bluuebunny/crossref_metadata_2025 huggingface dataset:
Epigenetic Markers of Aging Predict the Neural Oscillations Serving Selective Attention
Authors: Wiesman Alex I , Rezich Michael T , O’Neill Jennifer , Morsey Brenda , Wang Tina , Ideker Trey , Swindells Susan , Fox Howard S , Wilson Tony W
Published: July 2019

Chronological age remains an imperfect measure of accumulated physiological stress. Biological measures of aging may provide key advantages, allowing scientists focusing on age-related functional changes to use metrics derived from epigenetic factors like DNA methylation (DNAm), which could provide greater precision. Here we investigated the relationship between methylation-based age and an essential cognitive function that is known to exhibit age-related decline: selective attention. We found that DNAm-age predicted selective attention abilities and fully mediated the relationship between selective attention and chronological age. Using neuroimaging with magnetoencephalography, we found that gamma activity in the anterior cingulate was robustly predicted by DNAm-derived biological age, revealing the neural dynamics underlying this DNAm age-related cognitive decline. Anterior cingulate gamma activity also significantly predicted behavior on the selective attention task, indicating its functional relevance. These findings suggest that DNAm age may be a better predictor of cognitive and brain aging than more traditional chronological metrics.
Disrespectful treatment in primary care in rural Tanzania: beyond any single health issue
Authors: Larson Elysia , Mbaruku Godfrey , Kujawski Stephanie A , Mashasi Irene , Kruk Margaret E
Published: July 2019

Knowing how patients are treated in care is foundational for creating patient-centred, high-quality health systems and identifying areas where policies and practices need to adapt to improve patient care. However, little is known about the prevalence of disrespectful treatment of patients in sub-Saharan Africa outside of maternity care. We used data from a household survey of 2002 women living in rural Tanzania to describe the extent of disrespectful care during outpatient visits, who receive disrespectful care, and determine the association with patient satisfaction, rating of quality and recommendation of the facility to others. We asked about women’s most recent outpatient visit to the local clinic, including if they were made to feel disrespected, if a provider shouted at or scolded them, and if providers made negative or disparaging comments about them. Women who answered yes to any of these questions were considered to have experienced disrespectful care. We report risk ratios with standard errors clustered at the facility level. The most common reasons for seeking care were fever or malaria (33.9%), vaccination (33.6%) and non-emergent check-up (13.4%). Disrespectful care was reported by 14.3% of women and was more likely if the visit was for sickness compared to a routine check-up [risk ratio (RR): 1.6, 95% confidence interval (CI): 1.1–2.2]. Women who did not report disrespectful care were 2.1 times as likely to recommend the clinic (95% CI: 1.6–2.7). While there is currently a lot of attention on disrespectful maternity care, our results suggest that this is a problem that goes beyond this single health issue and should be addressed by more horizontal health system interventions and policies.
‘Not in the room, but the doctors were’: an Australian story-completion study about consumer representation
Authors: Scholz Brett , Bocking Julia , Hedt Peter , Lu Vinh N , Happell Brenda
Published: July 2019

Current mental health policy requires consumer involvement in all levels of health service management (i.e. planning, implementation, delivery and evaluation). However, current models often limit consumers to ‘representation’ roles that are criticized for silencing consumer views. This study compares understandings of consumer representatives’ and health professionals’ participation in decision-making processes in the mental health sector in Australia. Story completion methods were employed, with 34 participants (21 consumers, 8 health professionals and 5 people identifying both as consumer and health professional) completing a story stem about either a consumer representative or a health professional changing a committee meeting agenda. Using a thematic approach, three overarching themes were developed: how consumer representative roles remain unvalued, how such lack of value translates to not achieving co-production and how consumer representative roles can be better supported through allyship or subversion against organizational cultural norms. Findings suggest that organizational cultural norms in health settings need to be more inclusive of consumers to maximize the benefits of partnerships and fulfil policy expectations. Two methods for greater empowerment of consumers working in mental health are through allyship with non-consumer health professionals who support the goals of the consumer movement, and subversion of current practices.
Genetic and pharmacological inactivation of d-alanylation of teichoic acids sensitizes pathogenic enterococci to β-lactams
Authors: Coupri Delphine , Budin-Verneuil Aurélie , Hartke Axel , Benachour Abdellah , Léger Loïc , Lequeux Thierry , Pfund Emmanuel , Verneuil Nicolas
Published: July 2019

Background

Enterococci intrinsically resistant to cephalosporins represent a major cause of healthcare-associated infections, and the emergence of MDR makes therapeutic approaches particularly challenging.

Objectives

Teichoic acids are cell wall glycopolymers present in Gram-positive bacteria. Teichoic acids can be modified by d-alanylation, which requires four proteins encoded by the dltABCD operon. Our objective was to evaluate the Dlt system as a druggable target to treat enterococcal infections.

Methods

The susceptibility of a d-alanylation-deficient strain of Enterococcus faecalis to β-lactam antibiotics individually and/or in combination was analysed. Moreover, a DltA inhibitor was synthesized to test pharmacological inhibition of d-alanylation in vivo and in host using the animal model Galleria mellonella with different clinical isolates of E. faecalis and Enterococcus faecium.

