bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of Safe and Non-Self-Immunogenic Mucosal Adjuvant by Recombinant Fusion of Cholera Toxin A1 Subunit with Protein Transduction Domain
Authors: Shim Byoung-Shik , Cheon In Su , Lee Eugene , Park Sung-Moo , Choi Youngjoo , Jung Dae-Im , Yang Eunji , Choi Jung-ah , Chun June Young , Kim Jae-Ouk , Yun Cheol-Heui , Czerkinsky Cecil , Song Man Ki
Published: March 2018

Potential use of cholera toxin (CT) as a mucosal vaccine adjuvant has been documented in a variety of animal models. However, native CT is highly toxic to be used as a mucosal adjuvant in humans. Here, we demonstrate a new approach to generate a mucosal adjuvant by replacing the B subunit of CT with HIV-1 Tat protein transduction domain (PTD), which efficiently delivers fusion proteins into the cell cytoplasm by unspecific binding to cell surface. We compared the adjuvanticity and toxicity of Tat PTD-CTA1-Tat PTD (TCTA1T) with those of CT. Our results indicate that intranasal (i.n.) delivery of ovalbumin (OVA) with TCTA1T significantly augments the OVA-specific systemic and mucosal antibody responses to levels comparable to those seen with CT adjuvant. Moreover,in vivocytotoxic T lymphocyte activity elicited by TCTA1T was significantly higher than that elicited by a mutant TCTA1T (TmCTA1T) lacking ADP-ribosyltransferase function. In addition, coadministration of influenza M2 protein with TCTA1T conferred near complete protection against lethal influenza virus challenge. Importantly, TCTA1T, in contrast to CT, did not induce serum IgG antibody responses to itself and was shown to be nontoxic. These results suggest that TCTA1T may be a safe and effective adjuvant when given by mucosal routes.
Memory Distributed LMS for Wireless Sensor Networks
Authors: Xu Fangmin , Zheng Chenyang , Cao Haiyan
Published: March 2018

Due to the limited communication resource and power, it is usually infeasible for sensor networks to gather data to a central processing node. Distributed algorithms are an efficient way to resolve this problem. In the algorithms, each sensor node deals with its own input data and transmits the local results to its neighbors. Each node fuses the information from neighbors and its own to get the final results. Different from the existing work, in this paper, we present an approach for distributed parameter estimation in wireless sensor networks based on the use of memory. The proposed approach consists of modifying the cost function by adding extra statistical information. A distributed least-mean squares (d-LMS) algorithm, called memory d-LMS, is then derived based on the cost function and analyzed. The theoretical performances of mean and mean square are analyzed. Moreover, simulation results show that the proposed algorithm outperforms the traditional d-LMS algorithm in terms of convergence rate and mean square error (MSE) performance.
Feasibility of an AI-Based Measure of the Hand Motions of Expert and Novice Surgeons
Authors: Uemura Munenori , Tomikawa Morimasa , Miao Tiejun , Souzaki Ryota , Ieiri Satoshi , Akahoshi Tomohiko , Lefor Alan K. , Hashizume Makoto
Published: March 2018

This study investigated whether parameters derived from hand motions of expert and novice surgeons accurately and objectively reflect laparoscopic surgical skill levels using an artificial intelligence system consisting of a three-layer chaos neural network. Sixty-seven surgeons (23 experts and 44 novices) performed a laparoscopic skill assessment task while their hand motions were recorded using a magnetic tracking sensor. Eight parameters evaluated as measures of skill in a previous study were used as inputs to the neural network. Optimization of the neural network was achieved after seven trials with a training dataset of 38 surgeons, with a correct judgment ratio of 0.99. The neural network that prospectively worked with the remaining 29 surgeons had a correct judgment rate of 79% for distinguishing between expert and novice surgeons. In conclusion, our artificial intelligence system distinguished between expert and novice surgeons among surgeons with unknown skill levels.
Genetic Mechanisms of Immune Evasion in Colorectal Cancer
Authors: Grasso Catherine S. , Giannakis Marios , Wells Daniel K. , Hamada Tsuyoshi , Mu Xinmeng Jasmine , Quist Michael , Nowak Jonathan A. , Nishihara Reiko , Qian Zhi Rong , Inamura Kentaro , Morikawa Teppei , Nosho Katsuhiko , Abril-Rodriguez Gabriel , Connolly Charles , Escuin-Ordinas Helena , Geybels Milan S. , Grady William M. , Hsu Li , Hu-Lieskovan Siwen , Huyghe Jeroen R. , Kim Yeon Joo , Krystofinski Paige , Leiserson Mark D.M. , Montoya Dennis J. , Nadel Brian B. , Pellegrini Matteo , Pritchard Colin C. , Puig-Saus Cristina , Quist Elleanor H. , Raphael Ben J. , Salipante Stephen J. , Shin Daniel Sanghoon , Shinbrot Eve , Shirts Brian , Shukla Sachet , Stanford Janet L. , Sun Wei , Tsoi Jennifer , Upfill-Brown Alexander , Wheeler David A. , Wu Catherine J. , Yu Ming , Zaidi Syed H. , Zaretsky Jesse M. , Gabriel Stacey B. , Lander Eric S. , Garraway Levi A. , Hudson Thomas J. , Fuchs Charles S. , Ribas Antoni , Ogino Shuji , Peters Ulrike
Published: March 2018

To understand the genetic drivers of immune recognition and evasion in colorectal cancer, we analyzed 1,211 colorectal cancer primary tumor samples, including 179 classified as microsatellite instability–high (MSI-high). This set includes The Cancer Genome Atlas colorectal cancer cohort of 592 samples, completed and analyzed here. MSI-high, a hypermutated, immunogenic subtype of colorectal cancer, had a high rate of significantly mutated genes in important immune-modulating pathways and in the antigen presentation machinery, including biallelic losses of B2M and HLA genes due to copy-number alterations and copy-neutral loss of heterozygosity. WNT/β-catenin signaling genes were significantly mutated in all colorectal cancer subtypes, and activated WNT/β-catenin signaling was correlated with the absence of T-cell infiltration. This large-scale genomic analysis of colorectal cancer demonstrates that MSI-high cases frequently undergo an immunoediting process that provides them with genetic events allowing immune escape despite high mutational load and frequent lymphocytic infiltration and, furthermore, that colorectal cancer tumors have genetic and methylation events associated with activated WNT signaling and T-cell exclusion.

