bluuebunny/crossref_metadata_2025 huggingface dataset:
Mutation rates and the evolution of germline structure
Authors: Scally Aylwyn
Published: June 2016

Genome sequencing studies of de novo mutations in humans have revealed surprising incongruities in our understanding of human germline mutation. In particular, the mutation rate observed in modern humans is substantially lower than that estimated from calibration against the fossil record, and the paternal age effect in mutations transmitted to offspring is much weaker than expected from our long-standing model of spermatogenesis. I consider possible explanations for these discrepancies, including evolutionary changes in life-history parameters such as generation time and the age of puberty, a possible contribution from undetected post-zygotic mutations early in embryo development, and changes in cellular mutation processes at different stages of the germline. I suggest a revised model of stem-cell state transitions during spermatogenesis, in which ‘dark’ gonial stem cells play a more active role than hitherto envisaged, with a long cycle time undetected in experimental observations. More generally, I argue that the mutation rate and its evolution depend intimately on the structure of the germline in humans and other primates.

This article is part of the themed issue ‘Dating species divergences using rocks and clocks'.
Inferring species divergence times using pairwise sequential Markovian coalescent modelling and low-coverage genomic data
Authors: Cahill James A. , Soares André E. R. , Green Richard E. , Shapiro Beth
Published: June 2016

Understanding when species diverged aids in identifying the drivers of speciation, but the end of gene flow between populations can be difficult to ascertain from genetic data. We explore the use of pairwise sequential Markovian coalescent (PSMC) modelling to infer the timing of divergence between species and populations. PSMC plots generated using artificial hybrid genomes show rapid increases in effective population size at the time when the two parent lineages diverge, and this approach has been used previously to infer divergence between human lineages. We show that, even without high coverage or phased input data, PSMC can detect the end of significant gene flow between populations by comparing the PSMC output from artificial hybrids to the output of simulations with known demographic histories. We then apply PSMC to detect divergence times among lineages within two real datasets: great apes and bears within the genusUrsus. Our results confirm most previously proposed divergence times for these lineages, and suggest that gene flow between recently diverged lineages may have been common among bears and great apes, including up to one million years of continued gene flow between chimpanzees and bonobos after the formation of the Congo River.

This article is part of the themed issue ‘Dating species divergences using rocks and clocks'.
Mammal madness: is the mammal tree of life not yet resolved?
Authors: Foley Nicole M. , Springer Mark S. , Teeling Emma C.
Published: June 2016

Most molecular phylogenetic studies place all placental mammals into four superordinal groups, Laurasiatheria (e.g. dogs, bats, whales), Euarchontoglires (e.g. humans, rodents, colugos), Xenarthra (e.g. armadillos, anteaters) and Afrotheria (e.g. elephants, sea cows, tenrecs), and estimate that these clades last shared a common ancestor 90–110 million years ago. This phylogeny has provided a framework for numerous functional and comparative studies. Despite the high level of congruence among most molecular studies, questions still remain regarding the position and divergence time of the root of placental mammals, and certain ‘hard nodes’ such as the Laurasiatheria polytomy and Paenungulata that seem impossible to resolve. Here, we explore recent consensus and conflict among mammalian phylogenetic studies and explore the reasons for the remaining conflicts. The question of whether the mammal tree of life is or can be ever resolved is also addressed.

This article is part of the themed issue ‘Dating species divergences using rocks and clocks’.
Grouping substitution types into different relaxed molecular clocks
Authors: Lee Hui-Jie , Kishino Hirohisa , Rodrigue Nicolas , Thorne Jeffrey L.
Published: June 2016

Different types of nucleotide substitutions experience different patterns of rate change over time. We propose clustering context-dependent (or context-independent) nucleotide substitution types according to how their rates change and then using the grouping for divergence time estimation. With our models, relative rates among types that are in the same group are fixed, whereas absolute rates of the types within a group change over time according to a shared relaxed molecular clock. We illustrate our procedure by analysing a 0.15 Mb intergenic region to infer divergence times relating eight primates. The different groupings of substitution types that we explore have little effect on the posterior means of divergence times, but the widths of the credibility intervals decrease as the number of groups increases.

This article is part of the themed issue ‘Dating species divergences using rocks and clocks’.
The evolution of methods for establishing evolutionary timescales
Authors: Donoghue Philip C. J. , Yang Ziheng
Published: June 2016

The fossil record is well known to be incomplete. Read literally, it provides a distorted view of the history of species divergence and extinction, because different species have different propensities to fossilize, the amount of rock fluctuates over geological timescales, as does the nature of the environments that it preserves. Even so, patterns in the fossil evidence allow us to assess the incompleteness of the fossil record. While the molecular clock can be used to extend the time estimates from fossil species to lineages not represented in the fossil record, fossils are the only source of information concerning absolute (geological) times in molecular dating analysis. We review different ways of incorporating fossil evidence in modern clock dating analyses, including node-calibrations where lineage divergence times are constrained using probability densities and tip-calibrations where fossil species at the tips of the tree are assigned dates from dated rock strata. While node-calibrations are often constructed by a crude assessment of the fossil evidence and thus involves arbitrariness, tip-calibrations may be too sensitive to the prior on divergence times or the branching process and influenced unduly affected by well-known problems of morphological character evolution, such as environmental influence on morphological phenotypes, correlation among traits, and convergent evolution in disparate species. We discuss the utility of time information from fossils in phylogeny estimation and the search for ancestors in the fossil record.