Results

Most cephalosporins used as mono treatment had no impact on survival of the parental strain, but were slightly lethal for the dltA mutant of E. faecalis. Addition of a very low concentration of amoxicillin significantly increased killing of the dltA mutant under these conditions. The most spectacular effect was obtained with a combination of cefotaxime (1 mg/L) and amoxicillin (0.03 mg/L). In the presence of the inhibitor, the WT strain was as susceptible to this combination treatment as the dltA mutant. This molecule associated with the antibiotics was also effective in killing other E. faecalis clinical isolates and successfully prevented death of Galleria infected with either E. faecalis or E. faecium.

Conclusions

The combined results support the potential usefulness of the Dlt system as a target to potentiate antibiotic combination therapies for the treatment of drug-resistant enterococci.
Detecting the Boundaries of Disposition Bias on Moral Judgments of Media Characters’ Behaviors using Social Judgment Theory
Authors: Matthews Nicholas L
Published: July 2019

eople continuously morally judge the behaviors of media characters. This informs people’s dispositions toward characters. Their dispositions bias their subsequent moral judgments of behavior. Affective disposition theory (ADT) contends that limits to disposition bias exist, but empirical evidence is absent. Three experiments tested the utility of using the ordered alternatives procedure (OAP) from social judgment theory to observe character disposition bias boundaries. Studies 1 and 2 explored and refined methods for detecting the bounds of disposition biases on moral judgments. Study 3 observed the boundaries using preregistered hypotheses, analyses, and sampling. Findings reveal the pragmatic nature of disposition bias, indicating a dependency on the magnitude of moral violation. This outcome interacted with role (average person vs. hero-based roles), schema (pure heroes vs. morally ambiguous characters), and exemplification (prototypes vs. exemplars). Findings corroborate ADT, Raney’s extension of ADT, and Sanders’ character impression formation model, and demonstrate the OAP’s utility for broader communication research.
Database thinking and deep description: designing a digital archive of the National Synchrotron Light Source
Authors: Crease Robert , Graham Elyse , Folsom Jamie
Published: July 2019

Over the past few years, research carried out at large-scale materials science facilities in the USA and elsewhere has undergone a phase transition that affected its character and culture. Research cultures at these facilities now resemble ecosystems, comprising of complex and evolving interactions between individuals, institutions, and the overall research environment. The outcome of this phase transition, which has been gradual and building since the 1980s, is known as the New (or Ecologic) Big Science [Crease, R. and Westfall, C. (2016). The new big science. Physics Today, 69: 30–6]. In this article, we describe this phase transition, review the practical challenges that it poses for historians, review some potential digital tools that might respond to these challenges, and then assess the theoretical implications posed by “database history’.
Sexual Dysfunction in Male Canadian Armed Forces Members and Veterans Seeking Mental Health Treatment
Authors: Richardson J Don , Ketcheson Felicia , King Lisa , Forchuk Callista A , Hunt Renée , St. Cyr Kate , Nazarov Anthony , Shnaider Philippe , McIntyre-Smith Alexandra , Elhai Jon D
Published: July 2019

Introduction

There is mixed evidence regarding how posttraumatic stress disorder (PTSD) symptom clusters are associated with sexual dysfunction (SD), and most studies to date have failed to account for potentially confounding variables. Our study sought to explore the unique contribution of PTSD symptom clusters on (a) lack of sexual desire or pleasure, and (b) pain or problems during sexual intercourse, after adjusting for comorbidities and medication usage.

Materials and Methods

Participants included 543 male treatment-seeking veterans and Canadian Armed Forces (CAF) personnel (aged <65 years), referred for treatment between September 2006 and September 2014. Each participant completed self-report measures of demographic variables, depressive symptom severity, chronic pain, alcohol misuse, and psychotropic medication usage as part of a standard clinical intake protocol. Hierarchical ordinal logistic regression analyses were used to determine the incremental contribution of PTSD symptom clusters on sexual dysfunction.

Results

Nearly three-quarters (71.5%) of participants reported a lack of sexual desire or pleasure and 40.0% reported pain or problems during intercourse. Regression analyses suggested that avoidant/numbing symptoms were the only symptoms to be independently associated with lacking sexual desire or pleasure (AOR = 1.10; 95% CI 1.05–1.15). None of the PTSD symptom clusters were independently associated with pain or problems during intercourse.

Conclusions

Sexual dysfunction is prevalent among male treatment-seeking CAF personnel and veterans. Results suggest that PTSD symptoms are differentially associated with sexual desire or pleasure concerns. Assessing sexual function among CAF personnel and veterans seeking treatment for PTSD is critical in order to treat both conditions and improve overall functioning.
Delivering Cas9/sgRNA ribonucleoprotein (RNP) by lentiviral capsid-based bionanoparticles for efficient ‘hit-and-run’ genome editing
Authors: Lyu Pin , Javidi-Parsijani Parisa , Atala Anthony , Lu Baisong
Published: July 2019

