bluuebunny/crossref_metadata_2025 huggingface dataset:
The manifold roles of sialic acid for the biological functions of endothelial glycoproteins
Authors: D’Addio Marco , Frey Jasmin , Otto Vivianne I
Published: January 2020

Vascular endothelia are covered with a dense glycocalix that is heavily sialylated. Sialylation of vascular glycoconjugates is involved in the regulation of cell–cell interactions, be it among endothelial cells at cell junctions or between endothelial and blood-borne cells. It also plays important roles in modulating the binding of soluble ligands and the signaling by vascular receptors. Here, we provide an overview over the sialylation-function relationships of glycoproteins expressed in the blood and lymphatic vasculature. We first describe cellular interactions in which sialic acid contributes in a stereospecific manner to glycan epitopes recognized by glycan-binding proteins. Our major focus is however on the rarely discussed examples of vascular glycoproteins whose biological functions are modulated by sialylation through other mechanisms.
Seascape connectivity exerts differing effects for fish assemblages in distinct habitats of the surf zones of ocean beaches
Authors: Mosman Jesse D , Henderson Christopher J , Olds Andrew D , Gilby Ben L , Schlacher Thomas A
Published: January 2020

Animals move throughout coastal seascapes to disperse, feed, and spawn, including the surf zones of ocean beaches. Yet, the influences of seascape context on surf-zone fish are largely unquantified. We sampled surf-zone fish assemblages with baited remote underwater video deployments at 25 beaches across 50 km of coastline in eastern Australia to determine if variation in the spatial configuration of broader coastal seascapes shapes fish assemblages in different surf-zone habitats. We show that surf zones are not homogenous fish habitats, with offshore bars and nearshore troughs having distinct fish assemblages, shaped by different environmental variables. Fish assemblages of offshore bars were characterized by greater species richness and a higher abundance of indicator species (as identified by Dufrene–Legendre indicator species analysis) when close to rocky reefs and estuaries. In contrast, fish assemblages of nearshore troughs were characterized by greater species richness and a higher abundance of indicator species when far from estuaries, and off wider beaches. Our results highlight the importance of seascape connectivity in structuring surf-zone fish assemblages. Consequently, management approaches need to more thoroughly quantify the effects of seascape connectivity over smaller spatial scales and consider surf zones as key components of broader coastal habitat mosaics.
Religion in human rights law: A normative restatement
Authors: Khaitan Tarunabh , Norton Jane Calderwood
Published: January 2020

In a companion article published in the preceding issue of this journal, “The Right to Freedom of Religion and the Right against Religious Discrimination: Theoretical Distinctions,” we focused on the theoretical differences between the right to freedom of religion and the right against religious discrimination. We explained that the right to freedom of religion is best understood as protecting our interest in religious adherence (and non-adherence), understood from the committed perspective of the (non)adherent. On the other hand, the right against religious discrimination is best understood as protecting our non-committal interest in the unsaddled membership of our religious group. This follow-up article builds upon these theoretical insights to show how key doctrinal implications follow from this distinction between our interest in religious (non)adherence and our interest in unsaddled membership of a religious group. Doctrinal implications arise for the respective scope of the two rights, whether they may be claimed against non-state actors, and their divergent tolerance levels for religious establishment. We explain that these theoretical distinctions imply that the scope of religious freedom is extremely broad, whereas that of religious antidiscrimination is relatively narrow. Moreover, religious freedom should be restricted as a claim solely against the state (or, possibly, other state-like bodies), whereas a claim of religious discrimination may be permitted against certain non-state actors as well. Third, we demonstrate that certain forms of religious establishment, and other non-zero-sum benefits to particular religious groups, breach the antidiscrimination guarantee but not (necessarily) the religious freedom guarantee. In the final section of this article, we map the areas of overlap between the two rights and identify cases where one of these rights might be engaged but not the other.
Rebel Group Attrition and Reversion to Violence: Micro-Level Evidence from Syria
Authors: Mironova Vera , Alhamad Karam , Whitt Sam
Published: January 2020

Why might former rebel combatants ever revert to fighting? The purpose of this research note is to inform the scholarly community on rebel incentives to remobilize for violence, a topic which has been underexplored in the literature, using evidence from an ongoing conflict: the case of volunteer ex-combatants in the Syrian civil war. In late 2014 to early 2015, we conducted surveys with 196 ex-fighters who served with different rebel group brigades linked to the Free Syrian Army as well as moderate Islamist and jihadist groups. Interviews were conducted in Gaziantep, Turkey, a common destination for combatants exiting the battlefield in rebel-held territory in northern Syria. We find that ex-fighters who are ideologically committed to the defeat of the Assad regime and/or the establishment of an Islamic state are most likely to want to return to combat. However, rebel group organizational deficiencies and strategies keep many highly motivated fighters away. Our results illustrate how rebel fighters might quickly remobilize when disciplined, well-organized rebel groups emerge on the scene, as evidenced by the rapid ascent of the Islamic State (ISIS).
Light Forge: A Microfluidic DNA Melting-based Tuberculosis Test
Authors: Mbano Ian M , Mandizvo Tawanda , Rogich Jerome , Kunota Tafara T R , Mackenzie Jared S , Pillay Manormoney , Balagaddé Frederick K
Published: January 2020

Background

There is a well-documented lack of rapid, low-cost tuberculosis (TB) drug resistance diagnostics in low-income settings across the globe. It is these areas that are plagued with a disproportionately high disease burden and in greatest need of these diagnostics.

