bluuebunny/crossref_metadata_2025 huggingface dataset:
Predicting future learning from baseline network architecture
Authors: Mattar Marcelo G. , Wymbs Nicholas F. , Bock Andrew S. , Aguirre Geoffrey K. , Grafton Scott T. , Bassett Danielle S.
Published: June 2016

Human behavior and cognition result from a complex pattern of interactions between brain regions. The flexible reconfiguration of these patterns enables behavioral adaptation, such as the acquisition of a new motor skill. Yet, the degree to which these reconfigurations depend on the brain’s baseline sensorimotor integration is far from understood. Here, we asked whether spontaneous fluctuations in sensorimotor networks at baseline were predictive of individual differences in future learning. We analyzed functional MRI data from 19 participants prior to six weeks of training on a new motor skill. We found that visual-motor connectivity was inversely related to learning rate: sensorimotor autonomy at baseline corresponded to faster learning in the future. Using three additional scans, we found that visual-motor connectivity at baseline is a relatively stable individual trait. These results suggest that individual differences in motor skill learning can be predicted from sensorimotor autonomy at baseline prior to task execution.

Highlights

Sensorimotor autonomy at rest predicts faster motor learning in the future.

Connection between calcarine and superior precentral sulci form strongest predictor.

Sensorimotor autonomy is a relatively stable individual trait.
Phased Diploid Genome Assembly with Single Molecule Real-Time Sequencing
Authors: Chin Chen-Shan , Peluso Paul , Sedlazeck Fritz J. , Nattestad Maria , Concepcion Gregory T. , Clum Alicia , Dunn Christopher , O'Malley Ronan , Figueroa-Balderas Rosa , Morales-Cruz Abraham , Cramer Grant R. , Delledonne Massimo , Luo Chongyuan , Ecker Joseph R. , Cantu Dario , Rank David R. , Schatz Michael C.
Published: June 2016

While genome assembly projects have been successful in a number of haploid or inbred species, one of the current main challenges is assembling non-inbred or rearranged heterozygous genomes. To address this critical need, we introduce the open-source FALCON and FALCON-Unzip algorithms (https://github.com/PacificBiosciences/FALCON/) to assemble Single Molecule Real-Time (SMRT®) Sequencing data into highly accurate, contiguous, and correctly phased diploid genomes. We demonstrate the quality of this approach by assembling new reference sequences for three heterozygous samples, including an F1 hybrid of the model speciesArabidopsis thaliana, the widely cultivatedV. viniferacv. Cabernet Sauvignon, and the coral fungusClavicorona pyxidatathat have challenged short-read assembly approaches. The FALCON-based assemblies were substantially more contiguous and complete than alternate short or long-read approaches. The phased diploid assembly enabled the study of haplotype structures and heterozygosities between the homologous chromosomes, including identifying widespread heterozygous structural variations within the coding sequences.
First evidence of a menstruating rodent: the spiny mouse (Acomys cahirinus)
Authors: Bellofiore N. , Ellery S. , Mamrot J. , Walker D. , Temple-Smith P. , Dickinson H.
Published: June 2016

Background

Advances in research relating to menstruation and associated disorders (such as endometriosis and pre-menstrual syndrome) have been hindered by the lack of an appropriate animal model. Thus, many aspects of this phenomenon remain poorly understood limiting the development of efficacious treatment for women. Menstruating species account for only 1.5% of mammals, and less than 0.09% of these are non-primates. Menstruation occurs as a consequence of progesterone priming of the endometrial stroma and a spontaneous decidual reaction. At the end of each infertile cycle as progesterone levels decline the uterus is unable to maintain this terminally differentiated stroma and the superficial endometrium is shed. True menstruation has never been reported in rodents.

Objective

Here we describe the first observation of menstruation in a rodent, the spiny mouse (Acomys cahirinus).

Study Design

Virgin female spiny mice (n=14) aged 12-16 weeks were sampled through daily vaginal lavage for 2 complete reproductive cycles in our in-house colony at Monash Medical Centre, Clayton, Australia. Stage-specific collection of reproductive tissue and plasma was used for histology, prolactin immunohistochemistry, and ELISA assay of progesterone (n=5 / stage of the menstrual cycle). Normally distributed data are reported as the mean ± standard error and significant differences calculated using a one-way ANOVA. Non-normal data are displayed as the median values of replicates (with interquartile range) and significant differences calculated using Kruskal-Wallis test.

Results

Mean cycle length was 8.7 ± 0.4 days with red blood cells observed in the lavages over 3.0 ± 0.2 days. Cyclic endometrial shedding and blood in the vaginal canal concluding with each infertile cycle was confirmed in all virgin females. The endometrium was thickest during the luteal phase, when plasma progesterone peaked at ~102.1 ng/mL and the optical density for prolactin immunoreactivity was strongest. The spiny mouse undergoes spontaneous decidualisation, demonstrating for the first time menstruation in a rodent.