Transient expression of the CRISPR/Cas9 machinery will not only reduce risks of mutagenesis from off-target activities, but also decrease possible immune response to Cas9 protein. Building on our recent developing of a system able to package up to 100 copies of Cas9 mRNA in each lentivirus-like particle (LVLP) via the specific interaction between aptamer and aptamer-binding proteins (ABP), here we develop a lentiviral capsid-based bionanoparticle system, which allows efficient packaging of Cas9/sgRNA ribonucleoprotein (RNP). We show that replacing the Tetraloop of sgRNA scaffold with a com aptamer preserves the functions of the guide RNA, and the com-modified sgRNA can package Cas9/sgRNA RNP into lentivirus-like particles via the specific interactions between ABP and aptamer, and sgRNA and Cas9 protein. These RNP bionanoparticles generated Indels on different targets in different cells with efficiencies similar to or better than our recently described Cas9 mRNA LVLPs. The new system showed fast action and reduced off-target rates, and makes it more convenient and efficient in delivering Cas9 RNPs for transient Cas9 expression and efficient genome editing.
Clinical evaluation of fitness to drive in patients with brain metastases
Authors: Valencia-Sanchez Cristina , Gorelkin Vanessa C , Mrugala Maciej M , Sharma Akanksha , Vora Sujay A , Ashman Jonathan B , Daniels Thomas B , Halyard Michele Y , Rule William G , Zhang Nan , Butterfield Richard J , Schild Steven E , Porter Alyx B
Published: July 2019

Background

Guidelines to provide recommendations about driving restrictions for patients with brain metastases are lacking. We aim to determine whether clinical neurologic examination is sufficient to predict suitability to drive in these patients by comparison with an occupational therapy driving assessment (OTDA).

Methods

We prospectively evaluated the concordance between neurology assessment of suitability to drive (pass/fail) and OTDA in 41 individuals with brain metastases. Neuro-oncology evaluation included an interview and neurological examination. Participants subsequently underwent OTDA during which a battery of objective measures of visual, cognitive, and motor skills related to driving was administered.

Results

The mean age of patients who failed OTDA was age 68.9 years vs 59.3 years in the group members who passed (P = .0046). The sensitivity of the neurology assessment to predict driving fitness compared with OTDA was 16.1% and the specificity 90%. The 31 patients who failed OTDA were more likely to fail Vision Coach, Montreal Cognitive Assessment, and Trail Making B tests.

Conclusions

There was poor association between the assessment of suitability to drive by neurologists and the outcome of the OTDA in patients with brain metastases. Subtle deficits that may impair the ability to drive safely may not be evident on neurologic examination. The positive predictive value was high to predict OTDA failure. Age could be a factor affecting OTDA performance. The results raise questions about the choice of assessments in making recommendations about driving fitness in people with brain metastases. OTDA should be strongly considered in patients with brain metastases who wish to continue driving.
Concept for an X-ray telescope system with an angular resolution booster
Authors: Maeda Yoshitomo , Iizuka Ryo , Hayashi Takayuki , Sato Toshiki , Nakaniwa Nozomi , Takeo Mai , Suzuki Hitomi , Ishida Manabu , Ikeda Shiro , Morii Mikio
Published: July 2019

We present a concept for an X-ray imaging system with a high angular resolution and moderate sensitivity. In this concept, a two-dimensional detector, i.e., an imager, is put at a slightly out-of-focus position of the focusing mirror, rather than just at the mirror focus, as in the standard optics, to capture miniature images of objects. In addition, a set of multi-grid masks (or a modulation collimator) is installed in front of the telescope. We find that the masks work as a coded aperture camera and that they boost the angular resolution of the focusing optics. The major advantage of this concept is that a much better angular resolution, having an order of 2–3 or more than in the conventional optics, is achievable, while a high throughput (large effective area) is maintained, which is crucial in photon-limited high-energy astronomy, because any type of mirrors, including lightweight reflective mirrors, can be employed in our concept. If the signal-to-noise ratio is sufficiently high, we estimate that angular resolutions at the diffraction limit of 4″ and 0.″4 at ∼7 keV can be achieved with a pair of masks at distances of 1 m and 100 m, respectively.
Optimality of Debt under Flexible Information Acquisition
Authors: Yang Ming
Published: July 2019

This article studies a security design problem featuring flexible information acquisition. To raise liquidity, a seller issues a security backed by her asset in place at the price she proposes to a buyer. Before deciding whether to accept the offer, the buyer can acquire costly information about the underlying asset. This case differs from the existing literature on security design, in that the buyer has the full flexibility of choosing not only the amount of resources to spend in information acquisition, but also how to allocate them, depending on the shape of the security. Debt is shown to be the unique optimal security for the seller, as its payoff is the least sensitive to the value of its underlying asset. This minimizes the buyer’s incentive to acquire information and mitigates the resulting adverse selection. I do not assume monotonicity of the feasible securities nor impose various distributional assumptions on information structures. Instead, I identify conditions for general information costs that support the results.
Promotion of macrophage activation by Tie2 in the context of the inflamed synovia of rheumatoid arthritis and psoriatic arthritis patients
Authors: Kabala Pawel A , Malvar-Fernández Beatriz , Lopes Ana P , Carvalheiro Tiago , Hartgring Sarita A Y , Tang Man Wai , Conde Carmen , Baeten Dominique L , Sleeman Matthew , Tak Paul P , Connor Jane , Radstake Timothy R , Reedquist Kris A , García Samuel
Published: July 2019

Objective

To examine the role of Tie2 signalling in macrophage activation within the context of the inflammatory synovial microenvironment present in patients with RA and PsA.

Methods

Clinical responses and macrophage function were examined in wild-type and Tie2-overexpressing (Tie2-TG) mice in the K/BxN serum transfer model of arthritis. Macrophages derived from peripheral blood monocytes from healthy donors, RA and PsA patients, and RA and PsA synovial tissue explants were stimulated with TNF (10 ng/ml), angiopoietin (Ang)-1 or Ang-2 (200 ng/ml), or incubated with an anti-Ang2 neutralizing antibody. mRNA and protein expression of inflammatory mediators was analysed by quantitative PCR, ELISA and Luminex.

