bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bacterial proteostasis balances energy and chaperone utilization efficiently
Authors: Santra Mantu , Farrell Daniel W. , Dill Ken A. 
Published: March 2017

Significance
A cell’s proteins must be properly folded. Therefore, cells have chaperones that help other proteins, their clients, fold and not aggregate. The machinery is like a hospital: it assesses the “sickness” of the patient (finds improperly folded proteins), sends the patient to the right doctor (sorts the protein to the right chaperone), and cures the disease (folds or disaggregates the protein). How are sick proteins recognized and routed to the right chaperone? How does the machine handle different growth rates? Here, we model proteostasis. We find that it can handle any arbitrary client protein, that it spends the least energy on least sick proteins, and that the cell produces just enough chaperone to keep the proteome folded but no more.
Distinct recognition of complement iC3b by integrins αXβ2and αMβ2
Authors: Xu Shutong , Wang Jianchuan , Wang Jia-Huai , Springer Timothy A. 
Published: March 2017

SignificanceComplement is deposited on foreign antigens and particles and marks them for recognition by immune cells and removal by phagocytes. Immune cells have two homologous integrins, αXβ2and αMβ2, that recognize the complement fragment iC3b. Although it might have been suspected that these integrins would bind to the same site on iC3b, direct comparisons here show they do not. Using negative stain electron microscopy and purified integrin fragments and iC3b, we show that αXβ2binds to two distinct sites on iC3b. A single αMβ2integrin binds to two different sites on iC3b, each of which is distinct from those to which αXβ2binds. Our findings reveal remarkable diversity among integrins that recognize complement and suggest possible cooperative responses.
First Reproduction by Stocked Bonytail in the Upper Colorado River Basin
Authors: Bestgen Kevin R. , Schelly Robert C. , Staffeldt Richard R. , Breen Matthew J. , Snyder Darrel E. , Jones M. Tildon 
Published: March 2017

Abstract
Bonytail Gila elegans, a large-bodied cyprinid that is endemic to the Colorado River basin of the American Southwest, was historically widespread and abundant in large warmwater streams but is now critically endangered. To increase recovery prospects, over 500,000 Bonytails have been stocked in the upper Colorado River basin since 2000, but adult survival has been low and reproduction has not been detected. We provide the first documented evidence of successful reproduction by stocked Bonytails in the upper Colorado River basin. Adult Bonytails were stocked in the Green River and accessed Stewart Lake and Johnson Bottom (managed floodplain wetlands in the middle Green River, Utah) during high flows in May 2015 (Stewart Lake only) and 2016. Draining of Stewart Lake in September 2015 revealed 19 age-0 individuals of Gila sp. (37–64 mm TL) among over 405,000 fish. Four preserved specimens (41–48 mm TL) were verified as Bonytails by using morphological and molecular techniques. Otolith daily increment analysis confirmed reproduction by Bonytails in Stewart Lake. Bonytail reproduction was also noted during 2016 in Stewart Lake (probable) and Johnson Bottom. Young Bonytails survived despite the presence of abundant nonnative fish predators. Use of floodplain wetlands for reproduction may enhance the recovery of critically endangered Bonytail in the upper Colorado River basin.
Received September 1, 2016; accepted January 2, 2017 Published online March 15, 2017
Pellet‐free isolation of human and bovine milk extracellular vesicles by size‐exclusion chromatography
Authors: Blans Kristine , Hansen Maria S. , Sørensen Laila V. , Hvam Michael L. , Howard Kenneth A. , Möller Arne , Wiking Lars , Larsen Lotte B. , Rasmussen Jan T. 
Published: March 2017

