bluuebunny/crossref_metadata_2025 huggingface dataset:
Influences on emergency department length of stay for older people
Authors: Street Maryann , Mohebbi Mohammadreza , Berry Debra , Cross Anthony , Considine Julie
Published: February 2017

Objective

The aim of this study was to examine the influences on emergency department (ED) length of stay (LOS) for older people and develop a predictive model for an ED LOS more than 4 h.

Methods

This retrospective cohort study used organizational data linkage at the patient level from a major Australian health service. The study population was aged 65 years or older, attending an ED during the 2013/2014 financial year. We developed and internally validated a clinical prediction rule. Discriminatory performance of the model was evaluated by receiver operating characteristic (ROC) curve analysis. An integer-based risk score was developed using multivariate logistic regression. The risk score was evaluated using ROC analysis.

Results

There were 33 926 ED attendances: 57.5% (n=19 517) had an ED LOS more than 4 h. The area under ROC for age, usual accommodation, triage category, arrival by ambulance, arrival overnight, imaging, laboratory investigations, overcrowding, time to be seen by doctor, ED visits with admission and access block relating to ED LOS more than 4 h was 0.796, indicating good performance. In the validation set, area under ROC was 0.80, Hosmer–Lemeshow
P-value was 0.36 and prediction mean square error was 0.18, indicating good calibration. The risk score value attributed to each risk factor ranged from 2 to 68 points. The clinical prediction rule stratified patients into five levels of risk on the basis of the total risk score.

Conclusion

Objective identification of older people at intermediate and high risk of an ED LOS more than 4 h early in ED care enables targeted approaches to streamline the patient journey, decrease ED LOS and optimize emergency care for older people.
Genotype-guided diagnosis in familial hypercholesterolemia: clinical management and concerns
Authors: Hopkins Paul N. , Lane Stacey R.
Published: February 2017

Purpose of review

In this review, we examine benefits and concerns associated with genetic testing in the clinical management of familial hypercholesterolemia (FH).

Recent findings

Application of next-generation sequencing and other advances provide improved yield of causal mutations compared with older methods and help disclose underlying pathophysiology in many instances. Concerns regarding clinical application of genetic testing remain.

More widespread application of genetic testing for FH in the USA may be forthcoming. When a genetic cause of FH can be identified or is known for the family, test results can provide more accurate individual diagnosis of FH, clarification of underlying pathophysiology, and greater clinical insight. However, several concerns persist, particularly cost to FH patients, potential discrimination, and inappropriate denial of clinically indicated therapies for patients without definitive genetic testing results.
The role of registries and genetic databases in familial hypercholesterolemia
Authors: Kindt Iris , Mata Pedro , Knowles Joshua W.
Published: February 2017

Purpose of review

To review how leveraging familial hypercholesterolemia registries can impact molecular genetic research and precision medicine.

Recent findings

Familial hypercholesterolemia is both much more common and more phenotypically heterogeneous than previously thought with some evidence for significant genotype to phenotype correlations. Genetic testing for familial hypercholesterolemia is becoming both more widely available and cheaper, spurring conversations about its clinical utility.

In most countries, familial hypercholesterolemia is underdiagnosed and diagnosed later in life, often after the onset of coronary heart disease (CHD). Familial hypercholesterolemia is undertreated; low goal attainment and additional modifiable risk factors further increase CHD risk. Familial hypercholesterolemia epitomizes the goal of precision medicine to define a subset of individuals with a high risk of morbidity and mortality through genetic diagnosis to manage and treat the risk accordingly. Genetic cascade screening can be used to identify familial hypercholesterolemia patients at a younger age and start timely treatment to prevent CHD. Familial hypercholesterolemia registries are tools for clinical research and improving healthcare planning and patient care. As genotype and phenotype correlations in familial hypercholesterolemia become increasingly understood, this information will likely play a more important role in diagnosis and treatment especially as the cost of genetic testing continues to decline.
Is p16 an adequate surrogate for human papillomavirus status determination?
Authors: Jouhi Lauri , Hagström Jaana , Atula Timo , Mäkitie Antti
Published: February 2017

Purpose of review

In head and neck cancer management, immunoexpression of protein p16 is widely used as a surrogate marker for human papillomavirus (HPV) positivity due to challenges of direct HPV testing. Previously p16 has been reported to have good sensitivity but only moderate specificity in HPV-status determination. The aim of this review is to evaluate the existing information on sensitivity and specificity of p16 immunohistochemistry (IHC) in HPV-status determination among the recent studies.

Recent findings

We searched the time period from October 2014 to April 2016 and included 28 studies (a total of 31 analyses), which reported both p16 and HPV status in their series. The sensitivity of p16 in HPV determination ranged between 28.2 and 100.0%. The mean and median sensitivities were 90.5 and 95.4%, respectively. The specificity ranged between 31.1 and 100.0%. The mean and median specificities were 83.3 and 87.3%, respectively.

