bluuebunny/crossref_metadata_2025 huggingface dataset:
In Vivo Base Editing of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) as a Therapeutic Alternative to Genome Editing
Authors: Chadwick Alexandra C. , Wang Xiao , Musunuru Kiran
Published: July 2017

Objective—

High-efficiency genome editing to disrupt therapeutic target genes, such as
PCSK9
(proprotein convertase subtilisin/kexin type 9), has been demonstrated in preclinical animal models, but there are safety concerns because of the unpredictable nature of cellular repair of double-strand breaks, as well as off-target mutagenesis. Moreover, precise knock-in of specific nucleotide changes—whether to introduce or to correct gene mutations—has proven to be inefficient in nonproliferating cells in vivo. Base editors comprising CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats [CRISPR]-CRISPR-associated 9) fused to a cytosine deaminase domain can effect the alteration of cytosine bases to thymine bases in genomic DNA in a sequence-specific fashion, without the need for double-strand DNA breaks. The efficacy of base editing has not been established in vivo. The goal of this study was to assess whether in vivo base editing could be used to modify the mouse
Pcsk9
gene in a sequence-specific fashion in the liver in adult mice.

Approach and Results—

We screened base editors for activity in cultured cells, including human-induced pluripotent stem cells. We then delivered a base editor into the livers of adult mice to assess whether it could introduce site-specific nonsense mutations into the
Pcsk9
gene. In adult mice, this resulted in substantially reduced plasma PCSK9 protein levels (>50%), as well as reduced plasma cholesterol levels (≈30%). There was no evidence of off-target mutagenesis, either cytosine-to-thymine edits or indels.

Conclusions—

These results demonstrate the ability to precisely introduce therapeutically relevant nucleotide variants into the genome in somatic tissues in adult mammals, as well as highlighting a potentially safer alternative to therapeutic genome editing.
ADPase CD39 Fused to Glycoprotein VI‐Fc Boosts Local Antithrombotic Effects at Vascular Lesions
Authors: Degen Heidrun , Borst Oliver , Ziegler Melanie , Mojica Munoz Ann‐Katrin , Jamasbi Janina , Walker Britta , Göbel Silvia , Fassbender Julia , Adler Kristin , Brandl Richard , Münch Götz , Lorenz Reinhard , Siess Wolfgang , Gawaz Meinrad , Ungerer Martin
Published: July 2017

Background

GPVI (Glycoprotein VI) is the essential platelet collagen receptor in atherothrombosis. Dimeric
GPVI
‐Fc (Revacept) binds to
GPVI
binding sites on plaque collagen. As expected, it did not increase bleeding in clinical studies.
GPVI
‐Fc is a potent inhibitor of atherosclerotic plaque‐induced platelet aggregation at high shear flow, but its inhibition at low shear flow is limited. We sought to increase the platelet inhibitory potential by fusing
GPVI
‐Fc to the ectonucleotidase
CD
39 (fusion protein GPVI‐CD39), which inhibits local ADP accumulation at vascular plaques, and thus to create a lesion‐directed dual antiplatelet therapy that is expected to lack systemic bleeding risks.

Methods and Results

GPVI
‐
CD
39 effectively stimulated local
ADP
degradation and, compared with
GPVI
‐Fc alone, led to significantly increased inhibition of
ADP
‐, collagen‐, and human plaque–induced platelet aggregation in Multiplate aggregometry and plaque‐induced platelet thrombus formation under arterial flow conditions.
GPVI
‐
CD
39 did not increase bleeding time in an in vitro assay simulating primary hemostasis. In a mouse model of ferric chloride–induced arterial thrombosis,
GPVI
‐
CD
39 effectively delayed vascular thrombosis but did not increase tail bleeding time in vivo.

Conclusions

GPVI‐CD39 is a novel approach to increase local antithrombotic activity at sites of atherosclerotic plaque rupture or injury. It enhances
GPVI
‐Fc–mediated platelet inhibition and presents a potentially effective and safe molecule for the treatment of acute atherothrombotic events, with a favorable risk–benefit ratio.
Taxonomic review of Trans-Andean species of Pimelodus (Siluriformes: Pimelodidae), with the descriptions of two new species
Authors: VILLA-NAVARRO FRANCISCO ANTONIO , ACERO P. ARTURO , CALA PLUTARCO CALA
Published: July 2017

We review the trans-Andean species of Pimelodus from Colombia, Panamá, and Venezuela. Based on meristic and morphometric data of preserved specimens, four of five species reported from this region are considered valid and two new Colombian species are described. Here we review Pimelodus coprophagus Schultz, 1944 from Lake Maracaibo Basin of Venezuela and Colombia; Pimelodus grosskopfii Steindachner, 1879 from Magdalena River Basin; Pimelodus navarroi Schultz, 1944 from Lake Maracaibo Basin of Venezuela and Colombia; and Pimelodus punctatus (Meek & Hildebrand, 1913) from Atrato, Baudó, and Tuyra River Basins of Colombia and Panamá. Pimelodus crypticus new species is described from the upper Cauca river drainage. Pimelodus yuma new species is described from the Cauca, Magdalena, and Sinú river drainages. A key for species identification and geographical ranges is provided. We also reidentify trans-Andean specimens previously reported as Pimelodus blochii Valenciennes, 1840, a widespread cis-Andean species, or species complex, that ranges across the coastal rivers of the Guianas and Brazil and the Orinoco and Amazon Basins.
Resource Misgovernance and the Contradictions of Gas Flaring in Nigeria: A Theoretical Conversation
Authors: Akinola Adeoye O
Published: July 2017