This article is part of the themed issue ‘Dating species divergences using rocks and clocks’.
Latent infection of human bocavirus accompanied by flare of chronic cough, fatigue and episodes of viral replication in an immunocompetent adult patient, Cologne, Germany
Authors: Windisch Wolfram , Pieper Monika , Ziemele Inga , Rockstroh Jürgen , Brockmann Michael , Schildgen Oliver , Schildgen Verena
Published: June 2016

Introduction:

The human bocavirus (HBoV) is a parvovirus and is associated with mild to life-threatening acute or persisting respiratory infections, frequently accompanied by further pathogens. So far, there is limited knowledge on the mechanisms of persistence, and no reports on chronic infections or latency have been published so far.

Case presentation:

An immunocompetent male patient suffers from a chronic HBoV1 infection, i.e. viral DNA was detected in both serum and bronchoalveolar lavage (BAL) for >5 months without co-infections and with respiratory symptoms resolved spontaneously while receiving symptomatic treatment with montelukast and corticosteroids. Following the symptomatic medication of a chronic infection with HBoV1 viraemia indicating active viral replication lasting over 5 months, the patient cleared the viraemia and no further viral DNA was detectable in the BAL. However, by fluorescence in situ hybridization analyses of mucosal biopsies, it was shown that the virus genome still persisted in the absence of viral shedding but in a more compact manner possibly representing a supercoiled episomal form of this otherwise linear single-stranded DNA genome. This indicated the entry into a latency phase. Moreover, the cytokine profile and the IP-10/TARC ratio, a marker for fibrotization, seem to have been altered by HBoV1 replication. Although specific IgG antibodies were detectable during the whole observation period, they showed an apparently insufficient neutralising activity.

Conclusion:

On the one hand, these findings suggest that the symptomatic medication may have led to clearance of the virus from blood and airways and, moreover, that the viral DNA persists in the tissue as an altered episomal form favoured by lacking neutralising antibodies. This appears to be important in order to reduce possible long-term effects such as lung fibrosis.
Transposons passively and actively contribute to evolution of the two-speed genome of a fungal pathogen
Authors: Faino Luigi , Seidl Michael F. , Shi-Kunne Xiaoqian , Pauper Marc , van den Berg Grardy C.M. , Wittenberg Alexander H.J. , Thomma Bart P.H.J.
Published: June 2016

Genomic plasticity enables adaptation to changing environments, which is especially relevant for pathogens that engage in “arms races” with their hosts. In many pathogens, genes mediating virulence cluster in highly variable, transposon-rich, physically distinct genomic compartments. However, understanding of the evolution of these compartments, and the role of transposons therein, remains limited. Here, we show that transposons are the major driving force for adaptive genome evolution in the fungal plant pathogen Verticillium dahliae. We show that highly variable lineage-specific (LS) regions evolved by genomic rearrangements that are mediated by erroneous double-strand repair, often utilizing transposons. We furthermore show that recent genetic duplications are enhanced in LS regions, against an older episode of duplication events. Finally, LS regions are enriched in active transposons, which contribute to local genome plasticity. Thus, we provide evidence for genome shaping by transposons, both in an active and passive manner, which impacts the evolution of pathogen virulence.
Notes on the Nominal System of Bashkardi
Authors: Korn Agnes
Published: June 2016

This article studies the nominal system and noun phrase of Bashkardi, a language of the Iranian family spoken in Southern Iran in the region of Bashakerd. Bashkardi is a very little studied language, and is in particular need of being documented because it is a minority language endangered by heavy influence from Persian. The article is based on recordings made by Ilya Gershevitch in 1956. In discussing the Bashkardi nominal system, I compare it to that of geographically or historically neighbouring languages such as Balochi, spoken nearby in the province (and also in the form of the Koroshi dialect spoken in Fars province to the west). From a historical perspective, Middle Persian and Parthian, the only two Western Iranian languages attested from Middle Iranian times, are adduced to elucidate the development of the Bashkardi nominal system. I argue that the nominal system of Bashkardi agrees with Persian and other Western Ir. languages in having lost the distinction between direct and oblique case (preserved in Kurmanji, Balochi, etc.), but that a trace of the oblique case might be present in the possessive marker‐ī. Like Middle Persian, Bashkardi employs adpositions to mark syntactic relations, but none of these is used in a systematic way as of yet.
Hospital Quality Reporting in the United States: Does Report Card Design and Incorporation of Patient Narrative Comments Affect Hospital Choice?
Authors: Emmert Martin , Schlesinger Mark
Published: June 2016

Objective

To explore the impact of hospital report card design and incorporation of patient narrative comments on consumers' choices of hospitals.

Data Sources

Primary data collected from an online survey with 1,350 respondents in February, 2015.

Study Design

A randomized 2 (narrative comments: yes, no) × 3 (design: representation of clinical performance in textual, star, numerical formats) between‐subject online‐based cross‐sectional experiment.