Our review presents current information on the feasibility of p16 IHC in HPV status determination, which is in line with previous studies. Patients with HPV-positive tumors can be identified with p16 IHC, but a risk for misclassification of HPV-negative tumors as HPV positive exists. This fact has to be taken into consideration if HPV status will influence treatment planning.
Ex utero intrapartum treatment (EXIT) for upper airway obstruction
Authors: Butler Colin R. , Maughan Elizabeth F. , Pandya Pranav , Hewitt Richard
Published: February 2017

Purpose of review

Improvements in the antenatal diagnosis of congenital malformations have led to increased detection of fetal airway obstructing lesions, and pediatric ear, nose, and throat surgeons are increasingly involved in these cases.

Recent findings

This article outlines the typical range of pathology seen, the logistics in providing support for anticipated deliveries and the multidisciplinary management of complex airway cases.

Traditionally, difficulty in obtaining a patent airway at delivery was a major factor in the dismal prognosis of these pregnancies. The ex utero intrapartum treatment procedure, which involves controlled partial delivery of the fetus whilst maintaining placental circulation, allows various airway maneuvers to be performed to secure the airway in a controlled fashion.
Fecal Calprotectin in Cystic Fibrosis and Its Relation to Disease Parameters
Authors: Ellemunter Helmut , Engelhardt Alexander , Schüller Katharina , Steinkamp Gratiana
Published: February 2017

Objectives:

Fecal calprotectin (FC) is a marker of inflammation in the intestinal tract. We assessed FC levels longitudinally in patients with cystic fibrosis (CF) and evaluated the relation between FC results and relevant markers of disease.

Methods:

Calprotectin was measured in fecal samples starting in 2003 and values were stored in the center's patient database. In this retrospective analysis, we searched for associations of FC concentrations with disease severity and progression. Linear mixed effects models were used to model the logarithm of FC levels.

Results:

A total of 171 patients (0–61 years) had 2434 FC measurements between 2003 and 2015, with a total observation period of 1686 patient‐years. Median (interquartile range) FC concentrations were 60.9 (75.9) μg/g and 61% of the samples showed elevated FC concentrations (>50 μg/g). Despite some statistically significant effects, there was no clinically relevant association among FC and sex, age, forced expiratory volume in 1 second z score, or body mass index z score. Pancreatic insufficiency (ie, fecal elastase <100 μg/g stool) was associated with considerably higher FC values compared to normal pancreatic function (median FC 68 vs 29 μg/g, P < 0.0001). F508del homozygous subjects showed a trend to higher FC values than heterozygous patients (median 71 vs 62 μg/g, P = 0.173). In addition, a significant association with increasing serum C‐reactive protein concentrations (P < 0.0001) was observed.

Conclusions:

FC was elevated in two‐thirds of stool specimens. Increased FC was more common in patients with pancreatic insufficiency. Whether increased FC reflects intestinal inflammation in patients with CF remains to be determined.
Risk Factors for Birth Defects
Authors: Harris Benjamin S. , Bishop Katherine C. , Kemeny Hanna R. , Walker Jennifer S. , Rhee Eleanor , Kuller Jeffrey A.
Published: February 2017

Importance

Major congenital abnormalities, or birth defects, carry significant medical, surgical, cosmetic, or lifestyle consequences. Such abnormalities may be syndromic, involving multiple organ systems, or can be isolated. Overall, 2% to 4% of live births involve congenital abnormalities. Risk factors for birth defects are categorized as modifiable and nonmodifiable. Modifiable risk factors require thorough patient education/counseling. The strongest risk factors, such as age, family history, and a previously affected child, are usually nonmodifiable.

Objective

This review focuses on risk factors for birth defects including alcohol consumption, illicit drug use, smoking, obesity, pregestational diabetes, maternal phenylketonuria, multiple gestation, advanced maternal age, advanced paternal age, family history/consanguinity, folic acid deficiency, medication exposure, and radiation exposure.

Evidence Acquisition

Literature review via PubMed.

Results

There is a strong link between alcohol use, folic acid deficiency, obesity, uncontrolled maternal diabetes mellitus, uncontrolled maternal phenylketonuria, and monozygotic twins and an increased risk of congenital anomalies. Advanced maternal age confers an increased risk of aneuploidy, as well as nonchromosomal abnormalities. Some medications, including angiotensin converting enzyme inhibitors, retinoic acid, folic acid antagonists, and certain anticonvulsants, are associated with various birth defects. However, there are few proven links between illicit drug use, smoking, advanced paternal age, radiation exposure, and statins with specific birth defects.

Conclusions and Relevance

Birth defects are associated with multiple modifiable and nonmodifiable risk factors. Obstetrics providers should work with patients to minimize their risk of birth defects if modifiable risk factors are present and to appropriately counsel patients when nonmodifiable risk factors are present.

Target Audience

Obstetrician and gynecologists, family physicians, maternal-fetal medicine physicians, and genetic counselors.