Significance: This multi-omic analysis of 1,211 colorectal cancer primary tumors reveals that it should be possible to better monitor resistance in the 15% of cases that respond to immune blockade therapy and also to use WNT signaling inhibitors to reverse immune exclusion in the 85% of cases that currently do not. Cancer Discov; 8(6); 730–49. ©2018 AACR.

This article is highlighted in the In This Issue feature, p. 663
Recurrent Bleedings in Newborn: A Factor VII Deficiency Case Report
Authors: Cattivelli Kim , Distefano Cristina , Bonetti Lorenza , Testa Sophie , Siboni Simona Maria , Plebani Alessandro , Poggiani Carlo
Published: March 2018

Background: Major hemorrhages in newborns can be caused by several conditions, and knowledge of the differential diagnosis is essential in order to ensure prompt recognition and appropriate treatment. Case Report: We describe the case of a male newborn experiencing recurrent hemorrhages from the first days of life. Laboratory findings showed normal platelet count, hepatic function, and C-reactive protein. Coagulation tests detected an isolated prothrombin time (PT) prolongation and severe factor VII (FVII) deficiency. Conclusion: Inherited FVII deficiency is a rare autosomal recessive bleeding disorder. Clinical presentation is heterogeneous, and bleeding severity is not directly related to FVII levels. Acute bleeding episodes can be treated with human plasma-derived FVII (pdFVII) or recombinant activated FVII (rFVIIa). In case of severe deficiency, prophylaxis must be evaluated. Awareness of this condition is crucial in order to establish prompt diagnosis and treatment.
Esporotricose - gato como fonte de infecção em foco epidêmico familiar em Guarulhos, São Paulo: relato de caso
Authors: Galati Leandro Haroutune Hassesian , Tomimori Jane , Taborda Carlos Pelleschi , Michalany Nilceo Schwery , Larsson Júnior Carlos Eduardo , Larsson Carlos Eduardo
Published: March 2018

A esporotricose é uma dermatozoonose que tem como agentes etiológicos fungos do gênero Sporothrix. É responsável por quadros micóticos ditos de implantação. Essa micose, de características antropo e saprozoonóticas e cujas principais fontes de infecção são os felinos domésticos, o solo e os vegetais, tem sido responsável por surtos epizoóticos e epidêmicos no sul e sudeste brasileiro. Este relato apresenta o caso de um felino diagnosticado e tratado para esporotricose pelo Serviço de Dermatologia do Hospital Veterinário da FMVZ/USP, após ter sido encaminhado pelo Departamento de Dermatologia da EPM/Unifesp, onde os proprietários do animal estavam sendo tratados para esporotricose humana.
Cardiopulmonary Exercise Testing in Patients Following Massive and Submassive Pulmonary Embolism
Authors: Albaghdadi Mazen S. , Dudzinski David M. , Giordano Nicholas , Kabrhel Christopher , Ghoshhajra Brian , Jaff Michael R. , Weinberg Ido , Baggish Aaron
Published: March 2018

Background

Little data exist regarding the functional capacity of patients following acute pulmonary embolism. We sought to characterize the natural history of symptom burden, right ventricular (
RV
) structure and function, and exercise capacity among survivors of massive and submassive pulmonary embolism.

Methods and Results

Survivors of submassive or massive pulmonary embolism (n=20, age 57±13.3 years, 8/20 female) underwent clinical evaluation, transthoracic echocardiography, and cardiopulmonary exercise testing at 1 and 6 months following hospital discharge. At 1 month, 9/20 (45%) patients had New York Heart Association
II
or greater symptoms, 13/20 (65%) demonstrated either persistent
RV
dilation or systolic dysfunction, and 14/20 (70%) had objective exercise impairment as defined by a peak oxygen consumption (

V
˙

O
2
) of <80% of age‐sex predicted maximal values (16.25 [13.4–20.98] mL/kg per minute). At 6 months, no appreciable improvements in symptom severity,
RV
structure or function, and peak

V
˙

O
2
(17.45 [14.08–22.48] mL/kg per minute,
P
=
NS
) were observed. No patients demonstrated an exercise limitation attributable to either
RV
/pulmonary vascular coupling, as defined by a
VE
/
VCO
2
slope >33, or a pulmonary mechanical limit to exercise at either time point. Similarly, persistent
RV
dilation or dysfunction was not significantly related to symptom burden or peak

V
˙

O
2
at either time point.

Conclusions

Persistent symptoms, abnormalities of
RV
structure and function, and objective exercise limitation are common among survivors of massive and submassive pulmonary embolism. Functional impairment appears to be attributable to general deconditioning rather than intrinsic cardiopulmonary limitation, suggesting an important role for prescribed exercise rehabilitation as a means toward improved patient outcomes and quality of life.
Hypercholesterolemia‐Induced Loss of Flow‐Induced Vasodilation and Lesion Formation in Apolipoprotein E–Deficient Mice Critically Depend on Inwardly Rectifying K
+
Channels
Authors: Fancher Ibra S. , Ahn Sang Joon , Adamos Crystal , Osborn Catherine , Oh Myung‐Jin , Fang Yun , Reardon Catherine A. , Getz Godfrey S. , Phillips Shane A. , Levitan Irena
Published: March 2018

Background

Hypercholesterolemia‐induced decreased availability of nitric oxide (
NO
) is a major factor in cardiovascular disease. We previously established that cholesterol suppresses endothelial inwardly rectifying K
+
(Kir) channels and that Kir2.1 is an upstream mediator of flow‐induced
NO
production. Therefore, we tested the hypothesis that suppression of Kir2.1 is responsible for hypercholesterolemia‐induced inhibition of flow‐induced
NO
production and flow‐induced vasodilation (
FIV
). We also tested the role of Kir2.1 in the development of atherosclerotic lesions.