ABSTRACTStudies have suggested that nanoscale extracellular vesicles (EV) in human and bovine milk carry immune modulatory properties which could provide beneficial health effects to infants. In order to assess the possible health effects of milk EV, it is essential to use isolates of high purity from other more abundant milk structures with well‐documented bioactive properties. Furthermore, gentle isolation procedures are important for reducing the risk of generating vesicle artefacts, particularly when EV subpopulations are investigated. In this study, we present two isolation approaches accomplished in three steps based on size‐exclusion chromatography (SEC) resulting in effective and reproducible EV isolation from raw milk. The approaches do not require any EV pelleting and can be applied to both human and bovine milk. We show that SEC effectively separates phospholipid membrane vesicles from the primary casein and whey protein components in two differently obtained casein reduced milk fractions, with one of the fractions obtained without the use of ultracentrifugation. Milk EV isolates were enriched in lactadherin, CD9, CD63 and CD81 compared to minimal levels of the EV‐marker proteins in other relevant milk fractions such as milk fat globules. Nanoparticle tracking analysis and electron microscopy reveals the presence of heterogeneous sized vesicle structures in milk EV isolates. Lipid analysis by thin layer chromatography shows that EV isolates are devoid of triacylglycerides and presents a phospholipid profile differing from milk fat globules surrounded by epithelial cell plasma membrane. Moreover, the milk EV fractions are enriched in RNA with distinct and diverging profiles from milk fat globules. Collectively, our data supports that successful milk EV isolation can be accomplished in few steps without the use of ultracentrifugation, as the presented isolation approaches based on SEC effectively isolates EV in both human and bovine milk.
‘The age of entitlement has ended’: designing a disability insurance scheme in turbulent times
Authors: Miller Pavla 
Published: March 2017

AbstractIn a period of welfare state retrenchment, Australia's neo-liberal government is continuing to implement an expensive National Disability Insurance Scheme (NDIS). Australia is among the pioneers of welfare measures funded from general revenue. Until recently, however, attempts to establish national schemes of social insurance have failed. The paper reviews this history through the lenses of path dependence accounts. It then presents contrasting descriptions of the NDIS by its Chair, the politician who inspired him, and two feminist policy analysts from a carers’ organisation. Path dependence, these accounts illustrate, has been broken in some respects but consolidated in others. In particular, the dynamics of ‘managed’ capitalist markets, gendered notions of abstract individuals and organisations, and the related difficulties in accounting for unpaid labour are constraining the transformative potential of the NDIS.
Percutaneous coronary intervention vs. coronary artery bypass grafting for left main revascularization: an updated meta-analysis
Authors: Bajaj Navkaranbir S. , Patel Nirav , Kalra Rajat , Marogil Peter , Bhardwaj Ashwanikumar , Arora Garima , Arora Pankaj 
Published: March 2017

Abstract

Aims
The optimal revascularization strategy for left main coronary artery disease (LMD) remains controversial, especially with two recent randomized controlled trials showing conflicting results. We sought to address this controversy with our analysis.

Methods and results
Comprehensive literature search was performed. We compared percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) for LMD revascularization using standard meta-analytic techniques. A 21% higher risk of long-term major adverse cardiac and cerebrovascular event [MACCE; composite of death, myocardial infarction (MI), stroke, and repeat revascularization] was observed in patients undergoing PCI in comparison with CABG [risk ratio (RR) 1.21, 95% confidence interval (CI) 1.05–1.40]. This risk was driven by higher rate of repeat revascularization in those undergoing PCI (RR 1.61, 95% CI 1.34–1.95). On the contrary, MACCE rates at 30 days were lower in PCI when compared with CABG (RR 0.55, 95% CI 0.39–0.76), which was driven by lower rates of stroke in the PCI arm (RR 0.41, 95% CI 0.17–0.98). At 1 year, lower stroke rates (RR 0.21, 95% CI 0.08–0.59) in the PCI arm were balanced by higher repeat revascularization rates in those undergoing PCI (RR 1.78, 95% CI 1.33–2.37), resulting in a clinical equipoise in MACCE rates between the two revascularization strategies. There was no difference in death or MI between PCI when compared with CABG at any time point.