Methods

In this study, we compared the performance of Light Forge, a microfluidic high-resolution melting analysis (HRMA) prototype for rapid low-cost detection of TB drug resistance with a commercial HRMA device, a predictive “nearest-neighbor” thermodynamic model, DNA sequencing, and phenotypic drug susceptibility testing (DST). The initial development and assessment of the Light Forge assay was performed with 7 phenotypically drug resistant strains of Mycobacterium tuberculosis (M.tb) that had their rpoB gene subsequently sequenced to confirm resistance to Rifampin. These isolates of M.tb were then compared against a drug-susceptible standard, H37Rv. Seven strains of M.tb were isolated from clinical specimens and individually analyzed to characterize the unique melting profile of each strain.

Results

Light Forge was able to detect drug-resistance linked mutations with 100% concordance to the sequencing, phenotypic DST and the “nearest neighbor” thermodynamic model. Researchers were then blinded to the resistance profile of the seven M.tb strains. In this experiment, Light Forge correctly classified 7 out of 9 strains as either drug resistant or drug susceptible.

Conclusions

Light Forge represents a promising prototype for a fast, low-cost diagnostic alternative for detection of drug resistant strains of TB in resource constrained settings.
Method Consolidation to Improve Scope and Efficiency in Postmortem Toxicology
Authors: Gevorkyan Jirair , Wong Megan , Pearring Sue , Rodda Luke N
Published: January 2020

Systematic toxicological approaches that employ both ideology changes and improvements in instrumentation and sample extraction allow for improved toxicology testing efficiency through lower sensitivities, higher specificity and minimized resource use. Historically, the San Francisco Office of the Chief Medical Examiner relied heavily on a gas chromatography mass spectrometry (GC–MS) testing regime, comprised of individual drug-class confirmation and quantitation assays. Traditional methods utilizing GC–MS typically require iterations of testing, exhausting sample volume, and hindering productivity and turnaround times, particularly for polypharmacy cases frequently seen in modern postmortem toxicology. The method described here consolidated the scope of seven legacy methods into a single liquid chromatography tandem mass spectrometry (LC–MS/MS) method for better sensitivity, higher throughput, minimal sample consumption for the quantitation of drugs of abuse and improved quality assurance with the incorporation of smart, automated processing. About 100 μL of blood or urine were rapidly extracted using a simple acetonitrile protein crash and subsequent in-vial filtration and injected on to an LC–MS-MS system. The developed method was fully validated to SWGTOX and international guidelines and incorporated 55 analytes along with a customized query that facilitates rapid and consistent application of acceptability criteria for data processing and review. Applicability was demonstrated with the analysis of 1,389 samples (858 blood and 531 urine) where at least 41% of positive results may have been missed due to their decreased sensitivity and 11% of results were not within the scope of the previous analytical methods estimated. On average, cases in this study would have previously required three distinct GC–MS assays, 3 mL of blood, and upwards of 30 h of active staff time. The described LC–MS-MS analytical approach has mitigated the need to perform multiple assays, utilized only 0.1 mL of sample, significantly reduced analyst work time, incorporated 10 additional analytes and allowed for a more comprehensive testing regime to better inform cause of death determinations.
A Retrospective of Prevalence of Drugs of Abuse by Hair Analysis in Shanghai using LC–MS-MS
Authors: Wang Xin , Cui Jingjing , Zhuo Yue , Shen Baohua , Zhang Sujing , Liu Wei , Shen Min , Xiang Ping
Published: January 2020

This study presents a retrospective analysis of the prevalence of drug abuse in Shanghai by hair analysis. Files and toxicology analysis results of a total of 5,610 cases requesting for hair analysis of abused drugs at the Academy of Forensic Science (AFS) in Shanghai over 12 months between August 2018 and July 2019 were reviewed. All cases of drug abuse identified by hair analysis were from the public security organs in Shanghai, China. Hair samples were analyzed for drugs of abuse and related metabolites, mainly including amphetamine (AMP), methamphetamine (MA), 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA), tetrahydrocannabinol (THC), ketamine (K), norketamine (NK), cocaine (COC), benzoylecgonine, morphine, 6-acetylmorphine, flunitrazepam, and 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT), using liquid chromatography–tandem mass spectrometry (LC–MS-MS). Among the 5,610 cases, 1,713 (30.5%) were positive for drugs of abuse, with amphetamine-type stimulants (ATS) (57%), including amphetamines (AMP and MA) (48%), MDMA and MDA (9%), being the most frequently detected drugs, followed by THC (14%), COC (8%), 5-MeO-DIPT (8%), and K (7%). The majority (75%) of positive hair samples were from male subjects. Overall, 77% of abusers were younger than 44 years old. The proportion of female subjects (22.3%) under 24 years was larger than that of male subjects (7.8%). There were 132 cases (7.7%) in which more than one type of drug was detected among 1,713 drug-positive cases. The most common combination was MDMA and K. The present study characterizes the current toxicological profile of drug abuse cases and provides a scientific basis for drug abuse prevention. Moreover, the hair concentration distributions of the commonly abused drugs in positive cases have been reported.
Toxicokinetic Studies and Analytical Toxicology of the New Synthetic Opioids Cyclopentanoyl-Fentanyl and Tetrahydrofuranoyl-Fentanyl
Authors: Gampfer Tanja M , Wagmann Lea , Richter Matthias J , Fischmann Svenja , Westphal Folker , Meyer Markus R
Published: January 2020