Methods and Results

Kir2.1 currents are significantly suppressed in microvascular endothelial cells exposed to acetylated–low‐density lipoprotein or isolated from apolipoprotein E–deficient (
Apoe

−/−

) mice and rescued by cholesterol depletion. Genetic deficiency of Kir2.1 on the background of hypercholesterolemic
Apoe

−/−

mice,
Kir2.1

+/−

/Apoe

−/−

exhibit the same blunted
FIV
and flow‐induced
NO
response as
Apoe

−/−

or
Kir2.1

+/−

alone, but while FIV in
Apoe

−/−

mice can be rescued by cholesterol depletion, in
Kir2.1

+/−

/Apoe

−/−

mice cholesterol depletion has no effect on
FIV
. Endothelial‐specific overexpression of Kir2.1 in arteries from
Apoe

−/−

and
Kir2.1

+/−

/Apoe

−/−

mice results in full rescue of
FIV
and
NO
production in
Apoe

−/−

mice with and without the addition of a high‐fat diet. Conversely, endothelial‐specific expression of dominant‐negative Kir2.1 results in the opposite effect.
Kir2.1

+/−

/Apoe

−/−

mice also show increased lesion formation, particularly in the atheroresistant area of descending aorta.

Conclusions

We conclude that hypercholesterolemia‐induced reduction in
FIV
is largely attributable to cholesterol suppression of Kir2.1 function via the loss of flow‐induced
NO
production, whereas the stages downstream of flow‐induced Kir2.1 activation appear to be mostly intact. Kir2.1 channels also have an atheroprotective role.
Adipose‐Derived Exosomes Exert Proatherogenic Effects by Regulating Macrophage Foam Cell Formation and Polarization
Authors: Xie Zulong , Wang Xuedong , Liu Xinxin , Du Huaan , Sun Changbin , Shao Xin , Tian Jiangtian , Gu Xia , Wang Hailong , Tian Jinwei , Yu Bo
Published: March 2018

Background

Obesity is causally associated with atherosclerosis, and adipose tissue (
AT
)–derived exosomes may be implicated in the metabolic complications of obesity. However, the precise role of
AT
‐exosomes in atherogenesis remains unclear. We herein aimed to assess the effect of
AT
‐exosomes on macrophage foam cell formation and polarization and subsequent atherosclerosis development.

Methods and Results

Four types of exosomes isolated from the supernatants of ex vivo subcutaneous
AT
and visceral
AT
(
VAT
) explants that were derived from wild‐type mice and high‐fat diet (
HFD
)–induced obese mice were effectively taken up by
RAW
264.7 macrophages. Both treatment with wild‐type
VAT
exosomes and
HFD
‐
VAT
exosomes, but not subcutaneous
AT
exosomes, markedly facilitated macrophage foam cell generation through the downregulation of
ATP
‐binding cassette transporter (
ABCA
1 and
ABCG
1)–mediated cholesterol efflux. Decreased expression of liver X receptor‐α was also observed. Among the 4 types of exosomes, only
HFD
‐
VAT
exosomes significantly induced M1 phenotype transition and proinflammatory cytokine (tumor necrosis factor α and interleukin 6) secretion in
RAW
264.7 macrophages, which was accompanied by increased phosphorylation of
NF
‐κB‐p65 but not the cellular expression of
NF
‐κB‐p65 or
IκB
‐α. Furthermore, systematic intravenous injection of
HFD
‐
VAT
exosomes profoundly exacerbated atherosclerosis in hyperlipidemic apolipoprotein E–deficient mice, as indicated by the M1 marker (
CD
16/32 and inducible nitric oxide synthase)–positive areas and the Oil Red O/Sudan
IV
–stained area, without affecting the plasma lipid profile and body weight.

Conclusions

This study demonstrated a proatherosclerotic role for
HFD
‐
VAT
exosomes, which is exerted by regulating macrophage foam cell formation and polarization, indicating a novel link between
AT
and atherosclerosis in the context of obesity.
Effect of β‐Blockers Beyond 3 Years After Acute Myocardial Infarction
Authors: Park Jin Joo , Kim Sun‐Hwa , Kang Si‐Hyuck , Yoon Chang‐Hwan , Cho Young‐Seok , Youn Tae‐Jin , Chae In‐Ho , Choi Dong‐Ju
Published: March 2018

Background

The optimal duration of β‐blocker therapy in patients with acute myocardial infarction (
AMI
) is unknown. We aimed to evaluate the late effect of β‐blockers in patients with
AMI
.

Methods and Results

We enrolled all consecutive patients who presented with
AMI
at Seoul National University Bundang Hospital, between June 3, 2003 and February 24, 2015. The primary end point was 5‐year all‐cause mortality, depending on the use of β‐blockers at discharge, 1 year after
AMI
, and 3 years after
AMI
. Of 2592 patients, the prescription rates of β‐blockers were 72%, 69%, 63%, and 60% at discharge and 1, 3, and 5 years after
AMI
, respectively. The patients who were receiving β‐blocker therapy had more favorable clinical characteristics, such as younger age (62 versus 65 years;
P
<0.001). They received reperfusion therapy more often (92% versus 80%;
P
<0.001) than those without β‐blocker prescription. In the univariate analysis, the patients with β‐blocker prescription had lower 5‐year mortality at all time points. In the Cox model after adjustment for significant covariates, β‐blocker prescription at discharge was associated with a 29% reduced mortality risk (hazard ratio, 0.71; 95% confidence interval, 0.55–0.90;
P
=0.006); however, β‐blocker prescriptions at 1 and 3 years after
AMI
were not associated with reduced mortality.