Results

Tie2-TG mice displayed more clinically severe arthritis than wild-type mice, accompanied by enhanced joint expression of IL6, IL12B, NOS2, CCL2 and CXCL10, and activation of bone marrow-derived macrophages in response to Ang-2 stimulation. Ang-1 and Ang-2 significantly enhanced TNF-induced expression of pro-inflammatory cytokines and chemokines in macrophages from healthy donors differentiated with RA and PsA SF and peripheral blood-derived macrophages from RA and PsA patients. Both Ang-1 and Ang-2 induced the production of IL-6, IL-12p40, IL-8 and CCL-3 in synovial tissue explants of RA and PsA patients, and Ang-2 neutralization suppressed the production of IL-6 and IL-8 in the synovial tissue of RA patients.

Conclusion

Tie2 signalling enhances TNF-dependent activation of macrophages within the context of ongoing synovial inflammation in RA and PsA, and neutralization of Tie2 ligands might be a promising therapeutic target in the treatment of these diseases.
Disclosure against foreign clients and lawyers: lessons for trust lawyers from Kiobel v Cravath Swaine & Moore
Authors: Peacocke Teresa Rosen
Published: July 2019

The author highlights two cases in which the courts considered the impact of protective orders, also known as confidentiality clubs, in determining applications for disclosure of the protected material to parties, or for purposes, outside the terms of the orders. In both cases the applications failed. In the New York case of Kiobel v Cravath, Swaine & Moore LLP (2016), the litigation in which the protective order was imposed had closed, but the order was upheld. In HTC Corporation v Nokia Corporation (2013) in London, a party sought disclosure from its opponent that would circumvent the effect of the protective order made when the disclosure was made by a third party. The author considers the usefulness of such orders, notwithstanding certain weaknesses, for domestic and international contentious trust cases.
Comparison of clinical manifestations and outcomes of noncirrhotic and cirrhotic hepatocellular carcinoma patients with chronic hepatitis B
Authors: Hwan Yu Jung , Shin Jongbeom , Jin Young-Joo , Lee Jin-Woo
Published: July 2019

Aim

The differences of the clinical features and survival outcomes between cirrhotic and noncirrhotic hepatocellular carcinoma (HCC) patients with hepatitis B virus (HBV) infection remain to be determined. We evaluated clinical characteristics and survival outcomes of noncirrhotic HBV-associated HCC patients compared with cirrhotic patients.

Patients and methods

Between January 2005 and December 2015, 1345 patients were diagnosed to have HCC at our hospital. Of these, 860 HBV-associated HCC patients with (cirrhotic group, n = 519, 60.3%) or without cirrhosis (noncirrhotic group, n = 341, 39.7%) were retrospectively analyzed. Propensity score matching (PSM) was used to adjust for differences between the two groups.

Results

The noncirrhotic group had lower Child–Turcotte–Pugh (CTP) classes and greater tumor sizes and were less likely to have portal vein thrombosis than the cirrhotic group. Age and sex were not significantly different between the two groups. Cumulative overall survival (OS) rates at 2, 4, 6, and 8 years after treatment were significantly higher in the noncirrhotic group (67.2, 57.1, 43.2, and 38.3 vs. 58.3, 41.3, 33.2, and 27.8%, respectively, P < 0.001). However, no significant intergroup difference in OS rates was observed after PSM (P = 0.680). Significant predictive factors of OS were CTP class, tumor size, tumor number, and curative-intended treatment for the noncirrhotic group, and serum alanine aminotransferase, CTP class, tumor size, tumor number, and curative-intended treatment for the cirrhotic group.

Conclusion

After PSM, cumulative OS rates were similar between HBV-related HCC patients with and without cirrhosis, and they were clearly dependent on CTP class, regardless of the presence of cirrhosis itself both in cirrhotic and noncirrhotic patients.
Alternate Week Gemcitabine and Capecitabine
Authors: Johns Claire , Diaz Celso L. , Hwang Jimmy , Kerridge William D. , Ko Andrew H. , Tempero Margaret A.
Published: July 2019

Objective

Determine whether a regimen of fixed dose rate gemcitabine plus capecitabine is effective and tolerable for advanced pancreatic adenocarcinoma.

Methods

We performed a retrospective analysis of 62 patients with locally advanced or metastatic pancreatic adenocarcinoma treated at the University of California San Francisco between 2008 and 2016. Treatment was an alternate week schedule of fixed dose rate 1000 mg/m2 gemcitabine and capecitabine 1000 mg/m3 (58 patients), 1200 mg/m3 (12 patients), or 650 mg/m3 (1 patient) for intended 12 cycles. We evaluated overall survival (OS), progression-free survival (PFS), radiologic response, and adverse events necessitating treatment modification.

Results

For metastatic patients, median OS was 10.3 months (95% confidence interval [CI], 6.7–12.1 months), and PFS was 5.6 months (95% CI, 2.6–7.7 months). In locally advanced patients, OS was 12.0 months (95% CI, 4.9–17.1 months), and PFS was 5.4 months (95% CI, 2.5–9.4 months). Radiologic response for metastatic disease (42 patients) was 19% objective response, 45% stable disease, and 36% progressive disease. Treatment required modification for 22 patients due to adverse events, most frequently hand-foot syndrome (18 patients).