The growing number of new synthetic opioids (NSO) on the new psychoactive substances (NPS) market bears new challenges in toxicology. As their toxicodynamics and particularly their toxicokinetics are usually unknown, impact on human health is not yet fully understood. Detection of the 2 NSO cyclopentanoyl-fentanyl (CP-F) and tetrahydrofuranoyl-fentanyl (THF-F) was first reported in 2016. Both were involved in several fatal intoxication cases, but no detailed information about their toxicological characteristics is available so far. The main purpose of this study was therefore to investigate the in vitro toxicokinetics and in vivo analytical toxicology of CP-F and THF-F by means of liquid chromatography high-resolution tandem mass spectrometry (LC-HRMS/MS). These studies included metabolic stability, phase I and II metabolism, isozyme mapping, plasma protein binding and detectability in LC-HRMS/MS standard urine screening approaches (SUSA) using rat urine samples. In total, 12 phase I metabolites of CP-F and 13 of THF-F were identified, among them 9 metabolites described for the first time. Overall, N-dealkylations, hydroxylations and dihydroxylations were the main metabolic reactions. The cytochrome P450 (CYP) isozymes mainly involved were CYP2D6 and CYP3A4, leading to elevated drug levels and intoxications in CYP2D6 poor metabolizers. CP-F showed a high plasma protein binding of 99%, which may increase the risk of toxicity by simultaneous intake of other highly bound drugs. Detectability studies showed that neither the parent compounds nor their metabolites were detectable in rat urine using LC-HRMS/MS SUSA. However, a more sophisticated analytical strategy was successfully applied and should be used for analytical confirmation of an intake of CP-F and/or THF-F.
Developing and Validating a Fast and Accurate Method to Quantify 18 Antidepressants in Oral Fluid Samples Using SPE and LC–MS-MS
Authors: Shin Sanghee Sarah , Borg Damon , Stripp Richard
Published: January 2020

Antidepressant drugs are one of the most widely used medicines for treating major depressive disorders for long time periods. Oral fluid (OF) testing offers an easy and non-invasive sample collection. Detection of antidepressants in OF is important in clinical and forensic settings, such as therapeutic drug monitoring and roadside testing for driving under influence. We developed and validated a comprehensive liquid chromatography–tandem mass spectrometry method for 18 antidepressants (amitriptyline, bupropion, citalopram, clomipramine, cyclobenzaprine, desipramine, desvenlafaxine, doxepin, duloxetine, fluoxetine, imipramine, mirtazapine, nortriptyline, paroxetine, sertraline, trazodone, trimipramine, venlafaxine) in oral fluid collected by Quantisal® oral collection devices. One-half milliliter of Quantisal® OF (125 μL of neat OF) was submitted to solid-phase extraction. The chromatographic separation was performed employing a biphenyl column in gradient mode with a total run time of 5 min. The MS detection was achieved by multiple-reaction monitoring with two transitions per compound. The range for linearity of all analytes was from 10 to 1,000 ng/mL, with a limit of detection of 10 ng/mL. Intra and inter-day accuracy and precision (n = 15) were all within acceptable limits, ±20% error and ±15% relative standard deviation. Analyte recovery at 400 ng/mL concentration (n = 15) ranged from 91 to 129%. Matrix effect ranged from 73.7 to 157%. The internal proficiency test detected all antidepressants with accuracy ranging from 83.1 to 112.1%. The authentic patient sample showed a percentage difference compared to the previously calculated concentration of 86.3–111%. This method provides for the rapid detection of 18 antidepressants and metabolites in OF, which is readily applicable to a routine laboratory.
The safety and effectiveness of carbon nanoparticles suspension in tracking lymph node metastases of colorectal cancer: a prospective randomized controlled trial
Authors: Wang Renjie , Mo Shaobo , Liu Qi , Zhang Wenming , Zhang Zhaozhen , He Yiping , Cai Guoxiang , Li Xinxiang
Published: January 2020

Objective

This study was to evaluate the safety and effectiveness of carbon nanoparticles suspension in tracking lymph node metastases of colorectal cancer.

Methods

Eligible patients diagnosed with stages I–III colorectal cancer in Fudan University Shanghai Cancer Center between 1 May 2017 and 31 May 2018 fulfilling the inclusion criteria were included in this prospective randomized controlled study. All the patients were randomly allocated to two groups: the nanocarbon group and the control group. Patients’ clinicopathological characteristics were compared between the nanocarbon group and the control group. For continuous variables, data were presented as mean (±SD) and differences between the two groups were compared by the Mann–Whitney U test; for categorical variables, data was presented as frequency (%) and the Pearson’s chi-squared test was used to compare the differences between two groups.

Results

All the patients’ characteristics between two groups did not achieve statistical significance (P > 0.05). Patients in nanocarbon group were more likely to be associated with more lymph nodes retrieved totally compared with control group (19.84 ± 6.428 vs. 17.41 ± 7.229, P < 0.001). The number of lymph nodes retrieved in nanocarbon group were more likely to be ≥12 than that in the control group (P = 0.005).

