subclass (class and subclass polypharmacy). We also estimated the proportion of polypharmacy episodes involving one, two, three and four or more unique prescribers.

Results

The prevalence of class polypharmacy between 2006 and 2015 in people dispensed specific psychotropic classes was 5.9–7.3% for antipsychotics, 2.1–3.7% for antidepressants and 4.3–2.9% for benzodiazepines. The prevalence of antipsychotic polypharmacy was higher than expected given the prevalence of antipsychotic exposure and combinations of sedating agents were notably common. Overall, 26.7% of polypharmacy episodes involved multiple prescribers but having multiple prescribers occurred more frequently for class and subclass polypharmacy and people with four or more concomitant psychotropics.

Discussion

Psychotropic polypharmacy is common, despite limited evidence of risks and benefits. Increases in polypharmacy with multiple prescribers may be due to poor communication with patients and between health care professionals.
Intra‐Target Microdosing – A Novel Drug Development Approach: Proof of Concept, Safety, and Feasibility Study in Humans
Authors: Burt T , MacLeod D , Lee K , Santoro A , DeMasi DK , Hawk T , Feinglos M , Rowland M , Noveck RJ
Published: July 2017

Intra‐Target Microdosing (ITM) is a novel drug development approach aimed at increasing the efficiency of first‐in‐human (FIH) testing of new molecular entities (NMEs). ITM combines intra‐target drug delivery and “microdosing,” the subpharmacological systemic exposure. We hypothesized that when the target tissue is small (about 1/100th of total body mass), ITM can lead to target therapeutic‐level exposure with minimal (microdose) systemic exposure. Each of five healthy male volunteers received insulin microdose into the radial artery or full therapeutic dose intravenously in separate visits. Insulin and glucose levels were similar between systemic administration and ITM administration in the ipsilateral hand, and glucose levels demonstrated a reduction in the ipsilateral hand but not in the contralateral hand. Positron emission tomography (PET) imaging of 18F‐fluorodeoxyglucose (FDG) uptake demonstrated differences between the ipsilateral and contralateral arms. The procedures were safe and well‐tolerated. Results are consistent with ITM proof‐of‐concept (POC) and demonstrate the ethical, regulatory, and logistical feasibility of the approach.
Identification of OAT1/OAT3 as Contributors to Cisplatin Toxicity
Authors: Hu S , Leblanc AF , Gibson AA , Hong KW , Kim JY , Janke LJ , Li L , Vasilyeva A , Finkelstein DB , Sprowl JA , Sweet DH , Schlatter E , Ciarimboli G , Schellens JHM , Baker SD , Pabla N , Sparreboom A
Published: July 2017

Cisplatin is among the most widely used anticancer drugs and known to cause a dose‐limiting nephrotoxicity, which is partially dependent on the renal uptake carrier OCT2. We here report a previously unrecognized, OCT2‐independent pathway of cisplatin‐induced renal injury that is mediated by the organic anion transporters OAT1 and OAT3. Using transporter‐deficient mouse models, we found that this mechanism regulates renal uptake of a mercapturic acid metabolite of cisplatin that acts as a precursor of a potent nephrotoxin. The function of these two transport systems can be simultaneously inhibited by the tyrosine kinase inhibitor nilotinib through noncompetitive mechanisms, without compromising the anticancer properties of cisplatin. Collectively, our findings reveal a novel pathway that explains the fundamental basis of cisplatin‐induced nephrotoxicity, with potential implications for its therapeutic management.
Modelling the spatial variation of vital rates: An evaluation of the strengths and weaknesses of correlative species distribution models
Authors: Suárez‐Seoane Susana , Álvarez‐Martínez Jose Manuel , Wintle Brendan A. , Palacín Carlos , Alonso Juan C.
Published: July 2017

Aim

Species distribution models based on breeding occurrence data allow for identifying both environmental drivers and geographic areas potentially relevant for breeding. However, the interpretation of model predictions in terms of reproductive performance should be further investigated, as this information is crucial for conservation planning. We evaluated the strengths and weaknesses of a correlative modelling approach based on breeding occurrence data (presence–absence) against another approach based on vital rates’ data (breeding success) for gaining insights on species persistence in the case of Great Bustards (Otis tarda).