Learning Objectives

The learner should be better able to (1) outline the most common modifiable maternal risk factors that are associated with birth defects; (2) locate high-quality health information resources for patients; and (3) promote patient autonomy, responsibility, and motivation to pursue healthy lifestyle choices during pregnancy.
Combining Smoothened Agonist and NEL-Like Protein-1 Enhances Bone Healing
Authors: Lee Soonchul , Wang Chenchao , Pan Hsin Chuan , Shrestha Swati , Meyers Carolyn , Ding Catherine , Shen Jia , Chen Eric , Lee Min , Soo Chia , Ting Kang , James Aaron W.
Published: February 2017

Background:

Nonhealing bone defects represent an immense biomedical burden. Despite recent advances in protein-based bone regeneration, safety concerns over bone morphogenetic protein-2 have prompted the search for alternative factors. Previously, the authors examined the additive/synergistic effects of hedgehog and Nel-like protein-1 (NELL-1) on the osteogenic differentiation of mesenchymal stem cells in vitro. In this study, the authors sought to leverage their previous findings by applying the combination of Smoothened agonist (SAG), hedgehog signal activator, and NELL-1 to an in vivo critical-size bone defect model.

Methods:

A 4-mm parietal bone defect was created in mixed-gender CD-1 mice. Treatment groups included control (n = 6), SAG (n = 7), NELL-1 (n = 7), and SAG plus NELL-1 (n = 7). A custom fabricated poly(lactic-co-glycolic acid) disk with hydroxyapatite coating was used as an osteoinductive scaffold.

Results:

Results at 4 and 8 weeks showed increased bone formation by micro–computed tomographic analyses with either stimulus alone (SAG or NELL-1), but significantly greater bone formation with both components combined (SAG plus NELL-1). This included greater bone healing scores and increased bone volume and bone thickness. Histologic analyses confirmed a significant increase in new bone formation with the combination therapy SAG plus NELL-1, accompanied by increased defect vascularization.

Conclusions:

In summary, the authors’ results suggest that combining the hedgehog signaling agonist SAG and NELL-1 has potential as a novel therapeutic strategy for the healing of critical-size bone defects. Future directions will include optimization of dosage and delivery strategy for an SAG and NELL-1 combination product.
CD1d-Restricted Natural Killer T Cells Are Preserved in Indian Long-Term Nonprogressors
Authors: Singh Dharmendra , Ghate Manisha , Godbole Sheela , Kulkarni Smita , Thakar Madhuri
Published: February 2017

Background:

Natural killer T (NKT) cells act as a bridge between innate and adaptive immune responses. Limited information is available regarding the role of NKT cells in the HIV disease progression especially HIV-1 C infection.

Methodology:

NKT cells were characterized for their frequency and the activation, aging, exhaustion status, and their proliferation ability in 32 long-term nonprogressors (LTNPs), 40 progressors, 18 patients before and after suppressive combination antiretroviral therapy (cART) along with 35 HIV-1–negative subjects using multicolor flow cytometry.

Results:

The frequencies of total NKT cells and their subpopulation were significantly higher in LTNPs as compared with those obtained in progressors (P < 0.0001) and were significantly associated with higher CD4 counts and with lower plasma viral loads. The percentage of activated, aged, and exhausted NKT cells were significantly lower in LTNPs as compared with the progressors and inversely correlated with CD4 count and positively with plasma viral loads. The NKT cells from the LTNPs showed higher proliferation ability. The frequency and proliferation ability of the NKT cells were partially restored after 12 months of suppressive cART but still lower than the levels in LTNPs. The degree of restoration after cART was similar in both CD4+ and CD4− NKT cells.

Conclusion:

The findings demonstrate significant association of preserved NKT cells with the nonprogressive HIV infection and also showed that exhausted NKT cells are associated with disease progression. Further characterization of their functionality and assessment of sustenance in HIV infection will help to understand the HIV pathogenesis and to develop immune therapies.
Imaging Leukocyte Responses in the Kidney
Authors: Finsterbusch Michaela , Kitching A. Richard , Hickey Michael J.
Published: February 2017

The kidney can be negatively affected by a range of innate and adaptive immune responses, resulting in alterations in the functions of the kidney and, in some cases, progression to renal failure. In many of these responses, infiltration of blood-borne leukocytes into the kidney is central to the response. In addition, a large population of mononuclear phagocytes resident in the kidney can modulate these responses. A great deal of research has investigated both the mechanisms of leukocyte recruitment to the kidney and the actions of immune cells resident within the kidney. Because of the dynamic nature of the processes whereby leukocytes enter sites of inflammation, in vivo imaging has been one of the key approaches used for understanding leukocyte recruitment as it occurs throughout the body, and this is also true for kidney. However, imaging this organ and its complicated microvasculature during different forms of renal pathology presents a unique set of challenges. In this review, we examine the approaches used for intravital imaging of the kidney and summarize the insights gained from these studies regarding the mechanisms of leukocyte entry into the kidney during inflammation and the actions of immune cells within this organ.
Cognitive Performance Under Electroconvulsive Therapy (ECT) in ECT-Naive Treatment-Resistant Patients With Major Depressive Disorder
Authors: Ziegelmayer Christoph , Hajak Göran , Bauer Anne , Held Marion , Rupprecht Rainer , Trapp Wolfgang
Published: February 2017

Objectives

Although electroconvulsive therapy (ECT) is considered a safe and highly effective treatment option for major depressive disorder, there are still some reservations with regard to possible adverse cognitive adverse effects. This is the case despite a large body of evidence showing that these deficits are transient and that there even seems to be a long-term improvement of cognitive functioning level. However, most data concerning cognitive adverse effects stem from studies using mixed samples of treatment-resistant and non–treatment-resistant as well as ECT-naive and non–ECT-naive subjects. Furthermore, neurocognitive measures might partly be sensitive to practice effects and improvements in depressive symptom level.