Nigeria remains Africa’s largest energy producer and at the same time possesses one of the highest gas flaring rates in the continent. Gas flaring in the Niger Delta region, estimated at 75% of the entire gas produced in Nigeria, highlights the environmental abuse posed by resource extraction, and exposes the failure of successive governments to eliminate the threat it portends to human survival in the oil region. The federal government formally declared gas flaring illegal since 1984, but multinational oil companies continue to treat compliance as a matter of convenience and not of necessity. Despite persistent protests against environmental degradation by the oil-producing communities, the refusal of the oil companies to end gas flaring and complicity of the government remained sources of concern. In the light of these, the study examines the crux of the gas flaring imbroglio, assesses the cost–benefits of gas flaring, and explores how gas emissions to the atmosphere have threatened human existence and ecological sustainability in the Niger Delta oil region. The study reiterates the urgency to enforce a zero-gas-flaring policy in Nigerian oil communities.
Heterology, Transcendence and the Sacred: On Bataille and Levinas
Authors: Lechte John
Published: July 2017

This article examines the issues surrounding transcendence, the Other and base materialism in relation to Georges Bataille’s heterology and Emmanuel Levinas’s notion of the face of the Other as infinity and transcendence. The article concludes that there is no facet of human existence – including work and the economy – which is not touched by transcendence, and that the idea that there are societies based in subsistence and in nothing but a ‘struggle for existence’ is a prejudice of modernity.
The vascular basement membrane in the healthy and pathological brain
Authors: Thomsen Maj S , Routhe Lisa J , Moos Torben
Published: July 2017

The vascular basement membrane contributes to the integrity of the blood-brain barrier (BBB), which is formed by brain capillary endothelial cells (BCECs). The BCECs receive support from pericytes embedded in the vascular basement membrane and from astrocyte endfeet. The vascular basement membrane forms a three-dimensional protein network predominantly composed of laminin, collagen IV, nidogen, and heparan sulfate proteoglycans that mutually support interactions between BCECs, pericytes, and astrocytes. Major changes in the molecular composition of the vascular basement membrane are observed in acute and chronic neuropathological settings. In the present review, we cover the significance of the vascular basement membrane in the healthy and pathological brain. In stroke, loss of BBB integrity is accompanied by upregulation of proteolytic enzymes and degradation of vascular basement membrane proteins. There is yet no causal relationship between expression or activity of matrix proteases and the degradation of vascular matrix proteins in vivo. In Alzheimer’s disease, changes in the vascular basement membrane include accumulation of Aβ, composite changes, and thickening. The physical properties of the vascular basement membrane carry the potential of obstructing drug delivery to the brain, e.g. thickening of the basement membrane can affect drug delivery to the brain, especially the delivery of nanoparticles.
Brain atrophy following hemiplegic migraine attacks
Authors: Pelzer Nadine , Hoogeveen Evelien S , Ferrari Michel D , Poll-The Bwee Tien , Kruit Mark C , Terwindt Gisela M
Published: July 2017

Background

Patients with hemiplegic migraine (HM) may sometimes develop progressive neurological deterioration of which the pathophysiology is unknown.

Patient

We report a 16-year clinical and neuroradiological follow-up of a patient carrying a de novo p.Ser218Leu CACNA1A HM mutation who had nine severe HM attacks associated with seizures and decreased consciousness between the ages of 3 and 12 years.

Results

Repeated ictal and postictal neuroimaging revealed cytotoxic oedema during severe HM attacks in the symptomatic hemisphere, which later showed atrophic changes. In addition, progressive cerebellar atrophy was observed. Brain atrophy halted after cessation of severe attacks, possibly due to prophylactic treatment with flunarizine and sodium valproate.

Conclusion

Severe HM attacks may result in brain atrophy and prophylactic treatment of these attacks might be needed in an early stage of disease to prevent permanent brain damage.
Cortical Button Versus Cross-pin Femoral Fixation for Hamstring Anterior Cruciate Ligament Reconstruction: A Meta-analysis of Randomized Controlled Trials
Authors: Jiang Hai , Ma Guangzhi , Li Qi , Hu Yanqing , Li Jian , Tang Xin
Published: July 2017

Background:

Incidences of graft rupture are associated with postoperative knee laxity after anterior cruciate ligament (ACL) reconstruction. Reports of postoperative knee laxity after ACL reconstruction using different femoral fixation techniques in several studies are controversial.

Purpose:

To compare, via meta-analysis of randomized controlled trials (RCTs), the clinical outcomes and postoperative knee laxity of autogenous hamstring ACL reconstruction using cortical button versus cross-pin femoral fixation.

Study Design:

Meta-analysis.

Methods:

This study followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The online PubMed, EMBASE, and Cochrane Central Register of Controlled Trials databases were searched from inception to April 1, 2017. The study included only level 1 or 2 RCTs that compared cortical button and cross-pin femoral fixation for ACL reconstruction with hamstring autografts and that reported clinical outcomes or postoperative knee laxity. The Cochrane Collaboration’s risk of bias tool was used to assess the risk of bias for all included studies. For the meta-analysis, the investigators extracted data on clinical outcomes measured by postoperative International Knee Documentation Committee (IKDC) score or Lysholm score and postoperative knee laxity defined as >5 mm side-to-side difference by the arthrometric measurement, Lachman test ≥2+, and pivot-shift test ≥2+. The risk ratio (RR) and its corresponding 95% confidence interval (CI) were computed for dichotomous data. Heterogeneity was assessed by I2 tests.