Principal Findings

In 51 percent of all cases, respondents selected the hospital with the best clinical results. Report cards with a numerical design induced choices more focused on clinical ratings (56.0 percent chose the highest rated hospital) than those with textual information (48.1 percent) or star ratings (47.3 percent) (p < .001). Report cards without narrative comments (49.7 percent) and with narratives (51.4 percent) were not associated with significant difference in selecting top‐rated clinical hospitals (p = .376). But there were significant interactions affecting choice of hospitals among exposure to narratives, formatting of clinical performance, and respondents' education.

Conclusions

Consumers have a difficult time synthesizing quality data in various formats. Hospital report cards continue to pose challenging choices, especially for those with limited education. Narrative comments in their earliest emerging forms do not seem to be altering hospital choice as much as the literature has suggested for other providers, but they may have consequential impact on the choices of certain subsets of consumers.
How Low‐Income Subsidy Recipients Respond to Medicare Part D Cost Sharing
Authors: Stuart Bruce , Hendrick Franklin B. , Xu Jing , Dougherty J. Samantha
Published: June 2016

Objectives

To determine the magnitude and mechanisms of response to Medicare Part D cost sharing by low‐income subsidy (LIS) recipients using oral hypoglycemic agents (OHAs) and statins.

Data Sources

Medicare data for a 5 percent random sample of beneficiaries with diabetes enrolled in fee‐for‐service Part D drug plans in 2008.

Study Design

We evaluated the impact of differences between generic and brand cost sharing rates among cohorts of LIS and non‐LIS recipients to determine if wider price spreads increased the generic dispensing rate (GDR) and reduced total drug use and cost.

Principal Findings

We found little association between cost sharing and aggregate OHA and statin use. In adjusted analyses, non‐LIS beneficiaries who paid 46 percent of total OHA costs had 2.5 percent fewer OHA days supply than full benefit dual eligibles who paid just 5 percent of their therapy costs. For statins, the difference in days supply between those facing the lowest and highest cost sharing was 4.6 percent. Higher cost sharing was associated with filling fewer but larger prescriptions for both generics and brands.

Conclusions

Higher generic and brand copays had little association with OHA and statin use among LIS recipients. This implies that modest changes in required cost sharing for these medicines would have very little substantive impact on generic dispensing or utilization patterns among LIS recipients and thus would have little effect on total program spending. At the same time, any increases in out‐of‐pocket costs would be expected to shift costs and place greater financial burden on low‐income beneficiaries, particularly those in poor health.
Emergency weight estimation lookup tables for New Zealand children aged 5–10 years
Authors: Britnell Sally , Taylor Steve , Koziol‐McLain Jane
Published: June 2016

Objective

To derive novel emergency weight estimation tables for New Zealand children aged 5–10 years using ethnicity and sex to increase accuracy and precision.

Methods

Using an existing dataset (collected in five New Zealand primary schools during July 2013;n = 376), body mass index and current emergency weight estimates were calculated. Stepwise regression with Akanke Information produced two best‐fit models for predicting weight, one based on age and the other on height. Potential explanatory variables included ethnicity, sex and body habitus.

Results

The length‐based model included height, ethnicity and body habitus. Accuracy (weight estimates within 10% of actual weight) for the length‐based lookup table (74.8%) was similar to that for the Broselow–Luten tape (73.4%). The age‐based model included age, sex, ethnicity and body habitus. Accuracy (51.3%) for the age‐based lookup table was better than for existing formulae including Shann (45.7%), Advanced Paediatric Life Support (39.1%) and Theron (28.7%).

Conclusion

The most accurate method for weight estimation in Auckland children aged 5–10 years is either the novel length‐based lookup table or the existing Broselow–Luten tape. When length‐based methods are not possible, the age‐based lookup tables incorporating age, sex, ethnicity and body habitus are more accurate than existing methods of weight estimation.
Inflammatory breast disease: A pictorial essay with radiological‐pathological correlation
Authors: Gunawardena Rusiru P , Gunawardena Deepika , Metcalf Cecily , Taylor Donna , Wylie Liz
Published: June 2016

Inflammatory conditions of the breast are an important group of diseases that can mimic breast carcinoma on clinical and radiological grounds. This pictorial essay presents the radiological and pathological features of some of these entities.
Acoustic radiation force impulse accuracy and the impact of hepatic steatosis on liver fibrosis staging
Authors: Harris Nicole , Nadebaum David , Christie Michael , Gorelik Alexandra , Nicoll Amanda , Sood Siddharth , Gibson Robert
Published: June 2016

Introduction

The accuracy of Acoustic Radiation Force Impulse (ARFI) imaging has been validated in the setting of hepatitis C, however, the accuracy in the setting of fatty liver disease (FLD) has been less well‐established. The aim of this study was to assess the accuracy of ARFI in the setting of hepatic steatosis.

Methods

Patients with biopsy proven or sonographically diagnosed liver steatosis were assessed for ARFI trends including: inter‐operator concordance, interquartile range, ARFI failure rate, relationship between ARFI velocity and steatosis severity, and concordance between biopsy and ARFI fibrosis scores.

Results

Three hundred and forty‐nine patients were assessed (53 ‘biopsy’ cohort and 296 ‘ultrasound’ cohort), with 28 patients having biopsy on the same day as ARFI. Low stages of fibrosis (F0/1) were over‐estimated by ARFI in 62% of cases with biopsy correlation (n = 16, P < 0.001), with ARFI offering increased accuracy in regard to higher‐stage fibrosis (14/15 cases, 93%). In both the biopsy and ultrasound cohorts the failure rate and median inter‐quartile range increased with increasing steatosis, and the inter‐operator concordance remained good across all liver steatosis severities.