Conclusion

The spiny mouse is the first rodent species known to menstruate and provides an unprecedented natural non-primate model to study the mechanisms of menstrual shedding and repair, and may be useful in furthering our understanding of human specific menstrual and pregnancy associated diseases.
High habitat-specificity in fungal communities of an oligo-mesotrophic, temperate lake
Authors: Wurzbacher Christian , Warthmann Norman , Bourne Elizabeth , Attermeyer Katrin , Allgaier Martin , Powell Jeff R. , Detering Harald , Mbedi Susan , Grossart Hans-Peter , Monaghan Michael T.
Published: June 2016

Freshwater fungi are a poorly studied paraphyletic group that include a high diversity of phyla. Most studies of aquatic fungal diversity have focussed on single habitats, thus the linkage between habitat heterogeneity and fungal diversity remains largely unexplored. We took 216 samples from 54 locations representing eight different habitats in meso-oligotrophic, temperate Lake Stechlin in northern Germany, including the pelagic and littoral water column, sediments, and biotic substrates. We pyrosequenced with an universal eukaryotic marker within the ribosomal large subunit (LSU) in order to compare fungal diversity, community structure, and species turnover among habitats. Our analysis recovered 1024 fungal OTUs (97% criterion). Diversity was highest in the sediment, biofilms, and benthic samples (293-428 OTUs), intermediate in water and reed samples (36-64 OTUs), and lowest in plankton (8 OTUs) samples. NMDS clustering clearly grouped the eight studied habitats into six clusters, indicating that total diversity was strongly influenced by turnover among habitats. Fungal communities exhibited pronounced changes at the levels of phylum and order along a gradient from littoral to pelagic habitats. The large majority of OTUs could not be classified below the order level due to the lack of aquatic fungal entries in taxonomic databases. Our study provides a first estimate of lake-wide fungal diversity and highlights the important contribution of habitat-specificity to total fungal diversity. This remarkable diversity is probably an underestimate, because most lakes undergo seasonal changes and previous studies have uncovered differences in fungal communities among lakes.
Controlling Noise in the Timing of Intracellular Events: A First-Passage Time Approach
Authors: Ghusinga Khem Raj , Dennehy John J. , Singh Abhyudai
Published: June 2016

In the noisy cellular environment, gene products are subject to inherent random fluctuations in copy numbers over time. How cells ensure precision in the timing of key intracellular events, in spite of such stochasticity is an intriguing fundamental problem. We formulate event timing as a first-passage time problem, where an event is triggered when the level of a protein crosses a critical threshold for the first time. Novel analytical calculations are preformed for the first-passage time distribution in stochastic models of gene expression, including models with feedback regulation. Derivation of these formulas motivates an interesting question: is there an optimal feedback strategy to regulate the synthesis of a protein to ensure that an event will occur at a precise time, while minimizing deviations or noise about the mean. Counter-intuitively, results show that for a stable long-lived protein, the optimal strategy is to express the protein at a constant rate without any feedback regulation, and any form of feedback (positive, negative or any combination of them) will always amplify noise in event timing. In contrast, a positive feedback mechanism provides the highest precision in timing for an unstable protein. These theoretical results explain recent experimental observations of single-cell lysis times in bacteriophageλ. Here, lysis of an infected bacterial cell is orchestrated by the expression and accumulation of a stableλprotein up to a threshold, and precision in timing is achieved via feedforward, rather than feedback control. Our results have broad implications for diverse cellular processes that rely on precise temporal triggering of events.
Acoustic-based model estimation of snapping shrimp populations and the effects of a sponge die-off
Authors: Butler Jack , Butler Mark J , Gaff Holly
Published: June 2016

Human use of the ocean and its ecosystems continues to degrade coastal habitats around the world. Assessing anthropogenic impacts on these environments can be cost and manpower intensive; thus, developing rapid, remote techniques to assess habitat quality has become increasingly important. We employed autonomous hydrophone receivers to record the soundscapes of healthy hard-bottom habitat in Florida Bay, Florida (USA) and hard-bottom areas impacted by sponge die-offs. We also recorded sounds emanating from individual sponges of three species that were isolated in underwater sound booths, and then enumerated the invertebrates (mostly snapping shrimp) dwelling within the canals of each sponge. From these recordings, a modified cylindrical sound propagation model was used to estimate distances to snapping shrimp snaps. Using the programDistance, which applies distance sampling theory to cue count surveys, we estimated snapping shrimp population density and abundance within both habitat types. More snapping shrimp snaps per unit time were recorded in healthy hard-bottom areas as compared to degraded hard-bottom areas. In addition, the average distance to a snap source was greater within degraded hard-bottom areas than within healthy hard-bottom areas. As a consequence, the estimated density and abundance of snapping shrimp were one to two orders of magnitude greater within healthy habitat than within degraded habitat. This study demonstrates the feasibility of using acoustic sampling and modeling to rapidly assess populations of soniferous benthic indicator species, whose vocalizations may yield indirect estimates of habitat quality.
Female-female aggression in a sexual/unisexual species complex over resources
Authors: Makowicz Amber , Moore Tana , Schlupp Ingo
Published: June 2016

Kin selection theory predicts that closely related individuals should be more altruistic and less antagonistic towards one another. In addition, it would predict that the higher the relatedness value (R) between individuals, such as in clonal organisms, the more likely kin selection is to evolve. One benefit of kin selection is a reduction in aggression towards kininvarious social contexts, such as foraging. In the gynogenetic Amazon molly,Poecilia formosa,females have been shown to differentiate between clone types, preferring to associate with clonal sisters to non-sisters, and regulate their aggressive behaviors accordingly. We ask ifAmazon mollies in resource-limited environments: 1) still maintain the ability to regulate aggressive behaviors according to relatedness (heterospecific females, clonal sisters or non-sisters), and 2) how their aggressivebehaviors change relative to a female’s social partner? Using a repeated-measures design, we found that focal females regulated their aggressive behaviors depending on partner type (i.e., a heterospecific female, clonal sister, or non-sister). Heterospecific females and the non-sister clones spent more time behaving aggressively towards the focal females, and these females also received significantly more bites from heterospecific females. Interestingly, the clonal sisters, when compared to the other two female types, performed significantly more tail beats towards focal females.We are able to confirm that females do show more aggression towards heterospecific females and non-sister clones in a food-limited environment, andthat their aggression scales with relatedness (R).