Conclusions

Alternate week schedule of fixed dose rate gemcitabine and capecitabine was active and tolerable for advanced pancreatic adenocarcinoma. Overall survival and PFS were comparable to first-line treatments. Importantly, adverse effects appear less severe than first-line treatments.
Severity and Mortality Predictors of Pediatric Acute Respiratory Distress Syndrome According to the Pediatric Acute Lung Injury Consensus Conference Definition
Authors: Prasertsan Pharsai , Anuntaseree Wanaporn , Ruangnapa Kanokpan , Saelim Kantara , Geater Alan
Published: July 2019

Objectives:

The objective of this study was to assess the prevalence, severity, and outcomes of pediatric acute respiratory distress syndrome in a resource-limited country. In addition, we sought to explore the predisposing factors that predicted the initial severity, a change from mild to moderate-severe severity, and mortality.

Design:

Retrospective study.

Setting:

PICU in Songklanagarind Hospital, Songkhla, Thailand.

Patients:

Children 1 month to 15 years old with acute respiratory failure admitted to the PICU from January 2013 to December 2016.

Interventions:

None.

Measurements and Main Results:

From a total of 1,738 patients admitted to PICU, 129 patients (prevalence 7.4%) were diagnosed as pediatric acute respiratory distress syndrome using the Pediatric Acute Lung Injury Consensus Conference definition. The patients were categorized by severity. Fifty-seven patients (44.2%) were mild, 35 (27.1%) were moderate, and 37 (28.1%) were severe. After multivariable analysis was performed, factors significantly associated with moderate to severe disease at the initial diagnosis were Pediatric Risk of Mortality III score (odds ratio, 1.08; 95% CI, 1.03–1.15; p = 0.004), underlying oncologic/hematologic disorder (odds ratio, 0.32; 95% CI, 0.12–0.77; p = 0.012), and serum albumin level (odds ratio, 0.46; 95% CI, 0.27–0.80; p = 0.006), whereas underlying oncologic/hematologic disorder (odds ratio, 5.33; 95% CI, 1.33–21.4) and hemoglobin (odds ratio, 0.63; 95% CI, 0.44–0.89) predicted the progression of this syndrome within 7 days. The 30-day all-cause mortality rate was 51.2% (66/129). The predictors of mortality were the Pediatric Risk of Mortality III score (odds ratio, 1.12; 95% CI, 1.02–1.24; p = 0.017), underlying oncologic/hematologic disorder (odds ratio, 7.81; 95% CI, 2.18–27.94; p = 0.002), receiving systemic steroids (odds ratio, 4.04; 95% CI, 1.25–13.03; p = 0.019), having air leak syndrome (odds ratio, 5.45; 95% CI, 1.57–18.96; p = 0.008), and presenting with multiple organ dysfunction (odds ratio, 7.41; 95% CI, 2.00–27.36; p = 0.003).

Conclusions:

The prevalence and mortality rate of pediatric acute respiratory distress syndrome in a developing country are high. The oncologic/hematologic comorbidity had a significant impact on the severity of progression and mortality.
Matched Retrospective Cohort Study of Thiamine to Treat Persistent Hyperlactatemia in Pediatric Septic Shock*
Authors: Weiss Scott L. , Blowey Bridget , Keele Luke , Ganetzky Rebecca , Murali Chaya N. , Fitzgerald Julie C. , Sutton Robert M. , Berg Robert A.
Published: July 2019

Objectives:

Thiamine deficiency may propagate lactate production by limiting pyruvate dehydrogenase activity, and studies suggest benefit for thiamine administration in septic adults. We studied the effect of thiamine on physiologic and clinical outcomes for children with septic shock and hyperlactatemia.

Design:

Retrospective matched cohort study.

Setting:

Single academic PICU.

Patients:

Six thiamine-treated cases and nine matched controls.

Interventions:

None.

Measurements and Main Results:

The primary outcome was change in blood lactate from prethiamine (T0, cases) or maximum (T0, controls) lactate through 24 hours later (T24). Secondary outcomes were change in lactate over 48 hours (T48) and 72 hours (T72), time to lactate normalization, changes in vasoactive-inotrope score, organ dysfunction severity (daily Pediatric Logistic Organ Dysfunction 2 score), and creatinine, PICU length of stay, and hospital mortality. Lactate was greater than 5 mmol/L for a median of 39 hours (range, 16.1–64.3 hr) prior to thiamine administration for cases compared with 3.4 hours (range, 0–22.9 hr) prior to maximum lactate for controls (p = 0.002). There was no difference in median (interquartile range) change in lactate from T0 to T24 between thiamine-treated cases and controls (–9.0, –17.0 to -5.0 vs –7.2, –9.0 to –5.3 mmol/L, p = 0.78), with both groups exhibiting a rapid decrease in lactate. There were also no differences in secondary outcomes between groups.

Conclusions:

Treatment of pediatric septic shock with thiamine was followed by rapid improvement in physiologic and clinical outcomes after prolonged hyperlactatemia. Although we are not able to infer that thiamine provided benefit over usual care, the rapid decline in lactate after thiamine despite a prolonged period of hyperlactatemia raises the possibility that thiamine helped to reverse lactate production.
Rates and Predictors of Using Opioids in the Emergency Department to Treat Migraine in Adolescents and Young Adults
Authors: Connelly Mark , Glynn Earl F. , Hoffman Mark A. , Bickel Jennifer
Published: July 2019

Objectives

This study aimed to determine the rate and context in which opioids are used to treat migraine in adolescents and young adults seen in emergency care settings.