Location

Spain.

Methods

Breeding occurrence and breeding success were independently modelled using generalized linear models and multimodel inference analyses. Sensitivities to the way in which the population parameter (breeding success) was defined were explored by building five versions of the dependent variable. We evaluated differences in model performance and identified areas of congruence for breeding occurrence and breeding success.

Results

The agreement between the spatial predictions achieved by breeding occurrence and breeding success models differed substantially across databases, with the largest differences in occupied breeding areas. The deviance explained by the breeding occurrence model was 64.98% and ranged from 7.83% to 62.27% for the breeding success models. Model performance was higher for models calibrated within potential than within occupied breeding areas.

Main conclusions

The combination of data on both breeding occurrence and breeding success into a species distribution modelling framework showed the limitations of breeding occurrence models for inferring reproductive parameters. The definition of the population parameter as dependent variable was a key factor that strongly affected the inference of vital rates’ models. The approach allowed for discriminating between areas and landscape attributes necessary for the long‐term species persistence from others that may be relevant, but not so much for reproductive performance.
Deficits of ankle muscle strength not found in children, adolescents and young adults with haemophilic ankle arthropathy
Authors: Lobet S. , Croisier J.‐L. , Lantin A.‐C. , Hermans C. , Peerlinck K. , Vandesande J. , Pialat J.‐B. , Deschamps K.
Published: July 2017

Objectives

Adequate management of haemophilia patients requires early detection of joint impairment in relatively asymptomatic patients. This study sought to quantify the impact of the ankle's structural impairment on muscle strength in children, adolescent and young adults with haemophilia (CAAwH).

Methods

Twenty‐three CAAwH underwent bilateral magnetic resonance imaging (MRI) assessing the anatomical status of tibiotalar joint (TTJ) and subtalar joint (STJ) using the International Prophylaxis Study Group MRI scale. An isokinetic dynamometer enabled a detailed evaluation of muscle strength at slow and fast speed. In parallel, 10 typically developing healthy boys (TDB) participated in a 1‐week interval test‐retest assessment to assess the test's reliability.

Results

Forty‐six MRI ankle scores were obtained, with 11 patients unilaterally affected and one bilaterally. Of the 13 affected feet, nine showed abnormalities at TTJ, three at the posterior STJ and the remaining one at both joints. Muscle strength was not reduced in CAAwH exhibiting TTJ and/or STJ arthropathy, as compared to healthy TDB, nor was there any difference between the CAAwH's affected or unaffected sides.

Conclusion

Contrarily to adult patients, CAAwH with repeated ankle bleeding may be less impaired than current structural evaluations imply, with possibly a latency between the occurrence of structural and functional damage.
Acupuncture Attenuates Hyperglycaemia and Improves Ovarian Function in Female Rats Subjected to Continuous Light Exposure
Authors: Kang Xuezhi , Jia Lina , Li Yaming , Zhang Xu
Published: July 2017

Objective

Exposure to unnatural light cycles is increasingly associated with obesity and the metabolic syndrome. The purpose of this study was to examine the effects of electroacupuncture (EA) on glucose metabolism and ovarian function in female rats subjected to long-term continuous light exposure.

Methods

Female Sprague-Dawley rats (n=24) were divided into three experimental groups: an LD group that was maintained under a normal light-dark cycle (healthy control); an LL group that was exposed to continuous light for 21 weeks but remained untreated; and an LL+EA group that received EA at ST36 and SP6 during weeks 17 to 21 of continuous light exposure.