Conclusions

Our study confirmed the safety of using carbon nanoparticles suspension as a tracer in colorectal cancer. More importantly, nanocarbon could significantly increase the detected number of lymph nodes in colorectal cancer, which can help improve the accuracy of lymph node staging and even improve patients’ survival.
Symbolic demarcation: the role of status symbols in preserving interprofessional boundaries
Authors: Siebert Sabina
Published: January 2020

Interprofessional demarcation is one of the key themes in the study of the professions. This study aims to understand the symbolic resources activated when an elite profession faces challenges to its task jurisdiction from a new, emerging profession. I attempt to answer the following question: ‘How are status symbols used to maintain jurisdictional boundaries between professions?’ I analyzed ethnographic material concerning one of the most elite and ancient professions: Scottish advocates—known as barristers outside Scotland. I found that when faced with competition from other professions, advocates engaged in differentiation through the use of status symbols such as professional dress in and out of court, ceremonies, and everyday rituals. I observed two concurrent processes of differentiation: the maintenance of stability of status symbols and the maintenance of mobility of status symbols, that is, the ongoing cycle of imitation and avoidance, which happens on the boundary of two competing professions. Building on the Simmel effect (1890), I argue that imitation and distinctiveness preserve professional differentiation, and that managing the stability of some symbols and the mobility of others allow elite professionals to maintain their superior status.
Telomere maintenance in interplay with DNA repair in pathogenesis and treatment of colorectal cancer
Authors: Tomasova Kristyna , Kroupa Michal , Forsti Asta , Vodicka Pavel , Vodickova Ludmila
Published: January 2020

Colorectal cancer (CRC) continues to be one of the leading malignancies and causes of tumour-related deaths worldwide. Both impaired DNA repair mechanisms and disrupted telomere length homeostasis represent key culprits in CRC initiation, progression and prognosis. Mechanistically, altered DNA repair results in the accumulation of mutations in the genome and, ultimately, in genomic instability. DNA repair also determines the response to chemotherapeutics in CRC treatment, suggesting its utilisation in the prediction of therapy response and individual approach to patients. Telomere attrition resulting in replicative senescence, simultaneously by-passing cell cycle checkpoints, is a hallmark of malignant transformation of the cell. Telomerase is almost ubiquitous in advanced solid cancers, including CRC, and its expression is fundamental to cell immortalisation. Therefore, there is a persistent effort to develop therapeutics, which are telomerase-specific and gentle to non-malignant tissues. However, in practice, we are still at the level of clinical trials. The current state of knowledge and the route, which the research takes, gives us a positive perspective that the problem of molecular models of telomerase activation and telomere length stabilisation will finally be solved. We summarise the current literature herein, by pointing out the crosstalk between proteins involved in DNA repair and telomere length homeostasis in relation to CRC.
Machine-driven parameter screen of biochemical reactions
Authors: Poulain Stéphane , Arnaud Ophélie , Kato Sachi , Chen Iris , Ishida Hiro , Carninci Piero , Plessy Charles
Published: January 2020

The development of complex methods in molecular biology is a laborious, costly, iterative and often intuition-bound process where optima are sought in a multidimensional parameter space through step-by-step optimizations. The difficulty of miniaturizing reactions under the microliter volumes usually handled in multiwell plates by robots, plus the cost of the experiments, limit the number of parameters and the dynamic ranges that can be explored. Nevertheless, because of non-linearities of the response of biochemical systems to their reagent concentrations, broad dynamic ranges are necessary. Here we use a high-performance nanoliter handling platform and computer generation of liquid transfer programs to explore in quadruplicates 648 combinations of 4 parameters of a biochemical reaction, the reverse-transcription, which lead us to uncover non-linear responses, parameter interactions and novel mechanistic insights. With the increased availability of computer-driven laboratory platforms for biotechnology, our results demonstrate the feasibility and advantage of methods development based on reproducible, computer-aided exhaustive characterization of biochemical systems.
Neuroimaging of Intracerebral Hemorrhage
Authors: Rindler Rima S , Allen Jason W , Barrow Jack W , Pradilla Gustavo , Barrow Daniel L
Published: January 2020

Intracerebral hemorrhage (ICH) accounts for 10% to 20% of strokes worldwide and is associated with high morbidity and mortality rates. Neuroimaging is indispensable for rapid diagnosis of ICH and identification of the underlying etiology, thus facilitating triage and appropriate treatment of patients. The most common neuroimaging modalities include noncontrast computed tomography (CT), CT angiography (CTA), digital subtraction angiography, and magnetic resonance imaging (MRI). The strengths and disadvantages of each modality will be reviewed. Novel technologies such as dual-energy CT/CTA, rapid MRI techniques, near-infrared spectroscopy, and automated ICH detection hold promise for faster pre- and in-hospital ICH diagnosis that may impact patient management.
Soluble T-Cell Immunoglobulin Mucin Domain-3 Is Associated With Hepatitis C Virus Coinfection and Low-Grade Inflammation During Chronic Human Immunodeficiency Virus Infection
Authors: Hoel Hedda , Ueland Thor , Hove-Skovsgaard Malene , Hartling Hans Jakob , Gelpi Marco , Benfield Thomas , Ullum Henrik , Michelsen Annika E , Aukrust Pål , Nielsen Susanne Dam , Trøseid Marius
Published: January 2020

Background

In well treated human immunodeficiency virus infection (HIV), there is a residual immune activation and immune exhaustion that may contribute to increased risk of comorbidities. T-cell immunoglobulin mucin domain-3 (Tim-3) is an inhibitory molecule involved in HIV-associated T-cell dysfunction. The Tim-3 can be cleaved to soluble Tim-3 (sTim-3) that may serve as a soluble marker of immune exhaustion.