Lay Summary

Kin recognition allows individuals to adjust costly behaviors, such as aggression, according to the degree of genetic relatedness. We show that in a food-limited environment, a clonal species of fish, the Amazon molly, females regulate aggressive behaviors depending on how closely related they are to the recipient female, behaving more aggressively to both heterospecific females and non-sister clones. The ability to regulate costly behaviors under variable socialconditions is advantageous, especially when resources are limited.
Within-patient mutation frequencies reveal fitness costs of CpG dinucleotides and drastic amino acid changes in HIV
Authors: Theys Kristof , Feder Alison F. , Gelbart Maoz , Hartl Marion , Stern Adi , Pennings Pleuni S.
Published: June 2016

HIV has a high mutation rate, which contributes to its ability to evolve quickly. However, we know little about the fitness costs of individual HIV mutationsin vivo, their distribution and the different factors shaping the viral fitness landscape. We calculated the mean frequency of transition mutations at 870 sites of thepolgene in 160 patients, allowing us to determine the cost of these mutations. As expected, we found high costs for non-synonymous and nonsense mutations as compared to synonymous mutations. In addition, we found that non-synonymous mutations that lead to drastic amino acid changes are twice as costly as those that do not and mutations that create new CpG dinucleotides are also twice as costly as those that do not. We also found that G→A and C→T mutations are more costly than A→G mutations. We anticipate that our newin vivofrequency-based approach will provide insights into the fitness landscape and evolvability of not only HIV, but a variety of microbes.

Author summary

HIV’s high mutation rate allows it to evolve quickly. However, most mutations probably reduce the virus’ ability to replicate – they are costly to the virus. Until now, the actual cost of mutations is not well understood. We used within-patient mutation frequencies to estimate the cost of 870 HIV mutationsin vivo. As expected, we found high costs for non-synonymous and nonsense mutations. In addition, we found surprisingly high costs for mutations that lead to drastic amino acid changes, mutations that create new CpG sites (possibly because they trigger the host’s immune system), and G→A and C→T mutations. Our results demonstrate the power of analyzing mutant frequencies fromin vivoviral populations to study costs of mutations. A better understanding of fitness costs will help to predict the evolution of HIV.
The PAS domain-containing protein HeuR regulates heme uptake inCampylobacter jejuni
Authors: Johnson Jeremiah G. , Gaddy Jennifer A. , DiRita Victor J.
Published: June 2016

Campylobacter jejuniis a leading cause of bacterial-derived gastroenteritis. A previous mutant screen demonstrated that the heme uptake system (Chu) is required for full colonization of the chicken gastrointestinal tract. Subsequent work found identified a PAS domain-containing regulator, termed HeuR, as required for chicken colonization. Here we confirmthat both the heme uptake system and HeuR are required for full chicken gastrointestinal tract colonization, with theheuRmutant being particularlyaffected during competition with wild-typeC. jejuni.Transcriptomic analysis identified the chu genes-and those encoding other iron uptake systems-as likely regulatory targets of HeuR. Purified HeuR specifically bound thechuZApromoter region in electrophoretic mobility shift assays. Consistentwith a role forHeuR inchuexpression,heuRmutants wereunable to efficiently use heme asa source of iron in iron-limitingconditions and, mutants exhibited decreased levels of cell-associated ironby massspectrometry.Finally, we demonstrate that a heuR mutant ofC. jejuniisresistant to hydrogen peroxide, and that this resistance correlates to elevated levels ofcatalase activity.

Author Summary

Campylobacter jejunicauses millions of gastrointestinal infection every year. This is primarily due to the its ability to reside in the gastrointestinal tract of chickens.C.jejunicontaminates chicken meat during harvesting and processing. Following consumption of undercooked chicken or uncooked food that was contaminated with raw chicken juice, humans develop a debilitating illness that is characterized by diarrhea and abdominal cramps. As chickens are the source of most human infections, there is a need to understand howC. jejunicolonizes chickens so we can develop ways to reduce its presence in chickens and thereby improve food safety. Most organisms require iron to thrive and that some bacteria steal iron from host molecules, including hemoglobin. Here we demonstrate thatC. jejunimay need to get iron from hemoglobin in order to colonize the chicken and that aregulatory protein, HeuR, controls the ability ofthe bacteria to do this. If we can understand how this protein works, we may be able to develop ways to inhibit its function and reduce the ability ofC. jejunito get iron during chicken colonization. This would limit theamount ofC. jejuniin the chicken and make food safer.
Neurospora chromosomes are organized by blocks of importin alpha-dependent heterochromatin that are largely independent of H3K9me3
Authors: Galazka Jonathan M. , Klocko Andrew D. , Uesaka Miki , Honda Shinji , Selker Eric U. , Freitag Michael
Published: June 2016