Results:

A total of 6 RCTs with 445 patients were included. Statistical analysis of pooled data showed no significant difference between the cortical button and cross-pin groups on postoperative IKDC score (RR, 0.94; 95% CI, 0.88-1.02; P = .13; I2 = 4%) and Lysholm score (RR, 0.97; 95% CI, 0.91-1.04; P = .45; I2 = 0%). Postoperative knee laxity was reported in 5 studies, and no significant difference was found between the 2 groups (RR, 1.49; 95% CI, 0.83-2.68; P = .18; I2 = 37%).

Conclusion:

Cortical button femoral fixation for autogenous hamstring ACL reconstruction had no significant difference in terms of clinical outcomes and postoperative knee laxity compared with cross-pin femoral fixation.
Sustainability of Microbusinesses and Success of Microfinance
Authors: Chouksey Aradhana , Karmarkar Yamini
Published: July 2017

Emergence of microfinance facilities has raised self-employment opportunities for the disadvantaged group. There are many small and micro entrepreneurs who have started their business with funding support from microfinance agencies. Though this increased funding resource has increased the number of businesses that are started by entrepreneurs in rural areas, another important fact is that all these new businesses are not necessarily successful. In Malwa region of Madhya Pradesh (MP), only 20 per cent of businesses funded by microfinance agencies are profitable. There are multiple reasons behind this lack of success of microenterprises. There are paucity of information in selection of right opportunity, absence of technical assistance, lack of business knowledge and marketing and finance skills, which are few of them. This is an alarming sign for funding agencies as higher failure rate of microenterprises bound to jeopardize, the sustainability of the microfinance in long term and retard the development of region. This research conducted on microenterprises of Malwa region of MP tries to identify the specific training needs of microfinance clients. Further, this research tries to evaluate empirically what are the potential and sustainable microbusiness opportunities, which can be started and run by people of disadvantage groups. Empirical findings through a survey designed on a sample of 54 microenterprises of eight villages of Malwa region show that any microbusiness having higher ratio of working capital to fixed capital investment are successful in Malwa region. Also, it is found that the most important training need of these enterprises is in the field of ‘managing finance’ for small business.
On the extraction technique of the single-coil self-feedback signal on a standard vibration table
Authors: Chi Qinglei , Shang Shuaikun
Published: July 2017

In the process of calibration on vibration and shock transducers, it is necessary for the vibration table to generate a small sine-function form distortion as the excitation signal, and the closed-loop servo feedback technology is one of the proven effective ways to reduce low-frequency motion signal distortion of the vibration table. In this paper, we report a method based on the principle of closed-loop servo feedback that can directly extract induction electromotive force of the vibrator coil. This method solves the problems caused by using sensors in the process of getting the vibration signals. Furthermore, this device has some advantages such as small size, light weight, low cost and simple maintenance. In this article, the system components and technical indexes and analyzis of the control method of the vibration table are described. Next, we compare the wave distortion obtained using monocoil signal extraction technology and that obtained using relative speed sensor. Finally, the error analysis of monocoil signal extraction technology is carried out, and the experiment is finished to prove this analysis.
Localized pigmentation disorder after subcutaneous pegylated interferon beta-1a injection
Authors: Coghe Giancarlo , Atzori Laura , Frau Jessica , Fenu Giuseppe , Lorefice Lorena , Marrosu Maria Giovanna , Cocco Eleonora
Published: July 2017

We report the case of a 42-year-old female patient who developed peculiar skin lesions due to subcutaneous polyethylene glycol (PEG) interferon beta-1a. The dermatological examination showed hypochromic macules that had coalesced into a 10-cm-diameter patch. On the abdomen injection sites, there was a greyish diffuse hyperpigmentation arranged irregularly in annular macules. Fungal infection, vitiligo and pityriasis alba were excluded. After 6 months, the lesions had worsened. This is the first case of localized pigmentation disorder reported with interferon beta, and while the clinical findings are not ascribable to vitiligo or interferon-related facial/mucosal hyperpigmentation, they may partially share the underlining mechanisms.
Can resistance training impact MRI outcomes in relapsing-remitting multiple sclerosis?
Authors: Kjølhede Tue , Siemonsen Susanne , Wenzel Damian , Stellmann Jan-Patrick , Ringgaard Steffen , Pedersen Bodil Ginnerup , Stenager Egon , Petersen Thor , Vissing Kristian , Heesen Christoph , Dalgas Ulrik
Published: July 2017

Background:

Multiple sclerosis (MS) is characterised by accelerated brain atrophy, which relates to disease progression. Previous research shows that progressive resistance training (PRT) can counteract brain atrophy in other populations.

Objective:

To evaluate the effects of PRT by magnetic resonance imaging (MRI) and clinical measures of disease progression in people with MS.

Methods:

This study was a 24-week randomised controlled cross-over trial, including a Training ( n = 18, 24 weeks of PRT followed by self-guided physical activity) and Waitlist group ( n = 17, 24 weeks of habitual lifestyle followed by PRT). Assessments included disability measures and MRI (lesion load, global brain volume, percentage brain volume change (PBVC) and cortical thickness).