Conclusions

The beneficial effect of β‐blocker therapy after
AMI
may be limited until 1 year after
AMI
. Whether late β‐blocker therapy beyond 1 year after
AMI
offers clinical benefits should be confirmed in further clinical trials.
Combined Angiotensin Receptor–Neprilysin Inhibitors Improve Cardiac and Vascular Function Via Increased NO Bioavailability in Heart Failure
Authors: Trivedi Rishi K. , Polhemus David J. , Li Zhen , Yoo Daniel , Koiwaya Hiroshi , Scarborough Amy , Goodchild Traci T. , Lefer David J.
Published: March 2018

Background

There is a paucity of data about the mechanisms by which sacubitril/valsartan (also known as LCZ696) improves outcomes in patients with heart failure. Specifically, the effects of sacubitril/valsartan on vascular function and
NO
bioavailability have not been investigated. We hypothesized that sacubitril/valsartan therapy increases circulating
NO
levels and improves vascular function in the setting of heart failure.

Methods and Results

Male spontaneously hypertensive rats underwent myocardial ischemia/reperfusion surgery to induce heart failure and were followed for up to 12 weeks with serial echocardiography. Rats received sacubitril/valsartan (68 mg/kg), valsartan (31 mg/kg), or vehicle starting at 4 weeks after reperfusion. At 8 or 12 weeks of reperfusion, animals were euthanized and tissues were collected for ex vivo analyses of
NO
bioavailability, aortic vascular reactivity, myocardial and vascular histology, and cardiac molecular assays. Left ventricular structure and function were improved by both valsartan and sacubitril/valsartan compared with vehicle. Sacubitril/valsartan resulted in superior cardiovascular benefits, as evidenced by sustained improvements in left ventricular ejection fraction and end‐diastolic pressure. Ex vivo vascular function, as measured by aortic vasorelaxation responses to acetylcholine and sodium nitroprusside, was significantly improved by valsartan and sacubitril/valsartan, with more sustained improvements afforded by sacubitril/valsartan. Furthermore, myocardial
NO
bioavailability was significantly enhanced in animals receiving sacubitril/valsartan therapy.

Conclusions

Sacubitril/valsartan offers superior cardiovascular protection in heart failure and improves vascular function to a greater extent than valsartan alone. Sacubitril/valsartan‐mediated improvements in cardiac and vascular function are likely related to increases in
NO
bioavailability and explain, in part, the benefits beyond angiotensin receptor blockade.
ADP Platelet Hyperreactivity Predicts Cardiovascular Disease in the FHS (Framingham Heart Study)
Authors: Puurunen Marja K. , Hwang Shih‐Jen , Larson Martin G. , Vasan Ramachandran S. , O'Donnell Christopher J. , Tofler Geoffrey , Johnson Andrew D.
Published: March 2018

Background

Platelet function is associated with adverse events in patients with cardiovascular disease (
CVD
).

Methods and Results

We examined associations of baseline platelet function with incident
CVD
events in the community‐based FHS (Framingham Heart Study). Participants free of prevalent
CVD
and without recent aspirin treatment with available data in the Framingham Offspring cohort (1991–1995) and Omni cohort (1994–1998) were included. Platelet function was measured with light transmission aggregometry using collagen (1.9 μg/mL),
ADP
(0.05–15 μmol/L), and epinephrine (0.01–15 μmol/L). We used proportional hazards models to analyze incident outcomes (myocardial infarction/stroke,
CVD
, and
CVD
mortality) with respect to platelet measures. The study sample included 2831 participants (average age, 54.3 years; 57% women). During follow‐up (median, 20.4 years), we observed 191 composite incident myocardial infarction or stroke events, 432 incident
CVD
cases, and 117
CVD
deaths. Hyperreactivity to
ADP
and platelet aggregation at
ADP
concentration of 1.0 μmol/L were significantly associated with incident myocardial infarction/stroke in a multivariable model (hazard ratio, 1.68 [95% confidence interval, 1.13–2.50] [
P
=0.011] for hyperreactivity across
ADP
doses; and hazard ratio, 1.16 [95% confidence interval, 1.02–1.33] [
P
=0.029] for highest quartile of
ADP
response at 1.0 μmol/L versus others). No association was observed for collagen lag time or any epinephrine measures with incident myocardial infarction or stroke.

Conclusions

Intrinsic hyperreactivity to low‐dose
ADP
in our community‐based sample, who were free of
CVD
and any antiplatelet therapy, is associated with future arterial thrombosis during a 20‐year follow‐up. These findings reinforce
ADP
activation inhibition as a critical treatment paradigm and encourage further study of
ADP
inhibitor‐refractive populations.
Confessional Thoughts on Re-reading The Ideological Origins
Authors: Bailyn Bernard
Published: March 2018

This essay reflects Professor Bailyn's reaction upon re-reading The Ideological Origins. Struck by the revolutionaries. preoccupation with Power, he explores the vivid representations of its place in early modern political thought and examines the implications in the creation of a system intended to resolve the problems that attend its use and its misuse within a republican form of government.
What Kind of Book is The Ideological Origins of the American Revolution?
Authors: Nelson Eric
Published: March 2018

Most scholarship on the ideology of the American Revolution asks the question: “What did American patriots think about politics”? But The Ideological Origins asks instead: “ How did patriots think about politics”? At issue here is the distinction between political theory and political consciousness. Once we get this distinction properly into view, we can rethink the relationship between two great, and apparently rivalrous, historiographies on early American political thought.
The Fulfillment Revisited: Political Experience, Enlightenment Ideas, and the International Constitution
Authors: Hulsebosch Daniel J.
Published: March 2018