Eukaryotic genomes are organized into chromatin domains with three-dimensional arrangements that presumably result from interactions between the chromatin constituents—proteins, DNA, and RNA—within the physical constraints of the nucleus. We used chromosome conformation capture (3C) followed by high-throughput sequencing (Hi-C) with wild-type and mutant strains of Neurospora crassa to gain insight into the role of heterochromatin in the organization and function of the genome. We tested the role of three proteins thought to be important for establishment of heterochromatin, namely, the histone H3 lysine 9 methyltransferase DIM-5, Heterochromatin Protein 1 (HP1), which specifically binds to the product of DIM-5 (trimethylated H3 lysine 9 [H3K9me3]), and DIM-3 (importin alpha), which is involved in DIM-5 localization. The average genome configuration of the wild-type strain revealed strong intra- and inter-chromosomal associations between both constitutive and facultative heterochromatic domains, with the strongest interactions among the centromeres, subtelomeres, and interspersed heterochromatin. Surprisingly, loss of either H3K9me3 or HP1 had only mild effects on heterochromatin compaction, whereas dim-3 caused more drastic changes, specifically decreasing interactions between constitutive heterochromatic domains. Thus, associations between heterochromatic regions are a major component of the chromosome conformation in Neurospora, but two widely studied key heterochromatin proteins are not necessary, implying that undefined protein factors play key roles in maintaining overall chromosome organization.
A rare variant in CYP27A1 and its association with atopic dermatitis with high serum total IgE
Authors: Suzuki H. , Makino Y. , Nagata M. , Furuta J. , Enomoto H. , Hirota T. , Tamari M. , Noguchi E.
Published: June 2016

This study investigated rare variants associated with atopic dermatitis. We performed exome analyses on 37 patients who were diagnosed with atopic dermatitis by board‐certified dermatologists and had total serum IgE levels greater than 1000 IU/ml. The exome analysis identified seven variants with <1% allele frequency in Asian (ASN) population of 1000 Genomes Project phase 1 data and >5% allele frequency in the atopic dermatitis exome samples. We then conducted a replication study using 469 atopic dermatitis patients with total serum IgE ≥1000 IU/ml and 935 Japanese controls to assess the presence of these 7 candidate variants. The replication study confirmed that CYP27A1 rs199691576 (A/G) was associated with atopic dermatitis with high serum IgE levels (P = 0.012, odds ratio = 2.1). CYP27A1 is involved in the metabolism of vitamin D3, which plays important roles in modulating immune function. Previous studies have reported polymorphisms in vitamin D pathway genes that are associated with allergy‐related phenotypes. Our data confirm the importance of genes regulating the vitamin D pathway in the development of atopic dermatitis.
Beneficial effect of Lactococcus lactis NCC 2287 in a murine model of eosinophilic esophagitis
Authors: Holvoet S. , Doucet‐Ladevèze R. , Perrot M. , Barretto C. , Nutten S. , Blanchard C.
Published: June 2016

Background

Eosinophilic esophagitis (EoE) is a severe inflammatory disease of the esophagus which is characterized histologically by an eosinophilic infiltration into the esophageal tissue. The efficacy of probiotics in the context of atopic diseases has been well investigated but, to date, there has been no study which has evaluated probiotic effects on EoE inflammation. This study sought to identify a probiotic which improves esophageal inflammation in experimental EoE.

Methods

Two candidate probiotics, Lactococcus lactis NCC 2287 and Bifidobacterium lactis NCC 2818, were tested in a murine model of EoE elicited by epicutaneous sensitization with Aspergillus fumigatus protein extract. Administration of bacterial strains in drinking water was used, respectively, as a preventive or treatment measure, or continuously throughout the study. Inflammatory parameters were assessed in the esophagus, skin, and lungs after allergen challenge.

Results

In this EoE model, supplementation with L. lactis NCC 2287 significantly decreased esophageal and bronchoalveolar eosinophilia but only when given as a therapeutic treatment. No significant effect on eosinophilia was observed when NCC 2287 was given as a preventive or a continuous intervention. NCC 2287 supplementation had no significant effect on immunoglobulin levels, skin symptom scores, or on transepidermal water loss. Supplementation with another probiotic, B. lactis NCC 2818, had no significant effect on esophageal eosinophilia.

Conclusion

We identified a L. lactis strain, able to attenuate esophageal eosinophilic inflammation in a preclinical model of EoE. This effect is strain specific and depends on the timing and duration of bacterial supplementation. Confirmation of these observations in human clinical trials is warranted.
Is phytoestrogen intake associated with decreased risk of prostate cancer? A systematic review of epidemiological studies based on 17,546 cases
Authors: Zhang M. , Wang K. , Chen L. , Yin B. , Song Y.
Published: June 2016