Methods

We measured sTim-3 with enzyme-linked immunosorbent assay DuoSets in a cross-sectional cohort of 1010 people with HIV (PWH) on antiretroviral therapy (ART), and 76 controls from the Copenhagen Co-Morbidity in HIV Infection (COCOMO) study, and in a longitudinal cohort of 60 PWH before and during ART.

Results

In the cross-sectional cohort, levels of sTim-3 were elevated in PWH on ART compared with controls, especially in hepatitis C virus (HCV)-coinfected individuals, and were associated with HCV viremia and inflammation. In the longitudinal cohort, pretreatment sTim-3 correlated with HIV viral load and decreased after ART initiation. Pretreatment sTim-3 correlated inversely with CD4 counts, but it did not predict immunological response in multivariable analyses.

Conclusions

Levels of sTim-3 decreased after ART initiation. In a cross-sectional cohort, levels of sTIM-3 were higher in PWH than in controls and were independently associated with HCV coinfection and high-sensitivity C-reactive protein, representing a potential link between immune exhaustion, inflammation, and risk of comorbidities.
First-In-Human Experience With Integration of Wireless Intracranial Pressure Monitoring Device Within a Customized Cranial Implant
Authors: Mitchell Kerry-Ann S , Anderson William , Shay Tamir , Huang Judy , Luciano Mark , Suarez Jose I , Manson Paul , Brem Henry , Gordon Chad R
Published: January 2020

BACKGROUND

Decompressive craniectomy is a lifesaving treatment for intractable intracranial hypertension. For patients who survive, a second surgery for cranial reconstruction (cranioplasty) is required. The effect of cranioplasty on intracranial pressure (ICP) is unknown.

OBJECTIVE

To integrate the recently Food and Drug Administration-approved, fully implantable, noninvasive ICP sensor within a customized cranial implant (CCI) for postoperative monitoring in patients at high risk for intracranial hypertension.

METHODS

A 16-yr-old female presented for cranioplasty 4-mo after decompressive hemicraniectomy for craniocerebral gunshot wound. Given the persistent transcranial herniation with concomitant subdural hygroma, there was concern for intracranial hypertension following cranioplasty. Thus, cranial reconstruction was performed utilizing a CCI with an integrated wireless ICP sensor, and noninvasive postoperative monitoring was performed.

RESULTS

Intermittent ICP measurements were obtained twice daily using a wireless, handheld monitor. The ICP ranged from 2 to 10 mmHg in the supine position and from −5 to 4 mmHg in the sitting position. Interestingly, an average of 7 mmHg difference was consistently noted between the sitting and supine measurements.

CONCLUSION

This first-in-human experience demonstrates several notable findings, including (1) newfound safety and efficacy of integrating a wireless ICP sensor within a CCI for perioperative neuromonitoring; (2) proven restoration of normal ICP postcranioplasty despite severe preoperative transcranial herniation; and (3) proven restoration of postural ICP adaptations following cranioplasty. To the best of our knowledge, this is the first case demonstrating these intriguing findings with the potential to fundamentally alter the paradigm of cranial reconstruction.
Chronic Care for Attention-Deficit/Hyperactivity Disorder: Clinical Management from Childhood Through Adolescence
Authors: Moss Cierra M. , Metzger Kristina B. , Carey Meghan E. , Blum Nathan J. , Curry Allison E. , Power Thomas J.
Published: January 2020

Objective:

Impairments generally persist when children diagnosed with attention-deficit/hyperactivity disorder (ADHD) mature into adolescence. To examine changes in ADHD care during the transition from childhood to adolescence, we conducted a retrospective, longitudinal cohort study of patients diagnosed with ADHD before the age of 10 years to assess changes from preadolescence through adolescence in (1) frequency by which primary care providers offer ADHD care to patients, (2) range of concerns assessed during patient encounters, and (3) treatments implemented or recommended.

Methods:

We identified patients from 3 practices included in a large primary care network who (1) were born between 1996 and 1997, (2) were diagnosed with ADHD before the age of 10 years, and (3) received primary care continuously from age 9 through late adolescence. Clinical care was compared among patients in preadolescence (age 9–11), early adolescence (age 12–14), and late adolescence (age 15–18).

Results:

Children diagnosed with ADHD before the age of 10 years were less likely to have a documented visit for ADHD during late adolescence (41% of patients) compared with preadolescence (63%, p < 0.001). Evidence of monitoring for depression, suicide, and substance abuse increased from preadolescence to adolescence (p < 0.001) and occurred in about 90% of adolescent patients. However, monitoring for risky sexual activity occurred in only about 50% of adolescents. Discussions of medication diversion and driver readiness were essentially not documented.