Conclusion

In the setting of steatosis, ARFI is very sensitive in detecting, and accurate in diagnosing, higher stages of fibrosis regardless of steatosis severity. It tends to overestimate the fibrosis category in lower stages of fibrosis. The present study does not show conclusively if the presence of steatosis or its severity independently alters ARFI measurements.
The Effects of Vertical Pay Dispersion: Experimental Evidence in a Budget Setting
Authors: Guo Lan , Libby Theresa , Liu Xiaotao (Kelvin)
Published: June 2016

Vertical pay dispersion is the difference in pay across different hierarchical levels within an organization (Milkovich and Newman ). While vertical pay dispersion may be useful in attracting, retaining, and motivating highly skilled employees (Lazear and Rosen ; Lazear ; Prendergast ), our study investigates a potential disadvantage; specifically, the negative impact of perceived unfairness of vertical pay dispersion on employees' budgeting decisions. We predict and find that high vertical pay dispersion motivates subordinates to misreport costs to a greater extent than low vertical pay dispersion. Furthermore, we predict and find that superiors, on average, exercise more lenient cost controls when vertical pay dispersion is high rather than low. Supplemental analysis indicates superiors are more lenient on average because of their aversion to inequity caused by vertical pay dispersion. Our results suggest that high vertical pay dispersion can compromise the overall corporate budgeting environment, where higher levels of misreporting by subordinates goes unchecked by superiors.
Nursing Interventions and Outcomes for the Diagnosis of Impaired Tissue Integrity in Patients After Cardiac Catheterization: Survey
Authors: Pezzi Marian Valentini , Rabelo‐Silva Eneida Rejane , Paganin Angelita , de Souza Emiliane Nogueira
Published: June 2016

PURPOSE

Determine the outcomes and interventions for patients undergoing cardiac catheterization with nursing diagnosis of impaired tissue integrity.

METHODS

Survey with e‐questionnaires sent for expert nurses in two rounds.

FINDINGS

Only one nursing outcome was approved: tissue integrity—skin and mucosa and five related interventions, namely, pressure control, topical drug administration, care of incision site, care of injuries, and infection control.

CONCLUSIONS

The expected outcomes and the most significant interventions for the implementation of nursing care during the immediate recovery of patients with impaired tissue integrity following invasive hemodynamic procedures were defined.

IMPLICATIONS FOR NURSING PRACTICE

The study findings support selection of appropriate nursing outcomes and interventions for this patient profile.
Profitability and investment‐based factor pricing models
Authors: Elliot Brendan , Docherty Paul , Easton Stephen , Lee Doowon
Published: June 2016

Ex ante predictors of stock returns must exhibit explanatory power across the feasible set of investments. But empirical results of factor pricing models that incorporate firm investment and profitability cannot explain the apparently high returns of US small stocks with very high investment levels and very low profitability. Whilst these stocks comprise only a small fraction of US data sets, this is not the case across global markets. Using a data set that is concentrated with stocks that exhibit high investment despite low profitability, we demonstrate that such factor models are limited in their explanatory power over these stocks.
What keeps you strong? A systematic review identifying how primary health‐care and aged‐care services can support the well‐being of older Indigenous peoples
Authors: Davy Carol , Kite Elaine , Aitken Graham , Dodd Garth , Rigney Janice , Hayes Jenny , Van Emden Jan
Published: June 2016

Aim

The objective of this systematic review was to identify primary health‐care or aged‐care strategies that have or could support the well‐being of older Indigenous peoples.

Methods

A search was undertaken of primary databases including Medical Literature Analysis and Retrieval System Online and Cumulative Index to Nursing and Allied Health Literature. Papers which reported on the perspectives of older Indigenous peoples, community members and provider participants were included. Findings were pooled using a meta‐aggregative approach.

Results

Three high‐level synthesised findings – maintaining Indigenous identity, promoting independence and delivering culturally safe care – were believed to be important for supporting the well‐being of older Indigenous peoples.

Conclusions

As physical independence often diminishes with age, having the support of culturally safe primary health‐care and aged‐care services that understand the importance of maintaining an Indigenous identity and promoting independence will be crucial for the well‐being of older Indigenous peoples.
Optimising recovery after surgery: Predictors of early discharge and hospital readmission
Authors: Carter Jonathan , Philp Shannon , Wan King M.
Published: June 2016

Background

Fast track surgery (FTS) programs minimise the stress response after surgery and allow for enhanced recovery.

Aims

To document the frequency and incidence of adverse events in patients enrolled on a FTS program and to investigate factors associated with shorter length of stay and readmission to hospital.

Methods

A seven‐year updated surgical audit of patients undergoing laparotomy for suspected or confirmed malignancy on a FTS program.