This study uses current epidemiological data to evaluate whether phytoestrogen intake is associated with a reduced risk of prostate cancer. We performed a random‐effect meta‐analysis of published data retrieved from PubMed, Web of Science, ProQuest, and CNKI, which was supplemented by a manual search of relevant references. Study quality was assessed using the Newcastle–Ottawa Scale (NOS). Subgroup analysis and meta‐regression were performed to explore the source of heterogeneity. Sensitivity analysis was evaluated to assess the stability of the results. Egger's test and funnel plots were used to detect the existence of publication bias. We retrieved 507 papers, and 29 studies were ultimately confirmed as eligible. The meta‐analysis showed that phytoestrogen intake was significantly associated with a reduced risk of prostate cancer, with an odds ratio (OR) of 0.77 (95% CI 0.66–0.88; I2 = 77.6%). The food/nutritional sources that were significantly associated with a reduced risk of prostate cancer included soy and soy products, tofu, legumes, daidzein, and genistein. Subgroup analysis indicated that the associations were significant among Asians and Caucasians, but not among Africans. Meta‐regression revealed that the pooled OR increased with the number of cases in the studies. The results might be affected by publication bias based on the Eggers’ test (p = 0.011) and the asymmetry of the funnel plot. Phytoestrogen intake may reduce the risk of prostate cancer in Asians and Caucasians. Regular intake of food that is rich in phytoestrogens, such as soy/soy products or legumes, should be recommended.
Important prognostic significance of lymph node density in patients with node positive oral tongue cancer
Authors: Lieng Hester , Gebski Val J. , Morgan Gary J. , Veness Michael J.
Published: June 2016

Background

Lymph node density (LND) has been described as a prognostic factor for survival in patients with head and neck squamous cell carcinoma, particularly of the oral cavity. The aim of this study was to determine the prognostic significance of LND in patients with node positive oral tongue squamous cell carcinoma (OTSCC).

Methods

Patients with pathological node positive OTSCC were identified in a retrospective review of prospectively collected data. The optimal cut‐point for LND was determined using the minimum P‐value method and the log‐rank test. The impact of this LND cut‐point on time to disease progression and overall survival was determined.

Results

In 72 patients with OTSCC, an LND of 14.3% was found to have the greatest separation using the log‐rank test (P < 0.001). LND ≤14.3% was predicted for longer time to disease progression with a median time of 73 months compared to 9.4 months in patients with an LND >14.3% (hazard ratio: 3.43; 95% confidence interval: 1.76–6.70; P < 0.001). LND was also a significant predictor of overall survival with a median overall survival with LND ≤14.3% of 82.3 months, compared with 14.7 months in patients with an LND >14.3% (hazard ratio: 3.28; 95% confidence interval: 1.61–6.68; P = 0.001). Patients with an LND >14.3% experienced a higher rate of regional recurrence.

Conclusion

Our findings confirm the prognostic significance of LND in patients with node positive OTSCC, with a similar LND cut‐point value to other published series. Improving regional control in these high‐risk patients may improve outcome.
Geographical variation in the management of urolithiasis in Australia
Authors: Tran Minh A. , Chak‐Lee Ming , Bariol Simon V.
Published: June 2016

Background

To examine any geographical variation in the management of urolithiasis amongst the Australian states and territories.

Methods

Retrospective study with data obtained from the Medicare Australia database, the Royal Australasian College of Surgeons and the Urological Society of Australia and New Zealand.

Results

Minimally invasive stone treatment with shock wave lithotripsy (SWL) and ureteroscopy (URS) accounted for the majority of stone treatments in Australia (98%). Variation of stone treatment modalities exists amongst the Australian states and territories with an inverse relationship between the use of SWL and URS. We compared Western Australia (WA) and Queensland (QLD) which have a comparable geographical area. SWL accounts for 1% and 22% of stone treatments in WA and QLD, respectively. In WA, urologists are concentrated in two cities with no SWL available in the private sector. In QLD, urologists are distributed in 11 cities with SWL available in both the public and private sector. The three largest states or territories by geographical area – the Northern Territory, WA and QLD – have stone treatment rates of 1:1337, 1:1110 and 1:2432 per capita of privately insured patients, respectively. In comparison, smaller Australian states/territories such as Tasmania and Victoria have stone treatment rates of 1:619 and 1:765 per capita of privately insured patients, respectively.

Conclusion

The distribution of urologists and treatment modalities available in each state or territory appear to play a contributory role in choice of treatment modality. In addition, inequality to stone treatment access exists in geographically large Australian states/territories.
Haemodiafiltration at increased plasma ionic strength for improved protein‐bound toxin removal
Authors: Krieter D. H. , Devine E. , Körner T. , Rüth M. , Wanner C. , Raine M. , Jankowski J. , Lemke H.‐D.
Published: June 2016

Aim

Protein‐bound uraemic toxin accumulation causes uraemia‐associated cardiovascular morbidity. Enhancing the plasma ionic strength releases toxins from protein binding and makes them available for removal during dialysis. This concept was implemented through high sodium concentrations ([Na+]) in the substituate of pre‐dilution haemodiafiltration at increased plasma ionic strength (HDF‐IPIS).

Methods

Ex vivo HDF‐IPIS with blood tested increasing [Na+] to demonstrate efficacy and haemocompatibility. Haemocompatibility was further assessed in sheep using two different HDF‐IPIS set‐ups and [Na+] between 350 and 600 mmol L−1. Safety and efficacy of para‐cresyl sulphate (pCS) and indoxyl sulphate (IS) removal was further investigated in a randomized clinical pilot trial comparing HDF‐IPIS to HD and HDF.

Results

Compared to [Na+] of 150 mmol L−1, ex vivo HDF‐IPIS at 500 mmol L−1 demonstrated up to 50% higher IS removal. Haemolysis in sheep was low even at [Na+] of 600 mmol L−1 (free Hb 0.016 ± 0.001 g dL−1). In patients, compared to HD, a [Na+] of 240 mmol L−1 in HDF‐IPIS resulted in 40% greater reduction (48.7 ± 23.6 vs. 67.8 ± 7.9%; P = 0.013) in free IS. Compared to HD and HDF (23.0 ± 14.8 and 25.4 ± 10.5 mL min−1), the dialytic clearance of free IS was 31.6 ± 12.8 mL min−1 (P = 0.017) in HDF‐IPIS, but [Na+] in arterial blood increased from 132 ± 2 to 136 ± 3 mmol L−1 (0 vs. 240 min; P < 0.001).