Results:

While the MS Functional Composite score improved, Expanded Disability Status Scale, lesion load and global brain volumes did not differ between groups. PBVC tended to differ between groups and higher absolute cortical thickness values were observed in 19 of 74 investigated cortical regions after PRT. Observed changes were confirmed and reproduced when comparing relative cortical thickness changes between groups for four areas: anterior cingulate gyrus, temporal pole, orbital sulcus and inferior temporal sulcus.

Conclusion:

PRT seem to induce an increase in cortical thickness, indicating that PRT have a neuroprotective or even neuroregenerative effect in relapsing-remitting MS.
Modeling evacuation in institutional space: Linking three-dimensional data capture, simulation, analysis, and visualization workflows for risk assessment and communication
Authors: Lochhead Ian M , Hedley Nick
Published: July 2017

This article presents exploratory research to develop new workflows that address the challenges of adequately capturing the geometry and topology of complex institutional spaces, the analysis of prescriptive evacuation plans, and the simulation of human movement and behavior in emergency scenarios. We present a collection of geovisual analytical environments that were developed to permit new ways to view and assess risk, evacuation, and human movement. Part of this research considers how different approaches to the representation of complex institutional space, using three-dimensional capture technologies at multiple resolutions (or derived from conventional formats, such as building plans), have implicit advantages or liabilities in the analysis of risk and human evacuation. We combine three-dimensional data capture methods with geographical information science theory, three-dimensional game engines, three-dimensional evacuation simulations and spatial analyses that address the variability of campus populations, and draw upon three-dimensional modeling and photogrammetry for the assessment of real-world features in digital space. The outcome of this research demonstrates agile workflows that address emergency planning requirements, but could also enable enhanced visual analysis and interactive learning by all campus citizens. Furthermore, this work reveals key considerations and limitations associated with the dynamic nature of evacuation events and the static environments in which they have been simulated.
Maneuvering multimarket competition: The effects of multimarket contact and strategic alliances on performance of single-market firms
Authors: Chuang You-Ta , Thomson Kelly
Published: July 2017

Research on multimarket competition has focused on how multimarket contact shapes competitive behavior of firms that face each other in multiple markets. To date, there has been little attention to how multimarket contact affects single-market firms nor how single-market firms cope with multimarket competition. In this study, we examine the effects of multimarket competition and strategic alliances on single-market firms’ market share. Our analysis shows that the degree of multimarket contact firms had outside of a single-market firm’s market negatively affected the single-market firm’s market share. Yet, the number of strategic alliances a single-market firm had and having alliances with multimarket firms helped the single-market firm to cope with competitive pressure derived from multimarket contact and enhance its market share.
Successful endovascular treatment for thrombosed giant aneurysm of the V1 segment of the vertebral artery: A case report
Authors: Kiyohira Miwa , Ishihara Hideyuki , Oku Takayuki , Kawano Akiko , Oka Fumiaki , Suzuki Michiyasu
Published: July 2017

Thrombosed giant aneurysm of the V1 segment of the vertebral artery is rare, and there is controversy regarding the optimal method of treatment in this portion. Here, we report a thrombosed giant aneurysm of the V1 segment of the vertebral artery with a good clinical course with endovascular proximal artery occlusion of the vertebral artery.

A 59-year-old woman presented with a large mass in the left side of the neck. Echographic examination revealed a mass measuring 42 × 38 × 48 mm in the left neck. Angiography showed a thrombosed giant aneurysm of the V1 segment of the left vertebral artery. Endovascular proximal artery occlusion of the vertebral artery was performed, and the aneurysm lessened gradually. Although a number of procedures have been developed to treat extracranial vertebral artery aneurysms, endovascular proximal artery occlusion is a good option to treat aneurysms in this portion.
Chronic postsurgical pain: is there a possible genetic link?
Authors: James Sabu Kumar
Published: July 2017

Persistent or chronic postsurgical pain (CPSP) has been defined as ‘pain persisting beyond 2 months’. The cut-off limit of 2 months has been controversial, and some researchers argue for a 3-month period for the definition of CPSP. Multiple mechanisms, including both patient and surgical, have been shown to influence this transition. Patient factors include age, gender, anxiety, depression, somatisation, catastrophising, pre-existing pain anywhere and pain at the site of surgery. The various surgical factors include site and nature of surgery, infection, inflammation and repeat surgery. There is evidence that pre- or post-op chemotherapy and radiotherapy can also contribute towards the chronification of pain after surgery. The question of why pain following surgery or trauma persists long after the normal healing time is not yet fully explained by current evidence. This is frustrating to healthcare providers and intensely disappointing to the patients, many of whom suffer in silence for years. Genetics is now being shown to influence both the onset and the perpetuation of chronic pain in the susceptible patient. The main mechanisms are believed to be ‘single nucleotide polymorphisms’ (SNPs) and ‘epigenetics’, both of which will be discussed, with current and ongoing research and evidence, in this review. The influence of SNPs has not been replicated in recent studies and researchers advise caution in interpreting past studies. More research is needed to demonstrate the involvement of epigenetics as well as linking SNPs to the susceptible patient’s journey.
Introducing the Australian Hearing Hub
Authors: McAlpine David , McMahon Catherine , Dillon Harvey , Leigh Greg , Hungerford Jim , Patrick Jim , Cowan Robert , Dodd Louise
Published: July 2017

This special issue contains a collection of papers highlighting the collaborative research taking place at Macquarie University’s Australian Hearing Hub. Included in this introduction is a brief outline of the challenges in the hearing health and communication space and a brief description of the Australian Hearing Hub and its members, alongside an overview of the studies included in this special issue.
Outcome of pregnancies and deliveries before and after ischaemic stroke
Authors: Aarnio Karoliina , Gissler Mika , Grittner Ulrike , Siegerink Bob , Kaste Markku , Tatlisumak Turgut , Tikkanen Minna , Putaala Jukka
Published: July 2017

Introduction

Limited data exist on the outcome of pregnancies and deliveries in women with ischaemic stroke. We investigated the incidence of pregnancy- and delivery-related complications in women with ischaemic stroke before and after pregnancy compared with stroke-free matched controls.