Results

Five hundred and fifty patients comprise the study group. Average age and body mass index (BMI) were 55 years and 28, respectively. Mean length of stay (LOS) was 3.4 days with 194 (35%) patients discharged on day 2. Six (1%) patients had confirmed venous thromboembolism (VTE), three of whom were diagnosed on pre‐operative imaging. Overall, transfusion rate was 5%. Adverse events in decreasing frequency were hospital readmission (4%) and significant wound infection (3%). All other adverse events were uncommon with rates <0.5%. Factors associated with a discharge on or after day 3 include age, pathology, Eastern Cooperative Oncology Group performance status, incision type, operating time, blood transfusion and cyclo‐oxygenase 2 inhibitors. Factors associated with hospital readmission include longer operating time, performance of lymph node sampling/dissection, longer LOS, development of wound infection, febrile morbidity, return to the operating room, unplanned intensive care unit admission and presence of other complications.

Conclusions

Patients managed by a FTS protocol can expect enhanced outcomes when compared to historical controls.
Subjective outcome of 166 tension‐free vaginal tape procedures performed by a single surgeon: the Braemar experience
Authors: Roman Jose D.
Published: June 2016

Background

Long‐term outcomes of the tension‐free vaginal tape (TVT) procedure are needed to assess its efficacy.

Methods

This was a cross‐sectional study of the subjective outcome in patients with stress urinary incontinence (SUI) operated on consecutively by a single surgeon. Success was defined as the absence of SUI at the time of the study. The validated questionnaires Urogenital Distress Inventory‐6 (UDI‐6) and Incontinence Impact Questionnaire (IIQ‐7) were used to find the minimum important difference (MID) to support subjective reports of success.

Results

One hundred and sixty‐six patients were evaluated with a mean follow‐up time of 58 ± 28.6 months. Fifty‐five (33.1%) patients underwent the TVT procedure alone, and 111 (66.9%) underwent the TVT procedure with concomitant pelvic organ prolapse (POP) repair.

One hundred and thirty‐three (80.1%) patients reported being subjectively cured with no stress incontinence at the time of the study.

A total of 138 (83.1%) patients reported an MID > 11 points when comparing the postoperative to the pre‐operative UDI‐6 scores.

A total of 122 (73.5%) patients reported an MID > 16 points when comparing the postoperative to the pre‐operative IIQ‐7 scores.

There was no evident decline in the yearly percentage of patients who achieved an MID > 11 or MID > 16 in the UDI‐6 and IIQ‐7 scores, respectively.

Conclusions

The TVT procedure in a population in which 67% underwent a concomitant POP repair was associated with a subjective cure rate of 80% and an MID > 11 in 82.7% of patients in the UDI‐6 questionnaire and an MID > 16 in 75.1% patients in the IIQ‐7 questionnaire.
Treatment of scaphoid fractures using a memory alloy nail‐feet‐fixation device
Authors: Li Chuan , Xu Xiaoshan , Su Yongyue , Zhou Tianhua , Fan Xinyu , Xu Yongqing
Published: June 2016

Background

Scaphoid fracture is a common carpal fracture, and its treatment often requires fixation devices. This study aimed to investigate the efficacy and safety of a memory alloy nail‐feet‐fixation (MANFF) device in treating scaphoid fractures.

Methods

Sixty‐six patients with closed scaphoid fractures were treated using the MANFF device between August 2011 and November 2013. Surgical outcomes were assessed using the Mayo wrist score, including pain intensity, functional status, range of motion and grip strength. Postoperative radiographic evaluation was performed every month.

Results

Herbert score of fracture stability was A in 36 patients, B in 20 and C in 10. Forty‐five patients were treated using the simple MANFF device, 10 with an auxiliary Kirschner wire and 11 underwent MANFF after autologous bone graft. Patients were followed‐up for a mean of 6.5 ± 1.2 months (range, 6–12 months). Bone union was achieved in all patients. There was no infection, non‐union, arthritic change, tendon issues or any other complications. At postoperative 6 months, 50 patients achieved excellent outcomes, nine achieved good outcomes, and seven achieved fair outcomes, with a mean score of 89.5 ± 6.3. Therefore, the rate of satisfactory outcomes (excellent and good) was 89.4%.

Conclusions

Treatment of scaphoid fractures using the MANFF method has good surgical outcomes in bone union and patient satisfaction.
Limited sampling strategy for determining metformin area under the plasma concentration–time curve
Authors: Santoro Ana Beatriz , Stage Tore Bjerregaard , Struchiner Claudio José , Christensen Mette Marie Hougaard , Brosen Kim , Suarez‐Kurtz Guilherme
Published: June 2016

Aim

The aim was to develop and validate limited sampling strategy (LSS) models to predict the area under the plasma concentration–time curve (AUC) for metformin.

Methods

Metformin plasma concentrations (n = 627) at 0–24 h after a single 500 mg dose were used for LSS development, based on all subsets linear regression analysis. The LSS‐derived AUC(0,24 h) was compared with the parameter ‘best estimate’ obtained by non‐compartmental analysis using all plasma concentration data points. Correlation between the LSS‐derived and the best estimated AUC(0,24 h) (r2), bias and precision of the LSS estimates were quantified. The LSS models were validated in independent cohorts.