Results

Oestrous cycles of female rats kept in a continuously lit environment for 21 weeks were disordered and polycystic ovarian syndrome (PCOS)-like changes occurred, accompanied by increased fasting blood glucose (6.23±0.33 vs 5.27±0.40 mmol/L in week 17, p=0.015) and reduced fasting levels of serum testosterone (0.07±0.018 vs 0.12±0.058 ng/L, p=0.043) and insulin (0.89±0.20 vs 1.43±0.46 ng/L, p=0.006). After 5 weeks of EA treatment at ST36 and SP6, ovarian cycle disruption was mitigated and blood glucose levels showed a gradual decline (5.18±0.37 vs 5.80±0.55 mmol/L, p=0.017; and 5.73±0.31 vs 6.62±0.13 mmol/L, p=0.004; in the fourth and fifth weeks of EA treatment, respectively). EA also attenuated the reductions otherwise seen in serum insulin and testosterone levels.

Conclusion

Prolonged exposure to light can lead to a decline in ovarian and pancreatic function. EA at ST36 and SP6 may reduce abnormally elevated blood glucose levels and improve ovarian and pancreatic hormone levels.
Acupuncture for the Treatment of Gastro-Oesophageal Reflux Disease: A Systematic Review and Meta-Analysis
Authors: Zhu Jiajie , Guo Yu , Liu Shan , Su Xiaolan , Li Yijie , Yang Yang , Hou Liwei , Wang Guishu , Zhang Jiaxin , Chen Jiande JD , Wang Qingguo , Wei Ruhan , Wei Wei
Published: July 2017

Background

Gastro-oesophageal reflux disease (GORD) is one of the most common diseases presenting to gastroenterology clinics. Acupuncture is widely used as a complementary and alternative treatment for patients with GORD.

Objective

To explore the effectiveness of acupuncture for the treatment of GORD.

Methods

Four English and four Chinese databases were searched through June 2016. Randomised controlled trials investigating the effectiveness of manual acupuncture or electroacupuncture (MA/EA) for GORD versus or as an adjunct to Western medicine (WM) were selected. Data extraction and quality evaluation were performed by two authors independently and RevMan 5.2.0 was used to analyse data.

Results

A total of 12 trials involving 1235 patients were included. Meta-analyses demonstrated that patients receiving MA/EA combined with WM had a superior global symptom improvement compared with those receiving WM alone (relative risk (RR) 1.17, 95% CI 1.09 to 1.26; p=0.03; six studies) with no significant heterogeneity (I2=0%, p=0.41). Recurrence rates of those receiving MA/EA alone were lower than those receiving WM (RR 0.42,95% CI 0.29 to 0.61; p<0.001; three studies) with low heterogeneity (I2=7%, p=0.34), while global symptom improvement (six studies) and symptom scores (three studies) were similar (both p>0.05). Descriptive analyses suggested that acupuncture also improves quality of life in patients with GORD.

Conclusion

This meta-analysis suggests that acupuncture is an effective and safe treatment for GORD. However, due to the small sample size and poor methodological quality of the included trials, further studies are required to validate our conclusions.

Trial registration number

PROSPERO Systematic review registration no. CRD42016041916.
Late outcomes of gold weights and platinum chains for upper eyelid loading
Authors: Siah We Fong , Nagendran Sonali , Tan Petrina , Ali Ahmad Syed Mustafa , Litwin Andre S , Malhotra Raman
Published: July 2017

Aim

To identify late outcomes of gold weights (GWs) and platinum chains (PCs) for upper eyelid loading in the management of lagophthalmos.

Methods

A retrospective case series of upper eyelid GWs and PCs at a single centre over a 10-year period (2004–2013). Two independent, blinded assessors graded standard photographs for any weight-related morbidity (poor upper eyelid contour, weight prominence and migration).