Taking a cue from Bernard Bailyn's description of the constitutional debate as “the ideological fulfillment of the Revolution,” this essay analyzes the Constitution's contribution to a level of governance often slighted in histories focusing on the states and the federal government: the relationship of the United States to the other nations in the Atlantic world.
Fifteen-Year Journey to High Reliability in Pathology and Laboratory Medicine
Authors: Middleton Lavinia P. , Phipps Ron , Routbort Mark , Prieto Victor , Medeiros L. Jeffrey , Riben Michael , Contreras Alejandro , Kelley James , Patel Keyur , Bingham John , Wagar Elizabeth A.
Published: March 2018

Many high-reliability organizations in industries outside of health care have sustained high levels of excellence and prevention of harm while managing complex systems and risk. To date, no health care organizations has organized its efforts to achieve highly reliable results despite several decades of improvement science. Laboratorians were early adopters of quality initiatives and process improvements. In the late 1990s, the Division of Pathology and Laboratory Medicine at The University of Texas MD Anderson Cancer Center embarked on a major effort to improve quality and patient safety and to reduce waste. This article describes the institution’s journey toward approaching high reliability with the intent to share not only the tools and best practices, but also the ongoing reassessment of the problems detected on the journey. The authors hope that their experience will help the reader develop interventions to adapt in their own environment to facilitate more optimal patient care.
Application of Monte Carlo cross-validation to identify pathway cross-talk in neonatal sepsis
Authors: Zhang Yuxia , Liu Cui , Wang Jingna , Li Xingxia
Published: March 2018

To explore genetic pathway cross-talk in neonates with sepsis, an integrated approach was used in this paper. To explore the potential relationships between differently expressed genes between normal uninfected neonates and neonates with sepsis and pathways, genetic profiling and biologic signaling pathway were first integrated. For different pathways, the score was obtained based upon the genetic expression by quantitatively analyzing the pathway cross-talk. The paired pathways with high cross-talk were identified by random forest classification. The purpose of the work was to find the best pairs of pathways able to discriminate sepsis samples versus normal samples. The results found 10 pairs of pathways, which were probably able to discriminate neonates with sepsis versus normal uninfected neonates. Among them, the best two paired pathways were identified according to analysis of extensive literature.

Impact statement

To find the best pairs of pathways able to discriminate sepsis samples versus normal samples, an RF classifier, the DS obtained by DEGs of paired pathways significantly associated, and Monte Carlo cross-validation were applied in this paper. Ten pairs of pathways were probably able to discriminate neonates with sepsis versus normal uninfected neonates. Among them, the best two paired pathways ((7) IL-6 Signaling and Phospholipase C Signaling (PLC); (8) Glucocorticoid Receptor (GR) Signaling and Dendritic Cell Maturation) were identified according to analysis of extensive literature.
Return on investment in blended advanced cardiac life support training compared to face-to-face training in Singapore
Authors: George Pradeep Paul , Ooi Chee Kheong , Leong Edwin , Jarbrink Krister , Car Josip , Lockwood Craig
Published: March 2018

Background

Internet adoption during the past decade has provided opportunities for innovation in advanced cardiac life support (ACLS) training. With pressure on budgets across health care systems, there is a need for more cost-effective solutions. Recently, traditional ACLS training has evolved from passive to active learning technologies. The objective of this study is to compare the cost, cost-savings and return on investment (ROI) of blended ACLS (B-ACLS) and face-to-face ACLS (F-ACLS) in Singapore.

Methods:

B-ACLS and F-ACLS courses are offered in two training institutes in Singapore. Direct and indirect costs of training were obtained from one of the training providers. ROI was computed using cost-savings over total cost if B-ACLS was used instead of F-ACLS.

Results:

The estimated annual cost to conduct B-ACLS and F-ACLS were S$43,467 and S$72,793, respectively. Discounted total cost of training over the life of the course (five years) was S$107,960 for B-ACLS and S$280,162 for F-ACLS. Annual productivity loss cost account for 52% and 23% of the costs among the F-ACLS and B-ACLS, respectively. B-ACLS yielded a 160% return on the money invested. There would be 61% savings over the life of the course if B-ACLS were to be used instead of F-ACLS.

Conclusion:

The B-ACLS course provides significant cost-savings to the provider and a positive ROI. B-ACLS should be more widely adopted as the preferred mode of ACLS training. As a start, physicians looking for reaccreditation of the ACLS training should be encouraged to take B-ACLS instead of F-ACLS.
Do peer support groups have an effect on medication adherence? A study among people living with HIV/AIDS in Enugu State, Nigeria
Authors: Chime Onyinye Hope , Arinze-Onyia Sussan Uzoamaka , Obionu Christopher Ndukife
Published: March 2018

Background:

The health benefits of antiretroviral treatment greatly depend on the extent to which people living with HIV/AIDS adhere to the prescribed daily dosing regimens. Peer support groups are expected to have a high impact on adherence to medication among people living with HIV/AIDS.

Objectives:

This study was designed to determine factors affecting adherence to medication among people living with HIV/AIDS in peer support and non-support groups attending antiretroviral clinics in Enugu State, Nigeria.

Method:

This was a cross-sectional, comparative study using qualitative and quantitative instruments among 840 people living with HIV/AIDS attending antiretroviral clinics in Enugu, Nigeria. Quantitative data was analysed using IBM SPSS version 22. A Chi-square test of statistical significance, a student t-test and multivariate analysis using binary logistic regression were used in the analysis. Manual content analysis was done for the qualitative data.

Results:

The mean age of respondents was comparable in both study groups: support group 38.5±9.6; and non-support group 38.5±10.1. A significantly higher proportion of respondents in the support group (91.9%) achieved good adherence compared with those in the non-support group (87.1%). A good medication adherence self-rating was a predictor of adherence in both study groups: support group (AOR 5.8, 95% CI: 2.7–12.2, p=<0.001) and non-support group (AOR 0.2, 95% CI: 0.1–0.4, p=<0.001).