Methods

We examined neurocognitive performance in a sample of 20 treatment-resistant and ECT-naive subjects using repeatable neurocognitive tests, whereas changes in depressive symptom level were controlled. Cognitive functioning level was assessed before (baseline), 1 week, and 6 months (follow-up 1 and 2) after (12 to) 15 sessions of unilateral ECT treatment.

Results

No adverse cognitive effects were observed in any of the cognitive domains examined. Instead, a significant improvement in verbal working memory performance was found from baseline to follow-up 2. When changes in depressive symptom levels were controlled statistically, this improvement was no longer seen.

Conclusions

Although findings that ECT does not lead to longer lasting cognitive deficits caused by ECT were confirmed, our study adds evidence that previous results of a beneficial effect of ECT on cognition might be questioned.
Switching From Age-Based Stimulus Dosing to Dose Titration Protocols in Electroconvulsive Therapy
Authors: O’Neill-Kerr Alex , Yassin Anhar , Rogers Stephen , Cornish Janie
Published: February 2017

Objective

The aim of this study was to test the proposition that adoption of a dose titration protocol may be associated with better patient outcomes, at lower treatment dose, and with comparable cumulative dose to that in patients treated using an age-based stimulus dosing protocol.

Methods

This was an analysis of data assembled from archived records and based on cohorts of patients treated respectively on an age-based stimulus dosing protocol and on a dose titration protocol in the National Health Service in England.

Results

We demonstrated a significantly better response in the patient cohort treated with dose titration than with age-based stimulus dosing. Peak doses were less and the total cumulative dose was less in the dose titration group than in the age-based stimulus dosing group.

Conclusions

Our findings are consistent with superior outcomes in patients treated using a dose titration protocol when compared with age-based stimulus dosing in a similar cohort of patients.
Adult exposure to ocean acidification is maladaptive for larvae of the Sydney rock oyster
Saccostrea glomerata
in the presence of multiple stressors
Authors: Parker Laura M. , O'Connor Wayne A. , Byrne Maria , Coleman Ross A. , Virtue Patti , Dove Michael , Gibbs Mitchell , Spohr Lorraine , Scanes Elliot , Ross Pauline M.
Published: February 2017

Parental effects passed from adults to their offspring have been identified as a source of rapid acclimation that may allow marine populations to persist as our surface oceans continue to decrease in pH. Little is known, however, whether parental effects are beneficial for offspring in the presence of multiple stressors. We exposed adults of the oyster
Saccostrea glomerata
to elevated CO
2
and examined the impacts of elevated CO
2
(control = 392; 856 µatm) combined with elevated temperature (control = 24; 28°C), reduced salinity (control = 35; 25) and reduced food concentration (control = full; half diet) on their larvae. Adult exposure to elevated CO
2
had a positive impact on larvae reared at elevated CO
2
as a sole stressor, which were 8% larger and developed faster at elevated CO
2
compared with larvae from adults exposed to ambient CO
2
. These larvae, however, had significantly reduced survival in all multistressor treatments. This was particularly evident for larvae reared at elevated CO
2
combined with elevated temperature or reduced food concentration, with no larvae surviving in some treatment combinations. Larvae from CO
2
-exposed adults had a higher standard metabolic rate. Our results provide evidence that parental exposure to ocean acidification may be maladaptive when larvae experience multiple stressors.
High-protein paternal diet confers an advantage to sons in sperm competition
Authors: Zajitschek Felix , Zajitschek Susanne , Manier Mollie
Published: February 2017

Parental environment can widely influence offspring phenotype, but paternal effects in the absence of parental care remain poorly understood. We asked if protein content in the larval diet of fathers affected paternity success and gene expression in their sons. We found that males reared on high-protein diet had sons that fared better during sperm competition, suggesting that postcopulatory sexual selection is subject to transgenerational paternal effects. Moreover, immune response genes were downregulated in sons of low-protein fathers, while genes involved in metabolic and reproductive processes were upregulated.
Image-based modelling of skeletal muscle oxygenation
Authors: Zeller-Plumhoff B. , Roose T. , Clough G. F. , Schneider P.
Published: February 2017