Conclusion
Outcomes of CABG vs. PCI for LMD revascularization vary over time. Therefore, individualized decisions need to be made for LMD revascularization using the heart team approach.
The common developmental road: tensions among centripetal and centrifugal dynamics
Authors: Xu Zhongmin , Cheng Guodong , Ulanowicz Robert E , Song Xiaoyu , Deng Xiaohong , Zhong Fanglei 
Published: March 2017

AbstractWestern thought since the Enlightenment has been predominantly linear in scope, while Eastern philosophy has focused mostly on the cyclical. Recent advances in complex systems, however, have highlighted the importance of cycles in nature, thereby opening an avenue for new common endeavors. This analysis centers on the role of autocatalytic loops and addresses the evolutionary relationship between competition and cooperation. It posits an evolutionary chain running from individual competition, to individual cooperation, to collective competition, to deep cooperation. We identify the centripetality that is consequent to autocatalysis and define three types of centrifugalities. Development is defined in the context of the tension between these opposing directions. Finally, we propose an evolutionary process consisting of four stages: (i) autognosis, (ii) autocatalytic loop formation, (iii) self-control and (iv) self-realization (sensu Taoism). The developmental narrative promises to become a useful tool for facilitating communication between Eastern and Western cultures.
Informed consent in children and adolescents
Authors: Morton Wendy J , Westwood Michael 
Published: March 2017

Abstract
Confusion persists about when a minor can give informed consent to medical treatment. Physicians may be hesitant to treat minors, even as adolescents, without first obtaining parental or guardian consent for fear of being sued for battery or negligence. However, the common law in Canada is clear that a minor can give informed consent to therapeutic medical treatment, provided heorshe can understand the information regarding the proposed treatment and can appreciate the attendant risks and possible consequences. Courts have accepted that there is no precise age at which a minor can be presumed to have the capacity to give informed consent. Each minor must be individually assessed to determine whether he or she possesses the requisite maturity and level of understanding to comprehend the nature, benefits and risks of the proposed treatment. The responsibility for determining a minor's capacity rests with the physician or another health care provider who is seeking to obtain the informed consent. In the event that legal action is taken against the physician on the grounds the minor lacked the capacity to give informed consent, the court must be satisfied that the minor did have sufficient capacity. Examples of cases where the physician was sued by either the minor or the minor's parents are included. In addition, an overview of existing provincial legislation dealing with minors and informed consent is provided.
Protocol for the investigation of acute flaccid paralysis and suspected paralytic poliomyelitis
Authors:   Working Group on Polio Eradication, Bentsi-Enchill Adwoa 
Published: March 2017

Abstract
Despite the elimination of indigenous wild poliovirus in Canada, ongoing surveillance for poliomyelitis is important because of the risk of wild virus importation from endemic regions. Most recently, importation of wild poliovirus into Canada occurred in 1993 and 1996,inboth instances with no associated clinical illness. Since 1991, the active surveillance of acute flaccid paralysis (AFP) in children less than 15 years old has been carried out in Canada to monitor for suspected cases of paralytic poliomyelitis. AFP surveillance is currently implemented through the Canadian Paediatric Surveillance Program. All suspected cases of paralytic poliomyelitis reported to the Laboratory Centre for Disease Control are evaluated by the national Working Group on Polio Eradication. The proper laboratory and neurological investigation of all AFP cases younger than 15 years old and suspected cases of poliomyelitis of any age is essential for the rapid detection of paralytic poliomyelitis, the most important clinical specimen for laboratory investigation being a stool sample collected within two weeks after the onset of paralysis for viral studies. This paper provides guidelines for investigating all suspected cases of paralytic poliomyelitis, including AFP cases less than 15 years old. Guidelines are also provided for reporting confirmed or suspected cases of paralytic poliomyelitis as well as the incidental finding of wild strain poliovirus, with or without any clinical symptoms.
Meeting the needs of adolescent parents and their children
Authors: Thompson Gillian ,   Canadian Paediatric Society,   Adolescent Health Committee
Published: March 2017