Patients and methods

Of our 1008 consecutive patients aged 15–49 years with first-ever ischaemic stroke, 1994–2007, we included women with pregnancy data before or after stroke recorded in the Medical Birth Register (MBR) ( n = 152), and for them searched stroke-free controls matched by age, parity, year of birth, residential area and multiplicity ( n = 608). Data on hospital admissions and deaths (1987–2014) came from national health registries. Poisson regression mixed models allowed comparison of the incidence of complications.

Results

A total of 124 stroke mothers had 207 singleton pregnancies before and 45 mothers 68 pregnancies after stroke. The incidence rate ratio (IRR) for the composite outcome of pregnancy and delivery complications adjusted for socioeconomic status and maternal smoking was 1.43 (95% confidence interval [CI] 1.00–2.03, p = 0.05) for pre-stroke mothers, and 1.09 (95% CI 0.66–1.78) for post-stroke mothers, compared with matched controls. Similarly, the adjusted IRR for post-stroke hospital admission during pregnancy was 1.85 (95% CI 1.03–3.31). The IRR for perinatal death of the child was 3.43 (95% CI 0.57–20.53) before and 8.88 (95% CI 0.81–97.95) after stroke.

Discussion and conclusions

Compared with stroke-free mothers, we found a higher incidence of pregnancy- and delivery-related complications in mothers with ischaemic stroke. Larger studies are needed to verify our results.
MicroRNAs and acute myeloid leukemia: therapeutic implications and emerging concepts
Authors: Wallace Jared A. , O’Connell Ryan M.
Published: July 2017

Acute myeloid leukemia (AML) is a deadly hematologic malignancy characterized by the uncontrolled growth of immature myeloid cells. Over the past several decades, we have learned a tremendous amount regarding the genetic aberrations that govern disease development in AML. Among these are genes that encode noncoding RNAs, including the microRNA (miRNA) family. miRNAs are evolutionarily conserved small noncoding RNAs that display important physiological effects through their posttranscriptional regulation of messenger RNA targets. Over the past decade, studies have identified miRNAs as playing a role in nearly all aspects of AML disease development, including cellular proliferation, survival, and differentiation. These observations have led to the study of miRNAs as biomarkers of disease, and efforts to therapeutically manipulate miRNAs to improve disease outcome in AML are ongoing. Although much has been learned regarding the importance of miRNAs in AML disease initiation and progression, there are many unanswered questions and emerging facets of miRNA biology that add complexity to their roles in AML. Moving forward, answers to these questions will provide a greater level of understanding of miRNA biology and critical insights into the many translational applications for these small regulatory RNAs in AML.
Long-term outcomes of dasatinib-induced pulmonary arterial hypertension: a population-based study
Authors: Weatherald Jason , Chaumais Marie-Camille , Savale Laurent , Jaïs Xavier , Seferian Andrei , Canuet Matthieu , Bouvaist Hélène , Magro Pascal , Bergeron Anne , Guignabert Christophe , Sitbon Olivier , Simonneau Gérald , Humbert Marc , Montani David
Published: July 2017

This study aimed to describe the long-term outcomes of pulmonary arterial hypertension (PAH) induced by dasatinib.

21 incident, right heart catheterisation-confirmed cases of dasatinib-induced PAH were identified from the French Pulmonary Hypertension Registry. Clinical and haemodynamic variables were compared from baseline to last follow-up (median (range) 24 (1–81) months).

Median age was 52 years and 15 patients were female (71%). 19 patients received dasatinib for chronic myelogenous leukaemia for a median (range) duration of 42 (8–74) months before PAH diagnosis. No bone morphogenic protein receptor-2 (BMPR2) mutations were found in the 10 patients tested. Dasatinib was uniformly discontinued and 11 patients received PAH medications. Four patients died during follow-up. New York Heart Association functional class improved from 76% in class III/IV to 90% in class I/II (p<0.01). Median (range) 6-min walk distance improved from 306 (0–660) to 430 (165–635) m (p<0.01). Median (range) mean pulmonary arterial pressure improved from 45 (30–70) to 26 (17–50) mmHg (p<0.01) and pulmonary vascular resistance from 6.1 (3.2–27.3) to 2.6 (1.2–5.9) Wood units (p<0.01). Patients treated with PAH medications had worse baseline haemodynamics but similar long-term outcomes to untreated patients. PAH persisted in 37% of patients.