The supply of oxygen in sufficient quantity is vital for the correct functioning of all organs in the human body, in particular for skeletal muscle during exercise. Disease is often associated with both an inhibition of the microvascular supply capability and is thought to relate to changes in the structure of blood vessel networks. Different methods exist to investigate the influence of the microvascular structure on tissue oxygenation, varying over a range of application areas, i.e. biologicalin vivoandin vitroexperiments, imaging and mathematical modelling. Ideally, all of these methods should be combined within the same framework in order to fully understand the processes involved. This review discusses the mathematical models of skeletal muscle oxygenation currently available that are based upon images taken of the muscle microvasculaturein vivoandex vivo. Imaging systems suitable for capturing the blood vessel networks are discussed and respective contrasting methods presented. The review further informs the association between anatomical characteristics in health and disease. With this review we give the reader a tool to understand and establish the workflow of developing an image-based model of skeletal muscle oxygenation. Finally, we give an outlook for improvements needed for measurements and imaging techniques to adequately investigate the microvascular capability for oxygen exchange.
Historical gene flow constraints in a northeastern Atlantic fish: phylogeography of the ballan wrasseLabrus bergyltaacross its distribution range
Authors: Almada Frederico , Francisco Sara M. , Lima Cristina S. , FitzGerald Richard , Mirimin Luca , Villegas-Ríos David , Saborido-Rey Fran , Afonso Pedro , Morato Telmo , Bexiga Sérgio , Robalo Joana I.
Published: February 2017

The distribution and demographic patterns of marine organisms in the north Atlantic were largely shaped by climatic changes during the Pleistocene, when recurrent glacial maxima forced them to move south or to survive in northern peri-glacial refugia. These patterns were also influenced by biological and ecological factors intrinsic to each species, namely their dispersion ability. The ballan wrasse (Labrus bergylta), the largest labrid fish along Europe's continental margins, is a target for fisheries and aquaculture industry. The phylogeographic pattern, population structure, potential glacial refugia and recolonization routes for this species were assessed across its full distribution range, using mitochondrial and nuclear markers. The existence of a marked population structure can reflect both recolonization from three distinct glacial refugia and current and past oceanographic circulation patterns. Although isolated in present times, shared haplotypes between continental and Azores populations and historical exchange of migrants in both directions point to a common origin ofL. bergylta. This situation is likely to be maintained and/or accentuated by current circulation patterns in the north Atlantic, and may lead to incipient speciation in the already distinct Azorean population. Future monitoring of this species is crucial to evaluate how this species is coping with current environmental changes.
Both the elongation of attached crossbridges and residual force enhancement contribute to joint torque enhancement by the stretch-shortening cycle
Authors: Fukutani Atsuki , Misaki Jun , Isaka Tadao
Published: February 2017

This study examined the influence of the elongation of attached crossbridges and residual force enhancement on joint torque enhancement by the stretch-shortening cycle (SSC). Electrically evoked submaximal tetanic plantar flexions were adopted. Concentric contractions were evoked in the following three conditions: after 2 s isometric preactivation (ISO condition), after 1 s isometric then 1 s eccentric preactivation (ECC condition), and after 1 s eccentric then 1 s isometric preactivation (TRAN condition). Joint torque and fascicle length were measured during the concentric contraction phase. While no differences in fascicle length were observed among conditions at any time points, joint torque was significantly higher in the ECC than TRAN condition at the onset of concentric contraction. This difference would be caused by the dissipation of the elastic energy stored in the attached crossbridges induced by eccentric preactivation in TRAN condition due to 1 s transition phase. Furthermore, joint torques observed 0.3 and 0.6 s after concentric contraction were significantly larger in the ECC and TRAN conditions than in the ISO condition while no difference was observed between the ECC and TRAN conditions. Since the elastic energy stored in the attached crossbridges would have dissipated over this time frame, this result suggests that residual force enhancement induced by eccentric preactivation also contributes to joint torque enhancement by the SSC.
A construction of a large family of commuting pairs of integrable symplectic birational four-dimensional maps
Authors: Petrera Matteo , Suris Yuri B.
Published: February 2017

We give a construction of completely integrable four-dimensional Hamiltonian systems with cubic Hamilton functions. Applying to the corresponding pairs of commuting quadratic Hamiltonian vector fields the so called Kahan–Hirota–Kimura discretization scheme, we arrive at pairs of birational four-dimensional maps. We show that these maps are symplectic with respect to a symplectic structure that is a perturbation of the standard symplectic structure on

R

4

, and possess two independent integrals of motion, which are perturbations of the original Hamilton functions and which are in involution with respect to the perturbed symplectic structure. Thus, these maps are completely integrable in the Liouville–Arnold sense. Moreover, under a suitable normalization of the original pairs of vector fields, the pairs of maps commute and share the invariant symplectic structure and the two integrals of motion.
Eshelby's problem of a spherical inclusion eccentrically embedded in a finite spherical body
Authors: Zou W.-N. , He Q.-C.
Published: February 2017