Conclusion:

The findings raise concerns about how primary care providers manage adolescents with a history of ADHD. Improving monitoring of risky sexual behavior and driver readiness and providing patient education about medication diversion are needed.
Host heterogeneity mitigates virulence evolution
Authors: White P. Signe , Choi Angela , Pandey Rishika , Menezes Arthur , Penley McKenna , Gibson Amanda K. , de Roode Jacobus , Morran Levi
Published: January 2020

Parasites often infect genetically diverse host populations, and the evolutionary trajectories of parasite populations may be shaped by levels of host heterogeneity. Mixed genotype host populations, compared to homogeneous host populations, can reduce parasite prevalence and potentially reduce rates of parasite adaptation due to trade-offs associated with adapting to specific host genotypes. Here, we used experimental evolution to select for increased virulence in populations of the bacterial parasite
Serratia marcescens
exposed to either heterogeneous or homogeneous populations of
Caenorhabditis elegans
. We found that parasites exposed to heterogeneous host populations evolved significantly less virulence than parasites exposed to homogeneous host populations over several hundred bacterial generations. Thus, host heterogeneity impeded parasite adaptation to host populations. While we detected trade-offs in virulence evolution, parasite adaptation to two specific host genotypes also resulted in modestly increased virulence against the reciprocal host genotypes. These results suggest that parasite adaptation to heterogeneous host populations may be impeded by both trade-offs and a reduction in the efficacy of selection as different host genotypes exert different selective pressures on a parasite population.
The histone H3K4 demethylase JARID1A directly interacts with haematopoietic transcription factor GATA1 in erythroid cells through its second PHD domain
Authors: Karia Dimple , Gilbert Robert C. G. , Biasutto Antonio J. , Porcher Catherine , Mancini Erika J.
Published: January 2020

Chromatin remodelling and transcription factors play important roles in lineage commitment and development through control of gene expression. Activation of selected lineage-specific genes and repression of alternative lineage-affiliated genes result in tightly regulated cell differentiation transcriptional programmes. However, the complex functional and physical interplay between transcription factors and chromatin-modifying enzymes remains elusive. Recent evidence has implicated histone demethylases in normal haematopoietic differentiation as well as in malignant haematopoiesis. Here, we report an interaction between H3K4 demethylase JARID1A and the haematopoietic-specific master transcription proteins SCL and GATA1 in red blood cells. Specifically, we observe a direct physical contact between GATA1 and the second PHD domain of JARID1A. This interaction has potential implications for normal and malignant haematopoiesis.
Emergence of oscillations in a simple epidemic model with demographic data
Authors: Greer Meredith , Saha Raj , Gogliettino Alex , Yu Chialin , Zollo-Venecek Kyle
Published: January 2020

A simple susceptible–infectious–removed epidemic model for smallpox, with birth and death rates based on historical data, produces oscillatory dynamics with remarkably accurate periodicity. Stochastic population data cause oscillations to be sustained rather than damped, and data analysis regarding the oscillations provides insights into the same set of population data. Notably, oscillations arise naturally from the model, instead of from a periodic forcing term or other exogenous mechanism that guarantees oscillation: the model has no such mechanism. These emergent natural oscillations display appropriate periodicity for smallpox, even when the model is applied to different locations and populations. The model and datasets, in turn, offer new observations about disease dynamics and solution trajectories. These results call for renewed attention to relatively simple models, in combination with datasets from real outbreaks.
Analysis of statistical correlations between properties of adaptive walks in fitness landscapes
Authors: Reia Sandro M. , Campos Paulo R. A.
Published: January 2020

The fitness landscape metaphor has been central in our way of thinking about adaptation. In this scenario, adaptive walks are idealized dynamics that mimic the uphill movement of an evolving population towards a fitness peak of the landscape. Recent works in experimental evolution have demonstrated that the constraints imposed by epistasis are responsible for reducing the number of accessible mutational pathways towards fitness peaks. Here, we exhaustively analyse the statistical properties of adaptive walks for two empirical fitness landscapes and theoretical NK landscapes. Some general conclusions can be drawn from our simulation study. Regardless of the dynamics, we observe that the shortest paths are more regularly used. Although the accessibility of a given fitness peak is reasonably correlated to the number of monotonic pathways towards it, the two quantities are not exactly proportional. A negative correlation between predictability and mean path divergence is established, and so the decrease of the number of effective mutational pathways ensures the convergence of the attraction basin of fitness peaks. On the other hand, other features are not conserved among fitness landscapes, such as the relationship between accessibility and predictability.
Beyond the fold: experimentally traversing limit points in nonlinear structures
Authors: Neville Robin M. , Groh Rainer M. J. , Pirrera Alberto , Schenk Mark
Published: January 2020