AbstractAdolescent parents and their children present to health care practitioners as two paediatric patients, each with unique health care needs. Young parents and their children may be at risk for negative health outcomes, not directly as a consequence of maternal age but because of poverty and other inequities in the social determinants of health. The health needs of child and mother are best assessed using a nonjudgmental approach, appropriate screening tools and open questions that address both preventative and acute health issues. The dyad’s co-existing needs may be anticipated as they relate to growth and development, infant and adolescent mental health, nutrition and food security, safety, relationships, parenting, education, sexual health and the facilitation of supports and resources. Care providers who understand adolescent development and integrate medical home elements of a patient-centred ‘medical home’ into their practices are ideally positioned to facilitate positive health outcomes for both mother and child.
Respiratory Effects of the Nociceptin/Orphanin FQ Peptide and Opioid Receptor Agonist, Cebranopadol, in Healthy Human Volunteers
Authors: Dahan Albert , Boom Merel , Sarton Elise , Hay Justin , Groeneveld Geert Jan , Neukirchen Meike , Bothmer John , Aarts Leon , Olofsen Erik 
Published: March 2017

Abstract

Background
Cebranopadol is a novel strong analgesic that coactivates the nociceptin/orphanin FQ receptor and classical opioid receptors. There are indications that activation of the nociceptin/orphanin FQ receptor is related to ceiling in respiratory depression. In this phase 1 clinical trial, we performed a pharmacokinetic-pharmacodynamic study to quantify cebranopadol’s respiratory effects.

Methods
Twelve healthy male volunteers received 600 μg oral cebranopadol as a single dose. The following main endpoints were obtained at regular time intervals for 10 to 11 h after drug intake: ventilation at an elevated clamped end-tidal pressure of carbon dioxide, pain threshold and tolerance to a transcutaneous electrical stimulus train, and plasma cebranopadol concentrations. The data were analyzed using sigmoid Emax (respiration) and power (antinociception) models.

Results
Cebranopadol displayed typical opioid-like effects including miosis, analgesia, and respiratory depression. The blood-effect-site equilibration half-life for respiratory depression and analgesia was 1.2 ± 0.4 h (median ± standard error of the estimate) and 8.1 ± 2.5 h, respectively. The effect-site concentration causing 50% respiratory depression was 62 ± 4 pg/ml; the effect-site concentration causing 25% increase in currents to obtain pain threshold and tolerance was 97 ± 29 pg/ml. The model estimate for minimum ventilation was greater than zero at 4.9 ± 0.7 l/min (95% CI, 3.5 to 6.6 l/min).

Conclusions
At the dose tested, cebranopadol produced respiratory depression with an estimate for minimum ventilation greater than 0 l/min. This is a major advantage over full μ-opioid receptor agonists that will produce apnea at high concentrations. Further clinical studies are needed to assess whether such behavior persists at higher doses.
Measuring Patient Mobility in the ICU Using a Novel Noninvasive Sensor
Authors: Ma Andy J. , Rawat Nishi , Reiter Austin , Shrock Christine , Zhan Andong , Stone Alex , Rabiee Anahita , Griffin Stephanie , Needham Dale M. , Saria Suchi 
Published: March 2017

Objectives:
To develop and validate a noninvasive mobility sensor to automatically and continuously detect and measure patient mobility in the ICU.

Design:
Prospective, observational study.

Setting:
Surgical ICU at an academic hospital.

Patients:
Three hundred sixty-two hours of sensor color and depth image data were recorded and curated into 109 segments, each containing 1,000 images, from eight patients.

Interventions:
None.

Measurements and Main Results:
Three Microsoft Kinect sensors (Microsoft, Beijing, China) were deployed in one ICU room to collect continuous patient mobility data. We developed software that automatically analyzes the sensor data to measure mobility and assign the highest level within a time period. To characterize the highest mobility level, a validated 11-point mobility scale was collapsed into four categories: nothing in bed, in-bed activity, out-of-bed activity, and walking. Of the 109 sensor segments, the noninvasive mobility sensor was developed using 26 of these from three ICU patients and validated on 83 remaining segments from five different patients. Three physicians annotated each segment for the highest mobility level. The weighted Kappa (κ) statistic for agreement between automated noninvasive mobility sensor output versus manual physician annotation was 0.86 (95% CI, 0.72–1.00). Disagreement primarily occurred in the “nothing in bed” versus “in-bed activity” categories because “the sensor assessed movement continuously,” which was significantly more sensitive to motion than physician annotations using a discrete manual scale.