Conclusion

HDF‐IPIS is technically and clinically feasible. More effective HDF‐IPIS requires higher temporary plasma [Na+], but dialysate [Na+] has to be appropriately adapted to avoid sodium accumulation.
Initiation of strong prescription opioids in Australia: cohort characteristics and factors associated with the type of opioid initiated
Authors: Gisev Natasa , Pearson Sallie‐Anne , Blanch Bianca , Larance Briony , Dobbins Timothy , Larney Sarah , Degenhardt Louisa
Published: June 2016

Aims

To describe the characteristics of Australians initiating strong opioids and examine the factors associated with the type of opioid initiated.

Methods

Pharmaceutical Benefits Scheme dispensing records were extracted for a 10% sample of people who initiated a strong opioid treatment episode (buprenorphine, fentanyl, hydromorphone, morphine, oxycodone) between 29 September 2009 and 31 December 2013, as evidenced by the absence of a strong opioid dispensing for at least 90 days. The cohort was restricted to people with complete medicines ascertainment. Socio‐demographic characteristics, previous dispensing histories and index opioid use were examined. Multinomial logistic regression was used to calculate adjusted relative risk ratios (aRRRs) and 95% confidence intervals (CIs) to determine the factors associated with the type of opioid medicine initiated, relative to oxycodone.

Results

The cohort consisted of 125 335 people: 58.3% were female and 63.7% were aged ≥65 years. The most commonly initiated strong opioid was oxycodone (72.8%), usually 5 mg immediate‐release tablets (76.1%). Compared to people aged 18–44 years, those ≥85 years were 14.18 times as likely (95% CI 12.67–15.87) to initiate morphine than oxycodone. Compared to people without a cancer treatment history, those with a cancer treatment history were 2.34 times as likely (95% CI 2.11–2.60) to initiate morphine than oxycodone.

Conclusions

The most commonly initiated strong opioid was oxycodone, usually at lower strengths. Those who initiated oxycodone were more likely to be younger with no previous cancer treatment history. As these are high‐risk characteristics for potential harms, a judicious approach when initiating strong opioids for this group is necessary.
Determinants of hepatotoxicity after repeated supratherapeutic paracetamol ingestion: systematic review of reported cases
Authors: Acheampong Paul , Thomas Simon H. L.
Published: June 2016

Aims

To evaluate the role of reported daily dose, age and other risk factors, and to assess the value of quantifying serum transaminase activity and paracetamol (acetaminophen) concentration at initial assessment for identifying patients at risk of hepatotoxicity following repeated supratherapeutic paracetamol ingestion (RSPI).

Methods

Systematic literature review with collation and analysis of individual‐level data from reported cases of RSPI associated with liver damage.

Results

In 199 cases meeting the selection criteria, severe liver damage (ALT/AST ≥1000 IU l−1, liver failure or death) was reported in 186 (93%) cases including 77/78 (99%) children aged ≤6 years. Liver failure occurred in 127 (64%) cases; of these 49 (39%) died. Maximum ingested daily paracetamol doses were above UK recommendations in 143 (72%) patients. US–Australasian thresholds for repeated supratherapeutic ingestions requiring intervention were not met in 71 (36%) cases; of these 35 (49%) developed liver failure and 10 (14%) died. No cases developing liver damage had paracetamol concentration < 20 mg l−1 and a normal ALT/AST on initial presentation or when RSPI was first suspected, but both of these values were only available for 79 (40%) cases.

Conclusions

Severe liver damage is reported after RSPI in adults and children, sometimes involving reported doses below current thresholds for intervention. Paracetamol concentrations <20 mg l−1 with normal serum ALT/AST activity on initial assessment suggests a low risk of subsequent liver damage. These findings are, however, limited by low patient numbers, publication bias and the accuracy of the histories in reported cases.
Adrenal insufficiency in patients on long‐term opioid analgesia
Authors: Gibb Fraser W. , Stewart Alexandra , Walker Brian R. , Strachan Mark W. J.
Published: June 2016

Objective

Opioid analgesia has been implicated as a cause of secondary adrenal insufficiency, but little is known of the prevalence of this potentially serious adverse effect in patients with chronic pain.

Design

Cross‐sectional study of chronic pain patients on long‐term opioid analgesia.

Patients

Patients attending tertiary chronic pain clinics at the Western General Hospital, Edinburgh, treated with long‐term opioid analgesia (n = 48) with no recent exposure to exogenous glucocorticoids.

Results

Four patients (8·3%) had basal morning plasma cortisol concentrations below 100 nmol/l, of whom three failed to achieve a satisfactory cortisol response to exogenous ACTH1‐24 stimulation (peak cortisol >430 nmol/l). Basal cortisol was positively associated with age (R = 0·398, P = 0·005) and negatively associated with BMI (R = −0·435, P = 0·002).