Recent years have seen a paradigm shift regarding the role of nonlinearities and elastic instabilities in engineering science and applied physics. Traditionally viewed as unwanted aberrations, when controlled to be reversible and well behaved, nonlinearity can enable novel functionalities, such as shape adaptation and energy harvesting. The analysis and design of novel structures that exploit nonlinearities and instabilities have, in part, been facilitated by advances in numerical continuation techniques. An experimental analogue of numerical continuation, on the other hand, has remained elusive. Traditional quasi-static experimental methods control the displacement or force at one or more load-introduction points over the test specimen. This approach fails at limit points in the control parameter, as the immediate equilibrium beyond limit points is statically unstable, causing the structure to snap to a different equilibrium. Here, we propose a quasi-static experimental path-following method that can continue along stable and unstable equilibria, and traverse limit points. In addition to controlling the displacement at the main load-introduction point, the technique relies on overall shape control of the structure using additional actuators and sensors. The proposed experimental method enables extended testing of the emerging class of structures that exploit nonlinearities and instabilities for novel functionality.
Recurrent mutualism breakdown events in a legume rhizobia metapopulation
Authors: Gano-Cohen Kelsey A. , Wendlandt Camille E. , Al Moussawi Khadija , Stokes Peter J. , Quides Kenjiro W. , Weisberg Alexandra J. , Chang Jeff. H. , Sachs Joel L.
Published: January 2020

Bacterial mutualists generate major fitness benefits for eukaryotes, reshaping the host phenotype and its interactions with the environment. Yet, microbial mutualist populations are predicted to generate mutants that defect from providing costly services to hosts while maintaining the capacity to exploit host resources. Here, we examined the mutualist service of symbiotic nitrogen fixation in a metapopulation of root-nodulatingBradyrhizobiumspp.that associate with the native legumeAcmispon strigosus. We quantified mutualism traits of 85Bradyrhizobiumisolates gathered from a 700 km transect in California spanning 10 sampledA. strigosuspopulations. We clonally inoculated eachBradyrhizobiumisolate ontoA. strigosushosts and quantified nodulation capacity and net effects of infection, including host growth and isotopic nitrogen concentration. SixBradyrhizobiumisolates from five populations were categorized as ineffective because they formed nodules but did not enhance host growth via nitrogen fixation. Six additional isolates from three populations failed to form root nodules. Phylogenetic reconstruction inferred two types of mutualism breakdown, including three to four independent losses of effectiveness and five losses of nodulation capacity onA. strigosus. The evolutionary and genomic drivers of these mutualism breakdown events remain poorly understood.
Automatic Detection of Target Engagement in Transcutaneous Cervical Vagal Nerve Stimulation for Traumatic Stress Triggers
Authors: Gurel Nil Z. , Wittbrodt Matthew T. , Jung Hewon , Ladd Stacy L. , Shah Amit J. , Vaccarino Viola , Bremner J. Douglas , Inan Omer T.
Published: January 2020

Transcutaneous cervical vagal nerve stimulation (tcVNS) devices are attractive alternatives to surgical implants, and can be applied for a number of conditions in ambulatory settings, including stress-related neuropsychiatric disorders. Transferring tcVNS technologies to at-home settings brings challenges associated with the assessment of therapy response. The ability to accurately detect whether tcVNS has been effectively delivered in a remote setting such as the home has never been investigated. We designed and conducted a study in which 12 human subjects received active tcVNS and 14 received sham stimulation in tandem with traumatic stress, and measured continuous cardiopulmonary signals including the electrocardiogram (ECG), photoplethysmogram (PPG), seismocardiogram (SCG), and respiratory effort (RSP). We extracted physiological parameters related to autonomic nervous system activity, and created a feature set from these parameters to: 1) detect active (vs. sham) tcVNS stimulation presence with machine learning methods, and 2) determine which sensing modalities and features provide the most salient markers of tcVNS-based changes in physiological signals. Heart rate (ECG), vasomotor activity (PPG), and pulse arrival time (ECG+PPG) provided sufficient information to determine target engagement (compared to sham) in addition to other combinations of sensors. resulting in 96% accuracy, precision, and recall with a receiver operator characteristics area of 0.96. Two commonly utilized sensing modalities (ECG and PPG) that are suitable for home use can provide useful information on therapy response for tcVNS. The methods presented herein could be deployed in wearable devices to quantify adherence for at-home use of tcVNS technologies.
Microbial contributions to oxalate metabolism in health and disease
Authors: Liu Menghan , Devlin Joseph C. , Hu Jiyuan , Volkova Angelina , Battaglia Thomas W. , Byrd Allyson , Loke P’ng , Li Huilin , Ruggles Kelly V. , Tsirigos Aristotelis , Blaser Martin J. , Nazzal Lama
Published: January 2020

Over-accumulation of oxalate in humans may lead to nephrolithiasis and nephrocalcinosis. Humans lack endogenous oxalate degradation pathways (ODP), but intestinal microbiota can degrade oxalate and protect against its absorption. However, the particular microbes that actively degrade oxalatein vivoare ill-defined, which restricts our ability to disentangle the underlying taxonomic contributions. Here we leverage large-scale multi-omics data (>3000 samples from >1000 subjects) to show that the human microbiota in health harbors diverse ODP-encoding microbial species, but an oxalate autotroph-Oxalobacter formigenes-dominates this function transcriptionally. Patients with Inflammatory Bowel Disease (IBD) are at significantly increased risk for disrupted oxalate homeostasis and calcium-oxalate nephrolithiasis. Here, by analyzing multi-omics data from the iHMP-IBD study, we demonstrate that the oxalate degradation function conferred by the intestinal microbiota is severely impaired in IBD patients. In parallel, the enteric oxalate levels of IBD patients are significantly elevated and associated with intestinal disease severity, which is consistent with the clinically known nephrolithiasis risk. The specific changes in ODP expression by several important taxa suggest that they play different roles in the IBD-induced nephrolithiasis risk.
Stratification of Behavioral Response to Transcranial Current Stimulation by Resting-State Electrophysiology
Authors: Mastakouri Atalanti A.
Published: January 2020