Conclusion:

The peer-based intervention is a viable and effective tool for maintaining optimal adherence among people living with HIV/AIDS in resource-limited settings; hence, research should concentrate on interventions that do not focus on individuals alone, but rather on those that strengthen the capacity of groups to collectively participate in HIV programmes.
Time-frequency attributes based on complete ensemble empirical mode decomposition
Authors: Gaci Said
Published: March 2018

We suggest time-frequency attributes based on the complete ensemble empirical mode decomposition method. This technique consists of decomposing a signal into intrinsic oscillatory modes, called intrinsic mode functions (IMFs). Applied to Algerian seismic sections, it provides new instantaneous Hilbert spectral amplitude attributes, computed from the resulting IMFs, underlining subtle geologic anomalies (possible presence of gas) that cannot be inferred by the conventional attributes.
The development of an outcome measure for liaison mental health services
Authors: Guthrie Else , Harrison Mathew , Brown Richard , Sandhu Rajdeep , Trigwell Peter , Abraham Seri , Nawaz Shazada , Kelsall Peter , Thomasson Rachel
Published: March 2018

Aims and method

To develop and pilot a clinician-rated outcome scale to evaluate symptomatic outcomes in liaison psychiatry services. Three hundred and sixty patient contacts with 207 separate individuals were rated using six subscales (mood, psychosis, cognition, substance misuse, mind–body problems and behavioural disturbance) plus two additional items (side-effects of medication and capacity to consent for medical treatment). Each item was rated on a five-point scale from 0 to 5 (nil, mild, moderate, severe and very severe).

Results

The liaison outcome measure was acceptable and easy to use. All subscales showed acceptable interrater reliability, with the exception of the mind–body subscale. Overall, the measure appears to show stability and sensitivity to change.

Clinical implications

The measure provides a useful and robust way to determine symptomatic change in a liaison mental health setting, although the mind–body subscale requires modification.

Declaration of interest

None.
Preconception prediction of expectant fathers' mental health: 20-year cohort study from adolescence
Authors: Spry Elizabeth , Giallo Rebecca , Moreno-Betancur Margarita , Macdonald Jacqui , Becker Denise , Borschmann Rohan , Brown Stephanie , Patton George C. , Olsson Craig A.
Published: March 2018

We examined prospective associations between men's common mental disorders in the decades prior to offspring conception and subsequent paternal antenatal mental health problems. Data came from a prospective intergenerational cohort study which assessed common mental disorder nine times from age 14 to 29 years, and in the third trimester of subsequent pregnancies to age 35 years (N = 295 pregnancies to 214 men). Men with histories of adolescent and young adult common mental disorders were over four times more likely to experience antenatal mental health problems. Future research identifying modifiable perinatal factors that counteract preconception risk would provide further targets for intervention.

Declaration of interest

None.
Risk of suicide attempts in adolescents and young adults with attention-deficit hyperactivity disorder: a nationwide longitudinal study
Authors: Huang Kai-Lin , Wei Han-Ting , Hsu Ju-Wei , Bai Ya-Mei , Su Tung-Ping , Li Cheng-Ta , Lin Wei-Chen , Tsai Shih-Jen , Chang Wen-Han , Chen Tzeng-Ji , Chen Mu-Hong
Published: March 2018

Background

Attention-deficit hyperactivity disorder (ADHD) increases the risk of suicidal behaviours through psychiatric comorbidities; however, a significant direct association has not been observed between ADHD and suicide attempts.

Aims

To evaluate the risk of suicide attempt in adolescents and young adults with ADHD.

Method

Using a nationwide, population-based insurance claims database, this longitudinal cohort study enrolled 20 574 adolescents and young adults with ADHD and 61 722 age- and gender-matched controls between 2001 and 2009. Any suicide attempt was identified from enrolment to 31 December 2011. The association between ADHD medications and the likelihood of suicide attempt was assessed.

Results

ADHD was an independent risk factor for any suicide attempt (hazard ratio = 3.84, 95% CI = 3.19–4.62) and repeated suicide attempts (hazard ratio = 6.52, 95% CI = 4.46–9.53). Subgroup analyses of men, women, adolescents and young adults demonstrated the same trend. Methylphenidate or atomoxetine treatment did not increase the risk of suicide attempt or repeated suicide attempts. Long-term methylphenidate treatment was associated with a significantly decreased risk of repeated suicide attempts in men (hazard ratio = 0.46, 95% CI = 0.22–0.97).

Conclusion

ADHD was a risk factor for suicide attempt and a stronger predictor of repeated suicide attempts, independent of comorbidities. Further investigation is warranted to explore the mechanism underlying the association between ADHD and suicidal behaviours.

Declaration of interest

None.
Description of a Novel Set-up for Functional Echocardiographic Assessment of Left Ventricular Performance During Ex Vivo Heart Perfusion
Authors: Ruggeri Giulia Maria , Qua Hiansen Joshua , Pivetta Emanuele , Mashari Azad , Ballocca Flavia , Pinto Ribeiro Roberto Vanin , Xin Liming , Badiwala Mitesh , Thampinathan Babita , Meineri Massimiliano
Published: March 2018

Ex vivo heart perfusion (EVHP) is a new technology aimed at decreasing cold ischemia time and evaluating cardiac function before transplanting a donor heart. In an experimental EVHP swine model, we tested a 3D-printed custom-made set-up to perform surface echocardiography on an isolated beating heart during left ventricular loading. The views obtained at any time point were equivalent to standard transesophageal and transthoracic views. A decrease in left ventricular function during EVHP was observed in all experiments.
The Association Between Timing of Routine Preoperative Blood Testing and a Composite of 30-Day Postoperative Morbidity and Mortality
Authors: Ruetzler Kurt , Lin Peirong , You Jing , Schacham Yehoshua , Naylor Amanda J. , Sessler Daniel I. , Saager Leif
Published: March 2018

BACKGROUND:

Laboratory testing is a common component of preanesthesia evaluation and is designed to identify medical abnormalities that might otherwise remain undetected. While blood testing might optimally be performed shortly before surgery, it is often done earlier for practical reasons. We tested the hypothesis that longer periods between preoperative laboratory testing and surgery are associated with increased odds of having a composite of 30-day morbidity and mortality.