Conclusions

Suppression of the hypothalamic−pituitary−adrenal axis is present in a clinically significant proportion of chronic pain patients treated with opioid analgesia. Studies of larger populations should be conducted to better define the prevalence and potential clinical consequences of adrenal insufficiency in this context.
Early pregnancy thyroid hormone reference ranges in Chilean women: the influence of body mass index
Authors: Mosso Lorena , Martínez Alejandra , Rojas María Paulina , Latorre Gonzalo , Margozzini Paula , Lyng Trinidad , Carvajal Jorge , Campusano Claudia , Arteaga Eugenio , Boucai Laura
Published: June 2016

Objective

Thyroid dysfunction and obesity during pregnancy have been associated with negative neonatal and obstetric outcomes. Thyroid hormone reference ranges have not been established for the pregnant Hispanic population. This study defines thyroid hormone reference ranges during early pregnancy in Chilean women and evaluates associations of body mass index (BMI) with thyroid function.

Design, patients, measurements

This is a prospective observational study of 720 healthy Chilean women attending their first prenatal consultation at an outpatient clinic. Thyroid function [TSH, Free T4, Total T4 and antithyroid peroxidase antibodies (TPOAb)] and BMI were assessed at 8·8 ± 2·4 weeks of gestational age.

Results

Median, 2·5th percentile (p2·5), and 97·5th percentile (p97·5) TSH values were higher, while median, p2·5, and p97·5 free T4 values were lower in obese patients compared with normal weight patients. Obesity was associated with a median TSH 16% higher (P = 0·035) and a median free T4 6·5% lower (P < 0·01) than values from patients with normal weight. BMI had a small, but statistically significant effect on TSH (P = 0·04) and free T4 (P < 0·01) when adjusted by maternal age, TPO antibodies, parity, sex of the newborn, gestational age and smoking. In all TPOAb (‐) patients, median (p2·5‐p.97·5) TSH was 1·96 mIU/l (0·11–5·96 mIU/l) and median (p2·5‐p.97·5) free T4 was 14·54 pmol/l (11·1 – 19·02 pmol/l). Applying these reference limits, we found a prevalence of overt and subclinical hypothyroidism of 0·9% and 3·05% respectively.

Conclusions

TSH distributes at higher values and free T4 at lower values in obese pregnant women compared to normal weight pregnant women. Thyroid hormone reference ranges derived from Chilean patients with negative TPOAb are different from the fixed internationally proposed reference ranges and may be used in the Hispanic population.
Efficacy of parent‐delivered behavioral therapy for primary complex motor stereotypies
Authors: Specht Matthew W , Mahone E Mark , Kline Tina , Waranch Richard , Brabson Laurel , Thompson Carol B , Singer Harvey S
Published: June 2016

Aim

Primary complex motor stereotypies (CMS) are persistent, patterned, repetitive, rhythmic movements in young people with typical development. This study evaluated the efficacy of an instructional DVD as a home‐based, parent‐administered, behavioral therapy for primary CMS.

Method

Eighty‐one children with primary CMS were enrolled. Primary outcome measures included the Stereotypy Severity Scale (SSS) – Motor and Impairment scores, and Stereotypy Linear Analog Scale (SLAS). Mean CMS onset was 13.4 months (SD 13.1). Eligibility required observed CMS. Psychiatric disorders were not exclusionary and a stable medication regimen was required. Intellectual disability, neurological disorder, autism spectrum disorder, and tics were exclusionary. Initial assessments were completed via REDCap before receipt of the DVD. Fifty‐four of the 81 children (34 male, 20 female; mean age 8y 2mo, SD 1.42, range 7–14y) completed assessments at 1, 2, or 3 months after receiving the DVD.

Results

Reductions (baseline to last assessment) in SSS Motor, SSS Impairment, and SLAS scores (all p<0.001) represented change ratios of −15%, −24%, and a −20% respectively. Greatest relative treatment benefit was observed by younger children (ages 7–8y), and by 1 month after receipt of DVD, while a parent global assessment scale showed progressive improvement throughout the study.

Interpretation

An instructional DVD for parent‐delivered behavioral therapy was a safe, effective intervention for primary CMS.
Remittances during crises
Authors: Koczan Zsoka
Published: June 2016

This paper begins by examining the characteristics and determinants of remittances sent from Germany to ex‐Yugoslavia, and then takes a first look at how they were affected by the war and later political and economic crises in the first half of the 1990s. The findings tentatively suggest that the propensity to send among ex‐Yugoslavs increased in the early 1990s, despite a breakdown in formal remittance channels and in contrast with the roughly stable and even decreasing propensity to send among Turkish guest workers.
Impact of rosiglitazone safety alerts on oral antidiabetic sales trends: a countrywide study in Portugal
Authors: Herdeiro Maria T. , Soares Sara , Silva Tânia , Roque Fátima , Figueiras Adolfo
Published: June 2016