Resorting to the superposition principle, the solution of Eshelby's problem of a spherical inclusion located eccentrically inside a finite spherical domain is obtained in two steps: (i) the solution to the problem of a spherical inclusion in an infinite space; (ii) the solution to the auxiliary problem of the corresponding finite spherical domain subjected to appropriate boundary conditions. Moreover, a set of functions called the sectional and harmonic deviators are proposed and developed to work out the auxiliary solution in a series form, including the displacement and Eshelby tensor fields. The analytical solutions are explicitly obtained and illustrated when the geometric and physical parameters and the boundary condition are specified.
Early mortality saves energy: estimating the energetic cost of excess offspring in a seabird
Authors: Vedder Oscar , Zhang He , Bouwhuis Sandra
Published: February 2017

Offspring are often produced in excess as insurance against stochastic events or unpredictable resources. This strategy may result in high early-life mortality, yet age-specific mortality before offspring independence and its associated costs have rarely been quantified. In this study, we modelled age-specific survival from hatching to fledging using 24 years of data on hatching order (HO), growth and age of mortality of more than 15 000 common tern (
Sterna hirundo
) chicks. We found that mortality peaked directly after hatching, after which it declined rapidly. Mortality hazard was best described with the Gompertz function, and was higher with later HO, mainly due to differences in baseline mortality hazard, rather than age-dependent mortality. Based on allometric mass–metabolism relationships and detailed growth curves of starving chicks, we estimated that the average metabolizable energy intake of non-fledged chicks was only 8.7% of the metabolizable energy intake of successful chicks during the nestling phase. Although 54% of hatchlings did not fledge, our estimates suggest them to have consumed only 9.3% of the total energy consumption of all hatched chicks in the population before fledging. We suggest that rapid mortality of excess offspring is part of an adaptive brood reduction strategy to the benefit of the parents.
Adaptive shaping of the behavioural and neuroendocrine phenotype during adolescence
Authors: Zimmermann Tobias D. , Kaiser Sylvia , Hennessy Michael B. , Sachser Norbert
Published: February 2017

Environmental conditions during early life can adaptively shape the phenotype for the prevailing environment. Recently, it has been suggested that adolescence represents an additional temporal window for adaptive developmental plasticity, though supporting evidence is scarce. Previous work has shown that male guinea pigs living in large mixed-sex colonies develop a low-aggressive phenotype as part of a queuing strategy that is adaptive for integrating into large unfamiliar colonies. By contrast, males living in pairs during adolescence become highly aggressive towards strangers. Here, we tested whether the high-aggressive phenotype is adaptive under conditions of low population density, namely when directly competing with a single opponent for access to females. For that purpose, we established groups of one pair-housed male (PM), one colony-housed male (CM) and two females. PMs directed more aggression towards the male competitor and more courtship and mating towards females than did CMs. In consequence, PMs attained the dominant position in most cases and sired significantly more offspring. Moreover, they showed distinctly higher testosterone concentrations and elevated cortisol levels, which probably promoted enhanced aggressiveness while mobilizing necessary energy. Taken together, our results provide the clearest evidence to date for adaptive shaping of the phenotype by environmental influences during adolescence.
The transcriptional basis of quantitative behavioral variation
Authors: Benowitz Kyle M. , McKinney Elizabeth C. , Cunningham Christopher B. , Moore Allen J.
Published: February 2017

What causes individuals to produce quantitatively different phenotypes? While substantial research has focused on the allelic changes that affect phenotype, we know less about how gene expression accompanies variable phenotypes. Here, we investigate the transcriptional basis of variation in parental provisioning using two species of burying beetle,Nicrophorus orbicollisandNicrophorus vespilloides. Specifically, we used RNA-seq to compare the transcriptomes of parents that provided high amounts of provisioning behavior versus low amounts in males and females of each species. We found that there were no overarching transcriptional patterns that distinguish high from low caring parents, and no informative transcripts that displayed particularly large expression differences in females or males. However, we did find more subtle gene expression changes between high and low provisioning parents that are consistent across sexes as well as between the two species. Furthermore, we show that transcripts previously implicated in transitioning into parental care inN. vespilloideshad high variance in the levels of transcription and were unusually likely to display differential expression between high and low provisioning parents. Thus, quantitative behavioral variation appears to reflect many transcriptional differences of small effect. We show that nuanced regulation of the same gene products that are required for the transition of one behavioral state to another are also those influencing variation within a behavioral state.

Author Summary

Burying beetles in the genusNicrophorusbreed on vertebrate carcasses and provide advanced parental care to their offspring by regurgitating partially digested flesh. However, all adult beetles do not uniformly express this trait. Some provide a large amount of parenting to their offspring, and some only a little. Here, we investigate the genetic causes of why someNicrophorusbeetles feed their offspring more than others. We demonstrate that this difference is likely caused by many small changes in gene expression, rather than a few genes that have major effects. We also find that some of the same genes that help to turn on parental care behavior in burying beetles also seem to play a role in determining how much care a beetle gives. These results provide new angles on longstanding questions about the complexity of the mechanisms that underlie quantitative variation in populations.
Extremely rare variants reveal patterns of germline mutation rate heterogeneity in humans
Authors: Carlson Jedidiah , Locke Adam E , Flickinger Matthew , Zawistowski Matthew , Levy Shawn ,   The BRIDGES Consortium, Myers Richard M , Boehnke Michael , Kang Hyun Min , Scott Laura J , Li Jun Z , Zöllner Sebastian
Published: February 2017