Results

A two‐point (3 h and 10 h) regression equation with no intercept estimated accurately the individual AUC(0,24 h) in the development cohort: r2 = 0.927, bias (mean, 95% CI) –0.5, −2.7–1.8% and precision 6.3, 4.9–7.7%. The accuracy of the two point LSS model was verified in study cohorts of individuals receiving single 500 or 1000 mg (r2 = –0.933–0.934) or seven 1000 mg daily doses (r2 = 0.918), as well as using data from 16 published studies covering a wide range of metformin doses, demographics, clinical and experimental conditions (r2 = 0.976). The LSS model reproduced previously reported results for effects of polymorphisms in OCT2 and MATE1 genes on AUC(0,24 h) and renal clearance of metformin.

Conclusions

The two point LSS algorithm may be used to assess the systemic exposure to metformin under diverse conditions, with reduced costs of sampling and analysis, and saving time for both subjects and investigators.
Moderating the seductive details effect in multimedia learning with note‐taking
Authors: Wang Zhe , Sundararajan Narayankripa , Adesope Olusola O. , Ardasheva Yuliya
Published: June 2016

Although the seductive details effect, a phenomenon where interesting but irrelevant pictures impede comprehension, is well documented, studies examining ways of moderating its detrimental impact on learning remain few. The present study examined the effect of note‐taking on the seductive details effect. Chinese undergraduate participants (N = 91) were randomly assigned to three conditions that differed in terms of the presence of seductive details and learning strategy (presence or absence of note‐taking for the seductive details group). Mediation analyses results showed that seductive details undermined participants' performance on recall and transfer tasks as a result of increased cognitive load. Results from variance analyses indicated that participants in the seductive details and note‐taking condition outperformed those in the comparison group and that this effect differed depending on participants' prior knowledge and outcome measures (recall or transfer). Overall, our results suggest that note‐taking is an effective cognitive strategy that can help learners overcome the seductive details effect. Implications for theory, practice, and future research are discussed.
E‐portfolio evaluation and vocabulary learning: Moving from pedagogy to andragogy
Authors: Sharifi Maryam , Soleimani Hassan , Jafarigohar Manoochehr
Published: June 2016

Current trends in the field of educational technology indicate a shift in pedagogical assumptions and theoretical frameworks that favor active involvement of self‐directed learners in a constructivist environment. This study probes the influence of electronic portfolio evaluation on vocabulary learning of Iranian university students and the possible implications this influence affords. For this aim, the study recruited 66 students who were randomly assigned to the e‐portfolio group and the traditional assessment group. The experimental group kept an e‐portfolio in the intermediate level English language course while the traditional assessment group did not. The results revealed that the e‐portfolio group outperformed the traditional assessment group in terms of vocabulary learning on the posttest. The results also showed that e‐portfolio boosted students' motivation for learning new items. The perceptions of the participants in the e‐portfolio group reflected that they benefited from the integration of technology and various educational activities and enjoyed keeping an e‐portfolio. Finally, initial guidelines about how to use the instrument as part of the curriculum are discussed.
Methods and frequency of sharing of learning resources by medical students
Authors: Judd Terry , Elliott Kristine
Published: June 2016

University students have ready access to quality learning resources through learning management systems (LMS), online library collections and generic search tools. However, anecdotal evidence suggests they sometimes turn to peer‐based sharing rather than sourcing resources directly. We know little about this practice—how common it is, what sort of resources are involved and what impact it is likely to have on students' learning. This paper reports on an exploratory investigation of students' resource sharing habits, involving 338 respondents from the first 3 years of a 4‐year postgraduate medical curriculum. On average, students reported sharing learning resources with other students two or more times per week. They were most likely to share non‐curriculum resources (not available through their LMS) although curriculum and physical resources (eg, printed or handwritten notes and textbooks) were also often shared. Students employed a range of sharing technologies including email (most frequent), social media tools and cloud‐based file services. A cluster analysis revealed four distinct groups of students based on the frequency with which they share, the range of technologies they employ and whether they share both online and physical resources.
Cerebral Perfusion Enhancing Interventions: A New Strategy for the Prevention of Alzheimer Dementia
Authors: de la Torre Jack C.
Published: June 2016

Cardiovascular and cerebrovascular diseases are major risk factors in the development of cognitive impairment and Alzheimer's disease (AD). These cardio‐cerebral disorders promote a variety of vascular risk factors which in the presence of advancing age are prone to markedly reduce cerebral perfusion and create a neuronal energy crisis. Long‐term hypoperfusion of the brain evolves mainly from cardiac structural pathology and brain vascular insufficiency. Brain hypoperfusion in the elderly is strongly associated with the development of mild cognitive impairment (MCI) and both conditions are presumed to be precursors of Alzheimer dementia. A therapeutic target to prevent or treat MCI and consequently reduce the incidence of AD aims to elevate cerebral perfusion using novel pharmacological agents. As reviewed here, the experimental pharmaca include the use of Rho kinase inhibitors, neurometabolic energy boosters, sirtuins and vascular growth factors. In addition, a compelling new technique in laser medicine called photobiomodulation is reviewed. Photobiomodulation is based on the use of low level laser therapy to stimulate mitochondrial energy production non‐invasively in nerve cells. The use of novel pharmaca and photobiomodulation may become important tools in the treatment or prevention of cognitive decline that can lead to dementia.
Peripheral blood cell‐free DNA is an alternative tumor DNA source reflecting disease status in myelodysplastic syndromes
Authors: Suzuki Yasuhiro , Tomita Akihiro , Nakamura Fumika , Iriyama Chisako , Shirahata‐Adachi Mizuho , Shimada Kazuyuki , Akashi Akimi , Ishikawa Yuichi , Kaneda Norio , Kiyoi Hitoshi
Published: June 2016