METHODS:

We obtained preoperative data from 2,320,920 patients in the American College of Surgeons National Surgical Quality Improvement Program who were treated between 2005 and 2012. Our analysis was restricted to relatively healthy patients with American Society of Anesthesiology physical status I–II who had elective surgery and normal blood test results (n = 235,010). The primary relationship of interest was the odds of 30-day morbidity and mortality as a function of delay between preoperative testing and surgery. A multivariable logistic regression model was used for the 10 pairwise comparisons among the 5 laboratory timing groups (laboratory blood tests within 1 week of surgery; 1–2 weeks; 2–4 weeks; 1–2 months; and 2–3 months) on 30-day morbidity, adjusting for any imbalanced baseline covariables and type of surgery.

RESULTS:

A total of 4082 patients (1.74%) had at least one of the component morbidities or died within 30-days after surgery. The observed incidence (unadjusted) was 1.7% when the most recent laboratory blood tests measured within 1 week of surgery, 1.7% when it was within 1–2 weeks, 1.8% when it was within 2–4 weeks, 1.7% when it was between 1 and 2 months, and 2.0% for patients with most recent laboratory blood tests measured 2–3 months before surgery. None of the values within 2 months differed significantly: estimated odds ratios for patients within blood tested within 1 week were 1.00 (99.5% confidence interval, 0.89–1.12) as compared to 1–2 weeks, 0.88 (0.77–1.00) for 2–4 weeks, and 0.95 (0.79–1.14) for 1–2 months, respectively. The estimated odds ratio comparing 1–2 weeks to each of 2–4 weeks and 1–2 months were 0.88 (0.76–1.03) and 0.95 (0.78–1.16), respectively. Blood testing 2–3 months before surgery was associated with increased odds of outcome compared to patients whose most recent test was within 1 week (P = .002) and 1–2 weeks of the date of surgery.

CONCLUSIONS:

In American Society of Anesthesiologists physical status I and II patients, risk of 30-day morbidity and mortality was not different with blood testing up to 2 months before surgery, suggesting that it is unnecessary to retest patients shortly before surgery.
Excipients in Anesthesia Medications
Authors: Burbridge Mark A. , Jaffe Richard A.
Published: March 2018

Medications used in anesthesiology contain both pharmacologically active compounds and additional additives that are usually regarded as being pharmacologically inactive. These additives, called excipients, serve diverse functions. Despite being labeled inert, excipients are not necessarily benign substances. Anesthesiologists should have a clear understanding of their chemical properties and the potential for adverse reactions. This report catalogs the excipients found in drugs commonly used in anesthesiology, provides a brief description of their function, and documents examples from the literature regarding their adverse effects.
The Association of Targeted Cell Salvage Blood Transfusion During Cesarean Delivery With Allogeneic Packed Red Blood Cell Transfusions in a Maternity Hospital in China
Authors: Yan Haiya , Hu Ling-Qun , Wu Yun , Fan Qihui , Wong Cynthia A. , McCarthy Robert J.
Published: March 2018

BACKGROUND:

Autologous transfusion of intraoperative cell salvage blood may be a potential method to decrease the need for allogeneic packed red blood cell transfusions after cesarean delivery, although there are limited data on the benefits of this method. This study evaluated the implementation of targeted intraoperative cell salvage during cesarean delivery in women at increased risk for hemorrhage at the Women’s and Children’s Hospital in Ningbo, China.

METHODS:

All women who underwent cesarean delivery >28 weeks of gestation were included in the study. The period before intraoperative cell collection (October 1, 2010, to August 31, 2012, n = 11,322) was compared with the postimplementation period (September 1, 2012, to June 30, 2015, n = 17,456) using an interrupted time series analysis. In the postimplementation period, women suspected to be at increased risk of the need for a blood transfusion (1604, 9.2%) underwent intraoperative cell salvage collection. The primary outcomes were the monthly rate of allogeneic packed red blood cell use and the incidence of clinical manifestation of acute blood transfusion reactions.

RESULTS:

The mean (standard deviation) estimated monthly allogeneic packed blood cell transfusion rate at the end of the 57-month study was 2.2% ± 0.7% with the implementation compared with 2.7% ± 0.9% without, difference −0.5%, 95% CI, −1.4% to 0.3%; P = .22. The mean number of allogeneic units transfused per patient was 4.1 ± 0.4 units with implementation and 3.9 ± 0.9 units without, difference 0.2, 95% CI, −1.7 to 1.1 units; P = .69. Intraoperative cell salvage blood was reinfused in 757 (47%) and wasted in 847 (53%) cases. The monthly intraoperative allogeneic packed red blood cells use rate was lower after implementation (difference −0.7%, 95% CI, −0.1% to −1.4%; P = .03); however, the monthly postpartum allogeneic packed red blood cell use rate was unchanged (difference −0.2%, 95% CI, −0.4% to 0.7%; P = .56). The clinical manifestation of acute blood transfusion reactions rate was unchanged (difference −2%, 99% CI, −9% to 5%; P = .55) between the periods.

CONCLUSIONS:

Our findings suggest that targeted intraoperative cell salvage in women undergoing cesarean delivery was associated with less allogeneic blood exposure in the operating room, but not in the postoperative period. Intraoperative cell salvage in targeted cesarean deliveries was not associated with a lesser allogeneic red blood cell exposure over the hospital admission period. The lack of adverse events associated with intraoperative cell salvage supports the safety of intraoperative cell salvage in cesarean delivery.
A Device for the Quantification of Oxygen Consumption and Caloric Expenditure in the Neonatal Range
Authors: Nachman Einav , Clemensen Peter , Santos Katheryn , Cole Alexis R. , Polizzotti Brian D. , Hofmann Grace , Leeman Kristen T. , van den Bosch Sarah J. , Kheir John N.
Published: March 2018

BACKGROUND:

The accurate measurement of oxygen consumption (VO2) and energy expenditure (EE) may be helpful to optimize the treatment of critically ill patients. However, current techniques are limited in their ability to accurately quantify these end points in infants due to a low VO2, low tidal volume, and rapid respiratory rate. This study describes and validates a new device intended to perform in this size range.