Results

Primary upper eyelid loading (high-tarsal technique) was performed in 154 eyelids of 136 patients (facial nerve palsy, n=99; non-paralytic, n=37). A total of 127 eyelids of 110 patients had primary GW insertion. Of these, 40.9% (52/127) had revision surgery: exchange of GW for PC (58%), GW repositioning (25%) and removal of GW (17%). Only 22.2% (6/27 eyelids) with primary PCs required revision surgery. In those not requiring revision surgery, photograph grading showed that both GWs and PCs had weight-related morbidity at late follow-up (median=37.5 months, range 12–110 vs median=33.5 month, range 15–106). GWs had significantly higher rate of weight prominence (p=0.001) and migration (p<0.001) compared with PCs. All PC revisions required one procedure only compared with 10% of GWs revisions requiring two or more procedures. Incidence of gold allergy was 7% (8/110 patients). There was no association between the choice of weight material, physical weight or suture material and eyelid morbidities.

Conclusion

GWs were found to be associated with higher complications and twice more likely to require long-term revision surgery compared with PCs. Despite weight fixation at a high-tarsal location, prominence of PCs can still occur.
Systemic diseases in patients with HTLV-1-associated uveitis
Authors: Nakao Kumiko , Abematsu Noriko , Sakamoto Taiji
Published: July 2017

Background

Human T-lymphotropic virus type 1 (HTLV-1) carriers may develop severe systemic diseases, such as adult T cell leukaemia (ATL) or HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). This study aims to investigate systemic diseases of HTLV-1 carriers who had developed HTLV-1-associated uveitis (HAU).

Methods

We investigated the occurrence of systemic diseases in 200 patients with HAU by performing a retrospective investigation of their medical records and examining the results of a postal survey.

Results

The mean age of HAU onset was 49 years, and the total person-years from HAU onset was 1627. There were two cases of ATL. Of these, one was diagnosed with smouldering ATL at the time of HAU onset and the other developed acute-type ATL 4 years after HAU onset. There were 26 cases of HAM/TSP; of these, HAM/TSP occurred first in 13 cases and HAU occurred first in 11 cases. The interval between the onset of HAM/TSP and HAU ranged from 6 months to 6 years, with no significant difference observed based on whether HAM/TSP or HAU occurred first. Hyperthyroidism was noted in 45 cases and preceded onset in all cases. HAU onset occurred after starting thiamazole treatment, and in two cases HAU recurred each time thiamazole treatment was restarted.

Conclusion

HTLV-1 carriers with HAU may develop HAM/TSP more frequently than general carriers. HTLV-1 carriers undergoing treatment for hyperthyroidism may be prone to developing HAU.
Head impact velocities in FIS World Cup snowboarders and freestyle skiers: Do real-life impacts exceed helmet testing standards?
Authors: Steenstrup Sophie E , Mok Kam-Ming , McIntosh Andrew S , Bahr Roald , Krosshaug Tron
Published: July 2017

Introduction

Prior to the 2013–2014 season, the International Ski Federation (FIS) increased the helmet testing speed from a minimum requirement of 5.4 to 6.8 m/s for alpine downhill, super-G and giant slalom and for freestyle ski cross, but not for the other freestyle disciplines or snowboarding. Whether this increased testing speed reflects impact velocities in real head injury situations on snow is unclear. We therefore investigated the injury mechanisms and gross head impact biomechanics in four real head injury situations among World Cup (WC) snowboard and freestyle athletes and compared these with helmet homologation laboratory test requirements. The helmets in the four cases complied with at least European Standards (EN) 1077 (Class B) or American Society for Testing and Materials (ASTM) F2040.

Methods

We analysed four head injury videos from the FIS Injury Surveillance System throughout eight WC seasons (2006–2014) in detail. We used motion analysis software to digitize the helmet’s trajectory and estimated the head’s kinematics in two dimensions, including directly preimpact and postimpact.

Results

All four impacts were to the occiput. In the four cases, the normal-to-slope preimpact velocity ranged from 7.0(±SD 0.2) m/s to 10.5±0.5 m/s and the normal-to-slope velocity change ranged from 8.4±0.6 m/s to 11.7±0.7 m/s. The sagittal plane helmet angular velocity estimates indicated a large change in angular velocity (25.0±2.9 rad/s to 49.1±0.3 rad/s).