Dasatinib-induced PAH frequently improves after discontinuation but persisted in over one-third of patients, therefore systematic follow-up is essential.
Cognitive behavioural therapy attenuates the enhanced early facial stimuli processing in social anxiety disorders: an ERP investigation
Authors: Cao Jianqin , Liu Quanying , Li Yang , Yang Jun , Gu Ruolei , Liang Jin , Qi Yanyan , Wu Haiyan , Liu Xun
Published: July 2017

Background

Previous studies of patients with social anxiety have demonstrated abnormal early processing of facial stimuli in social contexts. In other words, patients with social anxiety disorder (SAD) tend to exhibit enhanced early facial processing when compared to healthy controls. Few studies have examined the temporal electrophysiological event-related potential (ERP)-indexed profiles when an individual with SAD compares faces to objects in SAD. Systematic comparisons of ERPs to facial/object stimuli before and after therapy are also lacking. We used a passive visual detection paradigm with upright and inverted faces/objects, which are known to elicit early P1 and N170 components, to study abnormal early face processing and subsequent improvements in this measure in patients with SAD.

Methods

Seventeen patients with SAD and 17 matched control participants performed a passive visual detection paradigm task while undergoing EEG. The healthy controls were compared to patients with SAD pre-therapy to test the hypothesis that patients with SAD have early hypervigilance to facial cues. We compared patients with SAD before and after therapy to test the hypothesis that the early hypervigilance to facial cues in patients with SAD can be alleviated.

Results

Compared to healthy control (HC) participants, patients with SAD had more robust P1–N170 slope but no amplitude effects in response to both upright and inverted faces and objects. Interestingly, we found that patients with SAD had reduced P1 responses to all objects and faces after therapy, but had selectively reduced N170 responses to faces, and especially inverted faces. Interestingly, the slope from P1 to N170 in patients with SAD was flatter post-therapy than pre-therapy. Furthermore, the amplitude of N170 evoked by the facial stimuli was correlated with scores on the interaction anxiousness scale (IAS) after therapy.

Conclusions

Our results did not provide electrophysiological support for the early hypervigilance hypothesis in SAD to faces, but confirm that cognitive-behavioural therapy can reduce the early visual processing of faces. These findings have potentially important therapeutic implications in the assessment and treatment of social anxiety.

Trial registration HEBDQ2014021
Changes in cardiac function and hemodynamics during robot-assisted laparoscopic prostatectomy with steep head-down tilt: a prospective observational study
Authors: Ono Naomi , Nakahira Junko , Nakano Shoko , Sawai Toshiyuki , Minami Toshiaki
Published: July 2017

Objective

Robot-assisted laparoscopic prostatectomy requires the patient to be placed in a steep head-down tilt. The aim of our study was to investigate changes in cardiac index and left ventricular end-diastolic volume in a steep had-down tilt. This is a prospective observational study. We investigated the influence of steep head-down tilt on cardiac function and hemodynamics without fluid restriction in 12 men of American Society of Anesthesiologists physical status I–II undergoing robot-assisted laparoscopic prostatectomy. We measured left ventricular ejection fraction, left ventricular end-diastolic volume and cardiac index by transesophageal echocardiography, cardiac index using a FloTrac® sensor, heart rate and arterial blood pressure, before and 5 min after tilting the operating table.

Results

The following variables changed significantly after tilting and establishment of the pneumoperitoneum: left ventricular ejection fraction (before 62.5%, after 55.5%; P = 0.040), systolic blood pressure (before 116 mmHg, after 128 mmHg; P = 0.001) and diastolic blood pressure (before 59 mmHg, after 70 mmHg; P = 0.002). There were no significant changes in cardiac index or left ventricular end-diastolic volume measured by transesophageal echocardiography, or cardiac index by FloTrac® sensor. Left ventricular ejection fraction decreased, whereas cardiac index and left ventricular end-diastolic volume did not change, indicating that steep head-down tilt and pneumoperitoneum during robot-assisted laparoscopic prostatectomy did not greatly influence cardiac function.

This study was registered as a clinical study with the Japanese Official Clinical Trial Registry (Trial Registration Number JMA-IIA00158 on 7th January, 2014)
Sparsity in compressive sensing
Authors: Ma Jianwei , Yu Siwei
Published: July 2017

Reducing the cost of seismic exploration is a long-standing problem. Compressive sensing (CS) provides a new routine for recovering signals when the seismic acquisition is under the criteria of Nyquist theory. The basic assumptions of CS are: (1) the signal is sparse under a certain transform, and (2) the acquisition or measurement is random in a certain way. The ratio of compressive samplings to Nyquist samplings is determined by the sparsity of the signal under random measurements. Sparsity has been introduced to seismic exploration from three sources: (1) borrowing from image processing, (2) training from seismic data, and (3) special design for seismic data. We review the sparse transforms used in seismic data acquisition and processing under the framework of CS and then discuss a new way of designing sparse transforms.
Differential Impact of Glucose Administered Intravenously and Orally on Circulating miR-375 Levels in Human Subjects
Authors: Yan Xin , Wang Zhen , Westberg-Rasmussen Sidse , Tarbier Marcel , Rathjen Thomas , Tattikota Sudhir G , Peck Bailey C E , Kanke Matt , Oxvig Claus , Frystyk Jan , Starup-Linde Jakob , Sethupathy Praveen , Friedländer Marc R , Gregersen Søren , Poy Matthew N
Published: July 2017

Background

To date, numerous nucleic acid species have been detected in the systemic circulation including microRNAs (miRNAs); however, their functional role in this compartment remains unclear.

Objective

The aim of this study was to determine whether systemic levels of miRNAs abundant in blood, including the neuroendocrine tissue-enriched miR-375, are altered in response to a glucose challenge.