Methods

Data from 2010 to 2016 in the Cerner Health Facts electronic health record data warehouse were analyzed using multilevel logistic regression to estimate the population likelihood of an opioid being used in the emergency department (ED) to treat a primary diagnosis of migraine in adolescents and young adults and to evaluate the extent to which this likelihood varies as a function of characteristics of the patient (age, sex, race, and insurance), encounter (referral source, provider specialty, and encounter duration and year), and ED (region, setting, size, payer mix, and academic status).

Results

The study identified 14,494 eligible ED encounters with unique patients, of which 23% involved an opioid. Likelihood of being treated with opioids was significantly higher for patients who were older, female, white, and seen by a surgeon and who had longer encounters and encounters earlier in the time period sampled. Sites varied widely in percentage of encounters involving opioids (mean, 26.4% ± 20.1%; range, 0–100%), with higher rates associated with smaller sites with relatively higher proportions of commercially insured patients.

Conclusions

Use of opioids in the ED to treat migraine in youth is fairly common, with rate variation reflecting broader trends in for whom opioids tend to be more likely to be prescribed. These findings may be helpful for benchmarking and informing quality improvement efforts aimed at reducing unwarranted opioid exposure in youth.
Blood Oxygen Level–Dependent Response Changes in the Ipsilateral Primary Somatosensory Cortex and Thalamus of Patients With Moyamoya Disease During Median Nerve Electrical Stimulation
Authors: Qiao Peng-Gang , Cheng Xu , Zuo Zhi-Wei , Han Cong , Yang Zheng-Han , Li Gong-Jie
Published: July 2019

Objective

The objective of this study was to investigate the changes in the blood oxygen level–dependent (BOLD) response in the ipsilateral primary somatosensory cortex (SI) and thalamus of patients with moyamoya disease (MMD) during sensory stimulation.

Methods

Sixty-four MMD patients, and 15 healthy volunteers were enrolled. Thirty-three MMD patients exhibited paroxysmal numbness or hypoesthesia in the unilateral limbs. Fifteen patients with acroparesthesia underwent unilateral encephaloduroarteriosynangiosis (EDAS). All volunteers underwent BOLD functional magnetic resonance imaging (BOLD-fMRI) under median nerve electrical stimulation (MNES). Blood oxygen level–dependent fMRI data were processed to obtain time-signal intensity curves in the activation areas of the bilateral SI and thalamus. Processed dynamic susceptibility contrast-enhanced magnetic resonance imaging data were used to measure the time to peak of the BOLD response in the regions of interest, including the bilateral SI, thalamus, and cerebellum. Changes in the time-signal intensity curve–related hemodynamic parameters in the ipsilateral SI and thalamus were examined between healthy controls, nonacroparesthesia patients, and asymptomatic and symptomatic sides of unilateral acroparesthesia patients during MNES. Changes in these parameters in MMD patients before and after EDAS were examined.

Results

Compared with healthy volunteers, 3 groups of MMD patients exhibited an increased peak of the positive BOLD response in the ipsilateral thalamus during MNES (0.65 ± 0.24 vs 0.79 ± 0.35, 0.94 ± 0.57, and 0.89 ± 0.50; P = 0.0335). The positive response peak in the ipsilateral SI markedly increased in MMD patients with acroparesthesia during MNES on the asymptomatic side (0.56 ± 0.37 vs 0.38 ± 0.27, P = 0.0243). The time to peak negative response in the ipsilateral SI was prolonged during MNES on the symptomatic side after EDAS (12.14 ± 8.90 seconds vs 18.86 ± 9.20 seconds, P = 0.0201).

Conclusions

During sensory stimulation treatment, BOLD response changes occurred in the ipsilateral SI and thalamus of MMD patients. These changes enabled the contralateral hemisphere of the brain to better deal with sensory stimuli.
Myeloproliferative Neoplasms: A Primer for Radiologists
Authors: Liput Joseph , Smith Daniel A. , Beck Rose , Ramaiya Nikhil H.
Published: July 2019

The myeloproliferative neoplasms (MPNs) are a heterogeneous group of diseases including polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Knowledge of the radiological and clinical features of MPNs and their associated complications is critical for interpreting radiologists. The purpose of this article is to provide a primer to radiologists summarizing the modern understanding of MPNs from an imaging-based perspective, including common disease-related findings and complications related to hematopoietic cell transplant.
Standardized measurement of breathlessness during exercise
Authors: Lewthwaite Hayley , Koch Emily M. , Tracey Lauren , Jensen Dennis
Published: July 2019

Purpose of review

Exertional breathlessness is common and pervasive across various chronic disease populations. To accurately assess response to intervention and optimize clinical (symptom) management, detailed assessment of exertional breathlessness is imperative. This review provides an update on current approaches to assess exertional breathlessness and presents the need for individualized assessment of breathlessness standardized for the level of exertion.

Recent findings

Breathlessness assessment tools commonly invite people to recall their breathlessness while at rest with reference to activities of daily living. To directly quantify breathlessness, however, requires assessment of the dimensions of breathlessness (e.g., sensory intensity, quality, and unpleasantness) in response to a standardized exercise stimulus. Different exercise stimuli (e.g., self-paced, incremental, and constant work rate exercise tests) have been used to elicit a breathlessness response. Self-paced (e.g., 6-min walk test) and incremental exercise tests assess exercise tolerance or endurance, and are not recommended for assessment of exertional breathlessness. Constant work rate tests, however, including recently validated 3-min constant-rate stair stepping and walking tests, standardize the exercise stimulus to enable the breathlessness response to be directly quantified and monitored over time.