Conclusion

The estimated normal-to-slope preimpact velocity was higher than the current strictest helmet testing rule of 6.8 m/s in all four cases.
Association of the DASH dietary pattern with insulin resistance and diabetes in US Hispanic/Latino adults: results from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL)
Authors: Corsino Leonor , Sotres-Alvarez Daniela , Butera Nicole M , Siega-Riz Anna María , Palacios Cristina , Pérez Cynthia M , Albrecht Sandra S , Espinoza Giacinto Rebecca A , Perera Marisa Judith , Horn Linda Van , Avilés-Santa M. Larissa
Published: July 2017

Objective

To examine the association between diet quality and both diabetes status and insulin resistance in Hispanic/Latino adults, and the extent to which differences in diet quality contribute to differences in outcomes across Hispanic/Latino heritage.

Research design and methods

Cross-sectional study. Data are from 15 942 individuals enrolled in the Hispanic Community Health Study/Study of Latinos. Diet was ascertained using two 24-hour dietary recalls, and diet quality was measured using the Dietary Approaches to Stop Hypertension (DASH) score (range: 0–80, lowest to highest). Diabetes status was defined based on self-reported diagnosis, use of antihyperglycemic medications, or unrecognized diabetes (determined by baseline laboratory measures). Insulin resistance was determined using homeostatic model assessment of β-cell function and insulin resistance (HOMA-IR). The association between DASH and diabetes status was examined using multinomial logistic regression. The association between DASH and HOMA-IR was assessed using linear regression, and we tested whether the association was modified by Hispanic/Latino heritage or diabetes status.

Results

DASH score was highest in those with self-reported diabetes (controlled) and no medications (44.8%). A higher DASH score was associated with a lower HOMA-IR, and the association was the same regardless of diabetes status (p>0.8 for the interaction).

Conclusions

The association between DASH and diabetes status was strongest for those with controlled self-reported diabetes and who were not taking antihyperglycemic medications. A higher DASH score was associated with less insulin resistance among Hispanics/Latinos. Differences in DASH scores by Hispanic/Latino heritage did not explain the differences in prevalence of diabetes and insulin resistance reported in the diverse Hispanic/Latino population.

Clinical trial number

NCT02060344
Standardized screening for periodontitis as an integral part of multidisciplinary management of adults with type 2 diabetes: an observational cross-sectional study of cohorts in the USA and UK
Authors: Pumerantz Andrew S , Bissett Susan M , Dong Fanglong , Ochoa Cesar , Wassall Rebecca R , Davila Heidi , Barbee Melanie , Nguyen John , Vila Pamela , Preshaw Philip M
Published: July 2017

Objective

To determine prevalence and factors predictive of periodontitis by using a standardized assessment model in adults with type 2 diabetes.

Research design and methods

We performed an observational cross-sectional study to determine the burden of periodontitis in adults with type 2 diabetes attending urban, ambulatory referral centers in the USA and UK. Full-mouth probing was performed and periodontitis was diagnosed based on either a low (≥5 mm at ≥1 site) or high pocket probing-depth threshold (≥6 mm at ≥1 site). Results were stratified into a five-stage schema and integrated with other clinical variables into the novel Diabetes Cross-Disciplinary Index to function as a balanced health scorecard. Corresponding demographic and routinely collected health data were obtained and comparisons were made between patients with and without periodontitis. Multivariable logistic regression was performed to identify factors predictive of the presence or absence of periodontitis.

Results

Between our two cohorts, 253 patients were screened. Caucasians comprised >90% and Hispanic Americans >75% of the UK and US cohorts, respectively. Males and females were equally distributed; mean age was 53.6±11 years; and 17 (6.7%) were edentulous. Of the 236 dentate patients, 128 (54.2%) had periodontitis by low threshold and 57 (24.2%) by high threshold. Just 17 (7.2%) were periodontally healthy. No significant differences in age, HbA1c, blood pressure, body mass index, low-density lipoprotein cholesterol, or smoking status (all p>0.05) were identified between those with or without periodontitis (regardless of threshold) and none was found to be a significant predictor of disease.