Design

Twelve healthy males were recruited for an acute crossover study that consisted of two tests each following an 8-hour fasting period. An oral glucose tolerance test (OGTT) was performed, and blood samples were collected over a 3-hour period. Following a period of at least 1 week, the same participants were administered an isoglycemic intravenous glucose infusion (IIGI) with the same blood-collection protocol.

Results

The glucose response curve following the IIGI mimicked that obtained after the OGTT, but as expected, systemic insulin levels were lower during the IIGI compared with the OGTT (P < 0.05). miR-375 levels in circulation were increased only in response to an OGTT and not during an IIGI. In addition, the response to the OGTT also coincided with the transient increase of circulating glucagon-like peptide (GLP)-1, GLP-2, and glucose-dependent insulinotropic polypeptide.

Conclusions

The present findings show levels of miR-375 increase following administration of an OGTT and, in light of its enrichment in cells of the gut, suggest that the gastrointestinal tract may play an important role in the abundance and function of this miRNA in the blood.
Lack of Association Between the Use of Nerve Blockade and the Risk of Persistent Opioid Use Among Patients Undergoing Shoulder Arthroplasty: Evidence From the Marketscan Database
Authors: Mueller Kathryn G. , Memtsoudis Stavros G. , Mariano Edward R. , Baker Laurence C. , Mackey Sean , Sun Eric C.
Published: July 2017

BACKGROUND:

Persistent opioid use following surgery has received increasing attention from policymakers, researchers, and clinicians. Perioperative nerve blockade has been hypothesized to decrease the risk of persistent opioid use. We examined whether nerve blockade was associated with a decreased risk of persistent opioid use among patients undergoing shoulder arthroplasty, a procedure with high rates of persistent postoperative pain.

METHODS:

Using health care claims data, we constructed a sample of 6695 patients undergoing shoulder arthroplasty between 2002 and 2012 and used billing data to identify the utilization of nerve blockade. We then used a multivariable logistic regression to estimate the association between nerve blockade and 2 measures of opioid use: having filled at least 1 prescription for an opioid between postoperative days (PODs) 0 and 90, and between POD 91 and 365. This regression adjusted for a variety of potential confounders, such as preoperative opioid use and medical history.

RESULTS:

There was no association between nerve blockade and our 2 measures of persistent opioid use: adjusted odds ratio, 1.12 (97.5% confidence interval, 0.939–1.34; P = .15) for opioid use between POD 0 and 90, and adjusted odds ratio, 0.997 (97.5% confidence interval, 0.875–1.14; P = .95) for opioid use between POD 91 and 365.

CONCLUSIONS:

Although the use of perioperative nerve blockade may offer short-term benefits, in this study, it was not associated with a reduction in the risk of persistent opioid use for patients undergoing shoulder arthroplasty.
A Novel Method of Evaluating Key Factors for Success in a Multifaceted Critical Care Fellowship Using Data Envelopment Analysis
Authors: Tiwari Vikram , Kumar Avinash B.
Published: July 2017

BACKGROUND:

The current system of summative multi-rater evaluations and standardized tests to determine readiness to graduate from critical care fellowships has limitations. We sought to pilot the use of data envelopment analysis (DEA) to assess what aspects of the fellowship program contribute the most to an individual fellow’s success. DEA is a nonparametric, operations research technique that uses linear programming to determine the technical efficiency of an entity based on its relative usage of resources in producing the outcome.

DESIGN:

Retrospective cohort study.

SUBJECTS AND SETTING:

Critical care fellows (n = 15) in an Accreditation Council for Graduate Medical Education (ACGME) accredited fellowship at a major academic medical center in the United States.

METHODS:

After obtaining institutional review board approval for this retrospective study, we analyzed the data of 15 anesthesiology critical care fellows from academic years 2013–2015. The input-oriented DEA model develops a composite score for each fellow based on multiple inputs and outputs. The inputs included the didactic sessions attended, the ratio of clinical duty works hours to the procedures performed (work intensity index), and the outputs were the Multidisciplinary Critical Care Knowledge Assessment Program (MCCKAP) score and summative evaluations of fellows.

RESULTS:

A DEA efficiency score that ranged from 0 to 1 was generated for each of the fellows. Five fellows were rated as DEA efficient, and 10 fellows were characterized in the DEA inefficient group. The model was able to forecast the level of effort needed for each inefficient fellow, to achieve similar outputs as their best performing peers. The model also identified the work intensity index as the key element that characterized the best performers in our fellowship.

CONCLUSIONS:

DEA is a feasible method of objectively evaluating peer performance in a critical care fellowship beyond summative evaluations alone and can potentially be a powerful tool to guide individual performance during the fellowship.
Medication Errors in Pediatric Anesthesia: A Report From the Wake Up Safe Quality Improvement Initiative
Authors: Lobaugh Lauren M. Y. , Martin Lizabeth D. , Schleelein Laura E. , Tyler Donald C. , Litman Ronald S.
Published: July 2017

BACKGROUND:

Wake Up Safe is a quality improvement initiative of the Society for Pediatric Anesthesia that contains a deidentified registry of serious adverse events occurring in pediatric anesthesia. The aim of this study was to describe and characterize reported medication errors to find common patterns amenable to preventative strategies.

METHODS:

In September 2016, we analyzed approximately 6 years’ worth of medication error events reported to Wake Up Safe. Medication errors were classified by: (1) medication category; (2) error type by phase of administration: prescribing, preparation, or administration; (3) bolus or infusion error; (4) provider type and level of training; (5) harm as defined by the National Coordinating Council for Medication Error Reporting and Prevention; and (6) perceived preventability.