To adequately guide symptom management and assess intervention efficacy, clinicians and researchers should assess breathlessness with multidimensional assessment tools in response to a standardized and individualized exercise stimulus.
Why treatment efficacy on breathlessness in laboratory but not daily life trials? The importance of standardized exertion
Authors: Ekström Magnus
Published: July 2019

Purpose of review

Treatments for chronic breathlessness, including opioids and oxygen, have shown efficacy in the controlled laboratory setting, whereas effects have been inconsistent or absent in trials in daily life. This review discusses the lack of standardized exertion as a potential cause of false negative findings for breathlessness in daily life.

Recent findings

The level of breathlessness can be modified by patients by changing their level of physical activity. Effects of opioids and oxygen have been shown at standardized level of exertion (iso-time) but not at the end of symptom-limited (peak) exertion. Trials in daily life reporting no effects on breathlessness did not standardize the exertion or employed insensitive methods, such as the 6-min walk test that should not be used for measuring breathlessness. Novel tests – the 3-min walk and stepping tests have been validated in chronic obstructive pulmonary disease and are responsive for measuring change in breathlessness.

Breathlessness should be measured at standardized exertion, otherwise treatment effects may be biased or overlooked. Tests for valid measurement of breathlessness in clinical practice and daily life are available and emerging.
A novel accessory respiratory muscle in the American alligator (Alligator mississippiensis)
Authors: Codd Jonathan R. , Rose Kayleigh A. R. , Tickle Peter G. , Sellers William I. , Brocklehurst Robert J. , Elsey Ruth M. , Crossley Dane A.
Published: July 2019

The muscles that effect lung ventilation are key to understanding the evolutionary constraints on animal form and function. Here, through electromyography, we demonstrate a newly discovered respiratory function for the iliocostalis muscle in the American alligator (Alligator mississippiensis). The iliocostalis is active during expiration when breathing on land at 28°C and this activity is mediated through the uncinate processes on the vertebral ribs. There was also an increase in muscle activity during the forced expirations of alarm distress vocalizations. Interestingly, we did not find any respiratory activity in the iliocostalis when the alligators were breathing with their body submerged in water at 18°C, which resulted in a reduced breathing frequency. The iliocostalis is an accessory breathing muscle that alligators are able to recruit in to assist expiration under certain conditions.
Full observability and estimation of unknown inputs, states and parameters of nonlinear biological models
Authors: Villaverde Alejandro F. , Tsiantis Nikolaos , Banga Julio R.
Published: July 2019

In this paper, we address the system identification problem in the context of biological modelling. We present and demonstrate a methodology for (i) assessing the possibility of inferring the unknown quantities in a dynamic model and (ii) effectively estimating them from output data. We introduce the term Full Input-State-Parameter Observability (FISPO) analysis to refer to the simultaneous assessment of state, input and parameter observability (note that parameter observability is also known as identifiability). This type of analysis has often remained elusive in the presence of unmeasured inputs. The method proposed in this paper can be applied to a general class of nonlinear ordinary differential equations models. We apply this approach to three models from the recent literature. First, we determine whether it is theoretically possible to infer the states, parameters and inputs, taking only the model equations into account. When this analysis detects deficiencies, we reformulate the model to make it fully observable. Then we move to numerical scenarios and apply an optimization-based technique to estimate the states, parameters and inputs. The results demonstrate the feasibility of an integrated strategy for (i) analysing the theoretical possibility of determining the states, parameters and inputs to a system and (ii) solving the practical problem of actually estimating their values.
An investigation of the glycosaminoglycan contribution to biaxial mechanical behaviours of porcine atrioventricular heart valve leaflets
Authors: Ross Colton J. , Laurence Devin W. , Richardson Jacob , Babu Anju R. , Evans Lauren E. , Beyer Ean G. , Childers Rachel C. , Wu Yi , Towner Rheal A. , Fung Kar-Ming , Mir Arshid , Burkhart Harold M. , Holzapfel Gerhard A. , Lee Chung-Hao
Published: July 2019

The atrioventricular heart valve (AHV) leaflets have a complex microstructure composed of four distinct layers: atrialis, ventricularis, fibrosa and spongiosa. Specifically, the spongiosa layer is primarily proteoglycans and glycosaminoglycans (GAGs). Quantification of the GAGs' mechanical contribution to the overall leaflet function has been of recent focus for aortic valve leaflets, but this characterization has not been reported for the AHV leaflets. This study seeks to expand current GAG literature through novel mechanical characterizations of GAGs in AHV leaflets. For this characterization, mitral and tricuspid valve anterior leaflets (MVAL and TVAL, respectively) were: (i) tested by biaxial mechanical loading at varying loading ratios and by stress-relaxation procedures, (ii) enzymatically treated for removal of the GAGs and (iii) biaxially mechanically tested again under the same protocols as in step (i). Removal of the GAG contents from the leaflet was conducted using a 100 min enzyme treatment to achieve approximate 74.87% and 61.24% reductions of all GAGs from the MVAL and TVAL, respectively. Our main findings demonstrated that biaxial mechanical testing yielded a statistically significant difference in tissue extensibility after GAG removal and that stress-relaxation testing revealed a statistically significant smaller stress decay of the enzyme-treated tissue than untreated tissues. These novel findings illustrate the importance of GAGs in AHV leaflet behaviour, which can be employed to better inform heart valve therapeutics and computational models.
Network-driven differences in mobility and optimal transitions among automatable jobs
Authors: Dworkin Jordan D.
Published: July 2019