Conclusions

Periodontitis is frequent in adults with type 2 diabetes and all should be screened. Periodontal health status can be visualized with other comorbidities and complications using a novel balanced scorecard that could facilitate patient–clinician communication, shared decision-making, and prioritization of individual healthcare needs.
Glucose-lowering effect of whey protein depends upon clinical characteristics of patients with type 2 diabetes
Authors: Almario Rogelio U , Buchan Wendy M , Rocke David M , Karakas Sidika E
Published: July 2017

Objective

Whey protein (WP) intake has been shown to reduce postprandial glycemia. Majority of WP research in type 2 diabetes (T2DM) involved acute challenge or weight loss studies. It is not known if WP supplementation can provide sustained glucose lowering. Our goal was to investigate the effects of WP on glycemia comprehensively by using continuous glucose monitoring (CGM) while avoiding the confounding effects of variable food intake through controlled feeding.

Research design and methods

This double-blinded and placebo (PL)-controlled study included 22 patients with T2DM patients (11 male, 11 female; age 57.1±12.6 years) on diet or metformin monotherapy. First, one serving (21 g) of WP was compared with PL in parallel-armed acute challenge studies. Next, in a crossover design, each patient underwent CGM twice, over 2 consecutive weeks, 3.5 days each week. Identical diets were provided by the study during both CGM periods. During the first CGM, one serving of either WP or PL was consumed before breakfast and another before dinner. During the second CGM, participants switched to the alternate supplement. Order of the supplements was randomized.

Results

During acute challenge studies, WP stimulated insulin and glucagon-like peptide (GLP)-1 secretion; suppressed ghrelin (all p<0.05), while PL had no effect. During CGM, glucose response to WP varied depending on the baseline characteristics of the patients. When evaluated using linear regression, the most predictive baseline variables were body mass index (BMI) (p=0.0006), triglycerides (p=8.3×10−5) and GLP-1 (p=0.006). Lower BMI, triglyceride and GLP-1 predicted decreased glucose levels on WP. Obesity, hypertriglyceridemia and high fasting GLP-1 concentrations predicted increased glucose levels.

Conclusions

Effects of WP supplementation on glycemia in T2DM depend on the baseline characteristics. Lower body weight, normal triglyceride and lower GLP-1 levels predict glucose lowering. In contrast, obesity, hypertriglyceridemia and high baseline GLP-1 predict increased glucose response.
Patients’ experiences of person-centred integrated heart failure care and palliative care at home: an interview study
Authors: Talabani Naghada , Ängerud Karin Hellström , Boman Kurt , Brännström Margareta
Published: July 2017

Objectives

Patients with severe heart failure (HF) suffer from a high symptom burden and high mortality. European and Swedish guidelines for HF care recommend palliative care for these patients. Different models for integrated palliative care and HF care have been described in the literature. No studies were found that qualitatively evaluated these models. The purpose of this study is to describe patients' experiences of a new model of person-centred integrated HF and palliative care at home.

Method

Interviews were conducted with 12 patients with severe HF (New York Heart Association class IIIâ€“IV) and included in the research project of Palliative advanced home caRE and heart FailurE caRe (PREFER). Qualitative content analysis was used for data analysis.

Results

Two themes and a total of five categories were identified. The first theme wasfeeling secure and safe through receiving care at homewith the categories:having access to readily available care at home, being followed up continuouslyandhaving trust in the team members' ability to help. The second theme wasbeing acknowledged as both a person and a patient, with the following two categories:being met as a person, participating in decisions about one’s careandreceiving help for symptoms of both HF and comorbidities.

Conclusions

Person-centred integrated HF and palliative care provides a secure environment and holistic care for patients with severe HF. This approach is a way to improve the care management in this population.

Trial registration number

NCT01304381; Results.