A detailed understanding of the genome-wide variability of single-nucleotide germline mutation rates is essential to studying human genome evolution. Here we use ∼36 million singleton variants from 3,560 whole-genome sequences to infer fine-scale patterns of mutation rate heterogeneity. Mutability is jointly affected by adjacent nucleotide context and diverse genomic features of the surrounding region, including histone modifications, replication timing, and recombination rate, sometimes suggesting specific mutagenic mechanisms. Remarkably, GC content, DNase hypersensitivity, CpG islands, and H3K36 trimethylation are associated with both increased and decreased mutation rates depending on nucleotide context. We validate these estimated effects in an independent dataset of ∼46,000de novomutations, and confirm our estimates are more accurate than previously published estimates based on ancestrally older variants without considering genomic features. Our results thus provide the most refined portrait to date of the factors contributing to genome-wide variability of the human germline mutation rate.
MITE-based drives to transcriptional control of genome host
Authors: Vaschetto Luis María
Published: February 2017

In a recent past, Transposable Elements (TEs) were referred as selfish genetic components only capable of copying themselves with the aim to increase the odds that will be inherited. Nonetheless, TEs have been initially proposed as positive control elements acting in synergy with the host. Nowadays, it is well known that TE movement into genome host comprise an important evolutionary mechanism capable to produce diverse chromosome rearrangements and thus increase the adaptive fitness. According to as insights into TE functioning are increasing day to day, the manipulation of transposition has raised an interesting possibility to setting the host functions, although the lack of appropriate genome engineering tools has unpaved it. Fortunately, the emergence of genome editing technologies based on programmable nucleases, and especially the arrival of a multipurpose RNA-guided Cas9 endonuclease system, has made it possible to reconsider this challenge. For such purpose, a particular type of transposons referred as Miniature Inverted-repeat Transposable Elements (MITEs) has shown a series of interesting characteristics for designing functional drivers. Here, recent insights into MITE elements and versatile RNA-guided CRISPR/Cas9 genome engineering system are given to outline an effective strategy that allows to deploy the TE potential for control of the host transcriptional activity.
Ongoing human chromosome end extension revealed by analysis of BioNano and nanopore data
Authors: Shao Haojing , Zhou Chenxi , Cao Minh Duc , Coin Lachlan J.M.
Published: February 2017

The majority of human chromosome ends remain incompletely assembled due to their highly repetitive structure. In this study, we use BioNano data to anchor and extend chromosome ends from two European trios as well as two unrelated Asian genomes. BioNano assembled chromosome ends are structurally divergent from the reference genome, including both missing sequence (10%) and extensions(22%). These extensions are heritable and in some cases divergent between Asian and European samples. Six ninths of the extension sequence in NA12878 can be confirmed and filled by nanopore data. We identify two sequence families in these sequences which have undergone substantial duplication in multiple primate lineages. We show that these sequence families have arisen from progenitor interstitial sequence on the ancestral primate chromosome 7. Comparison of chromosome end sequences from 15 species revealed that chromosome end missing sequence matches the corresponding phylogenetic relationship and revealed a rate of chromosome extension per chromosome of 0.0020 bp per year in average.
Biomedical Text Mining for Research Rigor and Integrity: Tasks, Challenges, Directions
Authors: Kilicoglu Halil
Published: February 2017

An estimated quarter of a trillion US dollars is invested in the biomedical research enterprise annually. There is growing alarm that a significant portion of this investment is wasted, due to problems in reproducibility of research findings and in the rigor and integrity of research conduct and reporting. Recent years have seen a flurry of activities focusing on standardization and guideline development to enhance the reproducibility and rigor of biomedical research. Research activity is primarily communicated via textual artifacts, ranging from grant applications to journal publications. These artifacts can be both the source and the end result of practices leading to research waste. For example, an article may describe a poorly designed experiment, or the authors may reach conclusions not supported by the evidence presented. In this article, we pose the question of whether biomedical text mining techniques can assist the stakeholders in the biomedical research enterprise in doing their part towards enhancing research integrity and rigor. In particular, we identify four key areas in which text mining techniques can make a significant contribution: plagiarism/fraud detection, ensuring adherence to reporting guidelines, managing information overload, and accurate citation/enhanced bibliometrics. We review the existing methods and tools for specific tasks, if they exist, or discuss relevant research that can provide guidance for future work. With the exponential increase in biomedical research output and the ability of text mining approaches to perform automatic tasks at large scale, we propose that such approaches can add checks and balances that promote responsible research practices and can provide significant benefits for the biomedical research enterprise.