Genetic alterations in myelodysplastic syndromes (MDS) are critical for pathogenesis. We previously showed that peripheral blood cell‐free DNA (PBcfDNA) may be more sensitive for genetic/epigenetic analyses than whole bone marrow (BM) cells and mononuclear cells in peripheral blood (PB). Here we analyzed the detailed features of PBcfDNA and its utility in genetic analyses in MDS. The plasma‐PBcfDNA concentration in MDS and related diseases (N = 33) was significantly higher than that in healthy donors (N = 14; P = 0.041) and in International Prognostic Scoring System higher‐risk groups than that in lower‐risk groups (P = 0.034). The concentration of plasma‐/serum‐PBcfDNA was significantly correlated with the serum lactate dehydrogenase level (both P < 0.0001) and the blast cell count in PB (P = 0.034 and 0.025, respectively). One nanogram of PBcfDNA was sufficient for one assay of Sanger sequencing using optimized primer sets to amplify approximately 160‐bp PCR products. PBcfDNA (approximately 50 ng) can also be utilized for targeted sequencing. Almost all mutations detected in BM‐DNA were also detected using corresponding PBcfDNA. Analyses using serially harvested PBcfDNA from an RAEB‐2 patient showed that the somatic mutations and a single nucleotide polymorphism that were detected before allogeneic transplantation were undetectable after transplantation, indicating that PBcfDNA likely comes from MDS clones that reflect the disease status. PBcfDNA may be a safer and easier alternative to obtain tumor DNA in MDS.
Human leucocyte antigen class I-redirected anti-tumour CD4+ T cells require a higher T cell receptor binding affinity for optimal activity than CD8+ T cells
Authors: Tan M P , Dolton G M , Gerry A B , Brewer J E , Bennett A D , Pumphrey N J , Jakobsen B K , Sewell A K
Published: June 2016

CD4+ T helper cells are a valuable component of the immune response towards cancer. Unfortunately, natural tumour-specific CD4+ T cells occur in low frequency, express relatively low-affinity T cell receptors (TCRs) and show poor reactivity towards cognate antigen. In addition, the lack of human leucocyte antigen (HLA) class II expression on most cancers dictates that these cells are often unable to respond to tumour cells directly. These deficiencies can be overcome by transducing primary CD4+ T cells with tumour-specific HLA class I-restricted TCRs prior to adoptive transfer. The lack of help from the co-receptor CD8 glycoprotein in CD4+ cells might result in these cells requiring a different optimal TCR binding affinity. Here we compared primary CD4+ and CD8+ T cells expressing wild-type and a range of affinity-enhanced TCRs specific for the HLA A*0201-restricted NY-ESO-1- and gp100 tumour antigens. Our major findings are: (i) redirected primary CD4+ T cells expressing TCRs of sufficiently high affinity exhibit a wide range of effector functions, including cytotoxicity, in response to cognate peptide; and (ii) optimal TCR binding affinity is higher in CD4+ T cells than CD8+ T cells. These results indicate that the CD4+ T cell component of current adoptive therapies using TCRs optimized for CD8+ T cells is below par and that there is room for substantial improvement.
The life cycle of a T cell after vaccination – where does immune ageing strike?
Authors: Kim C , Fang F , Weyand C M , Goronzy J J
Published: June 2016

Vaccination is the optimal intervention to prevent the increased morbidity and mortality from infection in older individuals and to maintain immune health during ageing. To optimize benefits from vaccination, strategies have to be developed that overcome the defects in an adaptive immune response that occur with immune ageing. Most current approaches are concentrated on activating the innate immune system by adjuvants to improve the induction of a T cell response. This review will focus upon T cell-intrinsic mechanisms that control how a T cell is activated, expands rapidly to differentiate into short-lived effector cells and into memory precursor cells, with short-lived effector T cells then mainly undergoing apoptosis and memory precursor cells surviving as long-lived memory T cells. Insights into each step of this longitudinal course of a T cell response that takes place over a period of several weeks is beginning to allow identifying interventions that can improve this process of T cell memory generation and specifically target defects that occur with ageing.
Exome sequencing revealed a novel splice site variant in the ALX1 gene underlying frontonasal dysplasia
Authors: Ullah A. , Kalsoom U.‐E , Umair M. , John P. , Ansar M. , Basit S. , Ahmad W.
Published: June 2016

Frontonasal dysplasia (FND) is a heterogeneous group of disorders characterized by hypertelorism, telecanthus, broad nasal root, wide prominent nasal bridge, short and wide nasal ridge, broad columella and smooth philtrum. To date one X‐linked and three autosomal recessive forms of FND have been reported in different ethnic groups. We sought to identify the gene responsible for FND in a consanguineous Pakistani family segregating the disorder in autosomal recessive pattern. Genome‐wide homozygosity mapping using 250KNsp array revealed five homozygous regions in the selected affected individuals. Exome sequencing found a novel splice acceptor site variant (c.661‐1G>C: NM_006982.2) in ALX1. Sanger sequencing confirmed the correct segregation of the pathogenic variant in the whole family. Our study concludes that the splice site variant identified in the ALX1 gene causes mild form of FND.
A qualitative study of reasons for seeking and ceasing opioid substitution treatment in prisons in New South Wales, Australia
Authors: Larney Sarah , Zador Deborah , Sindicich Natasha , Dolan Kate
Published: June 2016

Introduction and Aims

Opioid substitution treatment (OST) reduces drug‐related harms in custody and after release. However, OST providers in prisons have reported that some patients prefer to cease treatment prior to release, placing them at risk of fatal overdose. We aimed to examine reasons for seeking OST in custody, and intentions regarding continuation or cessation of treatment prior to and following release.