METHODS:

We created a customized device that quantifies inspiratory volume using a pneumotachometer and concentrations of oxygen and carbon dioxide gas in the inspiratory and expiratory limbs. We created a customized algorithm to achieve precise time alignment of these measures, incorporating bias flow and compliance factors. The device was validated in 3 ways. First, we infused a certified gas mixture (50% oxygen/50% carbon dioxide) into an artificial lung circuit, comparing measured with simulated VO2 and carbon dioxide production (VCO2) within a matrix of varying tidal volume (4–20 mL), respiratory rate (20–80 bpm), and fraction of inspired oxygen (0.21–0.8). Second, VO2, VCO2, and EE were measured in Sprague Dawley rats under mechanical ventilation and were compared to simultaneous Douglas bag collections. Third, the device was studied on n = 14 intubated, spontaneously breathing neonates and infants, comparing measured values to Douglas measurements. In all cases, we assessed for difference between the device and reference standard by linear regression and Bland–Altman analysis.

RESULTS:

In vitro, the mean ± standard deviation difference between the measured and reference standard VO2 was +0.04 ± 1.10 (95% limits of agreement, −2.11 to +2.20) mL/min and VCO2 was +0.26 ± 0.31 (−0.36 to +0.89) mL/min; differences were similar at each respiratory rate and tidal volume measured, but higher at fraction of inspired oxygen of 0.8 than at 0.7 or lower. In rodents, the mean difference was −0.20 ± 0.55 (−1.28 to +0.89) mL/min for VO2, +0.16 ± 0.25 (−0.32 to +0.65) mL/min for VCO2, and −0.84 ± 3.29 (−7.30 to +5.61) kcal/d for EE. In infants, the mean VO2 was 9.0 ± 2.5 mL/kg/min by Douglas method and was accurately measured by the device (bias, +0.22 ± 0.87 [−1.49 to +1.93] mL/kg/min). The average VCO2 was 8.1 ± 2.3 mL/kg/min, and the device exhibited a bias of +0.33 ± 0.82 (−1.27 to +1.94) mL/kg/min. Mean bias was +2.56% ± 11.60% of the reading for VO2 and +4.25% ± 11.20% of the reading for VCO2; among 56 replicates, 6 measurements fell outside of the 20% error range, and no patient had >1 of 4 replicates with a >20% error in either VO2 or VCO2.

CONCLUSIONS:

This device can measure VO2, VCO2, and EE with sufficient accuracy for clinical decision-making within the neonatal and pediatric size range, including in the setting of tachypnea or hyperoxia.
The Effect of Repeated Versus Initial Procalcitonin Measurements on Diagnosis of Infection in the Intensive Care Setting: A Prospective Observational Study
Authors: Levin Phillip D. , Cohen Matan J. , Ohev-Zion Eden , Tannus Samer , Stohl Sheldon , Avidan Alexander , Cohen-Poraduso Ronit , Moses Allon E. , Sprung Charles L. , Benenson Shmuel
Published: March 2018

Procalcitonin (PCT) measurement has been proposed to direct antibiotic use. We examined whether repeated PCT measurements (0, 6, and/or 12 hours) versus the initial measurement only (time 0) increased the sensitivity and specificity of PCT for diagnosing infection in intensive care unit patients. Infection was identified in 67/176 (38%) patients. The sensitivity of repeated versus the initial PCT measurement (with a cutoff value 0.5 ng/mL) was 52/67 (77%; 95% confidence interval [CI], 66%–87%) vs 46/67 (69%; 95% CI, 56%–79%; P = .04) and specificity 60/109 (55%; 95% CI, 45%–65%) vs 59/109 (54%; 95% CI, 44%–64%; P = 1.0). Repeat PCT evaluations over 12 hours did not provide a clinically significant improvement in diagnostic accuracy when compared to the initial single test.
Loss of Mob1a/b in mice results in chondrodysplasia due to YAP1/TAZ-TEAD-dependent repression of SOX9
Authors: Goto Hiroki , Nishio Miki , To Yoko , Oishi Tatsuya , Miyachi Yosuke , Maehama Tomohiko , Nishina Hiroshi , Akiyama Haruhiko , Mak Tak Wah , Makii Yuma , Saito Taku , Yasoda Akihiro , Tsumaki Noriyuki , Suzuki Akira
Published: March 2018

Hippo signaling is modulated in response to cell density, external mechanical forces, and rigidity of the extracellular matrix (ECM). The Mps one binder kinase activator (MOB) adaptor proteins are core components of Hippo signaling and influence Yes-associated protein 1 (YAP1) and transcriptional co-activator with PDZ-binding motif (TAZ), which are potent transcriptional regulators. YAP1/TAZ are key contributors to cartilage and bone development but the molecular mechanisms by which the Hippo pathway controls chondrogenesis are largely unknown. Cartilage is rich in ECM and also subject to strong external forces – two upstream factors regulating Hippo signaling. Chondrogenesis and endochondral ossification are tightly controlled by growth factors, morphogens, hormones, and transcriptional factors that engage in crosstalk with Hippo-YAP1/TAZ signaling. Here, we generated tamoxifen-inducible, chondrocyte-specific Mob1a/b-deficient mice and show that hyperactivation of endogenous YAP1/TAZ impairs chondrocyte proliferation and differentiation/maturation, leading to chondrodysplasia. These defects were linked to suppression of SOX9, a master regulator of chondrogenesis, the expression of which is mediated by TEAD transcription factors. Our data indicate that a MOB1-dependent YAP1/TAZ-TEAD complex functions as a transcriptional repressor of SOX9 and thereby negatively regulates chondrogenesis.