Pharmacovigilance systems are important to monitor the safety of on‐market drugs after approval. The aim of this study was to assess the impact of rosiglitazone safety alerts on trends in the sale of rosiglitazone and other oral antidiabetic drugs. An ecological study was conducted, using temporally aggregated data and linking safety alerts to countrywide sales of all oral antidiabetic drugs in Portugal from January 2002 to December 2012. Sales figures for oral antidiabetic drugs marketed in Portugal were supplied by IMS Health Portugal with a breakdown by active substance and fixed combinations. The number of defined daily doses per 1000 inhabitants per day (DIDs) of each oral antidiabetic drug sold to the estimated diabetic population using oral antidiabetic drugs in Portugal was calculated. Particular attention was paid to the case of rosiglitazone, with the results being adjusted for changes in rosiglitazone reimbursement policies. A total of four safety alerts were issued about rosiglitazone. Rosiglitazone sales registered an increase of 32.9% (0.202 DIDs; P < 0.001) after the first alert (risk of macular oedema or worsening of pre‐existent macular oedema) in January 2006. After subsequent alerts about cardiovascular risks, this trend was not, however, repeated and sales fell. Following the January 2006 and January 2008 safety alerts, rosiglitazone sales described a long‐term downward trend, with decreases of 3.75% (−0023 DIDs; P > 0.05) and 0.24% (−0.001 DIDs; P > 0.05), respectively. It is important to promote the dissemination and publication of drug safety alerts.
Notch signalling in ventricular chamber development and cardiomyopathy
Authors: D'Amato Gaetano , Luxán Guillermo , de la Pompa José Luis
Published: June 2016

The vertebrate heart is the first organ to form and function during embryogenesis. Primitive streak‐derived cardiac progenitors located bilaterally move rostral to form the primitive heart tube that subsequently undergoes rightward looping, remodelling and septation to give rise to the mature four‐chambered heart. Tightly regulated tissue interactions orchestrate the patterning, proliferation and differentiation processes that give rise to the adult ventricles. Studies in animal models have demonstrated the crucial function of the Notch signalling pathway in ventricular development and how alterations in human NOTCH signalling may lead to disease in the form of cardiomyopathies, such as left ventricular noncompaction (LVNC). In this review, we discuss how during trabecular formation and ventricular compaction, Dll4–Notch1 signals from chamber endocardium to regulate cardiomyocyte proliferation and differentiation in a noncell autonomous fashion and how, at later stages, myocardial Jag1 and Jag2 activate Notch1 in chamber endocardium to sustain chamber patterning and compaction with simultaneous coronary vessel development mediated by Dll4–Notch1. We suggest that alterations in these molecular mechanisms underlie MIB1‐related familial LVNC and favour the hypothesis that this cardiomyopathy has a congenital nature.
RubisCO selection using the vigorously aerobic and metabolically versatile bacterium Ralstonia eutropha
Authors: Satagopan Sriram , Tabita F. Robert
Published: June 2016

Recapturing atmospheric CO2 is key to reducing global warming and increasing biological carbon availability. Ralstonia eutropha is a biotechnologically useful aerobic bacterium that uses the Calvin–Benson–Bassham (CBB) cycle and the enzyme ribulose 1,5‐bisphosphate carboxylase/oxygenase (RubisCO) for CO2 utilization, suggesting that it may be a useful host to bioselect RubisCO molecules with improved CO2‐capture capabilities. A host strain of R. eutropha was constructed for this purpose after deleting endogenous genes encoding two related RubisCOs. This strain could be complemented for CO2‐dependent growth by introducing native or heterologous RubisCO genes. Mutagenesis and suppressor selection identified amino acid substitutions in a hydrophobic region that specifically influences RubisCO's interaction with its substrates, particularly O2, which competes with CO2 at the active site. Unlike most RubisCOs, the R. eutropha enzyme has evolved to retain optimal CO2‐fixation rates in a fast‐growing host, despite the presence of high levels of competing O2. Yet its structure‐function properties resemble those of several commonly found RubisCOs, including the higher plant enzymes, allowing strategies to engineer analogous enzymes. Because R. eutropha can be cultured rapidly under harsh environmental conditions (e.g., with toxic industrial flue gas), in the presence of near saturation levels of oxygen, artificial selection and directed evolution studies in this organism could potentially impact efforts toward improving RubisCO‐dependent biological CO2 utilization in aerobic environments.

Enzymes

d‐ribulose 1,5‐bisphosphate carboxylase/oxygenase, EC 4.1.1.39; phosphoribulokinase, EC 2.7.1.19
The effects of basement faults on thermal convection and implications for the formation of unconformity‐related uranium deposits in the Athabasca Basin, Canada
Authors: Li Z. , Chi G. , Bethune K. M.
Published: June 2016

The formation of the world‐class, high‐grade unconformity‐related uranium deposits in the Athabasca Basin (Canada) requires circulation of large amounts of fluids, the mechanisms for which are still not well understood. Recent studies advocate thermal convection as a possible driving force for the fluid flow related to uranium mineralization; however, little is known regarding how basement faults, which are spatially associated with most unconformity‐related uranium deposits, influence fluid convection and how this may affect the localization of mineralization. This study addresses these questions through simulations of thermal convection with various configurations of basement faults using the FLAC3D software. Modelling results indicate that the location, spacing, orientation and thermal conductivities of basement faults influence the size and location of thermally driven fluid convection. In a model with a single isolated fault, the fault coincides with an upwelling plume and the dip angle of the fault does not affect the fluid flow pattern; when the fault is moved laterally, the upwelling plume shifts accordingly. In the case of two vertical faults, the faults may either coincide with upwelling flow between two convection cells or be located below individual convection cells, depending on fault spacing. In the latter case, fluid may flow into and out of individual fault zones. Similar results were also obtained for models with two nonvertical (i.e. dipping) faults. Convective flow can penetrate the uppermost basement when the permeability is less than two orders of magnitude lower than that of the overlying sandstone. In this case, the basement faults not only can control the location of ascending flow, but also can passively act as fluid conduits of either flow from the basin into the basement (ingress), or flow from the basement into the basin (egress), depending on their thermal conductivities and relative locations in the models.