The potential for widespread job automation has become an important topic of discussion in recent years, and it is thought that many American workers may need to learn new skills or transition to new jobs to maintain stable positions in the workforce. Because workers’ existing skills may make such transitions more or less difficult, the likelihood of a given job being automated only tells part of the story. As such, this study uses network science and statistics to investigate the links between jobs that arise from their necessary skills, knowledge and abilities. The resulting network structure is found to enhance the burden of automation within some sectors while lessening the burden in others. Additionally, a model is proposed for quantifying the expected benefit of specific job transitions. Its optimization reveals that the consideration of shared skills yields better transition recommendations than automatability and job growth alone. Finally, the potential benefit of increasing individual skills is quantified, with respect to facilitating both job transitions and within-occupation skill redefinition. Broadly, this study presents a framework for measuring the links between jobs and demonstrates the importance of these links for understanding the complex effects of automation.
In slow motion: radula motion pattern and forces exerted to the substrate in the land snailCornu aspersum(Mollusca, Gastropoda) during feeding
Authors: Krings Wencke , Faust Taissa , Kovalev Alexander , Neiber Marco Thomas , Glaubrecht Matthias , Gorb Stanislav
Published: July 2019

The radula is the anatomical structure used for feeding in most species of Mollusca. Previous studies have revealed that radulae can be adapted to the food or the substrate the food lies on, but the real,in vivoforces exerted by this organ on substrates and the stresses that are transmitted by the teeth are unknown. Here, we relate physical properties of the radular teeth ofCornu aspersum(Müller. 1774Vermium terrestrium et fluviatilium, seu animalium infusoriorum, helminthicorum, et testaceorum, non marinorum, succincta historia. Volumen alterum. Heineck & Faber, Havniæ & Lipsiæ.), a large land snail, with experiments revealing their radula scratching force. The radula motion was recorded with high-speed video, and the contact area between tooth cusps and the substrate was calculated. Forces were measured in all directions; highest forces (106.91 mN) were exerted while scratching, second highest forces while pulling the radula upwards and pressing the food against its counter bearing, the jaw, because the main ingesta disaggregation takes place during those two processes. Nanoindentation revealed that the tooth hardness and elasticity in this species are comparable to wood. The teeth are softer than some of their ingesta, but since the small contact area of the tooth cusps (227 µm2) transmits high local pressure (4698.7 bar) on the ingesta surface, harder material can still be cut or pierced with abrasion. This method measuring the forces produced by the radula during feeding could be used in further experiments on gastropods for better understanding functions and adaptations of radulae to ingesta or substrate, and hence, gastropods speciation and evolution.
Elevated aggression is associated with uncertainty in a network of dog dominance interactions
Authors: Silk Matthew J. , Cant Michael A. , Cafazzo Simona , Natoli Eugenia , McDonald Robbie A.
Published: July 2019

Dominance hierarchies are widespread in animal societies and reduce the costs of within-group conflict over resources and reproduction. Variation in stability across a social hierarchy may result in asymmetries in the benefits obtained from hierarchy formation. However, variation in the stability and behavioural costs of dominance interactions with rank remain poorly understood. Previous theoretical models have predicted that the intensity of dominance interactions and aggression should increase with rank, but these models typically assume high reproductive skew, and so their generality remains untested. Here we show in a pack of free-living dogs with a sex–age-graded hierarchy that the central region of the hierarchy was dominated by more unstable social relationships and associated with elevated aggression. Our results reveal unavoidable costs of ascending a dominance hierarchy, run contrary to theoretical predictions for the relationship between aggression and social rank in high-skew societies, and widen our understanding of how heterogeneous benefits of hierarchy formation arise in animal societies.
Abcg2-Expressing Side Population Cells Contribute to Cardiomyocyte Renewal through Fusion
Authors: Yellamilli Amritha , Ren Yi , McElmurry Ron T. , Lambert Jonathan P. , Gross Polina , Mohsin Sadia , Houser Steven R. , Elrod John W. , Tolar Jakub , Garry Daniel J. , van Berlo Jop H.
Published: July 2019

The adult mammalian heart has a limited regenerative capacity. Therefore, identification of endogenous cells and mechanisms that contribute to cardiac regeneration is essential for the development of targeted regenerative therapies. The side population (SP) phenotype enriches for stem cells throughout the body, and SP cells have been identified in the heart. We generated a novel Abcg2-driven, genetic lineage-tracing mouse model and show efficient labeling of SP cells. Labeled SP cells give rise to terminally differentiated cells in bone marrow and intestines. In the heart, we find that Abcg2-expressing SP cells contribute to cardiomyocyte labeling, which is further enhanced in response to different forms of cardiac injury. We find that cardiac SP cells fuse with preexisting cardiomyocytes, which stimulates cardiomyocyte cell cycle entry and likely proliferation, instead of directly differentiating into cardiomyocytes. Our findings provide evidence that cardiac SP cells contribute to endogenous cardiac regeneration through cardiomyocyte fusion.