RESULTS:

From 2010 to the time of our data analysis in September 2016, 32 institutions had joined and submitted data on 2087 adverse events during 2,316,635 anesthetics. These reports contained details of 276 medication errors, which comprised the third highest category of events behind cardiac and respiratory related events. Medication errors most commonly involved opioids and sedative/hypnotics. When categorized by phase of handling, 30 events occurred during preparation, 67 during prescribing, and 179 during administration. The most common error type was accidental administration of the wrong dose (N = 84), followed by syringe swap (accidental administration of the wrong syringe, N = 49). Fifty-seven (21%) reported medication errors involved medications prepared as infusions as opposed to 1 time bolus administrations. Medication errors were committed by all types of anesthesia providers, most commonly by attendings. Over 80% of reported medication errors reached the patient and more than half of these events caused patient harm. Fifteen events (5%) required a life sustaining intervention. Nearly all cases (97%) were judged to be either likely or certainly preventable.

CONCLUSIONS:

Our findings characterize the most common types of medication errors in pediatric anesthesia practice and provide guidance on future preventative strategies. Many of these errors will be almost entirely preventable with the use of prefilled medication syringes to avoid accidental ampule swap, bar-coding at the point of medication administration to prevent syringe swap and to confirm the proper dose, and 2-person checking of medication infusions for accuracy.
End-Expiratory Occlusion Test Predicts Fluid Responsiveness in Patients With Protective Ventilation in the Operating Room
Authors: Biais Matthieu , Larghi Mathilde , Henriot Jeremy , de Courson Hugues , Sesay Musa , Nouette-Gaulain Karine
Published: July 2017

BACKGROUND:

End-expiratory occlusion test (EEOT) has been proposed to predict fluid responsiveness in mechanically ventilated intensive care unit patients. The utility of this test during low-tidal-volume ventilation remains uncertain. This study aimed to determine whether hemodynamic variations induced by EEOT could predict the effect of volume expansion in patients with protective ventilation in the operating room.

METHODS:

Forty-one patients undergoing neurosurgery were included. Stroke volume and pulse pressure variations were continuously recorded using pulse contour analysis before and immediately after a 30-second EEOT and after volume expansion (250 mL saline 0.9% given over 10 minutes). Patients with an increase in stroke volume ≥ 10% after volume expansion were defined as responders.

RESULTS:

Twenty patients were responders to fluid administration. EEOT induced a significant increase in stroke volume, which was correlated with the stroke volume changes induced by volume expansion (r2 = 0.55, P < .0001). A 5% increase in stroke volume during EEOT discriminated responders to volume expansion with a sensitivity of 100% (95% confidence interval [CI], 83%–100%), a specificity of 81% (95% CI, 58%–95%), a positive predictive value of 84% (95% CI, 64%–96%), and a negative predictive value of 100% (95% CI, 80%–100%). The gray zone ranged from 4% to 8%, including 17% of patients. The best pulse pressure variation threshold was 9%, with a sensitivity of 60% (95% CI, 36%–81%) and specificity of 86% (95% CI, 64%–97%). The area under the receiver operating characteristics curve generated for changes in stroke volume induced by EEOT (0.91, 95% CI, 0.81–1.00) was significantly higher than the one obtained for pulse pressure variations (0.75, 95% CI, 0.60–0.90); P < .05.

CONCLUSIONS:

Changes in stroke volume index induced by EEOT can predict fluid responsiveness in patients with protective ventilation in the operating room. This test may have potential applications.
EsGLUT4 and CHHBP are involved in the regulation of glucose homeostasis in the crustaceanEriocheir sinensis
Authors: Li Ran , Tian Jin-Ze , Wang Mo-Ran , Zhu Li-Na , Sun Jin-Sheng
Published: July 2017

Glucose is an essential energy source for both vertebrates and invertebrates. In mammals, glucose uptake is mediated primarily by glucose transporters (GLUTs), members of the major facilitator superfamily (MFS) of passive transporters. Among the GLUTs, GLUT4 is the main glucose transporter in muscles and adipocytes. In skeletal muscle cells, GLUT4 interacts with the lipid raft protein flotillin to transport glucose upon stimulation by insulin. Although several studies have examined GLUT4 function in mammals, few have been performed in crustaceans, which also use glucose as their main energy source. Crustacean hyperglycemic hormone (CHH) is a multifunctional neurohormone found only in arthropods. One of its roles is to regulate glucose homeostasis. However, the molecular mechanism that underlies CHH regulation and whether GLUT4 is involved in its regulation in crustaceans remain unclear. In the present study, we identified a full-length GLUT4 cDNA sequence (defined herein as EsGLUT4) from the Chinese mitten crab Eriocheir sinensis and analyzed its tissue distribution and cellular localization. By the ForteBio Octet system, two large hydrophilic regions within EsGLUT4 were found to interact with the CHH binding protein (CHHBP), an E. sinensis flotillin-like protein. Interestingly, live-cell imaging indicated that EsGLUT4 and CHHBP responded simultaneously upon stimulation by CHH, resulting in glucose release. In contrast to insulin-dependent GLUT4, however, EsGLUT4 and CHHBP were present within cytoplasmic vesicles, both translocating to the plasma membrane upon CHH stimulation. In conclusion, our results provide new evidence for the involvement of EsGLUT4 and CHHBP in the regulation of glucose homeostasis in crustacean carbohydrate metabolism.