Supplementary information

Supplementary material is available atBioRxiv.
Identification of the primary peptide inhibitor contaminant of fibrillation and toxicity in synthetic Amyloid-β42
Authors: Adams Daniel J. , Nemkov Travis , Mayer John P. , Old William M. , Stowell Michael H. B.
Published: February 2017

Understanding the pathophysiology of Alzheimer disease has relied upon the use of amyloid peptides from a variety of sources, but most predominantly synthetic peptides produced using t-butyloxycarbonyl (Boc) or 9-fluorenylmethoxycarbonyl (Fmoc) chemistry. These synthetic methods can lead to minor impurities which can have profound effects on the biological activity of amyloid peptides. Here we used a combination of cytotoxicity assays, fibrillation assays and high resolution mass spectrometry (MS) to identify impurities in synthetic amyloid preparations that inhibit both cytotoxicity and aggregation. We identify the Aβ42Δ39 species as the major peptide contaminant responsible for limiting both cytotoxicity and fibrillation of the amyloid peptide. In addition, we demonstrate that the presence of this minor impurity inhibits the formation of a stable Aβ42 dimer observable by MS in very pure peptide samples. These results highlight the critical importance of purity and provenance of amyloid peptides in Alzheimer’s research in particular, and biological research in general.
Can Ebola Virus evolve to be less virulent in humans?
Authors: Sofonea Mircea T. , Aldakak Lafi , Boullosa Luis Fernando , Alizon Samuel
Published: February 2017

This preprint has been reviewed and recommended by Peer Community In Evolutionary Biology (). Understanding Ebola Virus (EBOV) virulence evolution is not only timely but also raises specific questions because it causes one of the most virulent human infections and it is capable of transmission after the death of its host. Using a compartmental epidemiological model that captures three transmission routes (by regular contact, via dead bodies and by sexual contact), we infer the evolutionary dynamics of case fatality ratio (CFR) on the scale of an outbreak and on the long term. Our major finding is that the virus’s specific life cycle imposes selection for high levels of virulence and that this pattern is robust to parameter variations in biological ranges. In addition to shedding a new light on the ultimate causes of EBOV’s high virulence, these results generate testable predictions and contribute to informing public health policies. In particular, burial management stands out as the most appropriate intervention since it decreases theR0of the epidemics, while imposing selection for less virulent strains.

Impact Summary

The severe haemorrhagic fever caused by Ebola Virus (EBOV) usually kills more than one infected individual out of two in the absence of treatment, which makes this pathogen one of the most virulent known to humans. The recent outbreak in West Africa (2013-2016) revealed that the virus is able to spread and persist for months across countries. It is often thought that virulence could be due to the fact that the virus is adapted to its reservoir host. Given that microbes evolve rapidly, it is important to determine whether EBOV virulence is likely to decrease as the virus adapts to its human host. To address this problem, we developed a novel mathematical model tailored to EBOV’s life cycle, notably by capturing its three main transmission routes (by regular contact, sexual contact and via dead bodies). We investigated the evolutionary trends of EBOV’s virulence on different time scales (outbreak initiation, short term and long term). Our results reveal that the virulence of EBOV might not be due to the maladaptation of the virus, but could rather originate from its unique life cycle. These results are robust to the parameter values chosen. From a public health perspective, burial management stands out as the main leverage to fight the virulence of EBOV, both on the short and long terms.
Unifying Temporal Phenomena in Human Visual Cortex
Authors: Zhou Jingyang , Benson Noah C. , Kay Kendrick , Winawer Jonathan
Published: February 2017

Neuronal responses in visual cortex show a diversity of complex temporal properties. These properties include sub-additive temporal summation, response reduction with repeated or sustained stimuli (adaptation), and slower dynamics at low stimulus contrast. Here, we hypothesize that these seemingly disparate effects can be explained by a single, shared computational mechanism. We propose a model consisting of a linear stage, followed by history-dependent gain control. The model accounts for these various temporal phenomena, tested against an unusually diverse set of measurements - intracranial electrodes in patients, fMRI, and macaque single unit spiking. The model further enables us to uncover a systematic and rich variety of temporal encoding strategies across visual cortex: First, temporal receptive field shape differs both across and within visual field maps. Second, later visual areas show more rapid and pronounced adaptation. Our study provides a new framework to understand the transformation between visual input and dynamical cortical responses.

Author Summary

The nervous system extracts meaning from the distribution of light over space and time. Spatial vision has been a highly successful research area, and the spatial receptive field has served as a fundamental and unifying concept that spans perception, computation, and physiology. While there has also been a large interest in temporal vision, the temporal domain has lagged the spatial domain in terms of quantitative models of how signals are transformed across the visual hierarchy. Here we present a model of temporal dynamics of neuronal responses in human cerebral cortex. We show that the model can accurately predict responses at the millisecond scale using intracortical electrodes in patient volunteers, and that the same model generalizes to multiple types of other measurements, including functional MRI and action potentials from monkey cortex. Further, we show that a single model can account for a variety of temporal phenomena, including short-term adaptation and slower dynamics at low stimulus contrast. By developing a computational model and showing that it successfully generalizes across measurement types, cortical areas, and stimuli, we provide new insights into how time-varying images are encoded and transformed into dynamic cortical responses.