Conclusions:
Noninvasive mobility sensor is a novel and feasible method for automating evaluation of ICU patient mobility.
Activation-Associated Accelerated Apoptosis of Memory B Cells in Critically Ill Patients With Sepsis
Authors: Shankar-Hari Manu , Fear David , Lavender Paul , Mare Tracey , Beale Richard , Swanson Chad , Singer Mervyn , Spencer Jo 
Published: March 2017

Objective:
Sepsis is life-threatening organ dysfunction due to dysregulated host responses to infection. Current knowledge of human B-cell alterations in sepsis is sparse. We tested the hypothesis that B-cell loss in sepsis involves distinct subpopulations of B cells and investigated mechanisms of B-cell depletion.

Design:
Prospective cohort study.

Setting:
Critical care units.

Patients:
Adult sepsis patients without any documented immune comorbidity.

Interventions:
None.

Measurements and Main Results:
B-cell subsets were quantified by flow cytometry; annexin-V status identified apoptotic cells and phosphorylation of intracellular kinases identified activation status of B-cell subsets. B cell–specific survival ligand concentrations were measured. Gene expression in purified B cells was measured by microarray. Differences in messenger RNA abundance between sepsis and healthy controls were compared. Lymphopenia present in 74.2% of patients on admission day was associated with lower absolute B-cell counts (median [interquartile range], 0.133 [0.093–0.277] 109 cells/L) and selective depletion of memory B cells despite normal B cell survival ligand concentrations. Greater apoptotic depletion of class-switched and IgM memory cells was associated with phosphorylation of extracellular signal-regulated kinases, implying externally driven lymphocyte stress and activation-associated cell death. This inference is supported by gene expression profiles highlighting mitochondrial dysfunction and cell death pathways, with enriched intrinsic and extrinsic pathway apoptosis genes.

Conclusions:
Depletion of the memory B-cell compartment contributes to the immunosuppression induced by sepsis. Therapies targeted at reversing this immune memory depletion warrant further investigation.
A Phase II Study of Ganetespib as Second-line or Third-line Therapy for Metastatic Pancreatic Cancer
Authors: Cardin Dana B. , Thota Ramya , Goff Laura W. , Berlin Jordan D. , Jones Clyde M. , Ayers Gregory D. , Whisenant Jennifer G. , Chan Emily 
Published: March 2017

Objectives:
Heat shock protein 90 regulates multiple signaling proteins involved in key pathways of pancreatic cancer pathogenesis. Ganetespib binds to heat shock protein 90 and interferes with its binding to client proteins thus leading to inactivation and degradation of the signaling proteins that promote cancer progression. This phase II study was designed to evaluate the efficacy of ganetespib in patients with refractory metastatic pancreatic cancer (rMPC).

Methods:
Patients with rMPC received 175 mg/m2 ganetespib intravenously once weekly for 3 weeks in 4-week cycles. Primary endpoint was disease control rate at 8 weeks, with a goal of 70%. Secondary endpoints were progression-free survival, overall survival, and safety. Simon’s 2-stage design was used to assess futility and efficacy. Ganetespib was considered inactive if ≤8 patients among the first 15 treated had disease control after 8 weeks of treatment.

Results:
Fourteen patients were treated on study. Grade 3 treatment-related toxicities were diarrhea, abdominal pain, fatigue, nausea, vomiting, and hyponatremia. Disease control rate at 8 weeks was 28.6%, and median progression-free survival and overall survival were 1.58 months and 4.57 months, respectively. Early stopping rules for lack of clinical efficacy led to study closure.

Conclusions:
Single-agent ganetespib was tolerable with only modest disease control in rMPC. This disease is resistant to chemotherapy, and given the emerging data in lung and rectal cancers, as well as in pancreatic cancer cell lines, suggesting improved activity of ganetespib in combination with cytotoxic agents, studies combining this agent with chemotherapy in rMPC are more likely to yield success.