Transcranial alternating current stimulation (tACS) enables the non-invasive stimulation of brain areas in desired frequencies, intensities and spatial configurations. These attributes have raised tACS to a widely used tool in cognitive neuroscience and a promising treatment in the field of motor rehabilitation. Nevertheless, considerable heterogeneity of its behavioral effects has been reported across individuals. We present a machine learning pipeline for predicting the behavioral response to 70 Hz contralateral motor cortex-tACS from Electroencephalographic resting-state activity preceding the stimulation. Specifically, we show in a cross-over study design that high-gamma (90–160 Hz) resting-state activity predicts arm-speed response to the stimulation in a concurrent reaching task. Moreover, we show in a prospective stimulation study that the behavioral effect size of stimulation significantly increases after the stratification of subjects with our prediction method. Finally, we discuss a plausible neurophysiological mechanism that links high resting-state gamma power in motor areas to stimulation response. As such, we provide a method that can distinguish responders from non-responders to tACS, prior to the stimulation treatment. This contribution could eventually bring us a step closer towards translating tACS into a safe and effective clinical treatment tool.
Loss of Ena/VASP interferes with lamellipodium architecture, motility and integrin-dependent adhesion
Authors: Damiano-Guercio Julia , Kurzawa Laëtitia , Mueller Jan , Dimchev Georgi , Nemethova Maria , Pokrant Thomas , Bruehmann Stefan , Linkner Joern , Blanchoin Laurent , Sixt Michael , Rottner Klemens , Faix Jan
Published: January 2020

Cell migration entails networks and bundles of actin filaments termed lamellipodia and microspikes or filopodia, respectively, as well as focal adhesions, all of which recruit Ena/VASP family members hitherto thought to antagonize efficient cell motility. However, we find these proteins to act as positive regulators of migration in different cell lines. CRISPR/Cas9-mediated loss of Ena/VASP proteins reduced lamellipodial actin assembly and perturbed lamellipodial architecture, as evidenced by changed network geometry as well as reduction of filament length and number that was accompanied by abnormal Arp2/3 complex and heterodimeric capping protein accumulation. Loss of Ena/VASP function also abolished the formation of microspikes normally embedded in lamellipodia, but not of filopodia capable of emanating without lamellipodia. Ena/VASP-deficiency also impaired integrin-mediated adhesion accompanied by reduced traction forces exerted through these structures. Our data thus uncover novel, cellular Ena/VASP functions of these actin polymerases that are fully consistent with their promotion of cell migration.
Improvement in Inner Retinal Function in Glaucoma with Nicotinamide (Vitamin B3) Supplementation: A Crossover Randomised Clinical Trial
Authors: Hui Flora , Tang Jessica , Williams Pete A , McGuinness Myra B , Hadoux Xavier , Casson Robert J , Coote Michael , Trounce Ian A , Martin Keith R. , van Wijngaarden Peter , Crowston Jonathan G
Published: January 2020

Importance

Retinal ganglion cells endure significant metabolic stress in glaucoma but maintain capacity to recover function. Nicotinamide, a precursor of NAD+, is low in serum of glaucoma patients and its supplementation provides robust protection of retinal ganglion cells in preclinical models. However, the potential of nicotinamide in human glaucoma is unknown.

Background

To determine whether nicotinamide supplementation alongside conventional IOP-lowering therapy improves retinal ganglion cell function in glaucoma.

Design

Crossover, double-masked, randomised clinical trial. Participants recruited from two tertiary care centres.

Participants

Fifty-seven participants, diagnosed and treated for primary glaucoma, enrolled.

Methods

Participants received oral placebo or nicotinamide and reviewed six-weekly. Participants commenced 6-weeks of 1.5 grams/day then 6 weeks of 3.0 grams/day followed by crossover without washout. Visual function measured using electroretinography and perimetry.

Main outcome measures

Change in inner retinal function, determined by photopic negative response (PhNR) parameters: saturated PhNR amplitude (Vmax), ratio of PhNR/b-wave amplitude (Vmax ratio).

Results

PhNR Vmax improved beyond 95% coefficient of repeatability (COR) in 23% of participants following nicotinamide versus 9% on placebo. Overall, Vmax improved by 14.8% [95% CI: 2.8%, 26.9%], (p=0.02) on nicotinamide and 5.2% [−4.2%, 14.6%], (p=0.27) on placebo. Vmax ratio improved by 12.6% [5.0%, 20.2%], (p=0.002) following nicotinamide, 3.6% [−3.4%, 10.5%], (p=0.30) on placebo. A trend for improved visual field mean deviation was observed with 27% improving ≥1dB on nicotinamide and fewer deteriorating (4%) compared to placebo (p=0.02).

Conclusions

Nicotinamide supplementation can improve inner retinal function in glaucoma. Further studies underway to elucidate the effects of long-term nicotinamide supplementation.

Trial Registration

ANZCTR trial ID: ACTRN12617000809336https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=373001