Design and Methods

This qualitative study employed semi‐structured interviews with opioid‐dependent people currently incarcerated in New South Wales, Australia.

Results

Of 46 participants, 27 were currently in OST. Reported benefits of OST included withdrawal management and avoidance of high‐risk injecting. Over a third of participants in OST stated their intention to withdraw from OST prior to release. Reasons included concerns that attending community OST clinics could lead to drug use or offending, family opposition, inconvenience of clinic attendance, stigma and a perception that prison provided an opportunity to withdraw from OST more easily than in the community. Nineteen participants had already ceased OST in custody or had declined it, citing preferences to ‘be clean’ and the long‐term nature of OST.

Discussion and Conclusions

Balancing the preference of many patients to cease OST prior to release against patient safety post‐release is a substantial challenge for opioid treatment providers in correctional settings. These findings indicate the need for research on how best to attract and retain opioid‐dependent prisoners in treatment and the need to provide other interventions for prisoners uninterested in post‐release OST, such as take‐home naloxone. [Larney S, Zador D, Sindicich N, Dolan K. A qualitative study of reasons for seeking and ceasing opioid substitution treatment in prisons in New South Wales, Australia. Drug Alcohol Rev 2017;36:305–310]
Creating a neuroimaging classification system for children with cerebral palsy
Authors: Ditchfield Michael
Published: June 2016

This commentary is on the original article by Himmelmann et al. on pages 57–64 of this issue.
Euglycaemic glucose clamp: what it can and cannot do, and how to do it
Authors: Heise Tim , Zijlstra Eric , Nosek Leszek , Heckermann Sascha , Plum‐Mörschel Leona , Forst Thomas
Published: June 2016

The hyperinsulinaemic‐euglycaemic glucose clamp has always been regarded as the “gold standard” for the assessment of pharmacodynamic (PD) properties of insulin preparations; however, there has been controversy over a variety of methodogical details, such as study population, dosing time and the initial stabilization of blood glucose (BG) concentrations at the clamp target level, among clamp groups. As the impact of these details on PD results is unclear, the present review provides an overview of different methodological approaches for both the manual and the automated hyperinsulinaemic‐euglycaemic glucose clamp. The advantages and limitations of several methodological details are discussed as well as the relevance of clamp results for the prediction of clinical outcomes. Overall, the best method strongly depends on the exact objective of the trial. If, for instance, duration of action is the primary objective, studies should be carried out in patients with type 1 diabetes to avoid any interference of endogenous insulin. This is less important for variables such as onset of action or early metabolic activity. The hyperinsulinaemic‐euglycaemic glucose clamp has a high sensitivity to detect even minor differences between different insulin preparations. The practical relevance of potential differences, however, needs to be investigated in clinical studies. A major prerequisite for obtaining reliable glucose clamp results is the attainment of high clamp quality (i.e. keeping BG concentrations close to the clamp target throughout the experiments). Unfortunately, measures of clamp quality are often under‐reported, as is the variability in PD profiles, although these might explain some unconfirmed extreme results obtained in a few clamp studies.
Effect of thermal shrinkage during thermoforming on the thickness of fabricated mouthguards: Part 2 pressure formation
Authors: Takahashi Mutsumi , Satoh Yoshihide , Iwasaki Shin‐ichi
Published: June 2016

Background

The aim of this study was to examine the effect of thermal shrinkage, which occurs during thermoforming of ethylene vinyl acetate (EVA) sheets on the thickness of mouthguards fabricated by pressure formation.

Materials and methods

Mouthguards were fabricated from 4.0‐mm‐thick EVA sheets by utilizing a pressure‐forming machine. Two molding conditions were compared: The sheets were placed in the thermoforming machine with the sheet extrusion direction either vertical or parallel to the model's center line. The working model was trimmed to the height of 20 mm at the cutting edge of the maxillary central incisor and 15 mm at the mesiobuccal cusp of the maxillary first molar. The sheet was pressed against the working model for 2 min where the center of the softened sheet sagged 15 mm lower than the clamp. After fabrication, the thickness of mouthguard sheets was determined for the incisal (incisal edge and labial surface) and molar (cusp and buccal surface) portions, and dimensional measurements were made. Differences in molded mouthguard thickness with the sheet orientation of extruded sheets were analyzed by Mann–Whitney U‐test.

Result

In comparison with the parallel axis orientation, the sheets in vertical orientation with the model's centerline yielded significantly higher thickness measurements at the incisal edge, labial surface, and the cusp (P < 0.01, respectively).

Conclusion

The results suggest that the EVA sheet produced by extrusion molding in vertical axis orientation with the model's centerline can effectively reduce loss of thickness in mouthguards after pressure formation.